Medical Clinics of North America Vol 88 issue 01 2004 Innovative Concepts of Hypertension to Understand and Manage the Disease

Med Clin N Am 88 (2004) xiii–xxi Preface Innovative concepts of hypertension to understand and manage the disease Ed...

Author: Edward D. Frohlich

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Med Clin N Am 88 (2004) xiii–xxi

Preface

Innovative concepts of hypertension to understand and manage the disease

Edward D. Frohlich, MD, MACP, FACC Guest Editor

This issue of the Medical Clinics of North America is devoted once again to innovative concepts dealing with hypertensive disease. I say once again because this is the fourth time that we have organized an issue on this topic for this publication, and it has appeared approximately every 5 years. One could reasonably ask if enough new knowledge in this area mandates a new issue unless prior contents are reviewed. Indeed, our knowledge about the underlying mechanisms related to the pathophysiology of hypertension, new concepts about its prevention, and advances in patient management and therapy has drastically burgeoned, and the overall approach to this tremendously important clinical problem has remarkably matured and become far more sophisticated during the past 5 years. A cursory perusal of the content of this issue clearly attests to this assertion. Pathophysiology A recent sea change in advances in our pathophysiological understanding of the hypertensive diseases is demonstrated impressively throughout the first eight articles in this issue. Comprehension of the underlying genetic mechanisms of the hypertensive diseases is brilliantly explored by Dr. Friedrich C. Luft. We have long known from histories obtained from our patients that hypertension is a genetically predisposed disease because of exceptionally strong family histories of hypertension. However, to approach hypertension as a disease with a straightforward, single genetic causation is probably 0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/S0025-7125(03)00143-3

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E.D. Frohlich / Med Clin N Am 88 (2004) xiii–xxi

expecting too much. In the vast number of patients with hypertension, there are some with monogenetic causes; however, by and far, most patients have multifactorial underlying polygenetic mechanisms. Thus Professor Luft presents an up-to-date discussion of the single Mendelian forms of hypertensive diseases, leaving a larger segment of his chapter to a more difficult area dealing with far more complex disease traits. His erudite discussion is particularly lucid and is supplemented by a very useful list of references for the interested reader. In the succeeding discussion, Dr. Richard N. Re broadens our overall concept of the rennin–angiotensin–aldosterone system. At the outset of this series on innovations in hypertension, this system has been considered an important endocrine mechanism having positive and negative feedback controls. Its rate-limiting enzyme, renin, is released from the renal juxtaglomerular apparatus and acts on the hepatically synthesized protein substrate angiotensinogen to release angiotensin I from its protein attachment. Then, within a single circulation (through the lungs), this decapeptide is acted upon by the angiotensin converting enzyme (ACE) to form the potent octapeptide (angiotensin II) that constricts vascular smooth muscle, stimulates aldosterone release from the adrenal cortex, and stimulates thirst and other brain centers—just to mention a few of its very important (and growing) actions. However, in recent years this systemic endocrine concept system has expanded dramatically. Thus there is now a multiplicity of local rennin– angiotensin systems in such tissues as blood vessel, heart, liver, uterus, and brain, to mention those having benefitted from more extensive inquiry. These local systems have autocrine/paracrine as well as intracrine actions on their organ-specific tissues. For example, in the heart, angiotensin II has mitogenic, fibrosing, apoptotic, and other actions that help to explain its role in producing ventricular hypertrophy, extracellular fibrosis, apoptosis, and cardiac failure. Still more recent work has elucidated angiotensin’s role in endothelial dysfunction and in local aldosterone synthesis, opening the mind to additional pathophysiological explanations for disease and new modes of therapy. This and more is provided by Dr. Re, who has done much to open this area as well as our thinking about it. The following article by Drs. Ernesto L. Schiffrin and Carmine Savoia continues to expand our thinking with a clear discussion of important new peptides produced by or acting on the cardiovascular system. The roles of the atrial natriuretic peptide, endothelins, and adrenomedullin are explored. These agents received either no discussion or even ideation in previous issues. Whereas the atrial natriuretic peptide had been identified within the past two decades, its role in disease and in therapy have only recently been explored. Thus this peptide has been demonstrated to provide the logical negative physiological feedback for the overloaded circulation, and a similar peptide, produced by the brain (brain natriuretic peptide), has only recently been shown to be an index of occult (if not overt clinical) cardiac failure. The pharmaceutical industry has already taken advantage of this peptide


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by combining its metabolic enzyme (decarboxylase) with ACE to provide a potentially sound and potent antihypertensive compound. Similarly, the endothelins have provided a broader insight into their vasoconstrictor and mitogenic cardiovascular effects, leading to newer therapeutic modalities that are currently under clinical investigation (some have already been introduced clinically). The role of adrenomedullin is still in its infancy and is currently being explored in many basic and clinical laboratories. The relationship between hypertension and diabetes mellitus has been known for many years. With the introduction of the Benedict’s reagent as a test for blood glucose concentration as early as the 1920s, a number of clinical investigators have demonstrated the exceedingly high coexistence of these two diseases, a figure (in excess of 60%) that has not changed substantially over the ensuing generations. More recently, however, many investigators have explored further this classical relationship to describe in greater depth a metabolic syndrome involving the relationship of hypertension and diabetes with insulin, obesity, hyperlipidemia, and, of course, the potential linkages of theses diseases with atherosclerosis. In the following article, Dr. James R. Sowers and I discuss this potential role and the phenomenon of insulin sensitivity and other clinical aspects of hypertensive disease. These concepts are of great value when one considers not only its obvious pathophysiological import but the potential role of newer and important therapeutic agents for diabetes, insulin sensitivity, and hypertension. For many years we have recognized that left ventricular hypertrophy (LVH) is a major risk factor underlying coronary heart disease. For too long, however, our studies have been directed to the potential importance of therapeutically diminishing the increased mass of the left ventricle to possibly reduce that risk. Our experimental and clinical investigative approach to this area in the 1970s was among the first of its kind; however, in more recent years, I questioned whether there was a sufficiently clear understanding of the underlying mechanisms that would satisfactorily explain the intrinsic risk associated with LVH. Our studies (and those of others) have pointed to a number of mechanisms explaining the risk associated with LVH, including ventricular ischemia, fibrosis, and apoptosis. Among the more productive clinical investigators in this area has been Dr. Javier Diez and his team, including Dr. Arantxa Gonzalez. In their article, which explores the role of ventricular fibrosis in hypertension, they provide an excellent discussion of the implications of ventricular fibrosis in hypertension. We should conclude from this discussion that the laying down of fibrotic material in tissue should not be construed as the development of a permanent scarring of the cardiac wall that leads to impaired function, ischemia, failure, and death. First, they provide compelling evidence that the fibrosis is demonstrably reversible clinically and that it may be detectable— even quantitatively—by measuring the circulating proteolytic products of collagen in the circulation of patients. They are not alone in their experimental and clinical findings, and they have been confirmed and extended

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in other laboratories, including our own. Their work has also been expanded recently to demonstrate that angiotensin II is not only capable of producing ventricular fibrosis, but it also produces apoptosis of cardiac myocytes. This latter observation may lead to a keener insight into the repeated epidemiological finding that hypertension is the most common cause of cardiac failure. Indeed, Dr. Diez’s team’s most recent work has shown that therapy directed toward inhibition of angiotensin II not only diminishes ventricular fibrosis but also reverses the phenomenon of apoptosis. The references accompanying their discussion will be most valuable to the interested reader. The phenomenon of ventricular fibrosis is not only important as an underlying mechanism explaining the high risk associated with LVH, it is also inextricably intertwined with another mechanism underlying the risk associated with LVH: ischemia. One of the early workers in this area has been Dr. Bodo-Eckehard Strauer and his team, including Dr. Malte Klem. Professor Strauer reported early on in his studies of ischemic heart disease that coronary heart disease is associated with hypertension—specifically, that coronary blood flow reserve may be markedly restricted in hypertensive LVH, even without co-existent occlusive atherosclerotic epicardial coronary artery disease. In these studies, they demonstrated that the impaired coronary blood flow reserve can be significantly improved with newer therapies, including ACE inhibitors. Professor Strauer’s group was the first to demonstrate, through septal biopsy studies, that coronary perivascular arteriolar and ventricular fibrosis were dramatically reversed with this therapy (as monotherapy). He and his colleagues describe these phenomena in their discussion, and they go far to instill in us the concept that coronary heart disease associated with hypertension is a distinct phenomenon and need not be present with coexisting atherosclerotic coronary arterial disease. The innovative concept of remodeling and restructuring the ventricular wall experimentally and clinically must be credited to the work of Drs. Janice M. and Marc A. Pfeffer. They first demonstrated the heart’s ability to restructure itself using ACE inhibitory therapy in their studies of the spontaneously hypertensive rat with experimentally produced myocardial infarction; later, they demonstrated this in patients with myocardial infarction as well. Indeed, they coined this now-popular term. Their initial studies led to their landmark multicenter clinical trial known as the Survival and Ventricular Enlargement (SAVE) study, which demonstrated that ACE inhibition therapy was effective not only in preventing ventricular remodeling, but that prevention of this adverse consequence of myocardial infarction significantly reduced complicating congestive heart failure, repeated infarction, and death. Following this report, a number of other studies of similar concepts confirmed these findings. Not to be minimized by the foregoing discussions of cardiac complications of hypertension are the effects of hypertensive disease on the kidney. Too often, in a discussion of the renal consequences of hypertension, there is extensive discussion of the adverse physiological consequences of hypertension on renal function and the unrelentingly increasing problem of


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end-stage renal disease (ESRD) and its burdening costs to society in terms of disability, quality of life, death, and, most certainly, economics. In recent years, I have noted less discussion in reviews of hypertension dealing with clinical evaluation of renal function in patients with hypertension. Perhaps no individual in the area of experimental and clinical investigation of the renal complications of hypertension has been Dr. Norman K. Hollenberg. Doctor Hollenberg’s work (together with Dr. Gordon Williams) has been concerned with the relationships of renal involvement in hypertension with the rennin–angiotensin system, the clinical evaluation of hypertensive renal disease, and the evaluation of patients with ESRD and their kidney donors. With such extensive clinical experience, I thought it most appropriate to return to an earlier clinical discussion of evaluating the patient with renal functional impairment. I truly believe that this discussion is unique in this day and age, for it provides the important and vast clinical experience that Dr. Hollenberg brings to this important subject.

Management and therapy Over the years of coverage of innovative concepts in the Medical Clinics of North America, there have been dramatic introductions of new concepts developed about primary as well as secondary prevention of hypertension, as well as new classes of pharmacological agents introduced for its treatment. As part of the National High Blood Pressure Education Program, established by the National Heart Lung and Blood Institute in 1972, periodic guidelines have been promulgated by its Joint Coordinating Committee (JCC) to provide current updates on the detection, evaluation, treatment, and prevention of hypertension. Over the years, seven reports have been published; the most recent, JNC-7, was published in May 2003. These reports have provided new scientific information concerning hypertension, results of the periodic National Health and Nutrition Surveys that detail important demographic and other data as they relate to hypertension, results of outcomes of multicenter therapeutic trials conducted throughout the world, and the consensus of individuals currently representing the major related health organizations in this country. Several new concepts were presented in JNC-7. First, the number of individuals who are aware that they have hypertension and are currently receiving antihypertensive therapy, and whose pressures are under control, represent only 34% of all hypertensives. Although this number is greater than that reported in JNC-6, it is a far cry from a number that health care providers can be proud of. Clearly, we all have a better job to do in this respect. Second, the term prehypertension was introduced to cover all adults whose systolic pressures are between 120 and 139 mmHg and whose diastolic pressures are between 80 and 89 mmHg. These pressures were

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formerly designated as high normal pressures, a term that had been used ever since JNC-3 was published. To my way of thinking, the latter term still is more appropriate because there is no assuredness that individuals with prehypertension will be inappropriately rated for health insurances, especially because this term is to receive a diagnostic code. In choosing this new term, the JCC hoped that more people who were at subsequent risk of developing stage 1 hypertension (140–159 mmHg systolic and 90–99 mmHg diastolic) would receive primary prevention measures of lifestyle modification. Let us hope that these noble desires do not jeopardize the insurability of these people and the economics of health care delivery. A third issue in JNC-7 that continues to provoke controversy is the recommendation that antihypertensive therapy be initiated with a thiazide diuretic for all individuals with uncomplicated hypertension (having no other compelling conditions). Although this recommendation is not that different from prior reports, it has already been construed by many as a call for the initial treatment of all patients with a thiazide diuretic. This just isn’t so: the guidelines carefully point out that any of the other classes of agents may be employed to control pressure as determined by the responsible health care provider. My fourth concern is the recommendation to initiate therapy with two agents simultaneously in patients with stage 2 hypertension. Again, to my way of thinking, unless the situation is truly emergent, the simultaneous prescription of two agents is unwarranted. Should a side effect of treatment occur, the agent responsible would not be known. If pressure is not promptly controlled, then a second agent can be introduced. The report was published rapidly in a so-called ‘‘express’’ format, and a longer explanatory report is anticipated in the near future. In the very first discussion concerning management of hypertension in this issue of the Clinics, Dr. Norman M. Kaplan presents his overview of the subject. In it he ventures into what internists and primary care physicians, who most often see patients with hypertension, might expect from the new JNC-7 guidelines. A thoughtful leader in the field of hypertension for years, Dr. Kaplan’s discussion provides an excellent overview of the current status of his (and most key leaders’) work in the field. As stated above, the JNC reports have consistently recommended that therapy should be initiated with a thiazide diuretic. This report is no different, especially since its promulgation immediately followed the release of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). This large multicenter study demonstrated once again the value of diuretics and their equivalence in endpoints with other agents (ie, the calcium antagonists and the ACE inhibitors). Dr. Kaplan’s discussion of this concept is timely, clear, and especially important for the practitioner. The importance that multicenter clinical trials have assumed over the years in identifying endpoints and meaningful clinical outcomes for any therapeutic modality, be it in the area of hypertension or any other disease,


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cannot be minimized. This value should be of prime importance to the pharmaceutical industry, regulatory bodies, the practicing physician, and thirdparty providers. It becomes a major source of news (and controversy) in the lay media when the results of any new trial is published. This publicly announced information immediately whets the appetites and concerns of the public, who apply the reported findings to each individual’s health concerns. Thus, on the morning after a report is made public by the media, practicing physicians find stacks of notes reflecting the number of telephone messages from patients. For this reason, we have invited Drs. George L. Bakris and Kevin C. Abbott to review what we have learned and what we can take away from the recent and current trials of antihypertensive agents. Dr. Bakris speaks with great authority as an active participant in many multicenter clinical trials, in addition to being a highly sought-after consultant to industry and government. In this review, Drs. Bakris and Abbott speak to each of the major recent drug trials and provide valid points of view from their unbiased and enlightened authority. We then present a series of discussions concerning the specific classes of antihypertensive agents, beginning with an article on the diuretics and badrenergic receptor blocking agents by Drs. Marvin Moser and John F. Setaro. Dr. Moser has been a member of the JCC and has spoken to the value of the thiazide diuretics for these many years. In their article, he and Dr. Setaro provide an up-to-date review of the efficacy and safety of diuretics and b-adrenergic receptor blocking agents and the rationale for keeping these agents at the forefront of initial treatment of hypertension. One aspect of their discussion should be placed into perspective; they reiterate the point made above that although the use of diuretics for initial therapy is clear, JNC-7 does not state unequivocally that all patients must be started with that initial therapy. All classes of antihypertensive agents are included in the recommendation for initial therapy, and there are specific compelling indications for the use of other classes of antihypertensive therapy. The following discussion is by Drs. Murray Epstein and Vito M. Campese. Both authors are pre-eminent in the field of hypertension, have been members of the JCC for several years, and are eminently qualified to write on the evolving role of the calcium antagonists in the management of hypertension. They both have considerable experimental and clinical background on the subject and, in their discussion, they discuss many controversial points concerning this class of drugs. What was not said in their support of the use of these agents is that there are many patients with hypertension whose pressures may not respond to the diuretic or, for that matter, to ACE inhibitors or the angiotensin receptor blocking (ARB) agents. Moreover, they might not be able to take the b-adrenergic receptor blocker because of significant bradycardia. In these patients, the calcium antagonists become the major group of agents for consideration. Furthermore, there are those patients who may have bilateral occlusive renal arterial disease or, for other conditions (eg, pregnancy) and preclude the use of ACE inhibitors or the ARB agents.

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These additional clinical points provide additional need for a clear understanding of the calcium antagonists. As with the other discussions, the references included in their paper provide important reference for the interested clinician. In the light of the foregoing discussion concerning renal functional impairment in hypertensive disease, I have prepared the following discussion dealing with our experimental experiences in the laboratory with the spontaneously hypertensive rat of naturally occurring hypertension, as well as recent clinical studies dealing with ACE inhibitors and ARB agents. Thus, it is now possible to study an experimental model of hypertension that is a close counterpart of essential hypertension in man without the necessity to produce ESRD and hypertension by experimental extirpation of most of the animal’s renal tissue, administration of high dose steroids and salt, or even the administration of lethal or severe nephrotoxins. Thus, we must understand systemic and renal hemodynamics, glomerular dynamics, renal function, and the clinical consequences pathophysiologically without taking drastic measures. In our studies, we have also demonstrated that it is possible to reproduce the natural renal consequences associated with aging and hypertension by administering a specific agent that interferes with local endothelial production of nitric oxide, which naturally regulates local blood flow and renal function. In our studies, we demonstrated that the newer antihypertensive agents (ie, ACE inhibitors, angiotensin II type 1 receptor antagonists, and certain calcium antagonists) not only reversed naturally occurring ESRD but also prevented the development of this drastic consequence of hypertension. Therefore, we not only demonstrated reversibility of the renal consequence of hypertension, but we also demonstrated similar effects on the heart. Furthermore, we provide the necessary confirmatory support of our experimental findings with new clinical data that have been reproduced in many recent multicenter clinical studies. Hence, I believe that we are at the cusp of a new era in which there is a potential promise of the reversal of the cardiac and renal consequences of hypertension. In the final report of this issue, Dr. Marie Antoinette Krousel-Wood and her colleagues discuss the very reasonable expectation for the prevention of essential hypertension. This concept has been championed by the National High Blood Pressure Education Program and Dr. Krousel-Wood’s colleague Dr. Paul Whelton ever since his initial report of the working group of that program demonstrated feasibility of primary prevention of hypertension. The very real concept that essential hypertension can be prevented primarily by lifestyle modifications is rigorously supported and detailed in their report. Thus, we present a variety of innovative concepts on the pathophysiology of hypertensive diseases and the fundamental information that has permitted the demonstration of continued reduction of morbidity and mortality associated with essential hypertension and its involvement of the target organs of the disease. Hopefully, in our next pentannual report, we will


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provide additional new and exciting information concerning the pathogenesis and pathophysiologic underlying mechanisms of arterial pressure elevation and the therapeutic interventions that will continue to stimulate your interest and excitement about hypertension and its complications. Edward D. Frohlich, MD, MACP, FACC Alton Ochsner Distinguished Scientist Ochsner Clinic Foundation 1516 Jefferson Highway New Orleans, LA 70121, USA E-mail address: [email protected]

Med Clin N Am 88 (2004) 1–18

Present status of genetic mechanisms in hypertension Friedrich C. Luft, MD* Franz Volhard Clinic and Max Delbru¨ck Center for Molecular Medicine, Wiltberg Strasse 50, 13125 Berlin, Germany HELIOS Klinikum-Berlin Wiltberg Strasse 50, 13125 Berlin, Germany Medical Faculty of the Charite´, Humboldt University of Berlin, Wiltberg Strasse 50, 13125 Berlin, Germany

Mendelian hypertension is the bright spot in the area of molecular genetics of human hypertension. The attitude here is that by elucidating rare mendelian diseases, mechanisms of disease applicable to primary hypertension are understood [1]. This promise has been kept largely through the efforts and successes of Lifton et al [2]. Through their work, clinicians have been introduced to numerous disease mechanisms. Glucocorticoid-remediable aldosteronism Patients with glucocorticoid-remediable aldosteronism have autosomaldominant hypertension and are usually suspected of having primary aldosteronism. They have a volume expansion, a salt-sensitive form of hypertension, tend to metabolic alkalosis with hypokalemia, and respond to both thiazide diuretics and spironolactone. Their renin values are low, whereas the aldosterone values are elevated. The patients also have 18hydroxycortisol and 18-oxocortisol, steroids not normally found in urine. Recognizing these abnormal products (an intermediate phenotype) led to solving the mystery. Replacement amounts of prednisone ameliorate the hypertension, cause the abnormal steroids to disappear, and give the syndrome its name. The abnormal cortisol derivatives and the favorable effects of glucocorticoid treatment suggested that inner cortical zones, which Studies on autosomal-dominant hypertension and brachydactyly were supported by the Deutsche Forschungsgemeinschaft and by the Helmholtz Foundation. * Franz Volhard Clinic and Max Delbru¨ck Center for Molecular Medicine, Wiltberg Strasse 50, 13125 Berlin, Germany. E-mail address: [email protected] 0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/S0025-7125(03)00118-4

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F.C. Luft / Med Clin N Am 88 (2004) 1–18

express the gene for 17 b-hydroxylase (CYP17) and are adrenocorticotrophic hormone–responsive, were the source of the excess mineralocorticoids. Two distinct gene products, 11 b-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2), perform the terminal steps in glucocorticoid and mineralocorticoid biosynthesis, respectively. A linkage analysis in a large pedigree localized the responsible gene to chromosome 8q, the site where the genes for 11 b-hydroxylase and aldosterone synthase also reside [3]. In affected individuals, a chimeric gene consisting of the promotor-regulatory region of 11 b-hydroxylase and the structural portion of aldosterone synthase is located between CYP11B2 and CYP11B1. The chimeric gene results from a miotic mismatch and unequal crossing over (Fig. 1). The protein product performs all reactions required for aldosterone production; however, the protein is adrenocorticotrophic hormone rather than angiotensin (Ang) II–dependent. Ectopic expression of this protein in the inner cortical zones permits the formation of 18-hydroxycortisol and 18oxocortisol. Finally, suppressing steroidogenesis in the inner cortical zones with exogenous glucocorticoids alleviates the hypertension. Liddle’s syndrome Liddle described patients with autosomal-dominant monogenic hypertension who also tended to metabolic alkalosis with hypokalemia. His

Fig. 1. A chimeric gene is formed by miotic mismatch and unequal crossing over with the promoter region of the 11 b-hydroxylase gene (dark box) and the coding region of the aldosterone synthase gene (white box). As a result, the aldosterone synthase gene is under control of adrenocorticotrophic hormone in the inner cortical zone. Aldo, aldosterone; Ang II, angiotensin II.


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patients had low renin and low aldosterone values; however, they did not respond to spironolactone, whereas thiazides and triamterene reduced the blood pressure. This observation convinced Liddle that they probably did not have a form of mineralocorticoid excess. Liddle speculated that they would show a distal tubular defect of enhanced sodium and chloride reabsorption. A renal transplant performed on a patient with Liddle’s syndrome who developed renal failure cured the disease, providing strong evidence that the problem resided within the kidneys rather than in a regulatory system [4]. Shimkets et al [5] subsequently localized the responsible gene of a family with Liddle’s syndrome to chromosome 16p and were able to show that the gene encodes for the b subunit of the epithelial sodium channel (ENaC). The channel is amiloride and triamterene sensitive, explaining the efficacy of these drugs. The channel remains inappropriately permeable even in the face of high salt intake, thereby explaining the salt-sensitive hypertension. Subsequently a mutation in the c subunit of ENaC was found, which can also result in Liddle’s syndrome [6]. The molecular mechanisms of Liddle’s syndrome involve alteration or deletion in the cytoplasmic tails of the b or c subunits. As a consequence, the channels are not internalized (clathrin-coated pits pathway) or degraded (Nedd4 pathway), and instead remain activated on the cell surface [7].

Apparent mineralocorticoid excess Genetic apparent mineralocorticoid excess resembles the syndrome observed in persons ingesting large amounts of licorice. Licorice gluttony and treatment with carbenoxolone both cause a volume expansion, low renin, low aldosterone, salt-sensitive form of hypertension, which may also feature metabolic alkalosis and hypokalemia. Interestingly, the hypertension responds to both thiazide and spironolactone, but no abnormal steroid products are present in the urine. Both licorice and carbenoxolone contain glycyrrhetinic acid, which was found to inhibit the enzyme 11 bhydroxysteroid dehydrogenase. The renal isoform of 11 b-hydroxysteroid dehydrogenase is responsible for converting cortisol to cortisone. In the distal renal tubule, this step is crucial for protecting the mineralocorticoid receptor, which has the same affinity for cortisol as it does for aldosterone. This step protects humans from developing apparent mineralocorticoid excess. Inhibition of 11 b-hydroxysteroid dehydrogenase results in apparent mineralocorticoid excess. Interestingly, apparent mineralocorticoid excess may also occur as a rare, autosomal-recessive form of hypertension. The 11 b-hydroxysteroid dehydrogenase gene became a prime candidate. The clinical clues helpful in resolving this condition were volume-dependent salt-sensitive hypertension, tendency to hypokalemia and metabolic alkalosis, low renin and low aldosterone values, responsiveness to both thiazides and spironolactone despite absence of aldosterone or any

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abnormal mineralocorticoid products, and resemblance to licorice gluttony. Mune et al [8] found mutations in the renal-specific isoform gene for 11 bhydroxysteroid dehydrogenase that rendered the product incapable of converting cortisol to cortisone (Fig. 2). The mineralocorticoid receptor is unprotected from cortisol in these patients and cortisol functions to occupy the mineralocorticoid receptor. Li et al [9] raised the fascinating possibility that apparent mineralocorticoid excess might be relevant in the heterozygous state. They observed a patient with hypertension at age 38 years, who had a daughter with homozygous apparent mineralocorticoid excess. The patient had low renin and aldosterone concentrations and was found to have a mutation in the gene for 11 b-hydroxysteroid dehydrogenase. Mineralocorticoid receptor Geller et al [10] recently presented a new mendelian form of hypertension caused by an activating mutation in the mineralocorticoid receptor. The investigators screened for mutations in the mineralocorticoid receptor in seven unrelated patients referred for possible monogenic hypertension with

Fig. 2. A cortical collecting duct cell. The mineralocorticoid receptor has the same affinity for cortisol as for aldosterone. The enzyme 11 b-hydroxysteroid dehydrogenase protects the mineralocorticoid receptor by metabolizing cortisol to cortisone, which has no affinity. A mutated or an inhibited enzyme results in an increased intracellular concentration of cortisol and an increased activation of the mineralocorticoid receptor. A mutated mineralocorticoid receptor can result in an altered configuration so that the mineralocorticoid receptor is activated by sterols not containing a 21-hydroxyl group. Increased mineralocorticoid receptor activity causes enhanced Na+ reabsorption (ENaC, Na-K-ATPase) and K+ excretion. MR, mineralocorticoid receptor; 11-b HSD, 11 b-hydroxysteroid dehydrogenase.


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the single-strand conformation polymorphism technique. One patient had a heterozygous mutation at codon 810 in the mineralocorticoid receptor gene, resulting in a leucine for serine substitution. This residue lies in the hormone-binding domain. The patient’s relatives were carefully examined. The index case had severe hypertension, as did four relatives. Affected persons all exhibited the leucine for serine substitutions, had low plasma renin activities, and low aldosterone concentrations. Because the phenotype resembles Liddle’s syndrome, the investigators ruled out the presence of ENaC mutations. The authors speculate that the mineralocorticoid receptor gene mutation is an activating mutation in the receptor. Interestingly, affected women exhibit a worsening of hypertension during pregnancy, suggesting that progesterone occupancy of the receptor results in activation rather than inhibition of aldosterone-like effects. Similarly, spironolactone makes the blood pressure elevation worse, rather than better. Geller et al [10] were successful in elucidating the mechanism of the mutation. The MRS810L mutation allows mineralocorticoid receptor activation by steroids lacking 21-hydroxyl groups. The L810 residue in helix 5 of the ligandbinding domain makes a new van der Waals interaction with A773 in helix 3. This interaction eliminates the requirement for the 21-hydroxyl group of aldosterone to interact with N770 in helix 3. The modification explains why compounds that are normally antagonists now are agonists for the receptor. Pseudohypoaldosteronism type II Pseudohypoaldosteronism type II features familial hypertension with hyperkalemia, slight hyperchloremic metabolic acidosis, and otherwise normal kidney function. Thiazide diuretics are highly effective in this syndrome, commensurate with salt sensitivity. A multilocus linkage analysis demonstrated linkage to chromosomes 1q and 17p [11]. Interestingly, the chromosome 17p locus overlaps a syntenic interval in the rat that contains a blood pressure quantitative trait locus. Recently, Disse-Nicodeme et al [12] described a new locus on chromosome 12p13. They analyzed a large French kindred in which 12 affected members over three generations confirmed the autosomal-dominant inheritance. Affected subjects had hypertension together with long-term hyperkalemia, hyperchloremia, normal plasma creatinine, and low renin levels. The aldosterone values are elevated, probably because of the hyperkalemia. Wilson et al [13] unraveled the puzzle. They identified two genes causing pseudohypoaldosteronism type II. Both genes encode members of the WNK (with no lysine) family of serine-threonine kinases. Disease-causing mutations in WNK1 are large intronic deletions that increase WNK1 expression. The mutations in WNK4 are missense. They cluster in a short, highly conserved segment of the encoded protein. Both proteins are expressed in the distal nephron. WNK1 is cytoplasmic, whereas WNK4 localizes to tight junctions. These two gene products may represent new

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drug targets for future therapies. Recent work by Yang et al [14] used the Xenopus oocyte system to show that WNK4 suppresses the thiazide-sensitive sodium chloride cotransporter. Wilson et al [15] have presented similar findings. WNK1 expression prevents the WNK4 suppression of the cotransporter. The WNK kinases serve as a sodium regulatory pathway in the distal nephron (Fig. 3). Autosomal-dominant hypertension with brachydactyly Bilginturan et al [16] first described this form of monogenic hypertension in 1974. Affected family members, who feature brachydactyly type E, have a dramatic increase in blood pressure with age and die before the age of 50 years by multiple strokes. The Turkish family was re-examined in 1994 [17]. The hypertension easily can be distinguished from other mendelian hypertensive syndromes described thus far. The patients are not salt-sensitive and have normal renin, angiotensin, aldosterone, and catecholamine responses. By measuring plasma renin activity and plasma aldosterone supine and upright, other conditions can be conveniently excluded [18]. The phenotyping efforts showed that the patients do not respond to any particular form of medication [19]. b-Blocker, calcium antagonists, a-blocker, and angiotensin converting enzyme inhibitor all improve blood pressure without significant difference. A multidrug therapy is required for the treatment of patients. The mechanism of the hypertension is unknown. An additional phenotype was

Fig. 3. The distal nephron. The thiazide-sensitive Na, Cl cotransporter is overactive in pseudohypoaldosteronism type 2. As a result, less Na is available for the ENaC and less K and H ions are excreted in the cortical collecting duct. The syndrome features volume expansion, hypertension, hyperkalemia, and mild hyperchloremic metabolic acidosis. ‘‘With-no-lysine’’ kinase 4 down-regulates the cotransporter. When the kinase is mutated, the cotransporter is hyperactive. WNK1 regulates WNK4 downward. Gain-of-function mutations in WNK1 downregulate WNK4 causing cotransporter hyperactivity. WNK, with-no-lysine.


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discovered, however, which may provide a clue, namely anomalous vessels in the posterior fossa that may impinge on the brainstem [20]. Based on these results detailed autonomic testing was performed [21]. The author and his group found that the ability of the baroreflex to buffer changes in vascular tone was severely impaired. The hypertension could be related to abnormal baroreceptor reflex function in these subjects. Efforts are under way to clone the genes responsible, as reviewed in detail elsewhere [22].

Essential hypertension Hamilton, Roberts, Sowry, and Pickering first addressed hypertension as a complex genetic trait. They conducted studies in three groups of subjects: (1) a sample of the population at large, (2) first-degree relatives of patients with essential hypertension, and (3) first-degree relatives of persons without essential hypertension. Careful matching for age and gender was performed. The investigators found that the frequency distribution curves of arterial pressure gradually moved upward and spread out as age advances. At no age was there a clear division into normal or high blood pressure. These results were similar to those found by Francis Galton for height. Galton showed that height is inherited as a graded characteristic over the whole range of heights encountered. The results also introduced the notion that elevated blood pressure is not a function of one gene, but rather a host of genes, each contributing a small effect [23].

Association studies Most studies into the molecular genetics of hypertension have relied on association (Fig. 4). Hundreds of association studies on some aspect of hypertension or blood pressure have been reported. Unfortunately, the contribution of most association studies to the understanding of hypertension and its genetic determinants has been modest. Recently, criteria have been suggested for high-quality association studies. Reviewing these criteria is worthwhile because one can rest assured the reviewers judging subsequent association studies will review them carefully [24]. These criteria are large sample size, small P values, biologic plausibility, functional significance, independent replication in several populations, confirmation in family-based studies, and high odds ratios or high attributable risk. Renin-angiotensin-aldosterone system genes The angiotensin converting enzyme insertion-deletion polymorphism has perhaps been the most consistent mutation associated with cardiovascular disease in the general population. The demonstration of associations to blood pressure has been difficult. The insertion-deletion polymorphism is an

8


Fig. 4. Case control association studies, the candidate gene approach. Genotype frequencies in cases and controls are compared. The criteria for good association studies are not easy to meet. These criteria are large sample size, small P values, biologic plausibility, functional significance, independent replication in several populations, confirmation in family-based studies, and high odds ratios or high attributable risk. The difficulty lies in the recruitment of ideal controls.

Alu repeat in intron 16. Rieder et al [25] recently showed that 78 varying sites were present in the angiotensin converting enzyme gene, which resolved into 13 distinct haplotypes. Of the variant sites, 17 were in linkage dysequilibrium with the Alu repeat in intron 16. The D allele is associated with higher angiotensin converting enzyme levels and not surprisingly with heart disease, hypertension, response to angiotensin converting enzyme inhibitors, and so forth [26]. Interestingly, the D allele has also been associated with longevity. An interaction between the angiotensin converting enzyme polymorphisms and variants in the adducin (below) gene show how variants in several genes can be examined in terms of phenotypes in the same study [27]. The angiotensinogen gene has been an attractive candidate gene for hypertension. The M235T polymorphism has been the most widely studied. This polymorphism is in linkage disequilibrium with a promoter variant (A-6G) that may be of functional significance and is associated with angiotensinogen levels. The impact on blood pressure may be as high as 1 to 2 mm Hg. A meta-analysis of numerous association studies has been published [28]. CYP11B2 has been implicated in essential hypertension [29]. A 344T polymorphism was identified, in which hypertensive persons had a higher proportion of the T allele. A similar association was found in sibpairs; however, in that study, linkage could not be verified [30]. Multiple gene analysis in a large epidemiologic cohort has recently been reported [31]. This study concluded that angiotensin converting enzyme polymorphisms are associated with obesity. Epithelial sodium channel-related genes, adducin, and 11 b-hydroxysteroid dehydrogenase Ambrosius et al [32] investigated genetic variants in ENaC in relation to aldosterone and potassium excretion and risk for hypertension on 249 white


9

and 181 black young people. They studied five variants; all but one was more common in blacks than whites. G442V in the b-subunit was present in 16% of blacks and only one white. This variant was associated with greater sodium retention and lower aldosterone values. The variant could not be associated with hypertension, however, in an older cohort. Expression of variants in Xenopus oocytes did not result in changes in basal Na+ current. Persu et al [33] used single-strand conformation polymorphism to screen samples from 245 normal and 453 hypertensive subjects. The search was expanded to a subset of 65 patients with low renin hypertension. Four neutral polymorphisms were detected. The variants, however, were found in equal numbers in normotensive and hypertensive subjects. Regulators of ENaC have also received attention. The ENaC subunits contain PY motifs that are deleted in Liddle’s syndrome. Recent studies demonstrate that Nedd4 is a negative regulator of ENaC [34]. Any role for Nedd4 in hypertension, however, remains to be defined. Considerable work has been done on the cytoskeletal protein adducin. Ferrandi et al [35] recently carried knowledge in this area further. They found that both rat and human adducins stimulate Na+-K+-ATPase activity. In rats, adducins increase the ATP affinity for Na+-K+-ATPase. The mechanism of action involves a selective acceleration of conformational change in various pump proteins. Mutant human and rat adducins have higher affinities than wild-type adducins. The observations may be relevant to salt sensitivity. Nevertheless, the results of association studies involving adducin have been conflicting. Glorioso et al [36] recently tried to explain the discrepancies. They studied 490 hypertensives and 176 normotensives in Sassari, Italy, and 468 hypertensives and 181 normotensives from Milan, Italy. The subjects were genotyped for the Gly460Trp polymorphism. A positive association was found in the Milan cohort, but not in the Sassari cohort. Plasma renin activity was lower and the blood pressure response to diuretics greater, however, in persons carrying at least one 460Trp allele, compared with those not having this allele at both sites. The adducin gene hypothesis has been greatly strengthened by the demonstration that badducin gene deletion in the mouse results in hypertension [37]. Lovati et al [38] provided very interesting information implicating 11 bhydroxysteroid dehydrogenase in salt sensitivity of blood pressure. They studied 37 salt-sensitive and 112 salt-resistant normotensive persons. They showed that salt-sensitive persons excreted a ratio of cortisol to cortisone in their urine consistent with a reduced 11 b-hydroxysteroid dehydrogenase activity. They then used a polymorphic microsatellite marker in the gene and showed association between a marker variant and salt sensitivity of blood pressure. This study is the first to show convincing mechanistic genetic evidence concerning salt sensitivity and suggests that 11 bhydroxysteroid dehydrogenase variants could serve as a genetic marker for the condition. Claims for the glucocorticoid receptor gene and hypertension could not be confirmed. Lin et al [39] examined DNA from

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the so-called ‘‘4-corners’’ study. They studied a polymorphism in the gene to show association to high blood pressure and microsatellites to establish linkage of the gene locus to blood pressure. For the groups as a whole, no evidence for association or linkage was found. In gender subgroups, however, weak evidence for association to blood pressure was identified. G proteins and channels The putative role of G protein b3 subunit 8235T allele and hypertension has recently been reviewed elsewhere [40]. Baumgart et al [41] reported that carriers of 825T alleles more commonly exhibited ischemic events in response to a a2-adrenergic receptor agonist treatment during coronary angiography than those who did not carry this allele. Siffert et al [42] also identified an association between the 825T allele and obesity in a large, worldwide study. Jacobi et al [43] studied a small number of subjects in considerable detail and found that the 825T allele was associated with impaired left ventricular filling in hypertensive subjects. Dong et al [44] studied 428 men and women of African origin, 40% of who was hypertensive. They found a threefold higher risk of hypertension among the carriers of the T variant both as heterozygotes and homozygotes. The estimate of effect and the blood pressure values in the groups carrying the T variant suggested a dominant model for the T allele. Their study showed a high frequency of the 825T allele in black people, and provides evidence that the T allele may be a susceptibility factor for the development of hypertension in blacks. Given the high frequency of the T allele, even a twofold increased risk of hypertension among the carriers of the T allele might account for 44% of the cases of hypertension in blacks. Jia et al [45] examined whether or not the GNAS1 locus encoding the Gsa subunit is implicated in hypertension. They found a silent polymorphism (ATT!ATC, Ile131) in exon 5 of the Gsa gene. They then studied this polymorphism in 231 control subjects and 268 hypertensive persons. In untreated hypertensive persons, the polymorphism was related to systolic blood pressure, but not in normotensive individuals. In a multiple regression analysis performed in a b-blocker–treated subgroup, the Gs-a genotype was the sole independent predictor of blood pressure response to beta-blockade. The finding that calcium-regulated potassium channel subunit gene deletion causes hypertension in mice has focused attention on the human genes. Gollasch et al [46] recently found that the BK channel b1 subunit gene is associated with baroreflex regulation of blood pressure.

Endothelium-related factors Kato et al [47] studied 1165 persons and examined the relevance of the 298Glu variant in the endothelial nitric oxide synthase gene. They found no


11

support for any associations between the variant, hypertension, or blood pressure. Glenn et al [48] studied inducible nitric oxide synthase. They tested NOS2A markers for association and linkage with hypertension in affected Australian Anglo whites. No evidence supporting a relationship with blood pressure was found. Nevertheless, Herlitz et al [49] found that urine flow in response to L-arginine infusions in normal subjects was significantly less pronounced in persons with a positive family history of hypertension, compared with those with a negative family history. The Lys198ASn polymorphism in the endothelin-1 gene has been studied in an association study. Tiret et al [50] found that the polymorphism was associated with blood pressure levels in overweight people. Prostacyclin is a strong, endothelium-derived vasodilator. Iwai et al [51] detected a repeat polymorphism in the human prostacyclin synthase gene. This variant was tested for functional significance in human endothelial cells and was found to influence promoter activity. The authors then performed a very convincing association study in 4971 Japanese participants. Systolic blood pressure, pulse pressure, and the odds ratio of hypertension were all associated with the SS genotype of this polymorphism. The function of the glucagon receptor could conceivably influence vascular behavior on the basis of cAMP responses. A missense mutation (Gly40Ser) in exon 2 of the gene has been shown to exhibit reduced cAMP responses. Brand et al [52] performed an association study of 741 French hypertensive persons and compared them with 412 normotensive controls. The polymorphism may represent a risk for hypertension in men, but apparently not in women. Sympathetic tone, a-, and b-adrenergic receptors Leptin has been implicated in sympathetic tone. Paolisso et al [53] recently demonstrated that plasma leptin levels are associated with myocardial wall thickness in hypertensive insulin-resistant men. Ozata et al [54] observed that human leptin deficiency caused by a missense mutation features decreased sympathetic tone. Human a1B-adrenergic receptor polymorphisms have received attention. Bu¨scher et al [55] studied variability in phenylephrine response and essential hypertension. They searched for an effect of a1B-adrenergic receptor polymorphisms, but were not able to find polymorphisms in the coding region of the gene that accounted for variability in phenylephrine responses. Experimental evidence suggests that salt loading induces hypertension by a neurogenic mechanism mediated by the a2-adrenergic receptors. Makaritsis et al [56] studied genetically engineered mice and found that a full complement of a2B-adrenergic receptor genes was necessary to raise blood pressure in response to dietary salt loading, whereas complete absence of the a2C-adrenergic receptor subtype did not preclude salt-induced blood pressure elevations. The b2-adrenergic receptor and its variants have received considerable attention. Earlier studies have shown that the Arg16!Gly variant is

12


associated with hypertension. Gratze et al [57] showed that a b2-adrenergic receptor variant affects resting blood pressure and agonist-induced vasodilation in young whites. They found that the Gly variant was associated with higher blood pressures. Furthermore, homozygous Gly16 subjects showed a significantly decreased vasodilation during a salbutamol infusion compared with Arg16-Arg subjects. These results are consistent with data from an association study of African-Caribbeans reported earlier, but at variance with an association study from the Bergen Blood Pressure Study [58]. Human atrial natriuretic peptide and dopamine hANP is an attractive candidate gene for hypertension. Mice with a disrupted gene are relatively hypertensive. The role of atrial natriuretic peptide in salt excretion is well appreciated. Nannipieri et al [59] investigated polymorphisms in hANP and studied albuminuria and hypertension. Two hANP polymorphisms were studied, termed ScaI and BstXI. A clinical cohort of 1033 subjects including type 1 and type 2 diabetics participated. The prevalence of hypertension was 30% to 60% depending on the severity or proteinuria. The ScaI polymorphism was inversely associated with nephropathy. The mutated BstXI polymorphism was directly associated with microalbuminuria. The authors reasoned that certain hANP variants might confer a protective effect. Dopamine receptor coupling defects have been described in hypertension [60]. A defective coupling between the D(1) dopamine receptor and the G protein–effector enzyme complex in the proximal tubule of the kidney is associated with impaired renal dopaminergic action in genetic rodent and human essential hypertension. Felder et al [61] reported recently that, in human essential hypertension, single nucleotide polymorphisms of a G protein–coupled receptor kinase, GRK4gamma, increase G protein–coupled receptor kinase (GRK) activity and cause the serine phosphorylation and uncoupling of the D(1) receptor from its G protein-effector enzyme complex in the renal proximal tubule. They transfected Chinese hamster ovary cells and confirmed their suspicions in this cell system. Moreover, expressing GRK4gammaA142V but not the wild-type gene in transgenic mice produced hypertension and impaired the diuretic and natriuretic but not the hypotensive effects of D(1)-like agonist stimulation. Their findings provide a mechanism for the D(1) receptor coupling defect in the kidney and may explain the inability of the kidney properly to excrete sodium in genetic hypertension. Human linkage studies for new blood pressure loci and hypertension To find new genes responsible for blood pressure regulation and hypertension, their location must first be determined. Here, linkage studies


13

are necessary. Linkage is quantitated by the logarithm of the odds ratio, or LOD score. A LOD score of greater than or equal to 3 is regarded as significant. Analyses of large families, affected sibpair studies, identical by state or identical by descent are commonly used to link loci on the genome to blood pressure as a continuous trait or to hypertension. Microsatellite markers that feature variable numbers of repeats are used in these studies. The microsatellites are amplified with the polymerase chain reaction and sequenced. The goal is to find microsatellite variants that are always inherited with the trait. These variants are then linked to the trait and provide information regarding its location. The author has used dizygotic twin subjects (sibpairs) and their parents for this purpose (Fig. 5) to find so-called ‘‘quantitative trait loci’’ [62]. A large family-based total genome scan in Chinese hypertensive families recently showed linkage to chromosome 12p (LOD > 3), where the autosomal-dominant hypertension with brachydactyly locus resides [63]. Rankinen et al [64] recently reported on a genome scan for gene loci related to exercise-induced blood pressure elevations from the health risk factors, exercise training and genetics (HERITAGE) Family Study illustrating this approach. Levy et al [65] studied families from the Framingham cohort. They had the advantage of being able to study longitudinal blood pressure values and found a locus on chromosome 17 that yielded a multipoint LOD score of 4.7. For diastolic blood pressure the LOD value was 2. This locus is of interest because of earlier rat studies showing linkage at a site syntenic to this locus [66]. How are the cloning strategies for complex genetic diseases to be performed and how is the track record? Boerwinkel et al [67] recently

Fig. 5. Identity-by-descent linkage analysis, the gene mapping approach. Polymorphic markers (arrow) are selected. DNA is obtained from parents and offspring. If the parents have alleles a-b and b-c, it is expected that 25% of the offspring share no alleles in common, 50% share one allele in common, and 25% share both alleles in common. Statistical deviation from these expectations, either concordancy or discordancy, suggests linkage of the phenotypes are concordant or discordant, respectively. If parents are not available, an identity-by-state analysis must be done and many more pairs are necessary.

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presented a brief review on the basic strategy. The method relies on single nucleotide (bi-allelic) polymorphisms (SNPs) mutations that are distributed approximately every 1000 base pairs across the genome. The SNPs represent interindividual variability that distinguishes one person from another. Probably more than 3,000,000 SNPs reside within the genome. With the results of the human genome project soon to be available, investigators will be able to analyze all the SNPs that are likely to be informative. SNPs in coding, noncoding, and regulatory regions are all valuable. The SNPs can be used in haplotype analyses to determine if specific haplotypes are associated with the phenotype. Once SNP mapping is completed, the gene or genes must be sequenced for mutations. Eventually, experimental animal or cellular studies on the gene in question will be necessary to prove how the mutation works. Recent advances in molecular biology and technology have made it possible to monitor the expression levels of virtually all genes simultaneously [68]. As the tools for gene expression profiling have become more widely available, the number of investigators applying this technology in hypertension research, as in other fields of biomedical research, has grown rapidly. This approach obviously requires functioning cells or tissues for analysis. A direct application to the genetics of human hypertension requires biopsies of small vessels. Such approaches are technically feasible and will undoubtedly soon be applied. References [1] Luft FC, Schuster H, Bilginturan N, Wienker T. ‘‘Treasure your exceptions’’: what we can learn from autosomal dominant inherited forms of hypertension. J Hypertens 1995;13:1535–8. [2] Lifton RP, Gharavi AG, Geller DS. Molecular mechanisms of human hypertension. Cell 2001;104:545–56. [3] Lifton RP, Dluhy RG, Powers M, Rich GM, Cook S, Ulick S, et al. A chimaeric 11bhydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 1992;355:262–5. [4] Botero-Velez M, Curtis JJ, Warnock DG. Liddle’s syndrome revisited. N Engl J Med 1994;330:178–81. [5] Shimkets RA, Warnock DG, Bositis CM, Nelson-Williams C, Hansson JH, Schambelan M, et al. Liddle’s syndrome: heritable human hypertension caused by mutations in the b subunit of the epithelial sodium channel. Cell 1994;79:407–14. [6] Hansson JH, Nelson-Williams C, Suzuki H, Schild L, Shimkets R, Lu Y, et al. Hypertension caused by a truncated epithelial sodium channel g subunit: genetic heterogeneity of Liddle syndrome. Nat Genet 1995;11:76–82. [7] Palmer BF, Alpern RJ. Liddle’s syndrome. Am J Med 1998;104:301–9. [8] Mune T, Roberson FM, Nikkila¨ H, Agarwal AK, White PC. Human hypertension caused by mutations in the kidney isozyme of 11 b-hydroxysteroid dehydrogenase. Nat Genet 1995;10:394–9. [9] Li A, Li KX, Marui S, Krozowski ZS, Batista MC, Whorwood CB, et al. Apparent mineralocorticoid excess in a Brazilian kindred: hypertension in the heterozygous state. J Hypertens 1997;15:1397–402.


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[10] Geller DS, Farhi A, Pinkerton N, Fradley M, Moritz M, Spitzer A, et al. Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science 2000;289:119–23. [11] Mansfield TA, Simon DB, Farfel Z, Bia M, Tucci JR, Lebel M, et al. Multilocus linkage of familial hyperkalaemia and hypertension, pseudohypoaldosteronism type II, to chromosomes 1q13–42 and 17p11-q21. Nat Genet 1997;16:202–5. [12] Disse-Nicodeme S, Achard JM, Desitter I, Houot AM, Fournier A, Corvol P, et al. A new locus on chromosome 12p13.3 for pseudohypoaldosteronism type II, an autosomal dominant form of hypertension. Am J Hum Genet 2000;67:302–10. [13] Wilson FH, Disse-Nicodeme S, Choate KA, Ishikawa K, Nelson-Williams C, Disitter I, et al. Human hypertension caused by mutations in WNK kinases. Science 2001;293: 1107–12. [14] Yang CL, Angell J, Mitchell R, Ellison DH. WNK kinases regulate thiazide-sensitive Na-Cl cotransport. J Clin Invest 2003;111:1039–45. [15] Wilson FH, Kahle KT, Sabath E, Lalioti MD, Rapson AK, Hoover RS, et al. Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4. Proc Natl Acad Sci U S A 2003;100:680–4. [16] Bilginturan N, Zileli S, Karacadag S, Pirnar T. Hereditary brachydactyly associated with hypertension. J Med Genet 1973;10:253–9. [17] Schuster H, Wienker TF, Toka HR, Ba¨hring S, Jeschke E, Toka O, et al. Autosomal dominant hypertension and brachydactyly in a Turkish kindred resembles essential hypertension. Hypertension 1996;28:1085–92. [18] Weinberger MH, Fineberg NS. The diagnosis of primary aldosteronism and separation of two major subtypes. Arch Intern Med 1993;153:2125–9. [19] Schuster H, Toka O, Toka H, Busjahn A, O¨ztekin O¨, Wienker TF, et al. A cross-over medication trial for autosomal-dominant hypertension with brachydactyly. Kidney Int 1998;53:167–72. [20] Naraghi R, Schuster H, Toka HR, Bahring S, Toka O, Oztekin O, et al. Neurovascular compression at the ventrolateral medulla in autosomal dominant hypertension and brachydactyly. Stroke 1997;28:1749–54. [21] Jordan J, Toka H, Heusser K, Stabroth C, Tank J, Diedrich A, et al. Severely impaired baroreflex buffering in patients with monogenic hypertension and neurovascular contact. Circulation 2000;102:2611–8. [22] Luft FC, Toka O, Toka H, Jordan J, Ba¨hring S. Mendelian hypertension with brachydactyly as a molecular genetic lesson in regulatory physiology. Am J Phys 2003; 285:R709–14. [23] Pickering G. Systemic arterial hypertension. In: Fishman AP, Richards DW, editors. Circulation of the blood: men and ideas. Bethesda, MD: American Physiological Society; 1964. p. 487–544. [24] Anonymous. Freely associating. Nat Genet 1999;22:1–2. [25] Rieder MJ, Taylor SL, Clark AG, Nickerson DA. Sequence variation in the human angiotensin converting enzyme. Nat Genet 1999;22:59–62. [26] Niu T, Chen X, Xu X. Angiotensin converting enzyme gene insertion/deletion polymorphism and cardiovascular disease: therapeutic implications. Drugs 2002;62(7):977–93. [27] Sciarrone MT, Stella P, Barlassina C, Manunta P, Lanzani C, Bianchi G, et al. ACE and alpha-adducin polymorphism as markers of individual response to diuretic therapy. Hypertension 2003;41:398–403. [28] Kunz R, Kreutz R, Beige J, Distler A, Sharma AM. Association between the angiotensinogen 235T-variant and essential hypertension in whites: a systematic review and methodological appraisal. Hypertension 1997;30:1331–7. [29] Davies E, Holloway CD, Ingram MC. Aldosterone excretion rate and blood pressure in essential hypertension are related to polymorphic differences in the aldosterone synthase gene CYP11B2. Hypertension 1999;33:703–7.

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[30] Brand E, Chatelain N, Mulatero P. Structural analysis and evaluation of the aldosterone synthase gene in hypertension. Hypertension 1998;32:198–204. [31] Strazzullo P, Iacone R, Iacoviello L, Russo O, Barba G, Russo P, et al. Olivetti Prospective Heart Study. Genetic variation in the renin-angiotensin system and abdominal adiposity in men: the Olivetti Prospective Heart Study. Ann Intern Med 2003;138:17–23. [32] Ambrosius WT, Bloem LJ, Zhou L, Rebhun JF, Snyder PM, Wagner MA, et al. Genetic variants in the epithelial sodium channel in relation to aldosterone and potassium excretion and risk for hypertension. Hypertension 1999;34:631–7. [33] Persu A, Coscoy S, Houot A-M, Corvol P, Barbry P, Jeunemaitre X. Polymorphisms of the g subunit of the epithelial Na+ channel in essential hypertension. J Hypertens 1999;17: 639–45. [34] Abriel H, Loffing J, Rebhun JF, Pratt JH, Schild L, Horisberger JD, et al. Defective regulation of the epithelial Na+ channel by Nedd4 in Liddle’s syndrome. J Clin Invest 1999;103:667–73. [35] Ferrandi M, Salardi S, Tripodi G, Barassi P, Rivera R, Manunta P, et al. Evidence for an interaction between adducin and the Na+-K+-ATPase: relation to genetic hypertension. Am J Physiol 1999;277:H1338–49. [36] Glorioso N, Manunta P, Filigheddu F, Troffa C, Stella P, Barlassina C, et al. The role of alpha-adducin polymorphism in blood pressure and sodium handling regulation may not be excluded by a negative association study. Hypertension 1999;34:649–54. [37] Marro ML, Scremin OU, Jordan MC, Huynh L, Porro F, Roos KP, et al. Hypertension in beta-adducin-deficient mice. Hypertension 2000;36:449–53. [38] Lovati E, Ferrari P, Dick B, Jostarndt K, Frey BM, Frey FJ, et al. Molecular basis of human salt sensitivity: the role of the 11 b-hydroxysteroid dehydrogenase type 2. J Clin Endocrinol Metab 1999;84:3745–9. [39] Lin RCY, William YS, Morris BJ. Association and linkage analyses of glucocorticoid receptor gene markers in essential hypertension. Hypertension 1999;34:1186–92. [40] Siffert W, Rosskopf D, Erbel R, Ritz E. G protein beta3subunit 825T allele and hypertension. Hypertension 1999;34:e8. [41] Baumgart D, Naber C, Haude M, Oldenburg O, Erbel R, Heusch G, et al. G protein beta3 subunit 825T allele and enhanced coronary vasoconstriction on alpha(2)-adrenoceptor activation. Circ Res 1999;85:965–9. [42] Siffert W, Forster P, Jockel KH, Mvere DA, Brinkmann B, Naber C, et al. Worldwide ethnic distribution of the G protein beta3 subunit 825T allele and its association with obesity in Caucasian, Chinese, and Black African individuals. J Am Soc Nephrol 1999;10:1921–30. [43] Jacobi J, Hilgers KF, Schlaich MP, Siffert W, Schmieder RE. 85T allele of the G-protein b3 subunit (GNB3) is associated with impaired left ventricular diastolic filling in essential hypertension. J Hypertens 1999;17:1457–62. [44] Dong Y, Zhu H, Sagnella GA, Carter ND, Cook DG, Cappuccio FP. Association between the C825T polymorphism of the G protein b3-subunit gene and hypertension in blacks. Hypertension 1999;34:1193–6. [45] Jia H, Hingorani AD, Sharma P, Hopper R, Dickerson C, Trutwein D, et al. Association of the Gsa gene with essential hypertension and response to b-blockade. Hypertension 1999;34:8–14. [46] Gollasch M, Tank J, Luft FC, Jordan J, Maass P, Krasko C, et al. The BK channel beta1 subunit gene is associated with human baroreflex and blood pressure regulation. J Hypertens 2002;20:927–33. [47 Kato N, Sugiyama T, Morita H, Nabika T, Kurihara H, Yamori Y, et al. Lack of evidence for association between the endothelial nitric oxide synthase gene and hypertension. Hypertension 1999;33:933–6. [48] Glenn CL, Wang WY, Morris BJ. Different frequencies of inducible nitric oxide synthase genotypes in older hypertensives. Hypertension 1999;33:927–32.


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[49] Herlitz H, Jungerstein LU, Wikstrand J, Widgren BR. Effect of L-arginine infusion in normotensive subjects with and without a family history of hypertension. Kidney Int 1999;56:1838–45. [50] Tiret L, Poirier O, Hallet V, McDonagh TA, Morrison C, McMurray JJV, et al. The Lys198Asn polymorphism in the endothelin-1 gene is associated with blood pressure in overweight people. Hypertension 1999;33:1169–74. [51] Iwai N, Katsuya T, Ishikawa K, Mannami T, Ogata J, Higaki J, et al. Human prostacyclin synthase gene and hypertension: the Suita Study. Circulation 1999;100: 2231–6. [52] Brand E, Bankir L, Plouin P-F, Soubrier F. Glucagon receptor gene mutation (Gly40Ser) in human essential hypertension: the PEGASE Study. Hypertension 1999;34:15–7. [53] Paolisso G, Tagliamonte MR, Galderisi M, Zito GA, Petrocelli A, Carella C, et al. Plasma leptin level is associated with myocardial wall thickness in hypertensive insulin-resistant men. Hypertension 1999;34:1047–52. [54] Ozata M, Ozdemir IC, Licinio J. Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J Clin Endocrinol Metab 1999;84:3686–95. [55] Bu¨scher R, Herrmann V, Ring KM, Kailasam MT, O’Connor DT, Parmer RJ, et al. Variability in phenylephrine response and essential hypertension: a search for human a1badrenergic receptor polymorphisms. J Pharm Exp Ther 1999;291:793–8. [56] Makaritsis KP, Handy DE, Johns C, Kobilka B, Gavras I, Gavras H. Role of the alpha2Badrenergic receptor in the development of salt-induced hypertension. Hypertension 1999;33:14–7. [57] Gratze G, Fortin J, Labugger R, Binder A, Kotanko P, Timmermann B, et al. Beta-2 adrenergic receptor variants affect resting blood pressure and agonist-induced vasodilation in young adult Caucasians. Hypertension 1999;33:1425–30. [58] Timmermann B, Mo R, Luft FC, Gerdts E, Busjahn A, Omvik P, et al. Beta-2 adrenoceptor genetic variation is associated with genetic predisposition to essential hypertension: the Bergen Blood Pressure Study. Kidney Int 1998;53:1455–60. [59] Nannipieri M, Manganiello M, Pezzatini A, De Bellis A, Seghieri G, Ferrannini E. Polymorphisms in the hANP (Human Atrial Natriuretic Peptide) gene, albuminuria, and hypertension. Hypertension 2001;37:1416–22. [60] Jose PA, Eisner GM, Felder RA. Dopamine receptor-coupling defect in hypertension. Curr Hypertens Rep 2002;4:237–44. [61] Felder RA, Sanada H, Xu J, Yu PY, Wang Z, Watanabe H, et al. G protein-coupled receptor kinase 4 gene variants in human essential hypertension. Proc Natl Acad Sci U S A 2002;99:3872–7. [62] Luft FC, Arthur C. Corcoran Memorial Lecture: twins in cardiovascular genetic research. Hypertension 2001;37:350–6. [63] Gong M, Zhang H, Schulz H, Lee YA, Sun K, Bahring S, et al. Genome-wide linkage reveals a locus for human essential (primary) hypertension on chromosome 12p. Hum Mol Genet 2003;12:1273–7. [64] Rankinen T, An P, Rice T, Sun G, Chagnon YC, Gagnon J, et al. Genomic scan for exercise blood pressure in the HERITAGE Family Study. Hypertension 2001;38:30–7. [65] Levy D, DeStefano AL, Larson MG, O’Donnell CJ, Lifton RP, Gavras H, et al. Evidence for a gene influencing blood pressure on chromosome 17: genome scan linkage results for longitudinal blood pressure phenotypes in subjects from the Framingham Heart Study. Hypertension 2000;36:477–83. [66] Julier C, Delepine M, Keavney B, Terwilliger J, Davis S, Weeks DE, et al. Genetic susceptibility for human familial essential hypertension in a region of homology with blood pressure linkage on rat chromosome 10. Hum Mol Genet 1997;6:2077–85.

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[67] Boerwinkle E, Hixson JE, Hanis CL. Peeking under the peaks: following up on genomewide linkage analysis. Circulation 2000;102:1877–8. [68] Pravenec M, Wallace C, Aitman TJ, Kurtz TW. Gene expression profiling in hypertension research: a critical perspective. Hypertension 2003;41:3–8.

Med Clin N Am 88 (2004) 19–38

Tissue renin angiotensin systems Richard N. Re, MD Research Division, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA 70121, USA

The renin-angiotensin system (RAS) is a major determinant of blood pressure and intravascular volume. Studies of this system have led to the development of important new forms of treatment for hypertension and congestive heart failure, such as the angiotensin converting enzyme inhibitors (ACEIs) and the AT-1 angiotensin receptor blockers (ARBs) [1–16]. Furthermore, angiotensin seems to play an important role in the determination of vascular architecture (both in utero and in later life); in vascular inflammation; and in atherogenesis. Recently, aldosterone, the final element of the renin-angiotensin-aldosterone system (RAAS), has been shown to stimulate cardiac fibrosis and like angiotensin, aldosterone affects both hemodynamics and cardiovascular tissue architecture [2,17,18]. Indeed, a large and growing body of evidence points to important roles for the RAAS in cardiovascular function and architecture, inflammation and atherogenesis, tissue development, and in a wide variety of other processes [1–121]. Moreover, the available evidence indicates that in addition to the RAAS operative in the circulation, local systems (complete or partial) exist in a variety of tissues and play important roles in a variety of developmental and disease processes. This view was initially controversial because it was at first assumed that any such tissue system must be renin driven and it was difficult consistently to detect renin gene expression in nonrenal tissues. But a consensus has now emerged that these local RASs-RAASs exist and likely are functionally relevant [2,19–21]. This has occurred because (1) renin expression has been detected in some nonrenal tissues either normally or in pathologic states, (2) synthesis of RAS components other than renin has been shown in tissues leading to locally regulated angiotensin production, (3) tissue measurements of angiotensin can in some cases be shown either to be independent of the activity of the circulating RAS or to be only roughly

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predicted by that activity, and (4) the beneficial effects of converting enzyme inhibitors and angiotensin receptor blockers cannot reliably be predicted by measurements of the activity of the circulating RAS. In addition, the notion that angiotensin can act within cells in a so-called ‘‘intracrine manner’’ and the related idea that intracellular RASs exist are gaining currency in the research community [2,40]. It is likely that the manipulation of tissue and intracellular angiotensin action provides expanded opportunities for therapeutic intervention.

Tissue renin angiotensin systems By the 1970s, renin-like enzymatic activity had been reported in various tissues [2,19]. It was not clear, however, if this activity resulted from the presence of renin or from the presence of nonrenin proteolytic enzymes, such as cathepsins. It was also unclear if any true renin in tissues was synthesized locally or alternatively whether all tissue renin was simply taken up from plasma. The assumption that only the kidney could activate prorenin implied that any renin gene expression in tissues results in the synthesis of enzymatically inactive prorenin. The possible exceptions to this skepticism regarding local renin production were the brain and ovary, the latter producing prorenin [2,19–21,48–50,70]. When antibodies directed toward purified renin became available, the biosynthesis of renin in cultured canine arterial smooth muscle cells was demonstrated by detecting antibody-inhibitable renin activity, by immunohistochemistry, and by the immunoprecipitation of labeled biosynthetic products [23]. Antibody-inhibition of enzymatic activity in isolated rat cardiac myocytes also was later reported [24]. Many investigators, however, were unable consistently to detect renin mRNA in the vasculature and heart of several species [21]. Renin mRNA was more frequently detected in pathologic states than in normal heart suggesting a pathophysiologic role for its up-regulation [25]. Angiotensinogen, angiotensin I, and renin, however, could clearly be shown to be taken up into the vessel wall [1,2]. This further supported the opinion that renin production in the cardiovascular system (if it occurred at all) was of no physiologic relevance. Because at best only small amounts of renin expression could be detected in cardiovascular tissues, it was clear that effects of any locally produced renin on blood pressure are small compared with effect of circulation-derived renin and the angiotensin I it generated. For some time the relevance of the tissue RAS was dismissed. Tissue renin With respect to the tissue synthesis of renin, recently the situation has clarified somewhat, although the significance of tissue renin production remains controversial [2,25–39,41,44,45,71]. For example, considerable

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evidence supports the regulated synthesis of renin in the adrenal cortex [33,35,36,38,39]. Renin mRNA can be detected in rat adrenal glands and renin activity is present at readily detectable levels; low sodium diet and AT1 receptor blockade up-regulate adrenal renin [33,35]. The presence of renin mRNA and protein has been reported in the spiral arteries of human uterus and in decidual cells [28,50]. Renin message and protein are increased in vascular cells following carotid artery injury in the rat suggesting that locally synthesized renin plays a role in the (ACEI preventable) medial thickening that occurs [29]. Renin mRNA has been reported in the Muller cells of the eye and vitreous angiotensin II levels are levated in diabetic retinopathy [45,42,102]. Renin mRNA and protein, and other components of the RAS, are present in canine cardiac myocytes and these RAS components are upregulated by cardiac failure induced by ventricular pacing [27]. Cellassociated angiotensin II, apparently within cardiomyocytes, was also increased by pacing, suggesting a functional intracellular RAS in the cells. Moreover, up-regulation of the tissue RAS was associated with the activation of the apoptotic pathway in these canine myocytes indicating that the RAS is functional in these cells and likely plays a role in the development of congestive heart failure-related cell dropout. Renin upregulation was reported in rodent left ventricle following myocardial infarction; in this model, the renin expression first appeared in monocytes and later in myofibroblasts [30]. This suggests a dual role for the enzyme in the evolution of myocardial infarction. Also a second renin transcript lacking the coding region for the secretory signal peptide has been detected in brain, adrenal, and heart [32–35]. In the left ventricle this second transcript, so-called ‘‘renin 1A,’’ was the only transcript detected, whereas in the kidney only the full length transcript is found. Other tissues transcribe both forms. Interestingly, in rat left ventricle renin exon 1A increased dramatically following myocardial infarction [35]. The possibility has been raised that some groups who in the past searched for renin message in the heart may have used in their Northern analyses probes directed to the major prorenin transcript; these only poorly anneal to the renin 1A transcript. This could explain the negative results obtained by some investigators looking for cardiac renin message and is consistent with the detection of up-regulated renin mRNA in pathologic states [35]. In the adrenal cortex of the rat local renin synthesis is detected more easily. Here both full-length renin mRNA and the renin 1A transcript are detected. Moreover, in nephrectomized rats maintained on dialysis, renin increases and aldosterone synthesis is increased [33–35]. Renin exon 1A is up-regulated and seems to traffic to mitochondria. If an AT-1 receptor blocker is administered to the animals, aldosterone synthesis is blocked. Angiotensin infusion, however, also reduces aldosterone secretion. The authors of this study suggest that an intracellular RAS, inhibitable by internalized losartan, is operative in the nephrectomized animals and that intracellular angiotensin (produced by intracellular renin exon 1A) is more potent than extracellular angiotensin in stimulating

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aldosterone synthesis [35]. This could explain the reduction of aldosterone synthesis seen following angiotensin infusion because extracellular angiotensin is expected to suppress renin 1A synthesis by a negative feedback loop resulting in a net diminution in aldosterone synthesis despite its own stimulatory action. This study supports not only the existence of an adrenal RAS but also the existence of an intracellular or intracrine RAS [40]. Collectively, recent data support the participation of local renin synthesis in the regulation of some tissue RASs. Moreover, some examples of local renin synthesis also suggest that tissue renin production is physiologically relevant. The renin 1A transcript is up-regulated in left ventricle following myocardial infarction, suggesting that the renin up-regulation in the heart that had previously been reported was the result of accumulation of renin 1A message and raising the possibility that this renin up-regulation participates in the RAS activation seen following infarction. This is potentially important because the renin 1A product is expected to remain intracellular and to be synthesized in an active as opposed to a prorenin form [33–35]. This immediately suggests an intracellular role for renin in what has been termed the ‘‘intracrine (intracellular)’’ angiotensin system [2,40]. At the same time, however, the presence of this renin in the left ventricle could very well generate angiotensin for local paracrine effects on growth, apoptosis, and contractility. This idea is consistent with the finding that stretch induces angiotensin II release and angiotensinogen gene upregulation in cultured neonatal myocytes; indeed, in this model, the hypertrophy of the cells is dependent on angiotensin action and is blocked by an AT-1 blockade [26]. Also of note in this regard is the finding, already alluded to, that in rapidly paced diabetic canine hearts renin mRNA and protein are up-regulated and associated with cardiac myocyte apoptosis [27]. Finally, renin 1A is up-regulated in the adrenal gland following nephrectomy and seems to support aldosterone secretion in this circumstance. There is considerable evidence for the synthesis of renin outside the kidney and, based on these examples, it seems likely that this renin is acting to influence local, or even intracellular, angiotensin concentrations in important ways. Other renin-angiotensin system components The local production of angiotensinogen (aogen) and ACE in tissues has been demonstrated [1,2,19,25]. Pituitary cells have been shown to synthesize and secrete angiotensinogen (they also contain angiotensin II and renin suggesting an intracellular RAS) [43,44]. In experimental models of volume overload the up-regulation of cardiac renin and ACE has been reported, whereas models of pressure overload are associated with up-regulation of angiotensinogen and AT-1 receptor genes [25]. In humans, myocardial infarction has been reported to be associated with up-regulation of ventricular renin, angiotensinogen, and ACE expression and there are

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animal data demonstrating similar RAS gene activation following infarction [25]. ACE has been shown to be similarly up-regulated. In hypertrophied human heart, angiotensinogen is increased in the subendocardial myocardium [25]. Moreover, ACE is up-regulated in the human atherosclerotic plaque and more particularly at the shoulder of the plaque, the site most vulnerable for rupture [16,46]. Because for any level of renin activity angiotensin II synthesis can be altered by changes in the concentration of available angiotensinogen and ACE, up-regulation of these RAS components in tissues can alter tissue concentrations of angiotensin II [51]. It should also be noted that there exist non-RAS enzymes that can substitute for some RAS components in the generation of angiotensin II [52–55,65]. The enzyme chymase, which converts angiotensin I to angiotensin II, is found in human cardiac tissue and a recently described enzyme ACE2 seems to convert angiotensin I to angiotensin [1–9,52,53,109]. Although chymase likely plays a role in the generation of angiotensin II in the human heart, the role of ACE2 is unclear at this time. ACE can convert Ang(1-9) to the vasodilating peptide Ang(1-7) and this ACE2-ACE shunt may serve to dampen some angiotensin II actions [60–62]. There are nonrenin proteases capable of generating angiotensins and these may be physiologically relevant [53–55,57,65]. For example, cathepsins may be responsible for the generation of angiotensin II in some cells, either by generating angiotensin I from substrate or by converting angiotensin I to angiotensin II. In the case of monocyte-macrophages and adipocytes, RAS components and cathepsins are present and so it may be that renin-independent or ACE-independent angiotensin synthesis occurs [55,64,66,67]. Given the ability of angiotensin II to induce oxidative stress, inflammation, and the release of metalloproteases, the implications of the local monocyte-macrophage angiotensin system for plaque rupture are real and this local angiotensin system offers an explanation for some of the beneficial effects of ACEs and ARBs on vascular disease [16]. Also, angiotensinogen mRNA, along with several angiotensin-generating enzymes, is found in the adventitia of vessels, and in adipose tissue, where locally produced angiotensin could influence fat cell development [57,59,65,68]. Other proteases, such as the enzyme tonin, can also generate angiotensin I from angiotensinogen, so the potential for non-renin-generated angiotensin I theoretically exists in multiple locations [1,2]. Intracellular angiotensin generation A question receiving increasing interest is whether local RASs synthesize angiotensin intracellularly or alternatively whether all angiotensin II production occurs in the extracellular space. Neonatal cardiac myocytes and cardiac fibroblasts were shown to secret angiotensin in culture following stretch, but because the cells potentially could take up both renin and angiotensin II, it could not be determined definitively if the angiotensin were

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produced intracellularly or taken up from the media and later secreted; the up-regulation of angiotensinogen gene expression by stretch did, however, argue for local regulation of angiotensin production [26]. Indeed, recent findings support cellular synthesis of angiotensin II in cells, including heart cells. Evidence has been developed for angiotensin production in juxtaglomerular cells; the introduction of renin into cardiac myocytes produced conductance changes inhibitable by converting enzyme inhibition suggesting the intracellular generation of angiotensin; and the uptake of nonglycosylated renin by cardiac myocytes resulted in intracellular angiotensin generation and pathologic changes [27,72–76]. In addition, the apoptosis seen cardiac myocytes in human diabetic hearts and in the hearts of dogs paced to failure is associated with increased cellular content of angiotensin II [26,77]. Collectively these findings strongly support intracellular angiotensin generation. It has also been shown that circulating prorenin can bind to the insulin growth factor II-mannose receptor on cardiac myocytes, after which it is internalized and activated [78]. This indirectly supported the existence of a cardiac angiotensin system, but suggested that renal prorenin is the source of the renin that drives that system. Recently it has been suggested that mannose receptor-mediated renin uptake likely represents a clearance mechanism for renin and that a separate nonmannose receptor uptake likely results in physiologically relevant prorenin internalization and activation [76,78]. This physiologically relevant receptor does not seem to be the receptor recently reported to generate second messengers in response to renin-prorenin binding and to lead to enhanced enzymatic activity of receptor-bound prorenin-renin [78,80]. Prorenin-renin bound to that receptor does not seem to be internalized. It seems that there are multiple prorenin-renin receptors on target cells. But, in any case, there is growing evidence to support the physiologically relevant activity of prorenin-renin following internalization. This further supports the generation of intracellular angiotensin. There is a large and growing body of evidence to indicate the synthesis of RAS components in cardiovascular and other tissues.

Regulation of local renin angiotensin system activity Although renin is the driver of the RAS, variations in the concentrations of other components of the system can affect angiotensin generation and these components could be important determinants of angiotensin concentrations at target tissues [51]. For example, ACE has been shown to be upregulated at the collars of atherosclerotic plaques and this elevated ACE could well lead to locally augmented angiotensin production with deleterious effects on metalloproteinase activity and plaque rupture [16,46]. Physiologic and pathologic perturbations that up-regulate angiotensinogen or other RAS components effectively regulate the activity of the

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local RAS. Indeed, it may well be that some of the beneficial affects of ACE inhibitors in preventing myocardial infarction stem from this plaquestabilizing activity. Angiotensinogen has been similarly reported to be elevated in a variety of physiologic and pathologic states and this also could result in higher local concentrations of angiotensin II [25]. Indeed, when tissue and plasma angiotensin II concentrations are compared across a wide range of physiologic perturbations in rats, a correlation between tissue and plasma levels is seen as expected if circulating renin were the major determinant of angiotensin generation. At every level of plasma angiotensin, however, there is a wide variation (10- to 100-fold) in the concentrations seen in each organ [81], tissue angiotensin levels vary markedly from tissue to tissue. This suggests that the local tissues, either through altered uptake of circulating components of the RAS or through local synthesis of RAS components, affect angiotensin concentration at target cells sites. This has been demonstrated in a variety of experimental models and in human disease. When normal subjects were treated with a high- or low-sodium diet and angiotensin production across the heart was determined during catheterization, discordance between circulating RAS activity and cardiac angiotensin production was seen: low-sodium diet activated the circulating RAS but reduced cardiac angiotensin production, whereas high-sodium intake suppressed the circulating system and stimulated cardiac angiotensin generation [82]. This observation suggests a possible pathologic role of high sodium intake in left ventricular hypertrophy. In addition, studies of patients undergoing cardiac transplantation for heart failure demonstrated increased mRNA levels for angiotensinogen and ACE in the heart failure hearts and increased staining for angiotensin II (no renin mRNA was detected in this study). Catheterization studies revealed that cardiac angiotensin production paralleled plasma renin levels in severe heart failure (when circulating renin is very high) but not in milder forms of the disease [83]. It is also of note that others have shown that in both hypertension and in congestive heart failure cardiac production of aldosterone is also increased as assessed by catheterization studies indicating that the activation of the cardiac tissue renin system results in stimulation of local aldosterone production (ie, hypertension and congestive heart failure seem to stimulate the cardiac RAAS) [84,85]. Given the observations (1) that in rat models of myocardial infarction cardiac tissue levels of angiotensin II and aldosterone are increased and (2) that losartan or the aldosterone antagonist spironolactone reduce infarction-related cardiac fibrosis, it is likely that a functional tissue RAAS exists in the heart and plays a role in cardiac adaptation and pathology [17]. The additive beneficial effects of spironolactone when administered in addition to ACE inhibitors in patients suffering from congestive heart failure could well be the result of the interruption of this tissue system in addition to affects on the levels of circulating hormones [18]. Moreover, because aldosterone up-regulates ACE synthesis by cultured cardiac myocytes, it is possible that in some

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pathologic states, or in the face of high sodium chloride ingestion, the cardiac RAS is up-regulated with increased angiotensin production stimulating local ACE synthesis, forming a positive pathologic feedback loop. Also of interest is the recent report that brain natruretic peptide inhibits aldosterone synthesis by rodent cardiac myocytes in vitro [86]. Because it has been shown that brain natruretic peptide synthesis by the heart is increased in patients with congestive heart failure or hypertension, it may be that cardiac production of brain natruretic peptide acts as an endogenous inhibitor of cardiac RAAS action [84,85]. Although most analyses of tissue RASs concentrate on local systems in the cardiovascular system or the adrenal, regulated systems exist in a wide variety of tissues including pituitary; brain; endothelium; male and female reproductive tracts (ovary, uterus, prostate); pancreas; fat; and others [1,2,20,25,41,42,44,45,48–50,57,59,63,67–69]. For example, there is good evidence for the synthesis of all components of the RAS, including renin and angiotensin II, by monocyte cell lines; angiotensin II has also been reported in human monocytes [55,64,66,67]. The reported up-regulation of the monocyte cellular RAS during monocyte differentiation to macrophages is consistent with a role for intracrine or autocrine angiotensin action in differentiation, and this could be relevant to the development of vascular disease [66,67]. This is suggested by the observation that ARB therapy of hypercholesterolemic primates leads to a long-lasting inhibition of monocyte migration into the vascular wall, thereby reducing atherogenesis [88]. Moreover, certain neoplastic cell lines have been shown to express RAS components and inhibition of the synthesis of these moieties leads to reduced cell proliferation [2,89–96]. A local RAS may play a role in some forms of malignancy. Angiotensins Additional mechanisms for the local regulation of angiotensin action also exist. It is now clear that Ang(1-7) is biologically active having vasodilatory and antiproliferative effects among others [60–62]. An analogue of ACE, socalled ‘‘ACE2,’’ has been identified in cardiovascular tissues on the basis of sequence homology with ACE. ACE2, however, converts angiotensin I to Ang(1-9) and not to angiotensin II. Moreover, ACE can then convert Ang(1-9) to Ang(1-7). ACE2 knock-out animals demonstrate decreased left ventricular contractility and other cardiac abnormalities. The ACE2 system acts in a way to off-set or mitigate the activity of ACE and angiotensin II [58,109]. It should in that context be noted both ACEIs and ARBs elevate circulating and tissue concentrations of angiotensin I. This may contribute to their therapeutic utility. Still other angiotensin-derived peptides are biologically active. Angiotensin(3-8), known as ‘‘angiotensin IV,’’ is produced in a variety of tissues and acts through a specific receptor. The angiotensin IV seems to be

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identical to insulin-regulated aminopeptidase; large amounts of this receptor are expressed in heart. Ang IV plays an important role in the memoryenhancing effects of angiotensin in animal models. Angiotensin IV also participates in the angiotensin-induced up-regulation of plasminogen activator inhibitor-1 in endothelial cells. Treatment-induced alterations in Ang IV production could lead to difference in the responses to ACEIs and ARBs [97–101,121]. Angiotensin receptors It has also been recently reported that the function of the angiotensin AT1 receptor can be modulated through heterodimerization with the bradykinin B(2) receptor with the result that AT-1 receptor signaling to angiotensin is enhanced. Abnormalities in this dimerization may play a role in the pathogenesis of eclampsia [102]. Moreover, AT-1-AT-2 heterodimerization also seems to occur, again resulting in altered receptor function. Heterodimerization of the AT-1 and AT-2 receptors leads to diminished signaling by the AT-1 receptor. In this sense, the AT-2 receptor can serve as an AT-1 inhibitor [103]. The physiologic implications of these modes of receptor dimerization have yet to be fully explored. The AT-2 receptor is widely expressed during fetal development, becoming much less prominent during postnatal life. Presumably the relative abundance of AT-1 and AT-2 receptors expressed on a given fetal cell type can be regulated to change or modulate the effect of angiotensin on vascular structure; similar modulation of angiotensin action can also occur in adult tissues, which express both receptors [104–108]. Finally, a recent report suggests that infusion of Creactive protein in experimental animals enhances carotid intimal hyperplasia following angioplasty, an effect that is inhibited by the ARB losartan. This suggests that C-reactive protein, now appreciated as a marker for atherosclerotic diathesis, may actually produce vascular pathology by upregulating the AT-1 receptor or its signaling [104]. In sum, local angiotensin II activity can be regulated in multiple ways: (1) by regulation of the synthesis and uptake of RAS components; (2) by regulation of non-RAS angiotensin-generating factors; (3) by regulation of shunt and metabolic pathways, such as the ACE2 pathway, leading to variations in the concentration of angiotensin and of its metabolic fragments; and by (4) receptor dimerization or other receptor effects leading to altered angiotensin signaling. Other modes of angiotensin regulation also likely occur. There likely also are additional regulatory influences affecting non-angiotensin-mediated RAS actions, such as direct receptor signaling by prorenin. The function of tissue angiotensin Angiotensin II causes vasoconstriction and stimulates the secretion of aldosterone. It stimulates the growth of adrenal, vascular, and cardiac cells;

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can induce apoptosis; and regulates angiogenesis [1,2,107,108]. Moreover, angiotensin II stimulates collagen synthesis and fibrosis in the heart, thereby contributing to the pathobiology of left ventricular hypertrophy. Because it enhances superoxide production in the vessel wall, up-regulates the adhesion molecules, vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule 1, and possibly directly up-regulates NF-kB, angiotensin is proinflammatory and atherogenic [16]. It stimulates (possibly after conversion to Ang IV) the synthesis of plasminogen inhibitor activator 1 and as a result increases clotting diathesis [104]. Angiotensin can alter intercellular conductivity and can play a role in the development of arrhythmias [73–75]. Angiotensin also has neuromodulatory actions, stimulates thirst and drinking behavior, and augments memory in several systems; the latter action may be mediated by angiotensin IV (Ang 3-8) [97–100]. Angiotensin is multifunctional. It is difficult to dissect the action of locally regulated and produced angiotensin II from that of the peptide produced in the circulation because the effects of locally and systemically produced angiotensin II seem to be the same. One can approach this problem by studying the actions of tissue systems when the circulating (renal) system has been ablated. This is technically difficult, but has been done in selected cases (eg, in the adrenal after nephrectomy) [33,35,39]. Other approaches have also been used. For example, when ACE gene was introduced into rat carotid artery leading to a demonstrated increase in local production of ACE, vascular hypertrophy occurred only in the transfected vessel segment [47]. This hypertrophy was independent of any change in the circulating RAS. In this study, the elevations in ACE activity achieved in the walls of the ACE gene transfected animals were similar to those seen in pathologic conditions, thereby reinforcing the relevance of the model. Moreover, locally administered ACE antisense oligonucleotides were shown to inhibit neointima formation in a rat carotid artery injury model, thereby reinforcing the significance of local ACE in the genesis of vascular cell proliferation [110]. Transgenic animals that overexpress angiotensinogen in the cardiac ventricles have been developed and hypertrophy develops in these animals in both left and right ventricles, accompanied by elevated cardiac tissue angiotensin II concentrations, but normal blood levels of the peptide and normal blood pressure [111,112]. These studies confirm the potential of local up-regulation of the tissue RAS to participate in tissue remodeling. Cell culture studies Another approach to determining the role of local angiotensin-generating systems uses cell culture models. For example, human cultured mesangial cells and human neuroblastoma cells express angiotensinogen message and the proliferation of these cells is stimulated by exogenously applied angiotensin [92–95]. ACEIs and losartan inhibit their growth even in the

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absence of added angiotensin II pointing to the cellular generation and action of angiotensin II. The administration of angiotensinogen antisense oligonucleotides also reduces the growth of untreated cells and this growth is restored by the addition of angiotensin II to the cultured cells [92]. This demonstrates that the angiotensinogen the cells produce is responsible for their growth. That is, the cellular RAS regulates growth in an autocrine (or intracrine) fashion. The transfection, transgenic, and antisense studies described demonstrate the capacity of local angiotensin systems to affect cell growth and function. The observation that tissue angiotensin concentrations differ in various tissues indicates that local factors can alter the angiotensin II concentration at target cells. There is also evidence to indicate that in some circumstances locally regulated components of the RAS are important determinants of the tissue angiotensin concentration. Intracrine renin angiotensin action Many peptide hormones and growth factors have been reported to act or bind in the intracellular space either after retention in their cells of synthesis or internalization from the extracellular space. The author has termed this kind of peptide activity ‘‘intracrine’’ (Fig. 1) [40]. Somewhat surprisingly, similar intracrine action has been associated with several enzymes and with certain transcription factors, such as homeoproteins. A great deal of evidence has been developed over recent years to indicate that angiotensin is an intracrine. Labeled angiotensin localizes in the nuclei and mitochondria of cardiac myocytes after systemic administration. Specific high-affinity angiotensin II receptors have been identified associated with isolated nuclei and have been detected on both the nuclear membrane and in association with chromatin. These receptors are AT-1 like in that angiotensin binding is inhibited by losartan and angiotensin binding to these nuclear sites upregulates gene transcription, and in particular the transcription of renin, angiotensinogen, and platelet derived growth factor (PDGF). Electron microscopic-immunohistochemical studies have identified angiotensin immunoreactivity associated with the euchromatin of untreated animals and confocal microscopic studies have revealed the internalization and nuclear translocation of functional cell membrane AT-1 receptor fusion proteins after angiotensin binding. In addition, recent studies have demonstrated the existence of a renin transcript lacking the sequence encoding the secretory signal and likely to remain within the cell that synthesized it [40,114–116]. The author’s group recently stably transfected rat hepatoma cell expressing renin exon 1A and ACE with a construct encoding an angiotensinogen lacking the secretory signal sequence [113]. Transfected cells proliferated more rapidly than did naı¨ve cells and also up-regulated PDGF a chain expression. The ARB losartan but not candesartan inhibited this proliferation and PDGF up-regulation. Prior treatment of the cells with either

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Fig. 1. Peptide hormones can be secreted directly into the circulation to act at distant sites (endocrine action). In some cases secreted hormone factor does not circulate but acts on nearby cells in the same tissue (paracrine mode). In other cases secreted hormone acts on the cell that synthesized it (autocrine action). In each case the hormone binds to a cell surface receptor leading to the generation of intracellular second messengers. Some peptide hormone factors have been shown to act within their cells of synthesis without being secreted; in other cases, hormone is internalized by target cells to act within the cell. Both these latter modes of action are termed ‘‘intracrine’’ [40]. These various forms of action are not mutually exclusive. Evidence indicates angiotensin and prorenin-renin can function as intracrines.

candesartan or phenylarsine oxide (which blocks receptor internalization) eliminated the ability of losartan to reduce proliferation. Antibodies directed against angiotensin II did not inhibit proliferation, although antiPDGF antibodies did so modestly. Collectively, these studies suggest that renin exon 1A generated angiotensin intracellularly from a nonsecreted

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angiotensinogen and this angiotensin II acted within the cell to stimulate PDGF transcription and proliferation. Losartan but not candesartan was internalized by the AT-1 receptor and inhibited the intracellular action of angiotensin. This interpretation is consistent with prior reports suggesting an intracellular action of losartan in nephrectomized rats and is supported by recent AT-1 fluorescent fusion protein studies demonstrating the robust internalization of receptors following the administration of losartan [35,40]. There is substantial evidence to indicate that angiotensin binds to internal sites after either internalization or intracellular generation. Angiotensin is an intracrine. Similarly, recent evidence indicates that prorenin and renin bind to specific cell surface receptors on mesangial cells and vascular smooth muscle cells with the generation of second messengers and the generation of a physiologic effect [79,80]. The prorenin-renin molecule is a hormone. Recent reports that nonglycosylated prorenin can bind to cardiac cells, be internalized, generate angiotensin II, and produce pathologic changes indicate that prorenin-renin is also an intracrine [40,76]. The existence of a nonsecreted renin (renin exon 1A), which apparently traffics to mitochondria and generates angiotensin, coupled with other reports suggesting the generation of angiotensin by intracellular renin further support the suggestion that prorenin-renin is an intracrine. This conclusion may at first seem startling until one realizes that just as hormones and growth factors can act in an intracrine mode, so too can some transcription factors and enzymes. For example, angiotensin, phospholipase A2, and phosphoglucose isomerase are all intracrine enzymes [40]. The author has suggested that specific higher level physiologic functionality is associated with intracrine action and these ideas are explored elsewhere [40]. The observation that both angiotensin and prorenin-renin are intracrines, however, could have important implications for the understanding of RAS function. For example, the observation that renin exon 1A is upregulated in ventricle following myocardial infarction raises the possibility that interventions directed at intracellular renin activity could have specific physiologic or therapeutic effects.

Clinical implications Because angiotensin is a pleurifunctional protein with important effects on functions, such as vasoconstriction, aldosterone synthesis, neuromodulation, cellular growth, apoptosis angiogenesis, and inflammation among others, the interruption of its synthesis by ACEIs or of its action by ARBs could be expected to have important clinical consequences. Indeed, a growing number of studies have indicated a beneficial effect of ACEIs on the outcome of congestive heart failure, ventricular remodeling after myocardial infarction, and diabetic and nondiabetic nephropathy, among other disorders. Similarly ARBs have been shown to be effective in congestive heart failure, left

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ventricular hypertrophy, and the nephropathy of type II diabetes [1–15]. In all these cases it can be argued that the observed benefits transcended those achievable from blood pressure lowering alone, suggesting that interference with angiotensin generation or action provides therapeutic benefit in specific disorders. The ability of local systems to affect tissue angiotensin concentrations then suggests that tissue RASs participate in the genesis of vascular pathology and, conversely, that the interruption of these systems contributes to the therapeutic actions of ACEIs and ARBs. The fact that tissue angiotensin levels in humans and experimental animals do not always track the activity of the circulating RAS supports this view [81–83]. Similarly, the existence of RAAS in the heart suggests the possibility that the interruption of tissue angiotensin and tissue aldosterone synthesis plays a role in the clinical benefit provided in congestive heart failure by spironolactone, ACEIs, and ARBs [18,84,85]. Because of the generally comparable activities of locally and systemically generated angiotensin II it is not clear in most cases to what degree the interruption of tissue angiotensin generation is responsible for these beneficial effects. The apparent dissociation between the level of activity of the circulating RAS and the beneficial actions of ACEIs and ARBs suggests that these tissue systems are clinically responsible for some of the deleterious consequences of hypertension and atherosclerosis [2]. Moreover, the clinical efficacy of ACEI and ARBs in diabetic nephropathy is mirrored in physiologic studies in humans indicating an overactivity of the renal RAS in diabetes that is not predicted by circulating renin activity [117,118]. This possibility is indirectly supported by animal studies suggesting a tissue RAS in the renal parenchyma driven by the local synthesis of RAS components [119]. The up-regulation of the local RAS in the human diabetic eye is also consistent with the beneficial effects of ACEI therapy in diabetic retinopathy [12,42,45,108,120]. These observations support the notion that the interruption of local RASs in certain pathologic states accounts for at least some of the benefit of ACEI and ARB therapy in these disorders. The possible participation of intracrine renin and angiotensin in these disease processes and their therapy has been alluded to but remains to be defined [40]. Summary The RAAS is a powerful regulator of vascular tone and intravascular volume and of tissue architecture and a variety of other functions. The recent appreciation of the immunoregulatory role of angiotensin II and its possible involvement in the genesis of atherosclerosis and in plaque rupture all speak to the wide-ranging physiologic and pathophysiologic activities of the peptide. So do its actions in fat cell differentiation and in neuromodulation. The system exists in the circulation, and RAASs, whole or partial, exist in many tissues. These systems are regulated at many levels ranging from the synthesis of renin to the dimerization of angiotensin receptors. Regulation

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Significance of recently identified peptides in hypertension: endothelin, natriuretic peptides, adrenomedullin, leptin Carmine Savoia, MDa, Ernesto L. Schiffrin, MD, PhD, FRCPC, FACPb,* a

Experimental Hypertension Laboratory of the CIHR Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, West Montreal, QC, Canada b Experimental Hypertension Laboratory of the CIHR Multidisciplinary Research Group on Hypertension and Hypertension Clinic, Clinical Research Institute of Montreal, 110 Pine Avenue, West Montreal, QC H2W1R7, Canada

The function of the cardiovascular system is modulated by structural, hemodynamic, and neurohormonal factors. Among the latter are the sympathetic and parasympathetic nervous systems, the renin-angiotensinaldosterone system (RAAS), the endothelin (ET) system, the natriuretic peptide system, and nitric oxide (NO). These regulatory systems play a key role in modulating cardiac function, vascular tone, and structure, and accordingly cardiovascular hemodynamics and blood pressure. Although neurohumoral systems play an essential role in cardiovascular homeostasis, they may become maladaptive in disease states, such as hypertension, coronary artery disease, and heart failure. The endothelium plays a role in the local modulation of vascular structure and function by producing and releasing relaxing and contracting factors including NO, prostanoids, and ETs [1–4]. Some endotheliumderived substances stimulate the production of cytokines and growth factors, leading to inflammation, fibrosis, and smooth muscle cell proliferation. Although the physiologic role of endothelium-dependent contraction in the regulation of the cardiovascular system is unclear, these vasoconstrictor substances may become prominent under pathologic conditions [5,6]. Essential hypertension, one of the major risk factors for renal and * Corresponding author. E-mail address: ernesto.schiff[email protected] (E.L. Schiffrin). 0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/S0025-7125(03)00122-6

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cardiovascular damage, is characterized by an increased peripheral vascular resistance to blood flow associated with endothelial dysfunction and vascular remodeling [7,8]. Circulating and local regulatory mediators exhibit complex synergism and interactions especially in pathophysiologic conditions, such as hypertension. For instance, the sympathetic nervous system stimulates secretion of renin and generation of angiotensin II, which centrally and at the presynaptic level increases sympathetic nerve activity and enhances ET and vasopressin production. The natriuretic peptide system may play a role as an endogenous mechanism that counteracts the RAAS and ET. ET also modulates adrenomedullin (AM), a potent hypotensive peptide that in turn inhibits plasma renin and aldosterone. Finally, leptin is an adipocytederived peptide that plays a role in obesity-related hypertension by enhancing sympathetic nervous activity, and also induces ET-1 production in endothelial cells. This article discusses advances in the knowledge of some of these recently identified peptides, such as ET, natriuretic peptides, AM, and leptin, in the pathophysiology of hypertension and cardiovascular disease. Endothelins Endothelin is a potent 21-amino acid vasoconstrictor peptide initially found in endothelial cells [4]. Soon after the discovery of ET, analysis of the ET gene revealed the existence of two other ETs: ET-2 and ET-3. Today, these peptides are known to be produced by many different tissues, including vascular smooth muscle cells [9] and cardiomyocytes [10]. ETs regulate cardiovascular and noncardiovascular functions, including smooth muscle tone, digestive tract function, endocrine glands, renal and genitourinary system, and the nervous system. The precursor of human ET (preproET) has 212 amino acid residues. In endothelial cells, after cleavage of the signal peptide at the amino terminus, the resulting peptide proET is converted subsequently into big-ET (39 amino acids) by ET-converting enzyme, a metalloendopeptidase. Finally, ET-converting enzyme may cleave big ET into the active 21-residue ET inside or outside endothelial cells [11]. ET-1 production and secretion can be regulated by hemodynamic forces and especially shear stress. Increased shear stress down-regulates ET-1 release by endothelial cells [12]. NO production, which is stimulated by shear stress, seems to be a major regulator in this process. Indeed, NO inhibits ET-1 release [13]. ET-1 production by endothelial cells can be up-regulated by hypoxia or reactive oxygen species and by hormones, such as epinephrine; thrombin; vasopressin; angiotensin II; insulin; or cytokines and growth factors, such as transforming growth factor-b1 and leptin [14]. The latter may explain in part the increase of ET-1 in obesity and help in the understanding of obesity-related cardiovascular conditions, such as hypertension, atherosclerosis, or type 2 diabetes. Furthermore, it was recently demonstrated that peroxisome proliferator-activated receptors modulate


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ET-1 production in endothelial cells [15]. Indeed, the peroxisome proliferator-activated receptor-c agonist rosiglitazone, a drug used in the therapy of type 2 diabetes, may prevent the progression of hypertension and decrease vascular ET-1 levels in deoxycorticosterone acetate-salt rats, an experimental model of hypertension associated with increased vascular ET-1 production [16]. Endothelin-1 produced by endothelial cells is mainly secreted abluminally. Plasma ET results from spillover from the vascular wall or from secretion by the posterior pituitary. Plasma concentrations of immunoreactive ET reflect to some degree tissue production, particularly by the endothelium of blood vessels, but are not a very reliable indicator of activation of the system. In essential hypertension, ET-1 plasma levels are usually within normal limits or only slightly elevated. Vascular levels of ET1 are increased in patients with moderate to severe hypertension [8]. This could play a role not only in elevated blood pressure but also in accentuating hypertrophic remodeling of small arteries in patients with moderate to severe hypertension. Certain populations of hypertensives may specifically have activation of the ET system, such as African Americans [17], in whom hypertension is often severe and salt-sensitivity is a frequently detected pathophysiologic characteristic. Severity of blood pressure elevation and salt-sensitivity seem to be common denominators for activation of the ET system in both human and experimental animal models. Other forms of hypertension in which ETs may be involved in humans include rare cases of hemangioendothelioma producing ET, chronic renal failure, erythropoietinand cyclosporine-induced hypertension, pheochromocytoma, and pregnancyinduced hypertension. Endothelin-1 generated in the endothelium acts in a paracrine or autocrine manner on ETA and ETB receptors on adjacent smooth muscle cells or ETB receptors on endothelial cells. Both ET receptors are 7-transmembrane domain receptors with less than 70% sequence homology. ETA and ETB receptors are encoded by genes located in different chromosomes. They are G protein-coupled receptors signaling through activation of several intracellular pathways including phospholipases and calcium mobilization, protein kinase C, and other pathways including generation of reactive oxygen species leading to oxidant excess in the vascular wall, a powerful pathophysiologic mechanism. The receptors on smooth muscle mediate cell contraction, proliferation, and hypertrophy [18]. ETB receptors on endothelial cells stimulate the production of NO and prostacyclin and perhaps other vasodilators, and induce vasorelaxation and antiproliferative effects [6]. Mice in which the preproET-1 gene has been disrupted present slightly increased blood pressure associated with hypoxia caused by craniofacial abnormalities, and exhibit large conduit artery developmental defects [19]. The same phenotype is observed in mice in which the ETA receptor gene has been inactivated [20], suggesting that the ET-1/ETA axis is involved in the

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development of these organs. ETB gene knockout mice present pigmentary abnormalities and defects in migration of neural crest cells to the myenteric plexus, resulting in aganglionic megacolon, comparable with Hirschsprung’s disease in humans [21], which may also be caused in many familial cases by mutations in the ETB receptor gene. In humans ETA receptor antagonist infusion caused a greater vasodilation of the forearm circulation of essential hypertensive patients than normotensive subjects [22], suggesting a predominant role of ETA receptors in the control of vascular tone by endogenous ET-1. Whereas ETA receptor antagonists improved the impaired vasodilation in hypertensive patients, ETB antagonists had a vasoconstrictor effect in normotensive subjects but vasodilator action in hypertensive subjects [23,24]. Endothelin-1 may potentiate a-adrenergic and serotoninergic tone at low concentrations, a phenomenon that may be exaggerated in some hypertensive patients, particularly in presence of a polymorphism of the preproET-1 gene [25]. Another mechanism whereby ET-1 can participate in the pathophysiology of hypertension is through stimulation of oxidant stress and interaction with NO. ETA antagonists improve NO release by forearm vessels in humans [24]. In salt-loaded stroke-prone spontaneously hypertensive rats (SHRsp), whose hypertension has an ET-1-dependent component, administration of antioxidants corrected the remodeling of resistance arteries [26]. Oxidative stress contributes to ET-1-mediated remodeling and to the hypertrophic action of ET-1 on resistance arteries in hypertension. Remodeling of large and small arteries involves different processes, such as growth, apoptosis, inflammation, and fibrosis. ET-1 is involved in all of these. ET receptor activation causes hypertrophy in small arteries and promotes vascular fibrosis [27]. Smooth muscle cell growth and migration are stimulated by ET-1, which also may contribute to foam cell formation by stimulation of inflammatory mediators, such as NFkappaB, adhesion molecules, and chemokines. Macrophages produce cytokines in response to ET-1, and the ensuing inflammatory reaction associated with oxidant excess contributes to endothelial dysfunction. In aorta and other conduit arteries, ET-1 production is enhanced in part as a result of endothelial damage, hypertension, oxidized low-density lipoproteins, and increased oxidative stress. All of these contribute to progression of vascular disease and atherosclerosis [28]. ET-1 has angiogenic properties. It stimulates cell migration and vascular endothelial growth factor production [29]. In vivo studies, however, have provided conflicting results and the exact role of ET1 in angiogenesis (such as following ischemia or in tumor growth) remains to be clarified. Clinical trials in hypertensive patients suggest beneficial effects of administration of ET receptor antagonists on blood pressure. The nonselective ET receptor antagonist bosentan (500 to 2000 mg/d for 4 weeks) administered to patients with mild to moderate essential hypertension reduced blood pressure by 5.7 mm Hg, comparable with the reduction


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obtained with enalapril (20 mg/d) [30]. Darusentan, a selective ETA antagonist, reduced systolic blood pressure by 6 to 11 mm Hg [31]. Unlike bosentan, no elevation of liver enzymes was observed with darusentan, which could become a promising therapeutic tool in the management of essential hypertension and associated target organ damage. Endothelin-1 has been widely suggested to be involved in the development of end-organ damage associated with hypertension, such as myocardial hypertrophy, atherosclerosis, renal failure, and stroke. In the heart, ET-1 is produced by various cell types, including endothelial cells, smooth muscle cells fibroblasts, and cardiomyocytes in response to angiotensin II, wall stretch, or ischemia. ET stimulates secretion of atrial natriuretic factor, a naturally occurring antagonist of ET, and causes expression of proto-oncogenes, cell proliferation, hypertrophy, and fibrosis, which can be inhibited by ET antagonists [10]. ETA antagonism prevented vascular remodeling and cardiac and vascular fibrosis and inflammatory responses in mineralocorticoid-induced hypertension in rats [32–34]. The ET system modulates inflammation, fibrosis, apoptosis, and cell hypertrophy, processes that participate in cardiac remodeling [34]. Increased ET levels occur in animal models and patients with congestive heart failure, and correlate with increases in left ventricular end-diastolic volume, left atrial pressure, and pulmonary artery pressure. Increased ET production may contribute to the progression of congestive heart failure, and correlates with survival. It is a better predictor of outcome than other markers [35]. In animal models of heart failure, treatment with ET antagonists is associated with reduced systemic vascular resistance, improved hemodynamics, a reduced progression of left ventricular dysfunction, attenuation of left ventricular chamber remodeling, and increased survival [10]. In humans, treatment with bosentan resulted in improvement in systemic and pulmonary hemodynamics, without reflex tachycardia or increases in concentrations of angiotensin II or norepinephrine [36], and beneficial effects similar to those seen with angiotensin converting enzyme inhibitors. Preliminary data from ongoing trials, such as RITZ-2, suggest that an intravenous, nonselective ET antagonist improves hemodynamics and symptoms and possibly morbidity of severe heart failure [37]. The Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure study showed worsening heart failure in patients treated with bosentan [38]. The effect of ET antagonists in human heart failure remains controversial. Hypertensive nephroangiosclerosis is a frequent complication in hypertensive patients. Renal tubular cells synthesize ETs, and protein loading induces a dose-dependent increase in synthesis and release of ET-1. ET-1 can cause increased renal vascular resistance, decreased renal blood flow, and decreased glomerular filtration, effects that resemble those seen in renal failure. ET-1 contributes to the regulation of salt and water excretion, especially in salt-dependent hypertension, resulting in inhibition of sodium

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reabsorption by stimulation of ETB receptors [39]. In salt-loaded SHRsp increased renal ET-1 was associated with increased growth factors and collagen synthesis, which were normalized by a selective ETA antagonist, suggesting that ET-1 participates in the activation of growth factors and inflammation that contribute to the pathophysiology of renal fibrosis [40]. ET antagonists prevented renal failure in dogs after ischemic injury [41]. In diabetic animals with overt proteinuria, chronic use of nonselective ET antagonist improved blood pressure and proteinuria as effectively as an angiotensin converting enzyme inhibitor [42]. Indeed, in patients with diabetes, the ET system is activated, and endothelin antagonists improve vascular dysfunction [43]. ET receptor antagonists may help prevent diabetic complications. The atherosclerotic process involves endothelial cell injury; release of cytokines and growth factors; migration to the intima of smooth muscle cells through the internal elastic lamina; lipid accumulation; and synthesis of collagen, elastin, and proteoglycans. In response to vascular injury, ET-1 accumulates locally at the site of injury and in the systemic circulation and acts as a strong chemoattractant for monocytes and macrophages, and it may act as a co-mitogen for vascular smooth muscle cells with plateletderived growth factor. Elevated concentrations of plasma and tissue ET have been reported in patients with diffuse and advanced atherosclerosis [44]. ET immunoreactivity is enhanced in the coronary and systemic circulation in humans with coronary endothelial dysfunction and early atherosclerosis [45]. ET-1 may play a role in the initiation and early phases of atherogenesis. In experimental atherosclerosis, ET antagonists have an antiatherogenic effect. Plasma ET levels are also raised in pathologic conditions associated with atherosclerosis, such as myocardial infarction, stroke, and in subjects with risk factors for atherosclerosis, such as dyslipidemia and cigarette smoking. Interestingly, plasma ET levels and urinary ET excretion are increased in patients with severe degrees of coronary artery disease, and correlate with hemodynamic complications and 1-year mortality [46,47]. Patients who undergo successful thrombolysis with early reperfusion have lower ET levels than subjects who do not have early reperfusion. In humans, bosentan acutely caused coronary artery vasodilation. Further studies are needed, however, to determine the therapeutic potential of ET antagonists in patients with coronary artery disease. Endothelin has been implicated in both hemorrhagic and ischemic stroke. Indeed, patients with stroke have elevated plasma levels of ET [47]. In experimental animal models, ET antagonists have demonstrated therapeutic potential for treatment of hemorrhage-induced vasospasm, and reduction of infarct size after thrombotic occlusion. Endothelin-1 has been implicated in pulmonary disorders, especially pulmonary hypertension. ET-1 is synthesized, stored, released, and metabolized in the lung, suggesting that this peptide may be important in both physiologic functions and pathophysiologic processes in the lung [48].


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ETB receptors have been localized in lung parenchyma and small intrapulmonary resistance arteries, and ETA receptors are found in the pulmonary vasculature and bronchi. Pulmonary hypertension is characterized by pulmonary vasoconstriction, vascular smooth muscle cell proliferation, and increased pulmonary vascular resistance leading to right ventricular failure. ET plasma concentration and immunoreactivity and expression of mRNA for ET-1 in the endothelial cells of hypertrophied pulmonary vessels are increased in both primary and secondary pulmonary hypertension [47–50], and in patients with various other conditions leading to pulmonary hypertension, such as Takayasu’s arteritis, fenfluramine use, scleroderma, congenital heart disease, and postcardiopulmonary bypass surgery. Furthermore, ET contributes to increased pulmonary vascular tone in patients with left ventricular systolic failure [51], and to the secondary pulmonary hypertension in patients with chronic mild heart failure [52]. ET levels are positively correlated with the degree of pulmonary hypertension and negatively correlated with the prognosis [52]. With the development of pulmonary hypertension, pulmonary vasoconstriction is associated with apparent loss of NO synthase and ETB-mediated vasodilation, and increased ETA-mediated vasoconstriction. The clearance of ET-1 may be decreased in patients with primary pulmonary hypertension [53]. ET-1 may also play a role in the development of acute pulmonary hypertension caused by hypoxia. On the basis of studies in animal models and humans, the therapeutic role of ET receptor antagonists looks promising in preventing hypoxia-induced pulmonary hypertension and pulmonary artery remodeling and in improving exercise capacity and cardiopulmonary hemodynamics. Results from a multicenter, randomized, placebo-controlled trial [54] indicate that bosentan at a dose of 125 mg twice daily was beneficial in patients with primary pulmonary arterial hypertension and was well tolerated. Bosentan has been approved for the treatment of primary pulmonary hypertension, currently the only approved indication of ET receptor antagonists. Endothelins are potent vasoconstrictor, mitogenic, and proinflammatory agents, involved in multiple disease entities affecting various organ systems in both experimental animals and human beings. Beyond its blood pressurelowering effects, ET antagonism may present important pressure-independent beneficial actions on tissue growth, inflammation, and fibrosis that underscore its therapeutic potential in different cardiovascular conditions. Orally active nonpeptide ET antagonists and ET-converting enzyme inhibitors are under investigation, but clinical benefits and safety from adverse events have yet to be fully evaluated.

Natriuretic peptides The natriuretic peptide family consists of three structurally and physiologically similar peptides: (1) atrial natriuretic peptide (ANP),

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(2) brain natriuretic peptide (BNP), and (3) C-type natriuretic peptide (CNP). They act as endogenous antagonists of vasoconstrictor and salt- and water-retaining systems (eg, the RAAS, vasopressin, ET) in the body’s defense against blood pressure elevation and plasma volume expansion through direct vasodilator, diuretic, and natriuretic properties. Atrial natriuretic peptide is a 28-amino acid peptide produced primarily in cardiac atria, but also in the ventricles and in a variety of other tissues [55]. In the kidney alternative processing of the precursor generates a 32amino acid peptide called urodilatin [56], which may be important for the local regulation of sodium and water handling in the kidney. Mature ANP is released by the cleavage of a precursor protein (pro-atrial natriuretic peptide). Cleavage of human pro-atrial natriuretic peptide releases a 98amino acid fragment, also present in plasma, which may have some biologic actions similar to those of ANP. Both fragments circulate in plasma, and their concentrations are increased in patients with increased intravascular volume, such as congestive heart failure, in which they correlate with the severity of disease and with prognosis. Furthermore, ANP is a well-known marker of ventricular hypertrophy [57]. Elevated circulating levels are found in various forms and advanced stages of hypertension [58]. Increased atrial wall tension, reflecting increased intravascular volume, is the dominant stimulus for ANP release. Several hormones and neurotransmitters, such as ET, vasopressin, and catecholamines, directly stimulate secretion of ANP. Brain natriuretic peptide is 32-amino acid peptide found initially in the brain but present in considerably greater concentrations in the ventricles of the heart. BNP concentrations are high in patients with left ventricular hypertrophy, diastolic and systolic dysfunction, or congestive heart failure, and in subjects with hypertension [58] and in hypertension-prone individuals who later develop increases in blood pressure on follow-up [59]. BNP and ANP levels may also serve as prognostic indicators, particularly post myocardial infarction [60]. Measurement of plasma BNP may facilitate the diagnosis and optimization of treatment of patients with chronic heart failure. C-type natriuretic peptide is a 22-amino acid peptide found mainly in plasma and cerebrospinal fluid and renal proximal tubules and vasculature. Another higher molecular weight mature form of the peptide (CNP-53) predominates in tissues and may be a storage form of CNP. CNP is a powerful vasorelaxant [61] and antimitogenic factor in vascular smooth muscle cells [62]. Its location in endothelial cells of peripheral blood vessels suggests an important role in local vascular regulation. Its secretion is enhanced by ANP and BNP and several cytokines, including transforming growth factor-b and tumor necrosis factor [63]. Furthermore, natriuretic peptides augment tumor necrosis factor and interleukin-1-enhanced expression of inducible NO synthase and subsequent NO levels in vascular cells. Plasma CNP is elevated in chronic renal failure and cor pulmonale, but not in hypertensive patients or patients with congestive heart failure, although


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the latter have increased myocardial levels and urinary excretion of CNP [63]. CNP and ET may function as opposing mechanisms in the control of vascular tone. The exact physiologic role of CNP in humans and animals, however, remains to be clarified. Natriuretic peptides interact with three major types of high-affinity receptors on the surface of target cells (NPR-A, NPR-B, and NPR-C), with different affinities for the naturally occurring natriuretic peptides [64]. NPRA and -B are structurally similar and are linked to the production of c-GMP and mediate many of the cardiovascular and renal effects of natriuretic peptides. NPR-A binds both ANP and BNP with preference for ANP. CNP seems to be the natural ligand for the B receptor. Both receptors are expressed in large blood vessels, NPR-A being the most abundant. NPR-C has strong sequence homology with the other two receptors, but lacks the intracellular catalytic domains of guanylate cyclase. All three natriuretic peptides bind to this receptor with similar affinity. NPR-C is widely expressed in a variety of tissues. Although it has been postulated that this receptor signals through G-protein-linked cyclic AMP production [65] and is involved in the antigrowth properties of natriuretic peptides, it is generally accepted that NPR-C is involved in clearance of natriuretic peptides. Both ANP and BNP are rapidly removed from the circulation. The lung, liver, and kidney are important sites for elimination of endogenous natriuretic peptides. Circulating natriuretic peptides are also inactivated by neutral endopeptidases within renal tubular and vascular cells [66]. Neutral endopeptidase inhibition may exert part of its effects by modulation of natriuretic peptide levels. Atrial natriuretic peptide acts on the kidney, vessels, brain, and adrenals to induce potent diuretic, natriuretic, and vasorelaxant effects. It favors extravasation of fluids from the intravascular compartment through increases in endothelial permeability. In the kidney, ANP increases glomerular filtration rate through vasodilation of the afferent arteriole and vasoconstriction of the efferent arteriole [67]. It also relaxes mesangial cells and increases the effective surface area for filtration. Its natriuretic effect is also related to inhibition of sodium reabsorption in both the proximal and the distal tubule [68]. Inhibition of aldosterone synthesis contributes to the natriuretic effect and is exerted by inhibiting the action of angiotensin II, potassium, or adrenocorticotropic hormone [69]. In cortical collecting ducts, ANP inhibits tubular water transport by antagonizing vasopressin [70]. The combined systemic hemodynamic effects of ANP reduce both preload and afterload, improving cardiac performance [71]. ANP plays a major role in the regulation of blood pressure and salt and water balance. At low doses, ANP induced significant reduction in blood pressure largely secondary to reduction of systemic vascular resistance [71]. In the presence of high plasma ANP levels, a decrease in heart rate, central venous pressure, and stroke volume was observed [72]. ANP interacts with baroreflex control of the circulation by modulating arterial and cardiopulmonary baroreceptor-

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mediated vascular responses [73]. ANP reduces sympathetic tone in the peripheral vasculature, probably by dampening baroreceptors, by suppression of the release of catecholamines from autonomic nerve endings, and by suppression of sympathetic outflow from the central nervous system [74]. Natriuretic peptides have antimitogenic activity on both the cardiovascular and other organ systems [75], mainly through a cGMP-dependent mechanism. In addition, BNP-mediated vasorelaxation is endotheliumindependent and may be impaired in experimental atherosclerosis [76]. Natriuretic peptides may modulate growth within the vascular wall in such disorders as atherosclerosis, hypertension, and postangioplasty restenosis. Atrial natriuretic peptide increases in essential hypertension and in patients with pheochromocytoma. Obesity-related hypertension is associated with increased circulating concentrations of ANP, which decrease to the normal range with weight reduction-induced decrease of blood pressure [76]. Administration of ANP resulted in significant decrease in blood pressure levels in humans and in animal models. Studies in animals by molecular genetic approaches provide convincing evidence favoring a contribution of natriuretic peptides to the development of hypertension. Overexpression of ANP [77] and BNP [78] in transgenic mice reduced blood pressure. Also, transgenic mice overexpressing ANP do not develop pulmonary hypertension when exposed to chronic hypoxia. Inactivation of the ANP gene in mice was associated with development of salt-sensitive hypertension and significant cardiac enlargement [79]. Knockout of the NPR-A receptor gene caused hypertension, although not a salt-sensitive type [80], which suggests a role for another natriuretic peptide in prevention of hypertension under low-salt conditions, presumably acting through NPR-A. Atrial natriuretic peptide also plays a role in the natriuretic response to increased sodium retention caused by excess mineralocorticoids [81]. The ANP gene may influence blood pressure and participate as a contributing factor in certain forms of hypertension through either a peptide deficiency or impaired biologic function dependent on a structural alteration of the ANP gene. Increased frequency of hypertension in carriers of molecular variants of the ANP gene [82] supports the concept of a critical biologic function of ANP in cardiovascular regulation. Elevated ANP levels were observed following acute stroke [83]. In a cohort of the Physician’s Health Study [84], the allelic and genotypic characterization of ANP polymorphic markers (on exons 1 and 3 and on intron 2) has led to identification of a significant association with stroke independently of other conventional risk factors. The ANP gene co-localizes with the peak of linkage of a quantitative trait locus (QTL) for strokeproneness identified in SHRsp [85]. This QTL conferred a protective effect toward stroke, and contributed approximately 10% to the stroke phenotype variance. A detailed analysis of the ANP gene revealed an altered structure, regulation, and function in the stroke-prone strain [86]. Furthermore, ANP


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expression was dramatically reduced only in the brain of the stroke-prone rats [87]. The mutation in the stroke-prone ANP gene was associated with significantly lower ANP promoter activity. Reduced ANP transcription along with the pro-apoptotic role of ANP may explain the protection against stroke offered by this gene variant [85]. Atrial natriuretic peptide represents a critical factor in the regulation of cardiovascular function through its diuretic, natriuretic, and vasorelaxant effects and cardiovascular remodeling effects. Structural abnormalities of the ANP gene may serve as a tool for establishing predisposition to major cardiovascular conditions, with important implications for early prevention and treatment. The availability of drugs that augment ANP action should represent an important therapeutic advance for patients with cardiovascular disease. Several approaches have been explored including the use of native peptides, the development of natriuretic peptide mimetics, and the targeting of endogenous clearance of natriuretic peptides. The development of orally active agents to enhance endogenous natriuretic peptides through inhibition of breakdown by neutral endopeptidase is encouraging [88]. Research in this field has led to the development of dual inhibitors of neutral endopeptidase and angiotensin converting enzyme (so-called ‘‘vasopeptidase inhibitors’’) that simultaneously inhibit RAAS and potentiating the action of natriuretic peptides and the kinin system. The vasopeptidase inhibitor omapatrilat, acting in part through increases in natriuretic peptides, induces significant blood pressure reductions in different subsets of hypertensive patients. It also reduced pulse pressure and aortic stiffness, suggesting that aortic stiffness is maintained by partially reversible mechanisms, which may be modulated by natriuretic peptides [89]. Encouraging studies have also been obtained in patients with congestive heart failure [90]. There is serious concern about the greater rates of angioedema with omapatrilat, particularly in blacks, however, which may be related to higher levels of bradykinin and higher risk in susceptible individuals. Furthermore, addition of neutral endopeptidase (neprilysin; NEP) inhibition to angiotensin converting enzyme inhibition reduces angiotensin 1–7 levels and may increase ET levels, which could counteract benefits of angiotensin converting enzyme inhibition that depend on increased angiotensin 1–7 levels [91].

Adrenomedullin Adrenomedullin is a 52-amino acid vasodilatory peptide originally discovered in human pheochromocytoma tissue by monitoring activity that elevated rat platelet cAMP [92]. AM is widely distributed in humans and rodents and found in the cardiovascular system, including the heart and blood vessels, and kidney, lung, digestive organs, nervous system, and tumor cells. AM together with calcitonin gene-related peptide and amylin are now considered members of a peptide family sharing biologic effects and some

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cross-reactivity between receptors [93]. Cytokines, such as tumor necrosis factor-a and interleukin-1, lipopolysaccharides, circulating hormones, such as corticosteroids, thyroid hormones, angiotensin II, norepinephrine, ET-1, and bradykinin, and physical stress and stretch may stimulate AM synthesis and secretion [94]. The AM prohormone contains at the amino end another biologically active peptide known as PAMP (proadrenomedullin N-terminal 20 peptide). The secretion rate of AM and PAMP from a particular cell type depends on alternative splicing of the gene [95]. Both peptides are vasodilators, but PAMP acts through a different as yet unidentified receptor. PAMP reduces norepinephrine overflow from peripheral sympathetic nerve endings of mesenteric arteries, which in turn decreases blood pressure [96]. The AM receptor is a G protein-coupled receptor, which increases cytosolic cAMP and has two subunits: the calcitonin receptor-like receptor and the associated receptor activity modifying protein-2. Calcitonin gene-related peptide also binds calcitonin receptor-like receptor, but only when the calcitonin receptor-like receptor is associated with receptor activity modifying protein-1. Calcitonin gene-related peptide cannot bind to the AM receptor, and many of the actions of AM are not reproduced by calcitonin gene-related peptide. Two additional putative AM receptors have been identified: RDC1 and L1. AM increases intracellular cAMP levels in renal tubular, mesangial, endothelial, and vascular smooth muscle cells. NO may mediate some AM effects [97]. In bovine aortic endothelial cells, AM increases intracellular ionic calcium (Ca++) and causes accumulation of cAMP. Increased intracellular Ca++ may stimulate inducible NO synthase and subsequently NO, whereby AM may exert antiapoptotic effects by a paracrine mechanism in endothelial cells [98]. Adrenomedullin gene disruption was lethal because of cardiovascular defects [99]. In cultured vascular smooth muscle cells, AM inhibited ET-1 production induced by thrombin or platelet-derived growth factor [100]. In cultured cardiomyocytes and cardiac fibroblasts, AM may inhibit protein synthesis in an autocrine or paracrine manner that may contribute to modulate cardiac growth [101]. Adrenomedullin antagonizes angiotensin II-induced vascular smooth muscle cell proliferation and migration [102]. Knockout of the AM gene protected mice from coronary artery injury by angiotensin II and salt loading. This cardiovascular protective action may depend in part on inhibition of angiotensin II-induced oxidative stress and cell proliferation [103]. AM deficiency increased oxidative stress, resulting in insulin resistance possibly through impaired insulin signaling in aged AM-deficient mice [104]. An AM receptor antagonist inhibited carotid artery intimal formation in a rat balloon injury model [105] and cuff-induced intimal hyperplasia was markedly suppressed in an AM-overexpressing transgenic mouse [106]. AM overexpression reduced cell proliferation through eNOS-dependent NO generation [107]. AM may regulate vascular proliferation and remodeling and vascular tone.


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Adrenomedullin induces a long-lasting, dose-dependent hypotension accompanied by increased heart rate and cardiac output [108]. AM dilates resistance vessels in the kidney, brain, lung, hind limbs, and mesentery, and has positive inotropic actions [109]. Infusion into the brachial artery significantly increased forearm blood flow and reversed constriction of dorsal hand veins caused by preinjection of norepinephrine [110]. AM is a potent vasodilator in vivo of human resistance and capacitance vessels. Intrarenal arterial infusion of AM elicited a dose-dependent increase in renal blood flow, glomerular filtration rate, and urinary sodium excretion [111]. Plasma AM levels and urinary excretion of AM, and renal AM mRNA levels were higher in malignant hypertensive rats [112], which may have renoprotective effects in this experimental model. Studies of transgenicknockout mice have demonstrated the role of AM in the regulation of vascular tone and ischemic renal injury [113]. AM gene delivery attenuated renal damage in hypertensive rats [114]. Severe exercise stimulated AM release in association with increased plasma norepinephrine in humans [115]. Plasma AM concentration was increased in patients with cardiovascular disease, such as congestive heart failure, hypertension, primary aldosteronism, septic shock, and preeclampsia, which are often associated with increased renin and angiotensin II [116]. Plasma AM correlates with blood pressure elevation. Furthermore, in patients with malignant hypertension and renovascular hypertension [117], the increase in plasma AM was greater than in primary aldosteronism or essential hypertension [118]. Plasma AM correlated with plasma renin activity but not with plasma aldosterone concentration. Plasma AM concentration was not increased at rest or during hypertensive crisis in patients with pheochromocytoma, although epinephrine and norepinephrine were markedly elevated. The cardiac AM system may participate in the transition from left ventricular hypertrophy to heart failure [119]. Elevated levels of AM in heart failure correlate with the severity of disease. In patients with congestive heart failure, plasma AM correlated with pulmonary artery pressure, pulmonary capillary wedge pressure, left atrial dimension, plasma renin activity, and plasma concentrations of ANP and BNP [120]. Because AM has vasorelaxing and natriuretic activities, increased production of AM by the heart may play a compensatory role in congestive heart failure to maintain sodium balance and systemic vascular tone similarly to the role of BNP. A major difference with BNP is that AM production is increased only in the ventricle in congestive heart failure, whereas atrial and ventricular secretion of BNP is increased in the failing heart [121]. Because AM has positive inotropic effects [109], activated myocardial AM may act as an endogenous inotropic factor uniquely activated in congestive heart failure. Adrenomedullin infusion or gene delivery that markedly increases plasma and cardiac tissue AM levels attenuates left ventricular hypertrophy in hypertensive rats [122]. Intravenous infusion of human AM into patients

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with congestive heart failure improved cardiac function presumably by dilatation of resistance arteries, increased cardiac stroke index and urinary sodium excretion, and improvement of cardiac preload and after-load and cardiac contractility [123]. In patients with chronic renal failure, plasma AM concentration elevation was related to the degree of renal failure [124]. AM correlated closely with norepinephrine, ANP, and cAMP in plasma. Plasma AM concentration was further elevated in subjects with end-stage renal failure, and was unaltered by hemodialysis. End-stage renal disease patients with heart failure of NYHA classes II to IV or hypertension had significantly higher plasma AM compared with end-stage renal disease alone [125]. AM may also be involved in mechanisms preserving cardiovascular control and fluid metabolism by its potent vasodilatory and diuretic effects or other biologic activities on the kidney. Carotid artery atherosclerosis assessed by ultrasound, blood pressure, and risk factors correlated to AM levels. Severe atherosclerosis was associated with further elevation of AM levels in patients with systolic hypertension. Atherosclerosis elevates AM independently of blood pressure levels or presence of risk factors [126]. AM could play an inhibitory role in atherogenesis. Adrenomedullin is an autocrine or paracrine factor in cardiovascular and renal regulation that exerts protective effects against target organ damage. Development of receptor agonists or antagonists that may modulate the action of endogenous AM could be useful therapeutically. Another strategy could be to potentiate endogenous AM by inhibiting its degradation. Inhibition of NEP augments the natriuretic and diuretic action of AM in physiologic conditions and in experimental heart failure [127]. A concern is that AM promotes tumor growth by angiogenic and antiapoptotic effects [128]. Long-term effects of AM remain to be defined.

Leptin Leptin, the product of ob gene, is a 167-amino acid peptide expressed and secreted mainly by adipocytes. It acts on the central nervous system through a specific receptor and multiple neuropeptide pathways to decrease appetite and increase energy expenditure through sympathetic stimulation of brown adipose tissue. Leptin functions as the afferent component of a negative feedback mechanism to control adipose tissue mass. Obesity is associated with increased incidence of hypertension and cardiovascular mortality. The sympathetic nervous system may be involved in obesity-related hypertension. Leptin increases sympathetic activity to kidneys, hind-limb, and adrenal glands, indicating that the obesity-associated increase in sympathetic nerve activity could in part be caused by effects of leptin. Leptin expression and plasma concentrations are proportional to adipose tissue


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mass in genetic models of obesity, and in experimentally induced obesity [129]. Serum leptin levels in obese humans are increased and correlate with body mass index and percentage of body fat [130], suggesting that obese subjects are resistant to endogenous leptin. In some models of obesity, leptin resistance is selective, with preserved renal sympathetic effects despite loss of the metabolic actions of leptin [131]. Food intake, insulin, proinflammatory cytokines, such as tumor necrosis factor-a, and corticosteroids increase leptin expression [132]. Results from animal experimentation suggest interactions between leptin and the sympathetic nervous system, with leptin causing sympathetic activation and the sympathetic system exerting regulatory feedback inhibition over leptin release. Cold temperature and catecholamines decrease adipocyte expression of leptin in experimental models but not in humans with increased sympathetic tone, such as in congestive heart failure or hypertension [133]. Renal norepinephrine spillover correlated with plasma leptin but other measures of sympathoadrenal function did not [134]. In heart failure, elevated leptin resulted from reduced renal clearance, whereas in essential hypertension, in pure autonomic failure, and healthy aging, plasma leptin levels were normal. Leptin may stimulate the sympathetic nervous system, but feedback inhibition of leptin release by the sympathetic nervous system does not seem to occur in humans. Leptin binds to a selective receptor with single transmembrane domain similar to class I cytokine receptors. Several alternately spliced isoforms of the leptin receptor have been cloned; the full-length receptor is the most abundant isoform in the brain. In addition to the central nervous system, leptin receptor mRNA is expressed in adipose tissue, heart, kidneys, liver, spleen, pancreatic islets, testis, and in endothelial cells and atherosclerotic lesions. Beside effects on the central nervous system, leptin exerts important metabolic actions on peripheral tissues, including modulation of insulin action (reduced insulin secretion and improved insulin sensitivity) and modulation of the immune system. The widespread distribution of leptin receptors on vascular cells suggests that leptin may play an important role in vascular physiology. Leptin has angiogenic activity [135], increases oxidative stress in endothelial cells [136], up-regulates ET-1 production in human umbilical vein endothelial cells, and promotes vascular calcification and smooth muscle cell proliferation and migration [137]. In healthy adolescents, elevation in leptin was associated with impaired vascular function, independently of metabolic and inflammatory disturbances associated with obesity [138]. High leptin concentrations seem to be an important mechanism for the adverse influence of obesity on cardiovascular disease. Furthermore, leptin receptors have been demonstrated on platelets, and physiologic concentrations of leptin may promote platelet aggregation and arterial thrombosis [139], suggesting a potential link between increasing adiposity and thrombotic risk. Indeed, leptin is an independent risk factor for coronary events [140].

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Leptin is cleared principally by the kidney. Serum leptin concentrations are increased in patients with chronic renal failure and in those undergoing maintenance dialysis. The kidney expresses abundantly the truncated leptin receptor isoform. Direct or indirect effects of leptin on the kidney include activation of transforming growth factor-b contributing to glomerulosclerosis and proteinuria [141]. Leptin induces natriuresis, stimulates reactive oxygen species, and increases sympathetic nervous activity, raising blood pressure and causing sodium retention in obesity [142]. The kidney is not only a site of leptin metabolism, but also a target for leptin action. The effect of leptin on blood pressure depends on the balance between its cardiovascular, sympathetic system, and renal actions. Chronic elevations of leptin in experimental animals increase blood pressure by sympathetic stimulation [143]. The pressor effect of leptin is accompanied by increased renal vascular resistance and heart rate, consistent with sympathetic activation, and can be prevented by sympathetic blockade. Elevated leptin production could play a role in development of hypertension independently of obesity. Most studies have failed, however, to show elevation of leptin in hypertension [133,134], although in one, lean subjects with essential hypertension exhibited a significant positive correlation between mean blood pressure and leptin serum levels [144]. The endothelium may be a target for leptin action [135,136]. Leptin upregulates ET-1 production in human umbilical vein endothelial cells. Some actions of leptin, such as stimulation of NO formation [145] and enhancement of insulin sensitivity, may tend to reduce blood pressure in some conditions. Because obesity causes endothelial dysfunction and impaired NO release, blood pressure responses to leptin may be greater in obese than lean subjects. Leptin is a peptide with multiple effects potentially relevant not only to control of body fat but also to cardiovascular and renal regulation. It may represent one of the factors involved in raising blood pressure in obesity. Several drugs, among them b3-adrenergic agonists and the peroxisome proliferator-activated receptor-c activators (the antidiabetic thiazolidinediones or glitazones, such as rosiglitazone or pioglitazone), inhibit leptin gene expression and release [146], and leptin-induced endothelial cell migration and angiogenesis, all of which underlines the potential involvement of leptin in diabetes-associated complications [147].

Summary Arterial hypertension is one of the major risk factors in cardiovascular and renal disease. Advances in the study of pathophysiologic mechanisms and the relationship between several regulatory systems provide the basis for development of more selective therapeutic strategies. The increasing understanding of the role played by ETs, natriuretic peptides, AM, and leptin opens


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new frontiers in the care of hypertension and its complications, coronary artery disease and heart failure and other forms of cardiovascular disease.

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Med Clin N Am 88 (2004) 63–82

Insulin and insulin resistance: impact on blood pressure and cardiovascular disease James R. Sowers, MD, FACP, FAHA, FACEa,b,*, Edward D. Frohlich, MD, MACP, FACCc a

Division of Endocrinology, Diabetes and Hypertension, SUNY Downstate and VAMC, 450 Clarkson Avenue, Box 1205, Brooklyn, NY 11203, USA b Clinical Research, University of Missouri–Columbia, Columbia, MO, USA c Alton Ochsner Medical Foundation, 1514 Jefferson Highway, New Orleans, LA 70121, USA

Insulin (INS) resistance use is an integral component of the cardiometabolic syndrome, which often progresses to type 2 diabetes and cardiovascular disease (CVD) events. Hyperinsulinemia, an important component of the cardiometabolic syndrome, may predispose to the development of hypertension, another important part of this syndrome. Hyperinsulinemia may directly contribute to elevated blood pressure by enhancing sympathetic nervous system activity and promoting renal sodium retention. INS may also indirectly increase blood pressure by decreasing the signaling processes that are important for vascular relaxation. Further, an overexpression of the tissue renin-angiotensin system (RAS) seems to contribute to impaired INS use in skeletal muscle and fat tissue and diminished vasorelaxation. Therapeutic strategies that improve INS sensitivity may impede the progression of impaired INS sensitivity to that of clinical diabetes, and reduce blood pressure, renal disease progression, and CVD events. Counterregulatory roles of insulin and angiotensin II in regulation of vascular tissues Insulin resistance, or impaired INS-mediated glucose use, is a significant risk factor for development of hypertension and CVD [1–10]. Resistance Dr. Sowers’ investigational work is supported by NIH grant R01 HL066119-04 and VA Merit Review. * Corresponding author. E-mail address: [email protected] (J.R. Sowers). 0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/S0025-7125(03)00128-7

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to the glucoregulatory action of INS results in a higher plasma INS concentration, and this is often associated with hypertension, an atherogenic dyslipidemia, central-truncal obesity, increased cardiovascular inflammation and oxidative stress, hypercoagulability, microalbuminuria, and other components of the cardiometabolic syndrome [1–10]. Cardiovascular risk factors associated with visceral obesity include the following:

Blood pressures greater than 135/85 mm Hg Insulin resistance or hyperinsulinemia Low high-density lipoprotein cholesterol High triglyceride concentrations Increased apolipoprotein B concentrations Small, dense low-density lipoprotein cholesterol particles Increased fibrinogen concentrations Increased plasminogen activator inhibitor Increased C-reactive protein Increased tumor necrosis factor-a Increased interleukin-6 Microalbuminuria Increased blood viscosity Increased systolic and pulse pressure Increased left ventricular hypertrophy Premature atherosclerosis (coronary heart disease and stroke) Nonalcoholic fatty liver

An integral part of the cardiometabolic syndrome is a blood pressure of greater than 130/85 mm Hg. The importance of essential hypertension in this syndrome is underscored by the fact that even lean hypertensive patients manifest INS resistance [11,12], and patients with hypertension are several fold more likely to develop diabetes over a 3- to 5-year period than are normotensive persons [13,14]. There is accumulating evidence that INS resistance and hyperinsulinemia contribute to this increased propensity for development of essential hypertension [13,14]. Hyperinsulinemia-INS resistance seems to predispose to hypertension by both direct effects of elevated INS and indirectly through impaired INSmediated vascular signaling pathways associated with vasorelaxation [1–6]. Hyperinsulinemia may raise blood pressure by elevations in sympathetic nervous system activity and increased INS-induced renal sodium retention [1,2]. Impaired INS signaling through its metabolic phosphoinositol 3kinase and downstream protein kinase B (Akt) pathways that are increasingly recognized as being important for the generation of nitric oxide (NO) and other vasodilatory factors [15–20]. The generation of NO is important for INS-mediated glucose utilization and vasodilation [4–6]. A heightened vascular RAS system may also contribute to diminished vascular actions of INS [20–23] and other vasodilatory peptides (Figs. 1 and 2). Angiotensin (Ang) II in the vasculature results in increased generation of

Fig. 1. Interactions of angiotensin II and insulin and insulin-like growth factor-1 in vascular endothelial cells. IGF, insulin-like growth factor; INS, insulin.

66 J.R. Sowers, E.D. Frohlich / Med Clin N Am 88 (2004) 63–82 Fig. 2. Interactions of angiotensin II and insulin and insulin-like growth factor-1 in vascular smooth muscle cells. IGF, insulin-like growth factor; INS, insulin; VSMC, vascular smooth muscle cell.


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reactive oxygen species by stimulation of the NAD(P)H oxidase enzyme [24–36], which is expressed in endothelial cells (see Fig. 1) [30–35], vascular smooth muscle cells (see Fig. 2) [28,36–38], and vascular adventitial cells [39]. Increased generation of reactive oxygen species in turn results in increased NO destruction and its conversion to peroxynitrite [40,41]. Further, Ang II activates small molecular weight G proteins, such as Rho A, which when activated interfere with INS signaling through the phosphoinositol 3-kinase and downstream Akt pathways [42,43]. Further, Ang II increases intracellular calcium [Ca2+]i and Ca2+-myosin light chain sensitization, effects opposite that of INS [43]. Ang II also opposes the actions of INS to enhance glucose uptake in skeletal muscle reactive oxygen species, RhoA activation, and decreases in bioavailable NO [38–40], which is an important mediator of glucose transport (Fig. 3) [44,45].

Insulin resistance, hyperinsulinemia, hypertension, and cardiovascular disease There is accumulating evidence that INS resistance and the resulting hyperinsulinemia are causally related to hypertension and CVD. For example, untreated essential hypertensive patients often have higher fasting and postprandial INS levels than normotensive persons regardless of body mass; and a direct correlation exists between plasma INS concentrations and blood pressure levels [11,12]. Further, INS resistance and hypertension co-exist in genetic hypertension, such as that seen in the spontaneously hypertensive rat [46]; the Dahl salt-sensitive hypertensive rat [47–50]; and the Ren-2 hypertensive rat, which overexpresses renin in cardiovascular and other tissues (Fig. 4) [51–53]. Finally, the relationships between INS resistance and secondary hypertension do not occur with secondary causes of hypertension [54]. INS resistance and hyperinsulinemia are not consequences of hypertension, but rather a genetic predisposition may contribute to the coexistence of both disorders. This notion is supported by the observation of altered glucose metabolism in normotensive offspring of hypertensive parents [55,56]. Another report indicated that increased plasma INS levels predicted elevated blood pressures in children [57]. These data collectively suggest a relationship between INS resistance, hyperinsulinemia, and essential hypertension. The notion that INS resistance and resulting hyperinsulinemia are risk factors for coronary artery disease (CAD) is supported by three large prospective studies [58–60]. The highest association between hyperinsulinemia and CVD was observed in a Finnish population with a very high prevalence of CVD [58]. Another perspective study of 2103 men in Quebec [60] showed that a high fasting INS concentration was an independent predictor of CAD. Several other studies have shown a relationship between stroke, carotid wall atherosclerotic lesions, and INS levels and resistance

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Fig. 3. Interactions of angiotensin II and insulin and insulin-like growth factor-1 on skeletal muscle glucose transport.


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Fig. 4. Visceral obesity and the metabolic syndrome: a network of atherogenic factors. BP, blood pressure; CRP, C-reactive protein; HDL, high-density lipoprotein; IL-6, interleukin-6; LDL, low-density lipoprotein; PAI-1, plasminogen activator inhibitor type 1; RAS, renin angiotensin system; TNF-a, tumor necrosis factor-a.

[61–64]. Data from several studies [65–67] suggested that a high ratio of estrogen to testosterone combined with hyperinsulinemia predisposes to premature CAD and related mortality in men. Other reports [7,68,69] suggest that hyperinsulinemia and high androgen predispose to CVD in women. These observations suggest that hyperinsulinemia and altered sex hormone profiles may predispose to hypertension and CVD [10].

Relationship of obesity to insulin resistance and cardiovascular disease In Westernized, industrialized cultures, and increasingly in less industrialized nations, obesity plays an important role in INS resistance and associated CVD [70–83]. If obesity is defined as a body mass index (BMI) of 20% above desirable (BMI approximately 27 kg/m2), 36 million Americans can be considered obese [10,71]. Central-visceral obesity is an especially high risk factor for INS resistance and hyperinsulinemia, a metabolic dyslipidemia, increased cardiovascular oxidative stress, coagulation abnormalities, and premature CAD [70–83]. Indeed, the fat that is present in the omental and paraintestinal regions seems to be the nexus for the litany of actors comprising the cardiometabolic syndrome [71]. Compared with peripheral fat cells, visceral fat is more resistant to the metabolic effects of INS and is more sensitive to lipolytic hormones, including catecholamines and glucocorticoids [67,68]. Increased release of free fatty acids into the portal system provides increased substrate for hepatic triglyceride synthesis of INS. The dyslipidemia associated with visceral obesity is that of elevated triglycerides, decreased high-density lipoprotein cholesterol, and increases in the proportion of small dense lowdensity lipoprotein particles [10,67].

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The relationship between visceral obesity, other components of the cardiometabolic syndrome, and CVD seems to occur at a relatively young age [81,82,84]. Obesity in youth also predicts obesity in adulthood [81,82,84]. For persons with a BMI of 25 to 34.9 kg/m2, a waist circumference greater than 40 in men, and waist circumference greater than 35 in women there is a significantly increased risk of obesity-related CVD [70–83]. Indeed, a waist-to-hip ratio of 0.92 or greater is associated with a nearly threefold increased risk of CAD [70–72,80]. Trends in increasing prevalence of obesity and diabetes in this country are related to increased consumption of high-calorie food and decreased physical activity [71,77,85]. Aerobic exercise has been shown to reduce weight, enhance INS sensitivity, improved lipoprotein profile, and lower blood pressure, correcting many of the abnormalities associated with the INS resistance syndrome [78,85–87].

Visceral obesity, insulin resistance, hypertension, and cardiovascular disease The central adipose tissue is very active metabolically. For example, visceral fat cells have increased production of interleukin-6 and tumor necrosis factor-a (TNF-a) [71,88–95]. Elevated production of these cytokines is associated with increased plasma free fatty acids, fasting hypertriglyceridemia, elevated C-reactive protein, glucose intolerance, and hypertension [88–95]. Indeed, elevated interleukin-6 levels and C-reactive protein are predictive for the development of INS resistance, type 2 diabetes, microalbuminuria, and CVD [91–93]. Other products of adipose tissue include adiponectin, resistant leptin, plasminogen activator inhibitor-1 (PAI-1), TNF-a, and Ang II [96–106]. Adipocyte-secreted molecules are termed ‘‘adipokines’’ [107,108]. One of these, adiponectin, is a mediator of INS sensitivity [100,109–116]. Adiponectin increases INS sensitivity, in part by inhibition of hepatic glucoseoutput [100,110] and by increasing peripheral tissue (ie, skeletal muscle) INS actions [114]. In contrast, another adipokine, resistin, enhances gluconeogenesis by decreasing hepatic INS sensitivity [107–117]. Hotta et al [111] reported that adiponectin levels in serum are negatively correlated with BMI, plasma glucose, INS, and triglycerides. This group also reported decreased adiponectin levels in patients with diabetes, and when stratified by the co-association of CAD, those with CAD had lower adiponectin levels that those without CAD. They also reported that a modest weight reduction of 10% BMI led to a significant increase in serum adiponectin levels in overweight diabetic and nondiabetic patients. This effect of weight reduction was also reported by Yang et al [116], who observed in obese persons undergoing gastric by-pass surgery that postsurgical decreases in BMI and fasting glucose and INS levels, which were associated with an increase in adiponectin levels and corresponding increases in INS sensitivity. These observations are consistent with work showing that adiponectin


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administration lowers hepatic glucose production, in part, by lowering hepatic expression of the gluconeogenic enzymes, glucose 6-phosphatase and phosphoenolpyruvate carboxykinase [110]. The net impact of fat factors, adiponectin versus resistin, and TNF-a seems to be disparate in those with impaired glucose metabolism or diabetes mellitus compared with persons with normal glucose tolerance. Several recent observations suggest that adiponectin has anti-inflammatory and antiatherosclerotic properties [109–116]. Other adiposines, such as resistin, interleukin-6, TNF-a, and PAI-1, seem to have opposite effects [88– 117]. For example, TNF-a is known to induce INS resistance by inhibiting the activity of INS receptor tyrosine kinase and the expression and translocation of glucose transport 4 (GLUT-4) [96–99]. Adiponectin specifically inhibits the expression of TNF-a secretions by macrophages and adipocytes [118,119]. These observations suggest that the overall effects of adipokines on INS sensitivity and inflammation depend on the net balance of their production by fat. The coagulation abnormalities associated with INS resistance and hyperinsulinemia are driven, in part, by adipokines [90–95]. These coagulation abnormalities include increased platelet aggregation and activation [1,10] and elevated procoagulants, such as fibrinogen and von Willebrand’s factor [1,10]. Impaired fibrinolysis includes a high production and activity of PAI1, together with low levels of tissue fibrinogen activity [1,10]. Visceral obesity and hyperinsulinemia are associated with high levels of PAI-1 [105,120–122]. Indeed, levels of this atherogenic factor are particularly high in INSresistant type 2 diabetes mellitus [122–124] and those with CVD [124–126]. In this regard, low levels of tissue-type plasminogen activator levels and relatively high PAI-1 concentrations have been found in survivors of myocardial infarction [125] and in those with recurrent infarctions [126] compared with age-matched controls. This imbalance of the fibrinolytic balance may also reduce compliance and contribute to elevated systolic blood pressures, in part by altering the degradation of collagen and other glycoproteins [126–130]. Similarly, PAI-1 and angiotensinogen are two peptides secreted by adipose tissue that have opposite effects on the modulation of both fibrinolysis and blood pressure [124,131,132]. Obese persons and rodents have increased plasma levels of the peptide leptin directly related to increased body fat [108,126,131]. Leptin is a 16-kd product of the OB gene [133]. It inhibits food intake, reduces body weight, and stimulates energy expenditure. One of the mechanisms of action of leptin is to act as a cytokine. Leptin may contribute to blood pressure regulation by several mechanisms. In rodent models, intracerebral or chronic peripheral infusion of leptin increases blood pressure, heart rate, and sympathetic nerve activity to brown adipose tissue, kidney, and other tissues [132,133]. Leptin may lead to increases in pressure either directly by sympathetic activation or indirectly by inducing neurally mediated increases in sodium reabsorption in the renal tubule. Further, blood pressure is

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elevated in transgenic hyperleptinemic mice [134]. Several studies have reported higher plasma leptin concentrations in hypertensive patients than in normotensive persons, and correlations between plasma leptin and blood pressure levels in both adults and children [135–137]. Increased leptin levels are present in obese persons and may contribute to elevated blood pressure. The RAS is active in adipose tissue and seems to play an important role in modulating INS sensitivity and adipocyte differentiation [138–142]. According to this notion, failure adequately to expand adipose tissue to accommodate excess calories associated with overeating and obesity leads to the development of type 2 diabetes. Normally, Ang II inhibits adipocyte differentiation of human adipocytes by an AT1 receptor [140–142], and expression of Ang II–forming enzyme (angiotensin converting enzyme) in adipose tissue is inversely related to INS sensitivity. Ang II–induced failure to expand adipose tissue by differentiation promotes the storage of excess calories in muscles, liver, pancreas, heart, and so forth, thereby contributing to the development of INS resistance and b-cell failure (lipotoxicity hypothesis) [139]. This notion is supported by observations that large adipocyte size is the best correlate for diabetes in obese Pima Indians, and that newly differentiated adipocytes are greater in lean than in obese subjects [143]. Further, hepatic steatosis and excess lipid deposition in skeletal muscle and pancreas is found in obese, INS-resistant persons [143]. The role of RAS in this abnormality of adipocyte differentiation and INS resistance is suggested by reduced development of type 2 diabetes in animal models [144] and persons in clinical trials of angiotensin-converting enzyme and angiotensin II receptor blocker (ARB) drugs (see Fig. 4) [145]. Hygienic measures are of proved benefit in both prevention of the cardiometabolic syndrome and type 2 diabetes [40,71,145]. Aerobic exercise has been shown to improve INS sensitivity, improve lipoprotein profiles, and lower blood pressure, correcting many of the abnormalities associated with the cardiometabolic syndrome [46,146,147]. These beneficial effects may relate to improved blood flow to INS-sensitive tissues, increased INSsensitive slow twitch skeletal muscle fibers, reductions in visceral fat, and increased postreceptor INS action. Both aerobic exercise and reduced caloric intake may reduce the rise in INS resistance, hypertension, and associated CVD in the United States [146–148]. Microalbuminuria, cardiometabolic syndrome, and type 2 diabetes Many structural and functional similarities exist between the renal glomerulus and the vasculature [144]. Indeed, mesangial cells are structurally and functionally homologous to vascular smooth muscle cell and are derived from the same progenitor cell line [149]. Mesangial cells, similar to vascular smooth muscle cells, produce growth factors (ie, Ang II and INS-like growth factor-1 and cytokines), and NO and prostaglandins that counterbalance many of the effects of these growth factors [149]. The pathophysiologic


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changes of glomerulosclerosis closely parallel those of atherosclerosis and includes mesangial cell proliferation and hypertrophy, foam cell accumulation, build-up of extracellular matrix, and amorphous materials and evolving sclerosis. These changes lead to matrix expansion, basement membrane abnormalities, and loss of basement membrane permoselectivity, which lead to proteinuria [149]. In concert with the notion that glomerulosclerosis and atherosclerosis are parallel processes, early proteinuria (microalbuminuria) is associated with endothelial cell dysfunction, enhanced oxidative stress, increased inflammation, impaired fibrinolysis, elevated systolic blood pressures, nondipping, and a diabetic dyslipidemia [144,145]. Cardiovascular risk factors that cluster with microalbuminuria include the following:

Elevated blood pressure Central obesity INS resistance Low high-density lipoprotein cholesterol levels High triglyceride levels Small dense low-density lipoprotein particles Systolic hypertension Absent nocturnal drop in blood pressure and heart rate Salt sensitivity Male sex and postmenopausal or diabetic women Increased CV oxidative stress Impaired endothelial function Abnormal coagulation-fibrinolytic profiles Left ventricular hypertrophy Hyperuricemia Elevated C-reactive protein and other inflammatory markers Nonalcoholic fatty liver Increased inflammation

Microalbuminuria is typically defined as the presence of urinary albumin above normal levels, but below the range detectable with conventional dipstick methodology [150,151]. This translates to a urinary albumin excretion rate of 20 to 200 lg/min (30 to 300 mg/24 h). Microalbuminuria has been reported to predict the progression of diabetic nephropathy [150] and has been observed in nondiabetic first-degree relatives of patients with diabetes [150,151]. In prospective studies [152] microalbuminuria in nondiabetic persons has been shown to precede and predict the development of type 2 diabetes [153]. Persons who had not developed clinical diabetes after 3.5 years still displayed the CVD risk factor profile of hyperinsulinemia, metabolic dyslipidemia, and hypertension [152,153]. Proteinuria seems to be a relatively strong surrogate marker for endothelial dysfunction and accelerated atherosclerosis [154–162]. Patients with proteinuria have greater left ventricular mass, greater carotid medial thickening, and endothelial dysfunction [151]. They have a greater

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propensity to myocardial infarction, stroke, and greater mortality with these events [151–155]. Currently, it is not known if correction or reduction of proteinuria decreases CVD risk. Summary Cardiovascular disease is a major cause of mortality in individuals with diabetes. Many factors, including hypertension, contribute to the high prevalence of CVD in this population. Hypertension occurs approximately twice as frequently in patients with diabetes compared with patients without diabetes. Conversely, recent data suggest that hypertensive persons are more likely to develop diabetes than normotensive persons. In addition, up to 75% of CVD in patients with diabetes may be attributed to hypertension, leading to recommendations for more aggressive blood pressure control (ie, \130/85 mm Hg) in persons with coexistent diabetes and hypertension. Increasing obesity further contributes to both diabetes and hypertension and significantly increases CVD morbidity and mortality. Other important risk factors for CVD in these patients include atherosclerosis, dyslipidemia, microalbuminuria, endothelial dysfunction, platelet hyperaggregability, coagulation abnormalities, and diabetic cardiomyopathy. The current knowledge regarding these risk factors has been reviewed, placing special emphasis on the metabolic syndrome, hypertension, microalbuminuria, and the role of obesity in these disorders. Although not discussed in detail, it is acknowledged that both hygienic measures (weight loss and aerobic exercise) and treatment strategies that include aspirin, statins, INS sensitizers, and antihypertensive agents that reduce renin-angiotensin-aldosterone system activity have been shown to reduce inflammation, coagulation abnormalities, endothelial function, proteinuria, and in some cases reduce CVD and renal disease progression. Additional therapeutic agents are currently being developed specifically to improve INS sensitivity and other CVD risk factors that are components of the cardiometabolic syndrome. Acknowledgments The authors thank Paddy McGowan for her assistance in preparation of this article. References [1] Sowers JR, Sowers PS, Peuler JD. Role of insulin resistance and hyperinsulinemia in development of hypertension and atherosclerosis. J Lab Clin Med 1994;123:647–52. [2] Reaven GM, Lithell H, Landsberg L. Hypertension and associated metabolic abnormalities: the role of insulin resistance and sympathetic adrenal system. N Engl J Med 1996;334:374–81. [3] Nolan JJ, Ludvik B, Baloga J, Reuchart D, Olefsky JM. Mechanisms of the kinetic defect in insulin action in obesity and NIDDM. Diabetes 1997;46:494–500.


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Med Clin N Am 88 (2004) 83–97

Fibrosis in hypertensive heart disease: role of the renin-angiotensin-aldosterone system Arantxa Gonza´lez, BSca, Begonã Lo´pez, PhDa, Javier Dı´ ez, MD, PhDa,b,* a

Area of Cardiovascular Pathophysiology, Centre for Applied Medical Research, University of Navarra, C. Irunlarrea 1, 31080 Pamplona, Spain b Department of Cardiology and Cardiovascular Surgery, University Clinic, School of Medicine, University of Navarra, Pamplona, Spain

Organs are composed of highly differentiated, very specialized parenchymal cells surrounded by stroma consisting of extracellular matrix, tissue fluid, and undifferentiated pluripotent mesenchymal cells. Parenchymal cells distinguish one organ from another based on their unique morphologic features and their highly specialized functions. Disproportionate stromal growth, relative to parenchymal growth, termed ‘‘fibrosis’’ (sclerosis or cirrhosis), represents a pathologic structural remodeling of an organ [1]. Fibrosis presents in several different morphologic patterns. A reparative (replacement) fibrosis appears at sites of parenchymal cell loss. For example, microscopic scarring of ventricular myocardium follows cardiac myocyte necrosis [2–4], whereas a macroscopic scar follows segmental infarction [5,6]. A perivascular fibrosis of intramural vessels with extensions into the contiguous interstitial space has been referred to as a ‘‘reactive fibrosis’’ because loss of parenchyma is not a requisite [7]. A perivascular-interstitial fibrosis, for example, accompanies chronic elevations in the effector hormones of the renin-angiotensin-aldosterone system [8–11]. Absolute fibrosis is defined as increased collagen concentration of an organ and consists predominantly of fibrillar collagen types I and III that appear secondary to altered collagen turnover (synthesis greater than degradation). Collectively, fibrosis is a common pathway to organ failure. This holds true for such diverse organs as the heart [12,13], kidneys [14,15], lungs [16,17], and liver [18]. * Corresponding author. E-mail address: [email protected] (J. Dı´ ez). 0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/S0025-7125(03)00125-1

A. Gonza´lez et al / Med Clin N Am 88 (2004) 83–97

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Under certain circumstances, a regression of fibrous tissue occurs after the repair process has been completed. This is related to fibrillar collagen degradation by matrix metalloproteinases [19,20]. In other cases, there is a persistent fibrosis (eg, infarct scar of the myocardium) that is essential for organ integrity. Lastly, a progressive fibrosis can occur (eg, experimental glomerulonephritis, chronic elevation of circulating angiotensin II [ANGII] or aldosterone) and destroys organ architecture and accounts for its failure [20–23]. The need to prevent fibrosis or to regress it, once formed, represents a major challenge. Various strategies can be taken [14]. Myocardial fibrosis in hypertensive heart disease Clinical evidence The essential criterion in defining hypertensive heart disease (HHD) is a greater than normal heart mass in the absence of a cause other than arterial hypertension. It is now accepted, however, that besides left ventricular hypertrophy (LVH), alterations in myocardial structure as listed below account for loss of tissue homogeneity and pathologic remodeling that appears in HHD: Cellular alterations Cardiomyocytes Hypertrophy, atrophy, apoptosis, necrosis Noncardiomyocytes Hyperplasia and apoptosis of fibroblasts Hypertrophy or hyperplasia of vascular smooth muscle cells Noncellular alterations Interstitial and perivascular fibrosis Microscopic scarring Medial thickening of coronary arterioles Diminished number of capillaries A growing body of evidence indicates that myocardial fibrosis is one of the key pathologic features of myocardial remodeling in HHD. In fact, a number of studies performed in postmortem human hearts [24–26] and endomyocardial human biopsies [27–30] have shown that myocardial collagen volume fraction, a morphometric measure of the amount of tissue collagen, is constantly increased in patients with HHD compared with normotensive controls (Fig. 1). Furthermore, an exaggerate accumulation of fibrillar collagen types I and III within the myocardial interstitium and surrounding intramural coronary arteries and arterioles has been evidenced immunohistochemically in patients with HHD [31]. Potential mechanisms Collagen types I and III are the major fibrillar collagens produced by fibroblasts in the adult heart. They exhibit the characteristic triple helical


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Fig. 1. (A) Histologic sections of interventricular septal specimen biopsies from humans. Sections were stained with picrosirius red, and the interstitial collagen was identified in red (original magnification 20). (B) Collagen volume fraction (CVF) determined in interventricular septal specimen biopsies from humans. (Adapted from Querejeta R, Varo N, Lo´pez B, Larman M, Artinãno E, Etayo JC, et al. Serum carboxy-terminal propeptide of procollagen type I is a marker of myocardial fibrosis in hypertensive heart disease. Circulation 2000;101:1729–35; with permission.)

conformation formed by three polypeptide chains (a chains). Fibrillar collagen of the heart provides the structural scaffolding for cardiomyocytes and coronary vessels and imparts cardiac tissue with physical properties that include stiffness and resistance to deformation [12]. In addition, fibrillar collagen may also act as a link between contractile element of adjacent cardiomyocytes and as a conduit of information that is necessary for cell function. As in other organs, collagen turnover of normal adult heart results from the equilibrium between the synthesis and degradation of collagen types I and III molecules [32]. The synthesis of collagen molecules follows the

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normal pattern of protein synthesis, but it differs from the synthesis of many proteins in that the newly formed a chains undergo a number of posttranslational modifications. Extracellular degradation of collagen fibers is mediated by collagenase and other members of the matrix metalloproteinase family of zinc-containing endoproteinases. The active form of collagenase can be inhibited by interaction with naturally occurring specific tissue inhibitors of matrix metalloproteinases (TIMPs). As shown by in vivo experiments, chronic pressure overload stimulates both procollagen gene expression and collagen protein synthesis leading to excessive collagen deposition and fibrosis [33]. In addition, in vitro studies have shown that procollagen type I synthesis is stimulated in cardiac fibroblasts submitted to cyclic mechanical load [33]. Hemodynamic overload of the left ventricle caused by systemic hypertension may play a role in myocardial fibrosis. Nevertheless, two types of findings suggest that besides the mechanic factor, nonhemodynamic factors may also contribute to myocardial fibrosis in human hypertension. First, myocardial fibrosis has been found not only in the left ventricle but also in the right ventricle [25,34] and the interventricular septum [35] in postmortem studies of human hearts with HHD. Second, recent studies have shown that the ability of antihypertensive treatment to regress fibrosis in hypertensives with biopsy-proved myocardial fibrosis is independent of its antihypertensive efficacy [29,36]. The current view is that myocardial fibrosis may be the consequence of the loss of reciprocal regulation that normally exists between molecules that stimulate (eg, ANGII) and molecules that inhibit fibrillar collagen turnover [37]. Factors modulating collagen types I and III turnover in the myocardium include the following: Factors that facilitate the synthesis of collagen Vasoactive substances Angiotensin II, endothelin-1, catecholamines Growth factors Transforming growth factor-b1, platelet-derived growth factor, basic fibroblast growth factor, insulin-like growth factor-1 Hormones Aldosterone, deoxycorticosterone Cytokines Interleukin-1 Adhesion molecules Ostepontin Factors that facilitate the degradation of collagen Vasoactive substances Bradykinin, prostaglandins, nitric oxide, natriuretic peptides Growth factors Hepatocyte growth factor


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Hormones Glucocorticoids Cytokines Tumoral necrosis factor-a, interferon-c Endogenous peptides N-acetyl-seryl-aspartyl-lysyl-proline An excess of stimulators, caused by either absolute stimulator overproduction or by their relative overabundance because of a deficit in inhibitor formation can promote fibrosis. Clinical impact Several arguments support the concept that myocardial fibrosis has a particularly important influence in the process of heart failure associated with cardiac remodeling [38]. First, interstitial fibrosis contributes to ventricular wall stiffness and consequently impairs cardiac compliance, contributing to impaired diastolic function. Second, because neither the collagen network nor the fibroblasts contribute to systolic contraction, increased collagen deposition and fibroblast volume means that systolic work is being performed by a smaller proportion of the cardiac mass, contributing to systolic dysfunction. Third, perivascular fibrosis leads to increased distance that oxygen must diffuse and potentially lowers PaO2 for the working cardiomyocytes. Finally, electrical coupling on the cardiomyocytes may be impaired by the accumulation of collagen proteins and fibroblasts because such accumulation causes morphologic separation of cardiomyocytes. Role of angiotensin II in myocardial fibrosis Various lines of evidence support a role for ANGII as a critical candidate factor to induce myocardial fibrosis in HHD. In vivo evidence Animal models Endogenous elevations in circulating ANGII that accompany unilateral renal artery stenosis [39] or the infusion of exogenous ANGII [40] are associated with increased blood pressure and fibrosis. The appearance of such fibrous tissue formation is preceded by increased expression of ANGII type 1 (AT1) receptors, transforming growth factor-b1 (TGF-b1), and mRNA for collagen types I and III [41]. In addition, development of fibrosis involves proliferating fibroblasts and cell differentiation into myofibroblasts [42]. Two observations suggest that the ability of ANGII to induce cardiac fibrosis in these models is independent of its hypertensive action. First, fibrosis in the renal artery stenosis model develops in both low-pressure right and left atria and right ventricle and high-pressure left ventricle [43].

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Second, cardiac fibrosis in the ANGII infusion model can be prevented by either angiotensin converting enzyme (ACE) inhibitors or AT1 receptor antagonists, but not hydralazine or prazosin, despite a similar antihypertensive efficacy of these compounds [44,45]. The critical role of ANGII in hypertension-associated cardiac fibrosis is further supported by the observation that experimental infrarenal aortic binding, which does not induce ANGII, causes blood pressure elevation and cardiomyocyte hypertrophy but not cardiac fibrosis [43]. The hypertensive Ren2 rat provides a well-established model of ANGIIdependent cardiac hypertrophy [46]. Several studies have revealed that interstitial and perivascular fibrosis, along with extensive collagen types I and III deposition are present in Ren2 [47–49]. Increased cardiac renin and ANGII levels have been described in this transgenic rat model [46]. In addition, cardiac lesions are very sensitive to ACE inhibition and AT1 receptor antagonism in Ren2 rats [50]. As a result, the development of hypertrophy and fibrosis in the heart of these animals has been attributed, at least partially, to a local activation of the cardiac renin-angiotensin system. Pharmacologic studies Experimental findings. Pharmacologic interventions with ACE inhibitors or AT1 receptor antagonists have underscored the potential importance of ANGII in the mediation of cardiac fibrosis in pathologic conditions, such as primary hypertension. In rats with spontaneous hypertension and LVH, myocardial fibrosis has been shown to regress by treatment with the ACE inhibitor lisinopril [51]. This effect occurred independently of the drug’s antihypertensive effect [51]. It has been found that chronic AT1 receptor antagonism with losartan resulted in reversal of fibrosis, inhibition of the posttranscriptional synthesis of procollagen type I, inhibition of TIMP-1 expression, and stimulation of collagenase activity in the left ventricle of adult rats with spontaneous hypertension [52,53]. Analysis of the individual data showed that the intensity of these myocardial changes was independent of the antihypertensive efficacy of the drug [52,53]. Clinical findings. The fibrogenic role of ANGII in humans has been investigated in three recent prospective trials of limited size using biopsyproved myocardial fibrosis in patients with essential hypertension and LVH. Schwartzkopff et al [28] studied 14 patients before and after 1 year of treatment with the ACE inhibitor perindopril. Structural analysis revealed diminution of perivascular and interstitial fibrosis with treatment. The observed regression of fibrosis on ACE inhibitor treatment was observed in the non–pressure-overloaded right ventricle, indicating that the antifibrotic effect was not accounted for by left ventricular pressure reduction alone. Brilla et al [29] randomized 35 previously treated patients with controlled blood pressure to receive either the ACE inhibitor lisinopril or the diuretic hydrochlorothiazide for 6 months. Only patients randomized to lisinopril


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had a significant reduction in myocardial fibrosis. Blood pressure reduction was similar in patients treated with either lisinopril or hydrochlorothiazide. Finally, Lo´pez et al [36] studied 37 treated patients with uncontrolled blood pressure. After randomization, 21 patients were assigned to the AT1 receptor antagonist losartan and 16 to the calcium channel blocker amlodipine for 12 months. Whereas myocardial fibrosis decreased significantly in losartantreated patients, this parameter remained unchanged in amlodipine-treated patients. A similar reduction of blood pressure in losartan-treated patients than in amlodipine-treated patients was reported in this study. Collectively, these observations support the concept that in addition to pressure overload, ANGII induces myocardial fibrosis in essential hypertension. Cellular and molecular mechanisms Increasing evidence strongly indicates that ANGII exerts multiple profibrotic effects within the heart including induction of fibroblast hyperplasia, activation of collagen biosynthetic pathways, and inhibition of collagen degradative pathways (Fig. 2). In addition, available data indicate that these effects may result from either the direct action of ANGII or a synergistic cooperation between this peptide and other profibrotic factors. Stimulation of fibroblast proliferation In vitro studies of rat and human cardiac fibroblasts have shown that ANGII stimulates cell proliferation by the AT1 receptor [54]. Results in the literature indicate that the proliferative response of fibroblasts to ANGII might well be mediated by stimulation of the synthesis of growth or inflammatory substances like platelet-derived growth factor and cytokines, by integrin activation caused by adhesion proteins, or by a combination of these mechanisms [55,56]. For instance, ANGII strongly up-regulates the expression of osteopontin and its ligand aVb3 integrin in rat and human cardiac cells [57,58]. Interestingly, elevated left ventricular osteopontin expression has been reported in the Ren2 rat model characterized by high myocardial ANGII concentrations [49]. Monoclonal antibodies directed against either osteopontin or aVb3 completely blocked the mitogenic effect of ANGII on cultured rat

Fig. 2. Potential pathways involved in angiotensin II (ANG II)-mediated fibrosis.

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cardiac fibroblasts [58], suggesting that osteopontin mediates ANGII-induced fibroblast proliferation acting by an integrin-dependent pathway. Stimulation of collagen synthesis Although different signaling pathways of the AT1 receptor may subserve direct ANGII-induced collagen synthesis in cardiac fibroblasts [59], recent data suggest that the MAP/ER kinase pathway seems to play a major role [60]. The end result of signaling mechanisms is activation of transcription factors, which bind to various cis-acting elements in the regulatory sequences of a1 and a2 collagen type I and a1 collagen type III genes [60,61]. This, in turn, couples with gene expression and the synthesis of collagen types I and III precursor molecules [62,63]. A number of studies, however, provide strong evidence that ANGII indirectly regulates collagen synthesis by cardiac fibroblasts by specific growth factors [64]. The principal candidates include TGF-b1 and endothelin-1. In fact, ANGII has been shown to induce collagen type I gene expression by activation of TGF-b1 signaling pathways (eg, connective tissue growth factor and Smad proteins) and these effects were blocked by the AT1 receptor antagonist losartan [65]. ANGII has been also shown to increase the expression of TGF-b1 in cultured cardiac fibroblasts by stimulation of the AT1 [54]. Recent data suggest that a Kru¨ppel-like zinc-finger transcription factor 5 (also known as BTEB2 and IKLF) is critically involved in ANGIIinduced TGF-b1 expression, collagen synthesis, and development of cardiac fibrosis [66]. Besides up-regulation of cardiac gene TGF-b1 expression, ANGII has been reported to convert latent TGF-b1 to the active protein in vivo in the heart [67]. Endothelin-1 is synthesized and released by cardiac fibroblasts in response to the interaction of ANGII with the AT1 receptor [68] and has been shown to stimulate the synthesis of collagen types I and III in these cells [69]. In several rat models of arterial hypertension, blockade of endothelin receptors is associated with decrease in left ventricular collagen accumulation [70,71]. There is some in vivo evidence that ANGII also influences posttranslational processing of cardiac fibrillar collagen. It has been shown that ANGII infusion is associated with stimulation of prolyl 4-hydroxylase (an enzyme that mediates hydroxylation of procollagen a chains in the endoplasmic reticulum of cardiac fibroblasts) in the rat left ventricle [72]. In addition, it has been reported that immunoreactive prolyl 4-hydroxylase concentration decreases significantly in the ventricle of post–myocardial infarction rats treated with the AT1 receptor antagonist losartan [73]. Inhibition of collagen degradation In addition to collagen synthesis, ANGII stimulation of the AT1 receptor has been shown to regulate collagen degradation by attenuating interstitial collagenase activity in adult rat [54] and human [74] cardiac fibroblasts and by enhancing TIMP-1 production in rat heart endothelial cells [75].


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A number of factors may mediate the inhibitory effect of ANGII on cardiac collagen degradation (eg, TGF-b1 and plasminogen activator inhibitor-1). Cell culture studies on human fibroblasts show that exposure of these cells to TGF-b1 in the presence of other growth factors (eg, epidermal growth factor and basic fibroblastic growth factor) resulted in downregulation of collagenase and up-regulation of TIMP-1 [76,77]. Similar findings have been reported in the fibrotic myocardium of TGF-b1 transgenic mice [78]. Activation of the AT1 receptor in human cardiac fibroblasts has been shown to promote stimulation of plasminogen activator inhibitor-1 expression [79]. This stimulatory effect has been confirmed in the left ventricle of ANGII-induced hypertensive rats [80]. Plasminogen activator inhibitor-1 inhibits the activation of collagenase and other matrix metalloproteinases and thereby collagen degradation [81,82]. Interaction with aldosterone Experimental studies have demonstrated the central role of aldosterone in promoting cardiac fibrosis, probably through a direct action on the heart mediated by cardiac mineralocorticoid receptors [83–85]. In fact, aldosterone has been shown to stimulate collagen synthesis through the mineralocorticoid receptor in isolated cardiac fibroblasts [86]. In experimental studies on rats with renovascular hypertension, hyperaldosteronism, or spontaneous hypertension, however, the aldosterone antagonist spironolactone was able to prevent or reverse the development of myocardial fibrosis even though the drug did not normalize blood pressure and did not prevent LVH [8,43,87–89]. An increase in this mineralocorticoid may be a mechanism for ANGII-induced cardiac fibrosis in some forms of arterial hypertension. Interestingly, an increase in the density of AT1 receptors has been observed in the heart of aldosterone-salt–treated rats [90]. In addition, the AT1 receptor antagonist losartan prevents fibrosis and up-regulation of collagen types I and III mRNAs in the heart of aldosterone-salt–treated rats [91]. Taken together, these findings support the hypothesis that one mechanism by which aldosterone induces cardiac fibrosis involves ANGII acting through AT1 receptors. Because the production of aldosterone is activated in the hypertrophied left ventricle of rats with spontaneous hypertension [92] and hypertensive patients [93], it is possible that aldosterone contributes to ANGII-mediated myocardial fibrosis in primary hypertension. The potential clinical relevance of these interactions is given by several observations. In essential hypertension, a low dose of the aldosterone antagonist canrenone added to antihypertensive treatment has been shown significantly to improve left ventricular diastolic function [94]. This improvement, not accounted for by changes in blood pressure and left ventricular mass, can be ascribed to a direct action of the drug on the myocardium. This is further supported by recent studies showing that chronic administration

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of either spironolactone [95–99] or potassium canrenoate [100] is associated with a reduction in the circulating levels of markers of collagen turnover in patients with different cardiac diseases that evolve with myocardial fibrosis. Summary Structural homogeneity of cardiac tissue is governed by mechanical and humoral factors that regulate cell growth, apoptosis, phenotype, and extracellular matrix turnover. ANGII has endocrine, autocrine, and paracrine properties that influence the behavior of cardiac cells and matrix by AT1 receptor binding. Various paradigms have been suggested, including ANGIImediated up-regulation of collagen types I and III formation and deposition in cardiac conditions, such as HHD. A growing body of evidence, however, deals with the potential role of aldosterone, either local or systemic, in inducing cardiac fibrosis. Aldosterone might also mediate the profibrotic actions of ANGII. To reduce the risk of heart failure that accompanies HHD, its adverse structural remodeling (eg, myocardial hypertrophy and fibrosis) must be targeted for pharmacologic intervention. Cardioprotective agents must reverse not only the exaggerated growth of cardiac cells, but also regress existing abnormalities in fibrillar collagen. Available experimental and clinical data suggest that agents interfering with ACE, the AT1 receptor, or the mineralocorticoid receptor may provide such a cardioprotective effect. References [1] Weber KT. Fibrosis, a common pathway to organ failure: angiotensin II and tissue repair. Semin Nephrol 1997;17:467–91. [2] Tan LB, Jalil JE, Pick R, Janicki JS, Weber KT. Cardiac myocyte necrosis induced by angiotensin II. Circ Res 1991;69:1185–95. [3] Benjamin IJ, Jalil JE, Tan LB, Cho K, Weber KT, Clark WA. Isoproterenol-induced myocardial fibrosis in relation to myocyte necrosis. Circ Res 1989;65:657–70. [4] Ratajska A, Campbell SE, Sun Y, Weber KT. Angiotensin II associated cardiac myocyte necrosis: role of adrenal catecholamines. Cardiovasc Res 1994;28:684–90. [5] Sun Y, Cleutjens JP, Diaz-Arias AA, Weber KT. Cardiac angiotensin converting enzyme and myocardial fibrosis in the rat. Cardiovasc Res 1994;28:1423–32. [6] Jugdutt BI, Amy RW. Healing after myocardial infarction in the dog: changes in infarct hydroxyproline and topography. J Am Coll Cardiol 1986;7:91–102. [7] Weber KT, Brilla CG. Pathological hypertrophy and cardiac interstitium: fibrosis and renin-angiotensin-aldosterone system. Circulation 1991;83:1849–65. [8] Brilla CG, Pick R, Tan LB, Janicki JS, Weber KT. Remodeling of the rat right and left ventricles in experimental hypertension. Circ Res 1990;67:1355–64. [9] Sun Y, Ratajska A, Zhou G, Weber KT. Angiotensin-converting enzyme and myocardial fibrosis in the rat receiving angiotensin II or aldosterone. J Lab Clin Med 1993;122: 395–403. [10] Goldblatt H. Experimental hypertension induced by renal ischemia (Harvey Lecture). Bull N Y Acad Med 1938;14:523–53. [11] Hall CE, Hall O. Hypertension and hypersalimentation. I. Aldosterone hypertension. Lab Invest 1965;14:285–94.


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Med Clin N Am 88 (2004) 99–113

Coronary flow reserve measurements in hypertension Malte Kelm, MD, FESC*, Bodo E. Strauer, MD, FACC, FRCP Division of Cardiology, Pneumology, and Angiology, Department of Medicine, Heinrich Heine University, Moorenstrasse 5, 40225 Du¨sseldorf, Germany

Arterial hypertension can provoke a reduction in coronary flow reserve through several mechanisms that are not mutually exclusive (coronary artery disease, left ventricular hypertrophy, microvascular disease). The diagnostic management should include exploring these different targets with different diagnostic markers. In clinical practice one should keep in mind that assessing global cardiovascular risk of hypertensive patients into low, medium, high, and very high class is the primary goal. Global risk stratification follows the diagnostic routine procedures suggested by the 1999 World Health Organization-International Society of Hypertension guidelines: medical history, physical examination, and clinical blood pressure measurement; routine blood chemistry and urine analysis; and ECG [1]. In large cohort of hypertensive patients, however, Cuspidi et al [2] showed that this routine work-up may be too insensitive to detect patients belonging to high global risk category. Additional diagnostic procedures seem mandatory, such as routine cardiac [3,4] and vascular ultrasonography [2], to avoid this error [2]. This article discusses variables of coronary flow regulation as far as they seem crucial for the understanding of diagnostic procedures to assess coronary flow reserve in arterial hypertension. The coronary circulation is unique because it perfuses the organ that generates the perfusion pressure for the entire circulation. The major determinants of coronary blood flow are aortic pressure, extravascular compression, myocardial metabolism and energy demand, structural architecture, and neurohumoral and endothelial control of coronary vascular resistance. Interfering variables that affect maximum coronary blood flow and coronary * Corresponding author. E-mail address: [email protected] (M. Kelm). 0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/S0025-7125(03)00119-6

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reserve are perfusion pressure gradient along the coronary vascular tree, distribution of coronary vascular resistance, transmural gradients of coronary flow, heart rate, left ventricular mass and volume, left ventricular wall stress and end diastolic pressure, and rheologic parameters [5]. Architecture of coronary vasculature The coronary arteries branch into smaller arteries that intrude from the epicardium into the myocardium to reach the subendocardium by a dichotomic-fractal order. Coronary angiography can give information about coronary lumen diameters down to vessels of 500 to 1000 lm, still representing coronary conduit arteries. Coronary arteries that take part in the control of coronary resistance have diameters in the range of 100 to 300 lm, followed by coronary arterioles (10–100 lm). The preterminal coronary arterioles go into capillaries that represent the true exchange area of oxygen and substrate for myocytes. Coronary veins drain the exhausted blood from the capillary bed. The total coronary length is estimated to be composed by 60% to 75% of coronary arterioles, whereas intramural arteries contribute 15% to 25% and epicardial coronary arteries 5% to 10% [6]. From the anatomic point of view, arterioles represent an important part of the coronary circulation that escapes the analysis of coronary angiography. The coronary resistance is represented 50% to 60% by arterioles, whereas capillaries and venules contribute about 20% and small arteries 20% to 30% [7]. Coronary flow and coronary vascular resistance The effective perfusion pressure gradient for coronary inlet blood flow, predominately during diastole, is the aortic pressure minus the intramyocardial tissue pressure, and the coronary venous pressure. Only the coronary arteries supplying the right ventricle have less pronounced systolic-diastolic phase shift in coronary blood flow. Myocardial extravascular compression of the coronary circulation is related most easily to intraventricular pressure [8]. Back or venular pressure in the coronary circulation is most likely reflected by the right atrial pressure. The pressure in the aorta, in the right atrium, and in the left ventricle (alternatively the pulmonary wedge pressure) should be determined simultaneously in each patient under study for clinical assessment of coronary flow reserve. Coronary vascular resistance is defined by the ratio of mean aortic pressure minus right arterial pressure to the coronary blood flow. The ratio of coronary vascular resistance at maximal coronary vasodilation to that at baseline provides a more precise approach to describe the regulatory range of coronary vascular bed, taking into account differences in aortic pressure as the major determinant of coronary blood flow [5]. The coronary vascular resistance is critically controlled at the level of the resistive vessels (\300 lm), provided no stenosis is present in the epicardial


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conduit arteries [9]. The tone of prearterioles and smaller arteries (100–300 lm in diameter) is largely controlled by flow, distending pressure, myogenic tone, autonomic nervous system, and endothelial function [10]. In the distal compartment of resistive vessels the tone of the arterioles (\100 lm) is critically dependent on myocardial metabolism. Coronary resistance coexists in different arteriolar compartments and its distribution may change along the coronary vascular tree [9].

Transmural gradient of coronary blood flow The vessels in the inner subendocardial layers of the myocardium are exposed to greater intramyocardial pressure than those in the outer layers. The gradient of intramyocardial pressure from endocardium to epicardium is the basis for a potential difference in transmural blood flow distribution. Under baseline conditions the subendocardium uses a greater fraction of its maximum coronary flow than does the subepicardium (endo:epi ratio 1.1:1.2). During maximal coronary dilatation (eg, reactive hyperemia following ischemia or infusion of adenosine) the endo:epi ratio may change with relative redistribution of blood volume from subendocardium to the subepicardium. In addition, the ratio of endo:epi maximum coronary blood flow is highly dependent on heart rate and falls to 0.4 at heart rates exceeding 200 per minute [8]. The most likely explanation for this observation is that systolic myocardial extravascular compression limits maximal coronary blood flow more in the subendocardium than in the subepicardium. Taken together, measures of total coronary vasodilator reserve do not necessarily reflect changes in transmural coronary vasodilator reserve. Interfering variables, such as changes in heart rate and the stimuli for induction of maximum coronary vasodilation (ischemia, atrial pacing, and pharmacologic approaches), have to be tightly controlled during measurement of coronary flow reserve [8].

Pathophysiology of coronary circulation in arterial hypertension In arterial hypertension a reduced conductance of coronary circulation may be caused by several factors: disturbance of the coronary macrocirculation (conductance vessels); disturbance of the microcirculation (resistive vessels); and extravascular myocardial alterations [11]. The following section focuses on hypertension-associated alterations of coronary microvasculature. Functional alterations of coronary microcirculation Disturbances of coronary microcirculation may lead to profound reduction of coronary flow reserve and severe angina in hypertensive patients,

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although flow-limiting stenoses of epicardial arteries are excluded [5]. In line with the concept that coronary endothelium is crucial for metabolic vasodilation in human coronary circulation [12] it has been shown that endothelial dysfunction of the coronary microvasculature is associated with exercise-induced myocardial ischemia. A reduced coronary flow reserve in hypertensive patients with and without left ventricular hypertrophy, but without flow-limiting coronary stenosis, has been demonstrated in response to dipyridamole [13], acetylcholine [14], papaverine [15], and ergonovine in combination with arterial pacing [16]. In addition, with increasing left ventricular mass the luminal concentration of noradrenaline in the coronary circulation of hypertensive patients increases [17]. Because noradrenaline directly constricts coronary smooth muscle and simultaneously stimulates release of dilatory nitric oxide from coronary endothelium, an imbalance of vasoconstriction and vasodilation signaling pathways may lead to hypertension-associated increase of tone of coronary resistive vessels with consecutive impairment of coronary flow reserve. Taken together, these findings imply that several functional signal transduction cascades of the coronary vascular wall are profoundly altered in arterial hypertension, that are involved in the reduction of coronary flow reserve, because of an elevated coronary vascular resistance either at rest or during maximal dilation. Structural alterations of the coronary microcirculation Hypertensive pressure overload of the left ventricle as of the coronary circulation implicates several consequences for the coronary circulation: (1) capillaries and myocytes are menaced to suffer damage, if perfusion pressure in this part of the coronary circulation is increased, by hyperperfusion and insudation of plasma proteins; (2) arterial and arteriolar vascular walls may be under increased wall stress; and (3) hypertrophy of myocytes leads to an increased distance between parallel orientated arterioles (relative rarefication). According to Folkow et al [18] vascular wall stress is normalized by an increase in wall thickness accompanied by a reduction in lumen size. A reduced lumen size of arterioles can normalize terminal perfusion pressure in the capillaries but is associated with an impaired vasodilator capacity merely by geometric reasons. The thickening of the wall of resistance vessels can be caused by an increase in the number or diameter of the single smooth muscle cell in the media leading to an increase in the cross-sectional area of the vessel wall (hypertrophy) or by a reorganization of smooth muscle cells without increased vascular wall area (remodeling) [19,20]. Furthermore, a constriction of smooth muscle cells in a thickened arteriolar wall leads to an even more pronounced reduction of the lumen than under the condition of a normal wall:lumen ratio [21]. A relative or absolute decrease in the number of resistance vessels per myocardial volume in the presence of chronic increased coronary perfusion pressure may lead also to a normalized


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terminal perfusion pressure. Otherwise, it has to be considered that a diminished number of parallel resistance vessels reduce vasodilator capacity. Quantitative stereologic investigations revealed a significant increase of the mean arteriolar wall area accompanied by an increase of perivascular fibrosis that was associated with an impaired coronary vasodilator reserve [22]. Extravascular myocardial alterations At the level of the coronary resistive vessels left ventricular hypertrophy as a complication of chronic hypertension is associated with a profound impairment of the lower range of coronary autoregulation. Using tracer microspheres techniques it has been shown in the canine hypertrophic heart that this abnormality of local control of myocardial perfusion preferentially affects the subendocardium and may predispose the hypertrophied myocardium to ischemia in the setting of either coronary stenoses or systemic hypotension [23]. In hypertensive patients with left ventricular hypertrophy, coronary flow progressively and linearly declines at a gradual reduction of coronary perfusion pressure below 90 mm Hg. In contrast, in hypertensive patients without left ventricular hypertrophy and in normotensive controls the autoregulatory range is maintained over a broad range down to perfusion pressures of 60 mm Hg [24]. In hypertensive patients with left ventricular hypertrophy and shifted autoregulatory pressureflow relationship downward fluctuations of diastolic pressure may become dangerous to the hypertrophied myocardium. Furthermore, wall stress, as a determinant of myocardial perfusion, increases in the natural course of hypertension, which leads to an impaired left ventricular function in the end stage of hypertensive heart disease. Taken together with the aforementioned finding of a reduced maximum flow in these hypertensive patients coronary flow reserve can be profoundly impaired in hypertensive heart disease.

Diagnostic methods and assessment of coronary reserve In a large cohort of hypertensive patients Cuspidi et al [2] showed that the routine work-up for hypertensive individuals consisting of medical history, physical examination, routine blood and urine analysis, and ECG may be too insensitive to detect patients belonging to the high global risk category. Additional diagnostic procedures seem mandatory. In principle, noninvasive and invasive methods are available to estimate coronary flow reserve in hypertensive heart disease. The invasive approaches provide exact measurements of coronary flow reserve and are preferable for primary diagnosis of impaired microcirculation. The noninvasive procedures are more suitable for screening and follow-up studies to assess impact of therapeutic interventions.

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Electrocardiographic tests The ECG stress test can be used to screen patients with negative maximal test because of its high negative predicting value. In hypertensive patients without significant epicardial stenosis, left ventricular hypertrophy is often found with ST-segment depression during exercise and appropriate antihypertensive therapy (eg, with angiotensin converting enzyme inhibitors) can induce regression of hypertrophy paralleled by reduction of ST-segment depression [25]. In case of positive, uninterpretable, or ambiguous ECG stress tests image stress test should be warranted. After the exclusion of stenoses in epicardial coronary arteries, ECG abnormalities with STsegment depression are interpreted as the result of microvascular disturbances. This is supported by the observation that hypertensive patients exhibiting episodes of ST depression during ambulatory monitoring had significantly impaired coronary flow reserve when compared with both normotensive subjects and hypertensive patients without episodes of ST depression [26]. Left ventricular mass was not the important determinant of coronary flow reserve, a finding consistent with a previous report [16]. ECG investigations give some hints on hypertensive perfusion abnormalities and can be regarded as a monitoring and screening method. Myocardial scintigraphy Abnormal thallium 201 scintigraphic findings were reported in hypertensive patients without coronary artery disease but with an impaired coronary reserve of 2.2 0.8 [27] and 2.71 0.96 [28] as compared with hypertensive patients without reversible defects who had a coronary reserve of 3.5 1.2 and 3.7 0.8. Nevertheless, quantitative data cannot be derived from these methods and from pharmacologic and radiotracer characteristics, like cellular uptake (thallium 201, K+ analogon), long half-life, high radiation dose, limit this approach for the evaluation of coronary microcirculation. Thus a global reduction of coronary vasodilator capacity is difficult to quantify by a scintigraphic approach. Furthermore, homogenously reduced coronary vasodilator capacity might be difficult to be disclosed because of missing normal reference volume. Perfusion scintigraphy has a high accuracy in unselected hypertensive patients, but becomes low in hypertensive patients with exercise-induced ST-segment depression [29]. Because of its low specifity in these cases, myocardial perfusion scintigraphy should be replaced by stress echocardiography [30]. Echocardiography Contrast echocardiography combined with intracoronary or intra-aortic root injection of ultrasound contrast medium that passes through capillaries has been used to identify a region of defected myocardial contrast.


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The qualitative discrimination of perfusion defects has to be differentiated from the evaluation of quantitative perfusion analysis, which is still problematic for clinical use because of different scanning conditions, poor transthoracic ultrasound window, and insufficient enhancement of the myocardial intensity [31]. Transesophageal Doppler echocardiography can image the proximal segments of the left coronary artery. With a pulsed-wave Doppler sample volume, positioned on the diastolic flow of the left anterior descending coronary artery, coronary flow can be derived from flow velocity and internal coronary artery diameter [32]. Flow velocity was measured before and after intravenous administration of dipyridamole in hypertensive patients and was found to be impaired as compared with controls. Furthermore, calculated coronary resistance was increased [33]. This method is not expensive, relatively easy to repeat in ambulatory patients, and less risky than cardiac catheterization. It has to be taken into consideration that approximately 20% to 30% of the patients cannot be investigated by Doppler because of respiration, acute changes in cardiac volume, or inadequately stable position of the Doppler signal, giving lower velocities than the true value because of the angle between the ultrasound beam and vessel direction. Perfusion scintigraphy has a high accuracy in unselected hypertensive patients, but becomes low in hypertensive patients with exercise-induced ST-segment depression [29]. Because of its low specifity in these cases, myocardial perfusion scintigraphy should be replaced by stress echocardiography [30]. Positron emission tomography The positron emission tomography provides a noninvasive technique for regional myocardial flow measurement. Positron emission tomography allows quantitative flow measurements in segments containing less than 10 g of myocardium. Furthermore, myocardial metabolism can be evaluated, which gives the opportunity to match between myocardial flow and metabolism [34]. Tracers have been used, such as rubidium 82, gallium 68, carbon 11, ammonia N 13, or water O 15, to measure perfusion on a single passage, not influencing myocardial metabolism [35]. Regional coronary resistance may also be calculated from mean arterial blood pressure and coronary blood flow. The detection of viable myocardium is possible with fluorodeoxyglucose F 18, allowing comparing myocardial blood flow and metabolism. The short half-life of tracers is the basis for acute pharmacologic interventions to evaluate coronary reserve. Impaired coronary reserve has been found in several studies in hypertensive heart disease [34,36]. Reproducibility is high, with little intraobserver and interobserver variability. This makes positron emission tomography interesting for the follow-up of therapeutic interventions. Positron emission tomography has been shown to be useful for long-term follow-up of antihypertensive therapy [37].

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Nevertheless, the method is limited by the high technical and methodologic expenditure. It has to be taken into account that transmural coronary blood flow distribution cannot be evaluated because of limited spatial resolution and regional motion abnormalities of the heart.

MRI MRI has proved useful for images with excellent spatial resolution and without ionizing radiation. Combined anatomic and functional evaluation of the heart, including the evaluation of myocardial perfusion, is a promising aspect of this method, especially for serial investigations. Gadolinium chelates, which rapidly diffuse out of vascular space, are used to distinguish between normal and pathologically perfused myocardium [38]. Development of new blood pool contrast agents and the improvement of hardware and pulse sequences may give results for a clinically useful diagnostic acceptance of MRI. With respect to the significance of coronary insufficiency (with absent atherosclerosis) in patients with arterial hypertension (HT) it will be exciting to follow the progress in noninvasive approaches to detect coronary flow reserve and microvascular dysfunction (positron emission tomography, MRI, transthoracic Doppler indices) [39,40].

Coronary sinus catheterization Thermodilution in the coronary sinus, invented by Ganz et al [41], is an inexpensive, widely available technique for the measurement of coronary flow requiring only right heart catheterization. Coronary sinus blood flow is mainly provided by the left ventricular myocardial blood flow, although considerable variations in anatomy may occur [42,43]. The thermodilution method does not define the mass of myocardium being drained. This may become a relevant issue when comparing flow reserve in hypertensive patients with and without left ventricular hypertrophy because absolute values for autoregulated flow in coronary sinus rise with increasing left ventricular mass. In human coronary circulation the coronary flow reserve measured with the thermodilution method is consistently and substantially smaller than Doppler-derived measurements [44]. Furthermore, the reasonable time solution of coronary flow measurement is accompanied by failing spatial resolution. Coronary venous oxymetry, based on the Fick principle, is an indirect method that gives a continuous measurement of coronary blood flow. As coronary flow increases at maximum vasodilation the oxygen saturation in the coronary sinus increases. Some severe limitations of this method, however, have to be addressed. Right atrial reflux into the coronary sinus may affect measurement [45]. Coronary sinus oxygen saturation at baseline is not related to autoregulated coronary blood flow [46]. In addition, with


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increasing oxygen saturation at baseline the relative increase in oxygen saturation at maximum vasodilation is impaired and systematically underestimates coronary flow reserve [46]. In contrast, the gas chromatographic argon method allows exact measurement of coronary blood flow at baseline and during maximum vasodilation [11,47]. The principle of this gas clearance method is the gas chromatographic determination of argon in blood samples taken simultaneously from the coronary sinus and the aorta while the patient is breathing a mixture of oxygen (21%) and the inert gas argon (79%) for at least 5 minutes [48]. According to the formula of Kety flow data are given in mL/ min/100g, which allows direct comparison of hypertensive patients with different degree of left ventricular hypertrophy. The equipment required is simple and inexpensive and the method is safe. The spatial solution of blood flow measurement in the left ventricle is marginal and the time solution of measurement is limited, however, because a period for desaturation of administered argon gas has to be considered for each single intervention, so that only a few measurements can be performed within a single cardiac catheterization. This method is most suitable for patients in whom significant coronary stenosis has been excluded, to diagnose coronary microangiopathy and to dissect the impact of an altered resting and maximum coronary flow on reduced coronary flow reserve. In addition, the good reproducibility of this method with a low variation coefficient offers the possibility to assess the impact of therapeutic interventions (eg, antihypertensive long-term treatment in patients with arterial hypertension) on coronary flow reserve, provided possible differences in heart rate and blood pressure are controlled during follow-up catheterization. The clinical indication for the argon gas method refers to patients with hypertensive coronary microangiopathy, the detection of vascular involvement in patients with myocarditis, dilative and hypertrophic cardiomyopathy, and the evaluation of coronary microcirculation in the clinical course of long-term treatment of these diseases. Angiographic methods Angiographic methods for estimating myocardial perfusion have been reviewed recently [49]. In general these methods are based either on videodensitometry or quantification of the mean transit time for a bolus of contrast medium injected into coronary arteries. Because of the rapid development of computer software and hardware several suppliers offer packages for on-line analysis of myocardial perfusion reserve in catheterization laboratories, based on algorithms for videodensitometry evaluated recently [50]. The principle of this approach is to compare two digital subtraction angiographic images in a myocardial region of interest, obtained at baseline and during maximal vasodilation. As a prerequisite contrast medium must be injected automatically with a high pressure pump to keep

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volume and rate of injection reproducible and start of injection should be gated electrocardiographically to avoid heart cycle-dependent variations in coronary blood flow. Several problems with videodensitometric methods have to be addressed: (1) the possibility that contrast medium might affect coronary vasomotion and measurement of myocardial perfusion reserve; (2) the mistake because (blood) volume replacement during injection of contrast medium might differ at baseline and during maximum vasodilation given a constant injection rate; (3) to allow precise subtraction of digital frames the patient has to hold their breath at exactly the same position during injection of contrast medium; (4) substantial overlap of distinct myocardial regions with different systolic and diastolic regional function (normokinetic, hypokinetic, dyskinetic) may hamper exact analysis of regional myocardial perfusion reserve; (5) data can be given only as a relative ratio of resting to hyperemic myocardial perfusion. This approach, however, allows easy and simultaneous analysis of vasomotion in epicardial arteries and resistive vessels during routine coronary angiography. Taking into consideration the aforementioned obstacles these angiographic methods should be restricted to patients with preserved left ventricular function, without coronary stenosis, or only in those patients with coronary artery disease with a singlevessel disease, and not multivessel disease. An alternative angiographic approach to estimate myocardial perfusion is the measurement of mean transit times of a given bolus of contrast medium [51]. Very recently, a fairly easy to handle approach was invented by the TIMI 4 Study Group [52] aimed to be applicable in each catheterization laboratory: the TIMI frame count as quantitative measure of assessing coronary flow. The principle of the TIMI frame-counting method is to count off-line the cineframes required for a manually injected bolus of contrast medium to first reach standardized landmarks in the coronary artery at a given frame rate of angiograms during routine coronary angiography. Comparison with Doppler-guided assessment of coronary flow in patients with coronary artery disease [46,52] and with argon gas chromatographic method in hypertensive patients with coronary microangiopathy revealed that the frame count method yields reasonable estimates of coronary flow at low values (eg, for baseline flow) but by far underestimates maximum coronary blood flow with an unacceptable variation. Guidewire-based methods Intracoronary flow velocity can be measured with a steerable angioplasty guidewire with a piezoelectric ultrasound transducer integrated into the tip and coupled to a real-time spectrum analyzer [53]. Coronary flow reserve is computed as the ratio of the Doppler signal at maximum to baseline coronary blood flow velocity. More recent developments integrated the ultrasound transducer into a Judkins-style angiographic catheter to avoid


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the intracoronary use of guidewires [53]. The variation of coronary vasodilator reserve among the coronary branch arteries is less than 10%. The spatial and regional solution of Doppler measurement is excellent and allows assessing rapid changes in phasic and mean coronary flow. Doppler measurement of coronary flow reserve has been validated extensively in experimental studies [54], and in patients in comparison with exercise testing [55], positron emission tomography [56], and thallium scintigraphy [57]. In combination with either intravascular ultrasound or coronary angiography Doppler measurement allows one to calculate volumetric coronary flow with reasonable validity, and additionally this approach allows one simultaneously to assess coronary vasomotor function at the level of coronary conduit and resistive arteries [58]. Accuracy of volumetric flow measurement may be hampered by variation of the tip of the flow wire within the bloodstream. An impaired hyperemic flow velocity reserve less than 2 corresponded to reversible myocardial ischemia with high sensitivity and specificity (86% to 100%) [59]. A major limitation of this technique is instrumentation of the coronary artery with an angioplasty guidewire, which requires considerable operator experience. In more than 45,000 worldwide applications, however, less than 20 cases of complication have been reported in association with sensor-tipped guidewires [59]. Alternative techniques Apart from routine cardiac [3,4] and vascular ultrasonography [2] risk stratification may also be complemented by measurement of microalbuminuria with redefined thresholds [60,61] and peripheral artery endothelial function, recently shown to reflect the severity of disturbed circadian patterns of blood pressure [62]. The implementation of routine measurements [63] of carotid intima-media-thickness [2], peripheral vascular compliance, and endothelial dysfunction, however, depends on more reliable and effective methods making the accuracy and reproducibility more applicable for clinical routine [64].

Summary Taken together, the diagnostic algorithm is leaded by a simple ECG stress test. In case of ST-segment depression the preferred image test should be stress ECG to bring patients at high risk for significant epicardial coronary artery stenosis to coronary angiography (and revascularization). In case of the lack of wall motion abnormalities (during stress-echo test) or absence of epicardial stenosis one may further assess coronary flow reserve with noninvasive Doppler harmonic echocardiography. For ultimate quantitative assessment invasive procedures, such as argon dilution or intracoronary Doppler techniques, represent the appropriate approach [65].

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Med Clin N Am 88 (2004) 115–130

Cardiac remodeling in systemic hypertension Satish Kenchaiah, MD, MPHa,b,*, Marc A. Pfeffer, MD, PhDa,c a

Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA b Boston University School of Medicine, Boston, MA, USA c Partners Healthcare System, Boston, MA, USA

The cardiac chambers adapt in configuration and mass to the external work requirements. In utero right and left ventricular size and configuration are relatively similar. With an infant’s first breath dramatic changes in pulmonary and systemic vascular resistances occur so that the workload of the right ventricle becomes proportionally lower than that of the left ventricle. After birth, the proportional growth of the left ventricle exceeds the right in concert with their respective evolving hemodynamic patterns. The differential growth pattern of these chambers reflects the adaptive biologic hypertrophic response that continues to match structure to workload. So too across various species of adult animals a close relationship exists between cardiac chamber weight and stroke work [1]. These relationships between organ size and function underscore one of the basic biologic compensatory properties: inherent ability to increase or decrease mass (hypertrophy or atrophy) and to alter tissue configuration in direct relationship to functional requirements.

Historical perspective Pathologic associations, such as shrunken kidneys with heavy hearts, in subjects with ‘‘hardened arteries’’ are generally attributed to Bright [2].

Dr. Pfeffer receives honoraria or educational or research grants, or serves as a consultant for Astra Zeneca, Bristol-Myers Squibb, Mitsubishi, Novartis, and Pfizer. The Brigham and Women’s Hospital has been awarded patents regarding the use of inhibitors of the reninangiotensin system in selected survivors of myocardial infarction. Dr. Pfeffer is among the coinventors. The licensing agreements with Novartis and Abbott are not linked to sales. * Corresponding author. E-mail address: [email protected] (S. Kenchaiah). 0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/S0025-7125(03)00168-8

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It was Johnson [3], however, who apparently first associated elevated blood pressure (BP) with left ventricular hypertrophy (LVH). The ability of the heart to respond to elevated BP by augmenting ventricular mass was reported over 70 years ago in an animal model of hypertension produced by renal ischemia [4]. Chanutin and Barksdale [5] demonstrated a clear relationship between the height of the BP elevation and the increase in the heart weight to body surface area with the production of experimental hypertension. Moreover, they demonstrated that the weight of the heart was increased as a consequence of increased myocyte fiber diameter, a clear indication of hypertrophy rather than hyperplasia. Hypertension and left atrial remodeling Although the effect of hypertension on the left ventricle is well studied, that on the left atrium (LA) is less well defined. Electrocardiographic (ECG) or echocardiographic LA enlargement occurs commonly in hypertensive patients [6–10]. In one study 21% of hypertensive patients without ECG evidence of LVH had LA enlargement of greater than 4 cm [11]. In subjects with ECG LVH, the prevalence of LA enlargement is higher (56% in women and 38% in men) [10]. In older patients with isolated systolic hypertension, echocardiographic LA size is associated with systolic BP [9]. In the general population, LA enlargement is associated both with the duration of elevated BP and with the level of systolic BP [12]. LA size is significantly related to left ventricular (LV) mass and eccentric LVH [10], and the extent of atrial enlargement correlates with the degree of hypertension [10–15]. Also, LA enlargement may be an early adaptation to elevated BP that may occur before any evidence of LVH or atrial arrhythmia [8,16]. In several studies, LA enlargement has been found to be associated with an increased risk of atrial fibrillation and stroke [15,17–21]. Among 4731 participants of the Framingham study who underwent baseline echocardiography, after adjustment for established risk factors for atrial fibrillation, every 5-mm increment in LA size was associated with a 39% increase in the risk of atrial fibrillation [15]. Tsang et al [21] have reported that 30% increase in LA volume, measured echocardiographically using a biplane area-length method, was associated with a 43% increased risk of atrial fibrillation, and that LA volume was a more sensitive marker for this risk than conventional LA diameter [21]. The mechanisms by which hypertension might cause changes in LA size and function are speculative. LA enlargement in hypertensive patients may be secondary to LVH [12] or caused by changes in LV function. It may be the result of elevated LV filling pressures [22] and impairment of LV diastolic function [10,23–26]. In a small study of hypertensive patients, quinapril therapy was associated with a decrease in LA dimension with normalization of BP [27].


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Hypertension and left ventricular remodeling Systemic hypertension imparts a chronic augmentation of workload on the left ventricle and is the most common reason for LVH [28]. This structural change can be diagnosed in vivo either by ECG or by echocardiography [29,30]. Major ECG changes suggestive of LVH include increased amplitude; widening and notching of the QRS complex; left axis deviation; repolarization (ST-T wave) changes; and LA abnormality [31]. Although the specificities of various ECG criteria for the diagnosis of LVH, such as Sokolow-Lyon, Romhilt-Estes, and Cornell voltage criteria, are generally high (over 90%), their sensitivities are moderate or low, ranging from 7% to 60% [32,33]. The sensitivity of the ECG criteria is influenced by biologic factors (decreased by obesity and cigarette smoking, and increased by age and severity of LVH) and methodologic factors (increased when LV mass was indexed to body surface area instead of height) [32,33]. In the past 20 years quantitative echocardiography has been proven to be a more reliable and precise measure of chamber mass, wall thickness, and configuration providing a reproducible tool for noninvasive assessments of ventricular architecture. In a recent study from Framingham, whereas 19% of men and 24% of women satisfied the echocardiographic criteria for LVH, only 1.3% of the subjects had definite LVH by ECG criteria [34].

Mechanisms of left ventricular hypertrophy in hypertension The causal association between hypertension and the development of LVH is well established in laboratory and epidemiologic studies. Based on a 30-year follow-up data from the Framingham Heart Study, as compared with normotensive subjects, those with definite hypertension (BP 160/95 mm Hg) had a 10-fold increase in the incidence of ECG LVH [35]. Echocardiographic LVH has been reported in children and adolescents with borderline elevations in BP [36], and in subjects who have exaggerated transient elevations in BP during mental stress, job strain, or exercise [37–39]. Further, higher average ambulatory daytime BP, and absence of nocturnal fall in BP, may contribute to the increased risk of LVH [40,41]. The development of LVH is influenced by hemodynamic factors, such as increased wall stress, and nonhemodynamic factors, such as altered genotypes [42–45], myocytes [46], matrix [47], apoptosis [48], vasculature, neurohormones [49–52], and cytokines (Fig. 1). The development of myocardial hypertrophy in relation to external work load and duration of hypertension and its transition from compensated hypertrophy to functional decompensation is schematically represented in Fig. 2. There is evidence that elevated LV mass may precede the development of overt hypertension [53–56]. In the large Framingham cohort, after accounting for factors such as age, sex, body mass index, alcohol consumption, and systolic and diastolic BP, the risk of hypertension during

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Fig. 1. Mechanisms of cardiac remodeling in hypertension.

follow-up increased by 20% per increment of 26.5 g/m in LV mass index, and by 16% for every 2.5-mm increase in LV wall thickness [56]. Plausible explanations for these findings include the following: (1) increased LV mass in preclinical stages of hypertension may elevate BP because of increased contractile force; (2) LV mass is a better integrator of elevated BP than the dichotomous categorization (above and below a threshold value) of BP measurements recorded at one point in time; (3) there may be common nonhemodynamic factors, such as neurohormonal stimulation (angiotensin II, norepinephrine, epinephrine) [50–52], increased peripheral sympathetic drive [57], and endothelin [49], which may promote both hypertension and

Fig. 2. Schematic representation of the development of myocardial hypertrophy in relation to external workload and duration of hypertension, and its transition from compensated hypertrophy to functional decompensation.


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LVH; and (4) genetic factors may predispose to the development of both hypertension [58] and cardiac hypertrophy [59–64]. Prognostic significance of left ventricular hypertrophy Regardless of the methods (electrocardiographic or echocardiographic) used to detect LVH, its presence portends a poor prognosis. Although insensitive as a measure of mass, ECG LVH is associated with an increased risk of coronary heart disease [65], heart failure [66,67], ventricular arrhythmias [68–72], sudden death [73,74], peripheral arterial disease [75], and cerebrovascular disease [76]. The increase in cardiac risk seems to be highest in those patients in whom the ECG reveals ST segment and T wave changes indicative of a strain or ischemic pattern [77]. Echocardiographic LVH has been shown to be a risk factor for cardiovascular disease (composite of coronary heart disease, heart failure, stroke, transient ischemic attack, and intermittent claudication) [78], coronary heart disease [79], cardiovascular morbidity [80,81], ventricular arrhythmias [82–85], stroke [76,86], sudden cardiac death [87], cardiovascular death [78,81], and all-cause mortality [78,81,88]. Echocardiographic LVH is more prevalent and more sensitive for ventricular arrhythmias than ECG LVH [89]. Hypertensive patients with echocardiographically proven LVH who also meet ECG criteria have a greater LV mass than those without the expected ECG changes [90]. Mechanisms for increased risk The exact mechanism by which enlarged LV muscle mass increases the risk of adverse cardiovascular events is not known. LVH may increase myocardial oxygen consumption but with concomitant decrease in coronary flow reserve because of such factors as coexistence of subclinical coronary artery disease, reduced density of capillaries, direct compression of the endocardial capillaries, and limitation of the ability of the coronary arteries to dilate in response to decreased perfusion or during vasodilatory stress [77,91–94]. Electrophysiologic abnormalities, action potential prolongation, easily provocable early afterpotentials, altered repolarization, and excessive stretching of myocardial fibers because of increased systolic wall stress or diastolic distention may potentiate development of ventricular arrhythmias and sudden death [95–100]. Increased apoptosis or cardiac cell death has been demonstrated in hypertrophied myocardium [101]. Progressive systolic or diastolic dysfunction manifests as overt heart failure (see Figs. 1 and 2). Regression of left ventricular hypertrophy Animal studies In animal models of hypertension, the regression of LVH depends on the methods used to induce hypertension and the means employed to reduce the

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elevated BP [102]. When hypertension and cardiac hypertrophy is induced by mechanical means, such as aortic banding or clipping of renal artery, removal of the inciting stimulus causes a return of BP to baseline values and regression of LVH to near normal levels. In genetic hypertension models where antihypertensive agents are used to lower BP, despite equal efficacy in lowering BP, LVH may decrease (methyldopa [103], guanethidine, and angiotensin-converting enzyme [ACE] inhibitors); increase (minoxidil [104]); or remain unaffected (hydralazine) [102]. Human studies Several studies in humans have shown that adequate and aggressive BP control in hypertensive patients can prevent the development of LVH and reverse it when already present. In controlled trials, such strategies as weight loss, or dietary sodium restriction, and antihypertensive therapy aimed at lowering BP have been found to decrease cardiac mass in patients with LVH [29,105–108]. In Therapy in the Treatment of Mild Hypertension Study (TOMHS), where all 844 participants received nutrition-hygienic intervention (aimed at weight loss, lowering of sodium and alcohol intake, and increasing physical activity), the mean reduction in LV mass was 24 g in the active therapy group (receiving various class of antihypertensives as monotherapy) and 18 g in the placebo group [109]. The decline in LV mass with antihypertensive therapy varies with the type of therapy used. In the TOMHS study, nutritional-hygienic therapy alone was found to be equally effective as nutritional-hygienic therapy combined with various classes of pharmacologic agents (diuretic, b-blocker, a-antagonist, calcium channel blocker, and ACE inhibitor) in reducing LV mass. In the Department of Veterans Affairs Cooperative Study evaluating the effects of monotherapy on LV mass at 1 year, however, reduction of LV mass occurred in patients on captopril, hydrochlorothiazide, and atenolol but not in those on diltiazem, clonidine, or prazosin [110]. In several small studies, after 8 to 12 months of antihypertensive therapy, LV mass has been found to decline by 8 to 19 g with b-blockers, 26 to 45 g with ACE inhibitors, and 40 to 52 g with angiotensin I receptor blockers [111]. In the Losartan Intervention for Endpoint reduction (LIFE) trial, which compared losartan with atenolol in hypertensive patients with ECG evidence of LVH, regression of LVH occurred in 77% of patients [112], and the degree of regression, using ECG criteria, was approximately twice as great at 1 year with losartan than with atenolol [113]. In an updated meta-analysis of 80 double-blind, randomized, controlled clinical trials (up to September 2002) involving over 4000 patients evaluating the efficacy of various classes of antihypertensive agents on change in LV mass, the reduction in LV mass index was 10% to 13% with the use of angiotensin II receptor blockers, calcium channel blockers, or ACE inhibitors, and 6% to 8% with the use of diuretics, and b-blockers. Further, angiotensin II receptor blockers, calcium channel blockers, and ACE inhibitors were more effective at reducing LV


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mass than b-blockers. In comparison, regression is largely absent with direct vasodilators (eg, hydralazine or minoxidil) and with some calcium channel blockers despite adequate BP control [107,114,115]. The ineffectiveness of these drugs is probably explained by the reflex stimulation of hormones, such as norepinephrine and angiotensin II, which may directly promote the development of LVH [50,115]. In the recent PRESERVE (prospective randomized enalapril study evaluating regression of ventricular enlargement) trial, however, the largest prospective randomized trial, conducted on 303 ethnically diverse, hypertensive patients with LVH at baseline, enalapril therapy and long-acting nifedipine was associated with a similar reduction in BP and LV mass [116]. The time course in the regression of LVH seems to vary with the nature of the population studied. Whereas in the 844 mildly hypertensive patients of the TOMHS study the LVH regression occurred within 3 months and was maintained thereafter up to 4 years of follow-up [109], in the 754 moderately severe hypertensive participants of the LIFE study, all of whom had ECG evidence of LVH indicative of increased severity of LVH, a progressive decline in LV mass was noted over 2 years of follow-up: 27 g at 1 year with an additional decline of 11 g in the second year of therapy [111]. Regression of left ventricular hypertrophy and improvement in outcomes Regression of LVH induced by antihypertensive therapy is associated with improved LV systolic performance [117] and diastolic filling [112], enhanced stroke volume [117], reduced risk of premature ventricular beats, and decreased vulnerability to inducible ventricular fibrillation [118], without concomitant adverse effect on myocardial perfusion [119]. In over 500 subjects of the Framingham Heart Study who had ECG evidence of LVH, those with a serial decline in voltage had a 46% to 56% lower risk, whereas those with serial increase in voltage had a 61% to 86% greater risk for cardiovascular disease [120]. In the 430 hypertensive subjects from the Progetto Ipertensione Umbria Monitoraggio Ambulatorie (PIUMA) registry in Italy, a 54% decline in the risk of adverse cardiovascular events occurred in those who had a decrease in LV mass as compared with those who had an increase in LV mass [121]. In the Heart Outcomes Prevention Evaluation (HOPE) study, as compared with subjects with development and persistence of LVH, those with regression and prevention of LVH had a decreased incidence of cardiovascular death (3.4% versus 5.7%); myocardial infarction (8.7% versus 10.9%); heart failure (9.3% versus 15.4%); all-cause death (5.4% versus 8.9%); sudden death or cardiac arrest (1.9% versus 3.8%); and possibly stroke (3.5% versus 4.7%) [122]. Hypertension and myocardial fibrosis Although LVH is primarily caused by an increase in myocytes [123], in animal models of hypertension [124–127] and in humans [128–131]

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perivascular and interstitial myocardial fibrosis occurs and is a major determinant of myocardial stiffness and diastolic dysfunction [125–127,132]. Increased collagen synthesis and decreased collagen degradation have been proposed as the possible mechanisms for myocardial fibrosis [125,127, 133,134]. Disproportionate accumulation of nonmyocyte cells unrelated to myocyte growth or necrosis represents reactive fibrosis, and plays a major role in pathologic remodeling [135]. In experimental models, antihypertensive agents, such as ACE inhibitors [136–140], angiotensin receptor blockers [141,142], calcium antagonists [140,143–145], and aldosterone antagonists [146], have been found to prevent or regress myocardial fibrosis, whereas other antihypertensives, such as minoxidil [147], alpha methyldopa [148], hydrochlorothiazide [149], and hydralazine [141,150], have not been associated with regression of myocardial fibrosis. In small studies conducted on human subjects with hypertensive heart disease, ACE inhibition [151] and angiotensin receptor blockade [152] have been reported to regress myocardial fibrosis and improve LV diastolic function.

Summary Experimental and clinical studies provide evidence that hypertension is causally related to adverse cardiac structural changes, such as LA enlargement, LV hypertrophy and myocardial fibrosis, and functional changes inclusive of LV systolic and diastolic dysfunction. These changes are induced by both hemodynamic and nonhemodynamic factors. There is accumulating evidence from several small and large clinical trials that various classes of antihypertensive therapy prevent and regress LVH and myocardial fibrosis. Prevention and reversal of LVH are associated with an improvement in cardiac function and with a decline in risk of adverse cardiovascular outcomes. Prevention of LVH should be a priority in subjects with hypertension. In patients with hypertensive heart disease, the components of therapy must comprise optimization of BP and regression of LVH. Future targets of therapy in hypertensive heart disease may include regression of myocardial fibrosis, normalization of LA size, and improvement in LV diastolic function. References [1] Holt JP, Rhode EA, Kines H. Ventricular volumes and body weight in mammals. Am J Physiol 1968;215:704–15. [2] Bright R. Tubular view of the morbid appearances in 100 cases connected with albimunious urine: with observations. Guys Hosp Rep 1936;1:380–400. [3] Johnson S. On certain points in the anatomy and pathology of Bright’s diseases of kidney, II; on the influence of the minute blood-vessels upon the circulation. Med Chir Trans 1868;51:57–80.


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Med Clin N Am 88 (2004) 131–140

Renal function in the patient with hypertension Norman Kenneth Hollenberg, MD, PhD Departments of Radiology and Medicine, Brigham and Women’s Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA

Evaluation of kidney function in a patient with hypertension has several purposes [1]. The first involves ascertaining whether or not the patient has nephropathy as the cause of the hypertension. The second, should nephropathy be present, is to define its nature and activity. The third involves assessment of the degree of alteration of kidney function to permit accurate assessment of its management and course. The diagnosis of renal disease is usually obtained through urinalysis; assessment of kidney function (specifically, an index of glomerular filtration rate [GFR]); radiologic examination; occasionally renal biopsy; and assessment of special renal functions in specific patients. Rather than provide a brief summary of current monographs on the kidney, it is indicated when the reader should consult a nephrologist. Typically, the minimum amount of information available should include the findings of urinalysis, measurement of serum creatinine, urea nitrogen, and electrolyte concentration in serum. Although standard textbooks of medicine outline the interpretation of the findings, they rarely review situations in which one can be led astray. In the case of urinalysis, for example, examination of the collected urine should be performed as quickly as possible, preferably within 2 hours. Particularly, the formed elements in the urinalysis, cells, and casts are lost if the urine is allowed to stand around. More than one case of nephritis has been missed or the diagnosis delayed by ignoring this fact. Proteinuria provides compelling evidence of kidney involvement. Normally urine contains a small amount of protein originating either from plasma proteins as serum albumin, or from tubular cells as the mucoprotein of Tamm-Horsfall. Additional sources of proteinuria come from the urinary

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tract epithelium or adjacent glands, such as the prostate. Physiologic proteinuria averages less than 30 mg per day, although there is still debate on the optimal cutoff point. An important contributor to protein concentration in urine is the latter’s tonicity. In highly concentrated urine, the patient being dehydrated, a physiologic level of proteinuria may reach 10 to 20 mg/100 mL and become detectible by routine clinical methods. Conversely, if the sample is very dilute because of a water diuresis, an abnormal proteinuria level may not be detected by the usual method. As discussed later, one approach to solving this problem involves normalizing the protein excretion to creatinine excretion. Because the amount of protein loss varies from one sample to another during any 24-hour interval, the optimal assessment of proteinuria involves collection of a 24-hour urine sample. The next best choice, where this is difficult, involves collecting the overnight urine as the first void in the morning and analyzing the proteinuria data as a function of urinary creatinine. Microalbuminuria represents a concentration or quantity of albumin in the urine that is too low to be detected by dipstick or routine measurements of urinary protein. Identification and quantification of microalbuminuria depends on the application of much more sensitive tests, such as radioimmunoassay. Because there is so much information inherent in the identification of microalbuminuria, not only in the individual’s risk of renal disease but also of cardiovascular events [1,2], many advisory groups recommend strongly that the assay be made annually in patients at high risk, especially patients with diabetes mellitus or more than minor hypertension. Commercially available dipsticks provide a convenient and inexpensive screening method, but a definitive identification of microalbuminuria requires collection of urine and chemical measurement of microalbumin levels along with a measure of urinary creatinine. Rigorous assessment involves identification of significant levels of microalbuminuria in two of the three sequential collections. Although criteria vary from laboratory to laboratory, typically significant microalbumin levels are 30 to 300 mg per 24 hours. The reason that advisory groups are so aggressive in their recommendations that the measurement be made involves the fact that effective treatment is available. Blockade of the renin-angiotensin system clearly can change natural history very dramatically in the patient with microalbuminuria [3–5]. In the IDNT Trial, for example, performed in patients with type 2 diabetes mellitus and microalbuminuria, a 300 mg per day dose of irbesartan led to a 70% reduction in the rate at which microalbuminuria evolved to frank nephropathy [3]. No studies on blockade of the renin-angiotensin system have shown this large a treatment effect. Renal excretory function is a synonym for GFR [6]. Inulin is a polysaccharide that was not penetrate into cells, is not bound to plasma proteins, is totally ultrafilterable, and is not transported by tubular cells. Its clearance from plasma corresponds to GFR. Measurement of inulin clearance is far too cumbersome and expensive for routine clinical use.


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That function is subserved fairly closely by creatinine, both by measurement of the concentration in serum and the clearance by the kidney. Creatinine is a product of muscle metabolism, is totally ultrafiltrable by the glomerulus but, in addition, is secreted by tubular cells. When performed well, the measure of creatinine clearance provides a very good index of GFR but is prone to error because of inadequacies of collection. Serum creatinine has provided the most widely used index. The serum creatinine level, however, is affected by factors other than GFR making it ineffective in detecting earlier stages of chronic kidney disease [6,7]. Unfortunately, serum creatinine provides a relatively insensitive measure for early renal insufficiency. In one study, only 76 of 125 patients in whom GFR was reduced showed an increase in serum creatinine concentration. In the remainder serum creatinine concentration was normal or even low [8]. If the goal is to establish appropriate treatment early, then the insensitivity of serum creatinine as a measure of GFR is a serious issue. The major determinants of GFR in normal people include their age, body weight, muscle mass, and gender. The Cockroft-Gault formula estimates glomerular function in relation to these variables providing an improved measure of glomerular function, especially when serum creatinine is still in the normal range. For this reason it has been recommended by the American Diabetes association. The equations of Cockroft and Gault differ slightly in men and women. Men: Clearance ¼

ð140 ageÞ weight ðplasma creatinine 72Þ

Women: Clearance ¼

ð140 ageÞ weight ðplasma creatinine 85Þ

Alternative analytic approaches to adjusting serum creatinine for confounding factors have been used more recently [9]. Unfortunately, few laboratories report the results of this analysis when they report serum creatinine concentration. In view of the fact that all clinicians now receive reports by a computer, a computer program to add this information is invaluable, and is offered as a routine service in many centers. As an alternative to costly methods for estimating GFR based on exogenous markers, such as inulin or chromium–ethylenediaminetetraacetic acid (EDTA), cystatin-C has been proposed as an alternative marker for GFR [10]. Cystatin-C is a nonglycosylated protein belonging to the superfamily of cysteine protease inhibitors. The production of cysteine-C is not related to lean muscle mass, does not have a circadian rhythm, and is not altered by inflammatory conditions. Its rate of production seems to be constant. For all of these reasons, it provides an attractive alternative to serum creatinine measurement. Because its concentration in serum is almost totally dependent on GFR, it provides an excellent endogenous marker. Its attractiveness lies in the claim that it may be particularly valuable in patients

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with normal or slightly reduced GFR. Nonetheless, there still remain discrepancies between studies comparing cystatin-C with plasma creatinine by the Cockroft-Gault formula and isotopic measure of GFR in patients at risk, especially with diabetes. In view of the fact that clinicians are not likely to abandon serum creatinine concentration and mathematic approaches to estimation of GFR from that measurement what one really wishes to know is the incremental value of adding cystatin-C measurements to the Cockroft-Gault formula rather than used alone.

Renal involvement in the patient with hypertension The source of the first clue concerning renal involvement varies with the clinical condition involved. In the patient with intrinsic parenchymal renal disease, such as one of the glomerulonephritities, the first clue comes from the urinalysis where red cells, casts, and proteinuria indicate renal involvement often in the absence of any clue from medical history or the physical examination. In the patient with diabetes mellitus or apparently isolated hypertension, proteinuria and early on microalbuminuria often provide the first clue of renal involvement. In the patient with renovascular hypertension the first clue often comes from history and physical examination. The prominent historical feature is an unusual age of onset of hypertension, either below the age of 30 years or after the age of 50 years. The compelling physical sign is a characteristic bruit heard in the upper abdomen and flanks and often systolic and blowing. In the patient with lead nephropathy the historical clue often involves gout, which expresses itself as a prominent clinical feature. Identification of the source of the lead provides the second piece of historical evidence. In the Northeast United States, the most common source of lead is ‘‘white lightening.’’ This is home brew made in car batteries, which is the source of the lead. The history of gout in a younger woman is almost pathognomonic.

Renal function during treatment A loss of kidney excretory function with treatment of hypertension in the patient who is already azotemic is a common problem [1,11]. When I was a resident in medicine, the relevant section in Harrison’s Textbook of Medicine indicated that one should ‘‘titrate blood pressure against kidney function.’’ That section was written by John Merrill who directed the Nephrology Division at the Peter Bent Brigham Hospital in Boston. I could not figure out how to do this titration, and I joined Merrill at the Peter Bent Brigham Hospital in part to learn how he did it. He did not know how to do it either! The alternative to titration involves careful serial assessments of serum creatinine concentration and clinical judgment as to how to proceed. In many patients, serum creatinine concentration rises to a new higher level,


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but plateaus and becomes compatible with well-being despite the new elevated level. The patient in whom serum creatinine was 2 or 3 mg/dL, for example, is not aware that serum creatinine has risen to 4 to 5 mg/dL or suffers any clinical consequences in the short run. The patient clearly benefits from the improvement in blood pressure level and reduced risk of stroke and other complications, but even benefits from the perspective of the kidney. It is not unusual to see a gradual reduction in serum creatinine level over several months despite the new lower blood pressure level. This problem is more common with the advent of agents that block the renin-angiotensin system, the angiotensin converting enzyme (ACE) inhibitors and angiotensin-receptor blockers. Increased azotemia in patients treated with these agents raises the specter of renovascular hypertension. The optimal imaging technique for identifying bilateral renal artery stenosis or stenosis with a renal artery to a single kidney varies from center to center, as reviewed later.

Specific forms of nephropathy Attention is given here to three specific forms of nephropathy. They share a number of important features, which provides the rationale for giving them emphasis. First, in most patients with hypertension and nephropathy it is active urine sediment in the urinalysis that points to the kidney as the source of the hypertension. In patients with renovascular hypertension (ischemic nephropathy), lead nephropathy, and the nephropathy associated with phenacetin abuse (all causes of end-stage renal disease) it is not unusual for the urinary sediment to be noncontributory and the urinalysis to show only trace proteinuria. All three forms of nephropathy share, in addition, an important fact: correction of the underlying pathology can lead to stabilization of renal function or even, on occasion, striking improvements in kidney function. These are not clinical problems that can be ignored at little cost. Most clinicians can forgive themselves if they miss a diagnosis in a situation in which there is no specific effect of treatment. All would be extremely unhappy to miss a diagnosis when a specific and effective treatment is available. Ischemic nephropathy Renal artery stenosis caused by atherosclerosis is a relatively common and reversible cause of secondary hypertension [12,13]. When the lesion becomes sufficient to influence blood flow to the kidney, the resultant renal ischemia leads to a loss of renal mass and a progressive deterioration of renal function. If the lesion effects both renal arteries or is located in the arterial blood supply to a single functioning kidney, the consequence is renal insufficiency, designated as ‘‘ischemic nephropathy.’’ As atherosclerosis progresses slowly, the kidney is permitted to develop a collateral arterial

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circulation by a wide range of available routes. As a consequence, the renal parenchyma can continue to experience perfusion even after the principle renal artery becomes totally occluded. The consequence is filtration pressure that is very low with a highly significant reduction in GFR, a poorly functioning or nonfunctioning kidney or kidneys, and advanced renal failure. Although typically the progression is chronic and slow, acute anuric renal failure can occur in this situation because of thrombosis of the impaired renal arterial supply. Estimates of the frequency of ischemic nephropathy vary widely reflecting the fact that in many patients with end-stage renal disease, the precise mechanism has never been documented. Reasonable estimates range from 5% to 22% of patients suffering from end-stage renal disease, primarily involving men over 60 years of age. One feature of these patients is evidence of atherosclerotic lesions in other vascular beds, especially the iliac, coronary, and carotid arteries. The probability of a vascular mechanism increases in those who are 75 years of age or those who are hypertensive or diabetic. A history of cigarette smoking is also suggestive. Renal failure as a complication of the administration of an ACE inhibitor was described previously. Some physicians use the response to the administration of the ACE inhibitor as a diagnostic screening test for ischemic nephropathy. Although renal function typically recovers when the ACE inhibitor is discontinued, cases of nonreversible renal failure have been documented. Although renal arteriography remains the gold standard for identifying renal artery disease and is crucial if therapeutic decisions are to be made, there is risk of cholesterol atheroembolism in the smaller renal arterial tree and the risk of contrast-induced nephrotoxicity in the patient with renal insufficiency. Noninvasive tests include renal scintigraphy, duplex Doppler ultrasound examinations, and imaging tests based on MR angiography and spiral CT angiography. The selection of the diagnostic process to be used varies from center to center depending on local expertise. Revascularization either by vascular surgery or percutaneous angioplasty should be considered when there is progressive renal failure and as an emergency in cases of acute renal failure caused by thrombosis of the aorta or renal arteries. There is still discussion about the predictability of outcome. Angioplasty is preferred when lesions do not occur at the ostium or when surgery is contraindicated. Most atherosclerotic lesions are, in fact, at the ostium. The use of stents during angioplasty has been successful. Such patients merit careful attention to glycemic control, management of lipid abnormality, attention to the status of their platelets, and blood pressure control. Lead nephropathy Like ischemic nephropathy, lead nephropathy deserves a separate presentation because of the possibility that treatment cannot only arrest progression of renal destruction but even improve kidney function [14,15].


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An association between exposure to lead and renal injury has been recognized for centuries. Evidence linking the two has come from epidemiologic studies, examination of occupational exposure to lead, measurements of lead burden in patients with renal insufficiency, and the influence on kidney function of chelation treatment effective in reducing the body’s total lead burden. Lead can contribute to the progression of the loss of renal function not only in patients in whom exposure to lead was the primary insult but also in patients with other forms of renal disease that is complicated by exposure to lead. One’s index of suspicion is increased either by obtaining a history of exposure to lead or through a history of gout. Confirmation of lead exposure has come from several sources. Because bone is the long-term repository for lead, direct measurements of lead in bone biopsies has been powerful. A parallel comes from mobilization of lead from bone with the calcium EDTA test. A recent advance has been provided by the development of X-ray fluorescence techniques as a noninvasive method for measuring lead at various bone sites. The results of X-ray fluorescence of bone have correlated well with the results of calcium EDTA tests. A recent report of a study on the influence of chelation treatment with EDTA showed that progression in the loss of GFR was arrested within 3 months, and kidney function improved over 27 months [14]. Phenacetin nephropathy This process is also known as ‘‘analgesic nephropathy.’’ Analgesic abuse is much more common in women than in men and is associated with a significant range of nonrenal manifestations. In those who abuse analgesics that contain aspirin, peptic ulcers are very common. Anemia is also common, in part caused by gastrointestinal blood loss, chronic renal failure, and an abnormality in red blood cell metabolism that leads to a megaloblastic process. Psychologic manifestations are also common ranging from odd behavior to frank dementia. Whether the latter is a cause or consequence of analgesic abuse is not clear. Because medullary damage is common, early symptoms reflect a loss of concentrating power with permanent nocturia and polyuria. Analgesic nephropathy is one of the causes of papillary necrosis, which can be clinically silent or can be expressed dramatically as pain, fever, and hematuria. The urinary sediment might be quiescent, but hematuria and proteinuria are common. Impaired renal function is present in over 75% of patients at the time of initial diagnosis. Many patients deny excessive use of analgesics even when presented with proof of purchase. This is important because the long-term outlook of patients with analgesic nephropathy is good if patients can be persuaded to stop using analgesics. Most patients show stabilization of renal function or even improvement. In one study in the clinical course of 43 patients with

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severe renal failure at diagnosis, the cumulative 5-year survival rate was almost 75% [16]. There are few causes of chronic renal failure in which there is substantial survival at 5 years.

Hyperkalemia in the patient treated for hypertension The increasing use of agents that block the renin-angiotensin system in patients who are at risk of hyperkalemia and more recent interest in the use of aldosterone antagonists in such patients has increased the frequency and severity of hyperkalemia as a complication of hypertension management [17,18]. Although any patient with mild azotemia is at risk of hyperkalemia with blockade of the renin-angiotensin system or an aldosterone antagonist, the patient at greatest risk is the diabetic in whom mild azotemia was complicated by a borderline high serum potassium concentration before treatment was undertaken. The patients at specific risk also often show a degree of metabolic acidosis that is out of proportion to the level of azotemia. In patients specifically at risk, the author’s practice is to check the serum creatinine concentration and serum potassium concentration within 3 days of instituting treatment. The addition of a potassium-wasting diuretic, a thiazide, or a loop diuretic is often helpful in such patients. In diabetic patients who were hypertensive and had microalbuminuria, the use of a rather high dose of the aldosterone antagonist eplerenone was associated with a 20% frequency of hyperkalemia [19]. Although no one was injured by the hyperkalemia in that study, clearly clinicians are going to have to learn to prevent this complication by adjustment of the aldosterone antagonist dose and the judicious use of potassium-wasting diuretics. For reasons that are not yet clear, angiotensin-receptor blockers seem to produce less hyperkalemia than do the ACE inhibitors [18]. This advantage was first reported for losartan, which is the only angiotensin-receptor blocker that has an influence on renal tubular function, because losartan is uricosuric. Because there was a correlation between urate excretion and potassium excretion following losartan, it was reasonable to ascribe both to a tubular action. Valsartan does not have this tubular action on urate metabolism but also seems to produce less hyperkalemia than does ACE inhibition [18]. There is no obvious explanation.

Hypokalemia Two decades ago, there was substantial controversy on the importance of serum potassium and magnesium concentration and their contribution to sudden cardiac death in the patient treated for hypertension with high-dose thiazides. Hypertension is treated not only for today but also for the events that tomorrow brings. In the patient with hypertension that future event most commonly is a coronary event. With the catecholamine response to


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a myocardial infarction, the patient with a well-tolerated serum potassium level of 3 to 3.5 mEq/L may suffer a large fall in serum potassium concentration, thence a cardiac arrhythmia and sudden death. With the advent of much lower thiazide dosage, that has become an uncommon problem. The recent aggressive pulmonation of a message from the ALLHAT Study raises once again the specter of hypokalemia [20]. The diuretic used in the ALLHAT Study was chlorthalidone in doses of 12.5 and 25 mg per day. Although the article is written as though the chlorthalidone doses were identical to 12.5 and 25 mg of hydrochlorothiazide, in fact chlorthalidone is much longer acting than hydrochlorothiazide, and the doses probably represent a twofold to threefold higher equivalent of hydrochlorothiazide. In the ALLHAT Study, the chlorthalidone-treated patients showed a hypokalemia rate of 8.5% [20]. Reports on the clinical consequences are awaited. Summary An enormous number of articles have been written over the years in which the title is some variation of ‘‘The kidney in hypertension: Cause or consequence’’?. The answer, of course, is that it can be either, neither, or both, at least before treatment is undertaken. Once treatment is undertaken, all patients have an element of kidney involvement. References [1] DeLeeuw PW, Thijs L, Birkenhager WH, Voyaki SM, Efstratopoulos AD, Fagard RH, et al. Prognostic significance of renal function in elderly patients with isolated systolic hypertension: results from the Syst-Eur Trial. J Am Soc Nephrol 2002;13:2213–22. [2] Redon J, Williams B. Microalbuminuria in essential hypertension: redefining the threshold. J Hypertens 2002;20:353–5. [3] Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S. Arner P for the Irbesartan inpatients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345:870–8. [4] Viberti G. Wheeldon NM for the Microalbuminuria Reduction with Valsartan (MARVAL) Study Investigators. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect. Circulation 2002;106: 672–8. [5] The ACE Inhibitors in Diabetic Nephropathy Trialist Group. Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors? A meta-analysis of individual patient data. Ann Intern Med 2001;134:370–9. [6] Levey AS. Nondiabetic kidney disease. N Engl J Med 2002;347:1505–10. [7] Swedko PJ, Clark HD, Paramsothy K, Akbari A. Serum creatinine is an inadequate screening test for renal failure in elderly patients. Arch Intern Med 2003;163:356–60. [8] Shemesh O, Golbetz H, Kriss JP, Myers BD. Limitations of creatinine as a filtration marker in glomerulopathic patients. Kidney Int 1985;28:830–8. [9] Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461–70.

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[10] Tan GD, Lewis AV, James TJ, Altman P, Taylor RP, Levy JC. Clinical usefulness of cystatin-C for the estimation of glomerular filtration rate in type 1 diabetes. Diabetes Care 2002;25:2004–9. [11] Clase CM, Garg AX, Kiberd BA. Prevalence of low glomerular filtration rate in nondiabetic Americans: Third National Health and Nutrition Examination Survey (NHANES III). J Am Soc Nephrol 2002;13:1338–49. [12] Plouin P-E, Alanore ALB. Management of the patient with atherosclerotic renal artery stenosis: new information from randomized trials. Nephrol Dial Transplant 1999;14: 1623–6. [13] van Jaarsveld BC, Krijnen P, Pieterman H, Derkx FH, Deinum J, Postma CT, et al. The effect of balloon angioplasty on hypertension in atherosclerotic renal artery stenosis. N Engl J Med 2000;342:1007–14. [14] Lin J-L, Lin-Tan D-T, Hsu K-H, Yu C-C. Environmental lead exposure and progression of chronic renal diseases in patients without diabetes. N Engl J Med 2003;348:277–86. [15] Marsden PA. Increased body lead burden: Cause or consequence of chronic renal insufficiency? N Engl J Med 2003;348:345–7. [16] Kincaid-Smith P, Whitworth J, Fairley KF, Nanra RS. Clinical course of analgesic nephropathy with renal failure. In: Haschek H, editor. Problems on phenacetin abuse. Vienna: Facta Publications; 1973. p. 157. [17] Palmer BF. Renal dysfunction complicating the treatment of hypertension. N Engl J Med 2002;347:1256–61. [18] Bakris GL, Siomos M, Richardson D, Janssen I, Bolton WK, Hebert L, et al. ACE inhibition or angiotensin receptor blockade: impact on potassium in renal failure. Kidney Int 2000;58:2084–92. [19] Epstein M, Buckalew V, Altamirano J, Roniker B, Krause S, Kleinman J. Eplerenone reduces proteinuria in type 2 diabetes mellitus: implications for aldosterone involvement in the pathogenesis of renal dysfunction [abstract]. JACC 2003;249A. [20] The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Major outcomes in high-risk hypertensive patients randomized to angiotensinconverting enzyme inhibitor or calcium channel blocker vs. diuretic. JAMA 2002;288: 2981–97.

Med Clin N Am 88 (2004) 141–148

What can we expect from new guidelines? Norman M. Kaplan, MD Department of Medicine, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390–8899, USA

The recent publications of the seventh report of the Joint National Committee (JNC-7) [1] and the 2003 International Society of Hypertension statement on blood pressure lowering and stroke prevention [2] are the first in what will likely be another round of guidelines from multiple international and national expert committees. In the 5 or so years since the previous round, a number of expectations have surfaced that, it is hoped, will be addressed in the new guidelines. Before going into specifics, it is worth remembering the single purpose of guidelines: to improve the management of hypertension so that more people are protected from its complications. It is easy to miss this purpose because of irrational local preferences, disregard for solid evidence in favor of personal bias, and overriding concern about what can be rather than what should be accomplished. Constraints, particularly in developing societies, may severely limit what can be done, but denying therapy for people who need it because of a lack of money or facilities should not be excused as the best that can be done. As much as in the least developed societies, those in the richest and most capable society, the United States of America, are as derelict as any: reductions in health care are accepted while greater relief for the wealthy is provided. As noted in JNC-7 [1], things are getting a little better (Table 1) but note that 66% of hypertensives in the United States are still not being adequately protected. The point is well made by Lenfant in the preface of JNC-7: ‘‘None of this—neither the research studies nor the recommendations—will matter, unless the JNC-7 is applied.’’ The rising incidence of hypertension As people live longer and become urbanized, the incidence of hypertension increases. The forces of increasing longevity and spreading E-mail address: [email protected] 0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/S0025-7125(03)00120-2

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N.M. Kaplan / Med Clin N Am 88 (2004) 141–148

Table 1 Trends in awareness, treatment, and control of high blood pressure in adults ages 18–74

Awareness % Treatment % Controla %

NHANES II 1976–1980

NHANES III (phase 1) 1988–1991



51 31 10

73 55 29

68 54 27

70 59 34

a

SBP \140 mm Hg or DBP \90 mm Hg. High blood pressure is systolic blood pressure (SBP) 140 mm Hg or diastolic blood pressure (DBP) 90 mm Hg or taking antihypertensive medication. Data from Joint National Committee. The seventh report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JNC-7 Express. JAMA 2003;289:2560–71.

obesity likely will continue to overwhelm any potential for prevention. As developing societies become more addicted to physical inactivity [3], more and more of the consequences of the metabolic syndrome, including hypertension, will certainly appear. All guidelines include a list of lifestyle modifications that can at least delay or at best prevent the onset of hypertension (Table 2). Even when concerted efforts are made to modify lifestyles of individual patients, however, little effects on blood pressure are provided, simply because minimal changes in lifestyle are usually achieved [4]. The need for population-wide changes in lifestyle has become increasingly obvious. The impressive reduction in the prevalence of cigarette smoking in the United States over the last decade has almost certainly been accomplished more by population-wide influences than by individual practitioner’s therapeutic interventions. Similar benefits could likely be provided by removal of some of the salt now being added to processed foods and by provision of the means for increased physical activity in schools and urban areas. As shown in a thorough analysis of the costs and effectiveness of various nonpersonal (population-wide) health interventions, governmental action to reduce salt content of processed foods was estimated to provide over 21 million disability-adjusted years per year worldwide [5]. Although guidelines are largely directed at improving practitioners’ care for individual patients, the larger societal issues also need to be addressed. The recognition of hypertension As hypertension becomes more common, particularly among the elderly and the obese, the accurate ascertainment of the usual level of blood pressure assumes even greater importance. In particular, the ‘‘white-coat effect’’ needs to be recognized because it is even quantitatively greater in the elderly who may then be improperly diagnosed and treated for ‘‘white-coat

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N.M. Kaplan / Med Clin N Am 88 (2004) 141–148 Table 2 Lifestyle modifications to manage hypertension Modification

Recommendation

Weight reduction

Maintain normal body weight (body mass index 18.5–24.9 kg/m2) Consume a diet rich in fruits, vegetables, and low-fat dairy products with a reduced content of saturated and total fat Reduce dietary sodium intake to no more than 100 mmol per day (2.4 g sodium 6 g sodium chloride) Engage in regular aerobic physical activity, such as brisk walking (at least 30 min/d most days of the week) Limit consumption to no more than two drinks (1 oz or 30 mL ethanol [eg, 24 oz beer, 10 oz wine, or 3 oz 80-proof whiskey]) per day in most men and to no more than one drink per day in women and lighter weight persons

Adopt dietary approaches to stop hypertension (DASH) eating plan

Dietary sodium reduction

Physical activity

Moderation of alcohol consumption

Approximate SBP reduction (range) 5–20 mm Hg/10 kg

8–14 mm Hg

2–8 mm Hg

4–9 mm Hg

2.5–4 mm Hg

From Joint National Committee. The seventh report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JNC-7 Express. JAMA 2003;289:2560–71; with permission.

hypertension’’ [6]. Guidelines need to advocate more directly the routine use of out-of-the-office measurements, preferably by automatic ambulatory monitoring but, if unavailable, by self-measured readings with an electronic device [7]. Moreover, the need to recognize both the extent of nighttime blood pressure dipping [8] and the degree of the early morning surge [9] should prompt the advocacy of ambulatory monitoring because both of these patterns can only be ascertained accurately by automatic readings. Even though there remains no evidence from proper prospective trials of the ability to reduce cardiovascular events by moderating either the nocturnal dips or the morning surge, conventional wisdom favors both of these moves, if they can be identified. At the same time, the primacy of systolic levels in most hypertensive patients will certainly be recognized, even though disagreement about the added benefit of using pulse pressure [10] will likely keep it out of the criteria.

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Ascertainment of overall risk The prior group of guidelines issued in the late 1990s all incorporated attempts to determine not only the specific risk of hypertension but also the overall risk status from additional risk factors. These attempts were relatively crude and generally overestimated the degree of risk beyond that calculated from more detailed assessments [11]. Now that the enhanced risk of even ‘‘high-normal’’ blood pressure has been recognized [12], however, most new guidelines will undoubtedly call for more active intervention in those with lesser levels of hypertension. At the same time, they should provide more accurate estimates of an individual patient’s overall risk status [10], to help in the decisions both as to when to start antihypertensive therapy and as to the need to address other risk factors. The decision to treat with drugs As the risk of even minimally elevated blood pressure and the virtual inevitability of hypertension to develop with aging has been recognized [12,13], antihypertensive drug therapy will likely be recommended for more and more patients. This rush to active therapy will be accelerated by the increasing prevalence of three conditions that will accompany hypertension more frequently (diabetes, renal insufficiency, and heart failure), all three demanding more intensive reductions in systemic blood pressure. Some believe that the threshold for beginning drug therapy, even though lower than in the past, is still set too high [14]. The argument revolves around experimental evidence that even intermittent reductions of blood pressure may have prolonged antihypertensive efficacy [15] and the clinical evidence [12] that risks are present even before the level of blood pressure has reached the level of 140/90 mm Hg that has been rather arbitrarily determined to define the presence of hypertension. The argument for a lower threshold for earlier drug therapy has been advanced by a number of recent developments, including 1. The availability of effective drugs that have few if any more adverse effects than placebo. 2. The experiences from large prospective trials that drugs can protect vulnerable patients from heart attack [16] and stroke [17] even if they start with levels of blood pressure below 140/90. 3. The possibility that some drugs, in particular angiotensin converting enzyme (ACE) inhibitors, may provide cardiovascular and renal protection even if they do not lower blood pressure. In the HOPE trial [16], protection was seen by addition of an ACE inhibitor even though blood pressure may not have been reduced more than a few millimeters. In the PROGRESS trial, however, the ACE inhibitor was ineffectual in lowering blood pressure or recurrent stroke in the absence of a diuretic [17].


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4. The striking benefits of antilipid therapy in reducing cardiovascular events even in patients with normal or slightly elevated blood lipid levels [18], levels that until now have been considered to be below the threshold for lipid-lowering drug therapy. 5. The increasing awareness that risk rises with every increment above ‘‘normal,’’ estimated for blood pressure as below 120/80 [19]. Risk doubles for every 20/10 mm Hg rise in blood pressure across the entire spectrum. Waiting until the level reaches 140/90 may unnecessarily expose the larger population to risk. Despite these developments, caution in lowering the threshold further is advised. First, in all trials with all drugs, adverse effects have been observed. Witness the additional 10% hypokalemia and 2% of new-onset diabetes with low-dose diuretic in the ALLHAT trial [20], which concluded that such therapy is superior to other choices. Second, the benefits shown in various prospective trials are universally expressed in reductions of relative risk of 15% to 30% or 40%, figures that usually translate into absolute reductions of as little as 2% to 5%. Admittedly, short-time trials do not necessarily determine the potential long-term benefits that may accrue with continued reductions in blood pressure. Nonetheless, warnings should be recalled about the inappropriateness of therapies that may protect some while bothering or hurting others who do not receive benefit. Oh, that that world could become full of slim, active people who practice moderation in all things? Pharmaceutical companies might suffer but how much less expensive and more effective would be health care.

Choice of therapy The argument as to which drug is best for initial therapy, an argument that has consumed literally hundreds of authors and thousands of clinical trials, now seems moot. As now shown in multiple large trials comparing various drug classes one against others, the outcomes almost completely depend on the degree of blood pressure reduction and little on the choice of drug [20–22]. This conclusion will continue to be debated but in the biggest of them all [20], the diuretic was no better or worse than the ACE inhibitor or the calcium channel blocker on the primary end point of coronary disease and the differences in various secondary end points could very well reflect the differences in the extent of blood pressure reduction. I have long advocated the use of a low-dose thiazide diuretic for the initial drug for almost all patients (Fig. 1). The primary rationale for that advocacy, however, is the knowledge that most patients will not be controlled adequately on whatever the first drug may be and there are clearly compelling indications for all classes of drugs as shown in Fig. 1 whose efficacy will uniformly be enhanced by the presence of a low-dose diuretic.

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Fig. 1. An algorithm for the treatment of hypertension. ACE, angiotensin converting enzyme; ARB, angiotensin II receptor blocker; CCB, calcium channel blocker.

The JNC-7 and likely other new guidelines acknowledge the need for two or more drugs to achieve the appropriate goal of therapy for most patients and advocate the initiation of therapy with two drugs if the initial blood pressure is 20/10 mm Hg or more above that goal [1]. As noted by Williams [23]: The key message from [the ALLHAT] trial is that what matters most is getting blood pressure controlled, and that this is overwhelmingly more important than the means. Combinations of several drugs will be required for most patients, and such an antihypertensive treatment cocktail should include a thiazide diuretic. ALLHAT perhaps heralds the end of an era of initial treatment comparisons for hypertension and points to a new need for ‘‘real world research.’’ In managing hypertension we have a range of effective and safe drugs and a robust evidence base for treatment. But if patients are to benefit from this trial, and all before it, we now need to define the best way of implementing the evidence in clinical practice.

For now, the algorithm shown in Fig. 1 seems the most logical way to choose the combination best suited for most patients who have one or more compelling indications for specific agents. If no such compelling indications are present, some would start younger and non-black patients (who usually have a more active renin-angiotensin system) on a renin-inhibiting drug (bblocker, ACE inhibitor, or angiotensin II receptor blocker) and would start older and black patients (who usually have a less active renin-angiotensin system) on either a diuretic or a calcium channel blocker [24]. This approach seams rational but I see no greater logic in it than in starting most everyone on a low-dose diuretic as advocated in JNC-7.


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Adherence to therapy As less attention is given to what is the best initial and subsequent therapy, more attention needs to be given to the inability to keep patients on medication that is usually needed life-long. Unfortunately, little is known to improve long-term adherence [25] but the maneuvers listed next are likely to help: Providing instruction and instructional materials Simplifying the regimen (e.g., less frequent dosing, controlled release dosage forms) Counseling about the regimen Support group sessions Reminders (manual and computer) for medications and appointments Cuing medications to daily events Reinforcement and awards Self-monitoring with regular physician review and reinforcement Involving family members and significant others As seen in Table 1, physician noncompliance may be as common as patient noncompliance. Almost twice as many known hypertensive patients are being treated as are being adequately controlled. More attention needs to be directed to health care professionals to ‘‘treat to goal,’’ thereby maximally to protect the hypertensive patient.

References [1] Joint National Committee. The seventh report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JNC-7 Express. JAMA 2003;289:2560–71. [2] International Society of Hypertension Writing Group. International Society of Hypertension (ISH): statement on blood pressure lowering and stroke prevention. J Hypertens 2003;21:651–63. [3] Hu FB, Li TY, Colditz GA, et al. Television watching and other sedentary behaviors in relation to risk of obesity and type 2 diabetes mellitus in women. JAMA 2003; 289:1785–91. [4] Kastarinen MJ, Puska PM, Korhonen MH, et al. Non-pharmacological treatment of hypertension in primary health care: a 2-year open randomized controlled trial of lifestyle intervention against hypertension in eastern Finland. J Hypertens 2002;20:2505–12. [5] Murray CJL, Lauer JA, Hutubessy RCW, et al. Effectiveness and costs of interventions in lower systolic blood pressure and cholesterol: a global and regional analysis on reduction of cardiovascular-disease risk. Lancet 2003;361:717–25. [6] Verdecchia P, O’Brien E, Pickering T, et al. When can the practicing physician suspect white coat hypertension? Statement from the Working Group on Blood Pressure Monitoring of the European Society of Hypertension. Am J Hypertens 2003;16:87–91. [7] Hond ED, Celis H, Fagard R, et al. Self-measured versus ambulatory blood pressure in the diagnosis of hypertension. J Hypertens 2003;21:717–22. [8] Kario K, Pickering TG, Matsuo T, et al. Stroke prognosis and abnormal nocturnal blood pressure falls in older hypertensives. Hypertension 2001;38:852–7.

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[9] Marfella R, Gualdiero P, Siniscalchi M, et al. Morning blood pressure peak, QT intervals, and sympathetic activity in hypertensive patients. Hypertension 2003;41:237–43. [10] Haider AW, Larson MG, Franklin SS, Levy D. Systolic blood pressure, diastolic blood pressure, and pulse pressure as predictors of risk for congestive heart failure in the Framingham Heart Study. Ann Intern Med 2003;138:10–6. [11] Yikona JINM, Wallis EJ, Ramsay LE, Jackson PR. Coronary and cardiovascular risk estimation in uncomplicated mild hypertension: a comparison of risk assessment methods. J Hypertens 2002;20:2173–82. [12] Vasan RS, Larson MG, Leip EP, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med 2001;345:1291–7. [13] Vasan RS, Beiser A, Seshadri S, et al. Residual lifetime risk for developing hypertension in middle-aged women and men: the Framingham Heart Study. JAMA 2002;287:1003–10. [14] Kaplan NM. Treatment of hypertension: why, when, how far. In: Kaplan’s clinical hypertension. 8th edition. Philadelphia: Lippincott Williams & Wilkins; 2002. p. 176–205. [15] Julius S. Of rat and man. J Hypertens 2003;21:705–6. [16] Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensinconverting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342:145–53. [17] PROGRESS Collaborative Group. Randomised trial of a perindopril-based bloodpressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet 2001;358:1033–41. [18] Sever PS, Dalho¨f B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomized controlled trial. Lancet 2003;361:1149–58. [19] Prospective Studies Collaboration. Age-specific relevance of usual blood pressure in vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903–13. [20] Officers ALLHAT and Collaborators. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981–97. [21] Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Lancet 2000;355:1955–64. [22] Lindon MHW, Reid CM, Ryan P, et al. A comparison of outcomes with angiotensinconverting-enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 2003;358:583–92. [23] Williams B. Drug treatment of hypertension. BMJ 2003;326:61–2. [24] Brown MJ, Cruickshank JK, Dominiczak AF, et al. Better blood pressure control: how to combine drugs. J Hum Hypertens 2003;17:81–6. [25] Haynes RB, McDonald HP, Garg AX. Helping patients follow prescribed treatment: clinical applications. JAMA 2002;288:2880–3.

Med Clin N Am 88 (2004) 149–165

Evolving role of calcium antagonists in the management of hypertension Murray Epstein, MDa,*, Vito M. Campese, MDb a

Department of Medicine, University of Miami School of Medicine, Miami, FL, USA b Division of Nephrology and Hypertension, KECK School of Medicine at USC, Los Angeles, CA, USA

Since their introduction more than 30 years ago, calcium antagonists have emerged as one of the most attractive and widely used classes of antihypertensive agent. Of the 20 to 25 million patients receiving medication for hypertension in the United States, about one quarter are taking calcium antagonists [1]. Their wide appeal is attributable to several features, including efficacy; beneficial characteristics, such as the ability to maintain metabolic neutrality; and the occurrence of relatively few nuisance-type side effects [2,3]. In addition, recent investigations have focused on their possible protective effects on target organs, such as the heart and kidney [4,5], further enhancing their appeal. Despite these attributes, a number of retrospective analyses have suggested that calcium antagonists may be detrimental and may promote adverse cardiovascular events. Subsequently, Pahor et al [6,7] have proposed that calcium antagonists increase the risk of cancer by interfering with apoptosis. The first meta-analysis of the effects of 1,4-dihydropyridines on outcome included 21 clinical trials and suggested an adverse trend on mortality and the development of subsequent myocardial infarction [8]. Subsequently, Furberg and Psaty [9] reported the findings of an observational, case-control study of patients who had suffered a myocardial infarction (cases) and those who had not (controls) with respect to their prior use of various antihypertensive drug therapies. They concluded that hypertensive patients receiving calcium antagonists had a significantly greater risk of myocardial infarction compared with those receiving b-blockers (relative risk = 1.63,

* Corresponding author. Nephrology Section, VA Medical Center, 1201 NW 16th Street, Miami, FL 33125. E-mail address: [email protected] (M. Epstein). 0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/S0025-7125(03)00123-8

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95% confidence interval = 1.23–2.16). On the basis of this and other retrospective analyses, Furberg and Psaty [9] have proposed that the use of calcium antagonists as first-line antihypertensive agents should be discontinued. Undoubtedly, many readers are familiar with concerns raised about the study including the fact that the retrospective, population-based, casecontrol design used by Furberg and Psaty [9] precluded randomization of treatment allocation [10,11]. Although meta-analyses and observational studies clearly have limits [12,13], Psaty et al [14] have raised an important question that deserves consideration whether calcium antagonists, as a group, promote adverse cardiovascular events. Furthermore, media reporting of the presentation triggered concern among users of calcium antagonists and even among those taking other antihypertensive drug therapies. This underlines the importance and relevance of critically considering the issues raised by Psaty et al [14]. One of the authors has previously debated Furberg on these issues and has suggested that the allegations are not relevant to the newer and more highly developed calcium antagonists in current usage [15,16]. This article expands on these earlier formulations and counters the arguments that calcium antagonists, as a group, are dangerous. Remarks are not limited to the merits of Furberg and Psaty’s [9] retrospective analysis and the constraints of the experimental design, which have been discussed extensively [11,12]. Rather, this article focuses on a number of key issues that the authors believe are pivotal to this discussion. First reviewed are the markedly disparate effects of differing calcium antagonist formulations and their clinical implications, which are clearly relevant to this controversy. The unique attributes of some newer intrinsically long-acting calcium antagonists are considered in-depth. Finally, data derived from recent prospective studies that are inconsistent with Furberg’s findings are presented. Why calcium antagonists are uniquely suitable for managing hypertension Recently one of the authors (ME) reviewed the pharmacologic effects of calcium antagonists on renal hemodynamics and renal electrolyte excretion [17,18]. The striking effects of calcium antagonists on renal hemodynamics and renal sodium handling support their use in the treatment of hypertension [2,17]. Medications, such as hydralazine, that directly reduce peripheral vascular resistance have been used in antihypertensive therapy for many years, but their effectiveness is limited by reactive stimulation of renal and hormonal responses that counteract their antihypertensive actions [17,18], and by the induction of sodium retention. The consequent volume expansion results in pseudotolerance to the antihypertensive effects of hydralazine. In contrast to direct-acting vasodilators, such as hydralazine and minoxidil, calcium antagonists attenuate the expected adaptive changes in peripheral vascular resistance, heart rate, cardiac output, and extracellular


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fluid volume that lead to a reduction in the initial blood pressure–lowering response of direct vasodilators As examples, calcium antagonists interfere with angiotensin II and a-adrenergic–mediated vasoconstriction. They also countervail the sodium-retaining effects of decreased renal perfusion [17]. This property renders calcium channel blockers (CCBs) particularly suitable in the management of salt-sensitive patients with hypertension, because blood pressure reduction seems to be more pronounced in this subgroup of patients [19,20]. The greater antihypertensive efficacy of CCBs in saltsensitive individuals may be caused by specific renal effects of these drugs, and their ability to counterbalance calcium entry into cells stimulated by a variety of pressor agents. Effects of calcium channel blockers on cytosolic calcium and its relationship to blood pressure control The concentration of [Ca2+]i in platelets of hypertensive patients is greater than in normotensive subjects. In addition, some agonists cause a greater increase in the entry and mobilization of [Ca2+] in platelets of hypertensive patients compared with normotensive subjects. Oshima et al [21] showed that an increase in dietary sodium intake raised intracellular sodium and free cytosolic calcium [Ca2+]i in lymphocytes of salt-sensitive patients with essential hypertension. Alexiewicz et al [22] also showed that the rise in blood pressure during high sodium chloride diet is associated with increased cytosolic calcium [Ca2+]i in lymphocytes of saltsensitive patients [22]. In salt-resistant patients there was no change in mean arterial pressure or in [Ca2+]i during sodium chloride loading. In addition, a direct and significant correlation was present between the changes in [Ca2+]i and the changes in mean arterial pressure. Similar results have been obtained using platelets instead of lymphocytes [23]. These studies suggest the existence of a linkage between dietary sodium chloride intake [Ca2+]i and blood pressure in salt-sensitive patients with essential hypertension. The mechanisms whereby a high sodium chloride intake results in increased [Ca2+]i are unclear. Several investigators [24] have proposed that high salt intake and the ensuing volume expansion stimulate the secretion of a circulating inhibitor of the Na+K+ ATPase pump. This results in increased intracellular sodium, which in turn alters the Na + -Ca2+ exchange system and results in increased [Ca2+]i in vascular smooth muscle cells. Vincenzi et al [25] have shown a decreased activity of the calcium pump in red blood cell lysate of hypertensive subjects and have proposed that this might be responsible for the increase in [Ca2+]i. Other studies point to a dialyzable humoral factor in the plasma of hypertensive subjects, which may elevate the intracellular concentration of calcium in platelets and neutrophils and sensitize platelets to the calciumincreasing effect of adenosine diphosphate and to platelet-activating factor [26–28].

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It remains to be established whether the salt-induced increase in [Ca2+]i in lymphocyte or platelets of salt-sensitive hypertensive subjects reflects a similar rise in vascular smooth muscle; whether the salt-induced increase in [Ca2+]i is a cause or consequence of salt-induced increases in blood pressure; and whether salt-induced increase in intracellular sodium precedes salt-induced rise in [Ca2+]i [29]. It is noteworthy that nifedipine prevented the rise in [Ca2+]i and in blood pressure induced by a high sodium chloride intake. This may explain the greater efficacy of CCBs in the management of hypertension among saltsensitive individuals. It should also be emphasized that oxidized lipids also increase intracellular calcium, an effect that is counteracted by dihydropyridine calcium antagonists. Furthermore DHPs also decrease the cellular damage induced by oxidized LDI [30]. Recent studies have also demonstrated that hypoglycemia also tends to increase cytosolic calcium which can clearly constitute a platform for producing the myriad adverse effects on the vasculature in the diabetic patient. Of interest, investigations of polymorphonuclear leukocytes in diabetic rats demonstrate that this adverse effect can be reversed by amlodipine [31]. Effects of calcium channel blockers on the kidney Long-term therapy with CCBs does not normally cause changes in glomerular filtration rate, renal blood flow, plasma volume, or body weight [32–34]. Treatment with nitrendipine, 20 mg/d, caused a negative sodium balance of approximately 150 mEq and an average weight loss of 1 kg [35]. Krusell et al [36] observed 40% increase in lithium clearance in patients treated with isradipine. The authors observed different effects of a nifedipine gastrointestinal therapeutic system, a long-acting formulation of nifedipine, on renal hemodynamics and renal sodium handling in black patients with hypertension divided according to their blood pressure sensitivity to salt. During high salt intake glomerular filtration rate did not change, renal blood flow increased, and filtration fraction decreased in salt-resistant patients. By contrast, renal blood flow decreased and filtration fraction rose in salt-sensitive patients. Nifedipine reduced blood pressure, renal vascular resistance, and filtration fraction and raised renal blood flow in salt-sensitive individuals [37]. Nifedipine also normalized the renal function curve. A similar finding was observed by Nicholson et al [20] using verapamil. In summary, calcium antagonists are highly efficacious vasodilators, concomitantly countervailing the counter-regulatory adaptive changes that tend to offset the desired primary effects of blood pressure lowering on the kidney and renal sodium excretion. Of great interest are the effects of CCBs on the renal microcirculation. Because potential-dependent calcium channels predominate at the afferent arteriole [38,39], CCBs reverse vasoconstriction of the afferent arteriole


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induced by norepinephrine, thromboxane mimetics, endothelin, and angiotensin II, whereas the efferent arteriolar constriction induced by these vasopressors is refractory to CCBs [40,41]. These effects on the microcirculation have been demonstrated with dihydropyridine and with benzothiazepine CCBs. Novel CCBs with selective action on T-type calcium channel [42], such as mibefradil, or with dual action on the L and T-type calcium channel, such as efonidipine, nilvadipine, and aranidipine, cause prominent efferent and afferent arteriolar dilation [43].

Calcium antagonists and renal disease A large body of evidence suggests that CCBs are less protective against progression of experimental kidney diseases than angiotensin converting enzyme (ACE) inhibitors or angiotensin AT1 receptor blockers even when similar blood pressure control is achieved. This has been attributed largely to preferential vasodilatory action of CCBs on the afferent arterioles, as opposed to more effective vasodilation of efferent arterioles induced by drugs that inhibit the renin-angiotensin system. As a consequence of these microcirculatory differences, CCBs reduce intraglomerular pressure less effectively that ACE inhibitors or angiotensin receptor blockers (ARBs). Some have observed greater degree of renal protection with nondihydropyridine than with dihydropyridine CCBs [44]. This has been attributed largely to diverse effects of these two classes of drugs on intraglomerular pressure [45]. Dihydropyridine CCBs either increase or fail to reduce intraglomerular pressure, whereas nondihydropyridines reduce it, although not to the same extent as ACE inhibitors [46]. T-type CCBs reduce glomerular pressure as effectively as ACE inhibitors [46]. The clinical implications of these observations are less clear. Two prospective randomized trials in patients with chronic kidney disease support the concept that CCBs are less effective than inhibitors of the reninangiotensin system in retarding the progression of renal disease. The AASK trial was designed to compare the effects of three different treatments on progression of renal disease in African Americans with a clinical diagnosis of hypertensive glomerulosclerosis [47]. One group received amlodipine, one received an ACE inhibitor, and one a b-blocker as initial therapy. Additional drugs were used to achieve two levels of mean arterial pressure, 92 or 107 mm Hg. The amlodipine arm was stopped prematurely because of a more rapid decline in glomerular filtration rate in patients treated with amlodipine than in those treated with the ACE inhibitor. The difference, however, was significant only in a minority of patients with proteinuria greater than 220 mg/g creatinine, whereas no difference was apparent in most patients with less proteinuria [47]. In a study of patients with type II diabetes, proteinuria, and chronic kidney disease (the IDNT trial) patients treated with amlodipine or with

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placebo had greater probability of progression of renal disease than patients treated with irbesartan [48]. By contrast, in the Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT), which compared amlodipine with lisinopril and chlorthalidone in the management of hypertension in patients with no obvious proteinuria (although urinalysis was not measured), the decline in glomerular filtration rate in patients treated with amlodipine was significantly lower than in patients treated with chlorthalidone and lisinopril [49]. The body of evidence seems to indicate that, when used as first-line therapy, ACE-inhibitors seem to provide greater renal protection in patients with nephropathy and significant proteinuria than other classes of antihypertensive drugs, including CCBs. In contrast, in patients without significant proteinuria, there is no conclusive evidence that one class of drugs offer benefits over the other. Because most hypertensive patients with renal disease require multiple antihypertensive agents to achieve adequate control, it appears that administration of CCBs in addition to ACE inhibitors or ARBs is effective and safe. There is no substantial clinical evidence to suggest that dihydropyridine CCBs are inferior to nondihydropyridine in the management of hypertension in patients with chronic kidney disease with or without diabetes mellitus, particularly when these agents are used in combination with ACE inhibitors or ARBs. Race and ethnicity as a determinant of the responsiveness to calcium antagonists Although it has long been suspected that genetic variation plays an important role in determining interindividual differences in therapeutic and toxic responses to many medications, success in identifying particular genes and allelic variants responsible for such differences has been limited [50]. Nevertheless, it is readily evident that race constitutes a determinant of the clinical response to antihypertensive medications [51,52]. Flack and ElAchar [51] have recently reviewed the attributes of calcium antagonists as antihypertensive agents in African American patients. Their review confirmed that, like diuretics, calcium antagonist monotherapy lowers blood pressure more effectively than either ACE inhibitors or b-blockers. Furthermore, lowering of blood pressure is minimally affected by high levels of sodium intake, a highly important pharmacologic attribute in salt-sensitive hypertensive African Americans. Chan et al [52] have recently published a comprehensive review of antihypertensive therapy in Asian patients. Both long- and short-term studies show that Chinese hypertensive patients are particularly responsive to the blood pressure–reducing effects of calcium antagonists [52]. Chinese patients seem to have a higher incidence of ACE inhibitor–related cough than whites. Although this finding may be caused in part by the high background cough rates in some Asian cities, such as Hong


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Kong, the reasons for these interethnic differences in side effects require further investigation. The increased frequency of the ACE II genotype in Asian populations may be a contributory factor [52].

Different formulations of the same calcium antagonist can produce markedly different pharmacokinetic and pharmacodynamic effects First, it must be recognized that to group all of the markedly heterogeneous calcium antagonists together as if they represent uniform and identical agents is erroneous. The fact that calcium antagonists are heterogeneous, and consist of chemically dissimilar agents, is well established [53,54]. Perhaps what is not so well appreciated is the fact that different formulations of the same chemical moiety can produce markedly different hemodynamic and neurohormonal effects [55–58]. The earliest calcium antagonists were short acting. Subsequently, the drug delivery systems for the short-acting agents were modified to provide more fully and consistently maintained calcium antagonist activity. After administration of a nifedipine capsule, plasma drug concentration peaks rapidly within 1 hour to high levels and then falls rapidly. In contrast, plasma drug concentration of nifedipine gastrointestinal therapeutic system, which uses an osmotic pump system to deliver the drug in a steady infusion over the 24-hour interval [59], attains a plateau slowly, peaking at approximately 6 hours, and maintains a relatively constant drug level over 24 hours. Such new slow-release formulations were developed primarily to produce a sustained 24-hour therapeutic effect. An added benefit that is equally important, albeit not widely appreciated, is that these uniform plasma concentrations avoid provoking activation of the renin-angiotensin and sympathetic nervous systems [55,58]. The rate of drug delivery into the systemic circulation has profound effects on the hemodynamic and neurohumoral responses to a dihydropyridine calcium antagonist. Kleinbloesem et al [56] conducted a study of intravenously administered nifedipine, which showed clearly that the rate of drug delivery determined the pattern of response. They compared the effects a rapid bolus dose and a slow infusion on systemic hemodynamics. The rapid attainment of an effective plasma concentration by a rapid intravenous bolus dose (and exponential infusion) caused no appreciable fall in blood pressure because there was an associated increase in adrenergic activity and a marked increase in heart rate, and presumably also in cardiac output. In contrast, if an identical plasma nifedipine concentration was gradually attained over several hours by means of a slow intravenous infusion, there was no adrenergic response and no increase in heart rate, but there was a significant decrease in blood pressure. These studies emphasize the importance of the rate of attainment of plasma levels in determining the consequent adrenergic and cardioacceleratory response.

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During chronic treatment with dihydropyridines, major fluctuations in blood pressure (rapid onset and offset of antihypertensive effects) during the dosing interval may persist for short-acting drugs and formulations [57,58,60–63]. In contrast, slow-release formulations of otherwise rapidly absorbed dihydropyridines or intrinsically long-acting calcium antagonists achieved a more gradual and sustained antihypertensive effect.

Differences in pharmacokinetic profiles: clinical relevance Although the primary hemodynamic effects of dihydropyridines are rather similar for the whole class, differences in pharmacokinetic profile (even for different formulations of the same dihydropyridine) have a pronounced effect on the pattern of hemodynamic changes [64]. Plasma concentrations of rapid-acting, short-acting agents increase quickly and often markedly after dosing, leading to a rapid decrease in blood pressure. Plasma concentrations also diminish quickly because of the short elimination half-life, with a return of blood pressure to predosing levels [58,59,64]. Frequent administration of relatively low doses provides more sustained blood pressure control than higher or less frequent doses (eg, nifedipine capsule, 10 mg, one every 6 hours versus two every 12 hours). Newer formulations of the previously mentioned subclass show a decreased rate of absorption and a more gradual and less marked increase in plasma concentrations. Speed of onset and duration of antihypertensive effect are clearly different. For example, the slower and more steady rate of absorption of nifedipine from nifedipine gastrointestinal therapeutic system (ie, Procardia XL or Adalat Oros) results in fairly stable plasma concentrations and stable antihypertensive effect over 24 hours during maintenance treatment [65,66]. What is not widely appreciated, however, is that not all once daily, slow-release formulations demonstrate this consistency. For example, with once-daily dosing the extended-release felodipine tablet exhibits a clear peak-to-trough variation in plasma drug concentration [67], which may result in fluctuations in the extent of antihypertensive effect over 24 hours [68]. The intrinsically long-acting agents (eg, amlodipine and lacidipine) are absorbed fairly slowly. The long half-life of amlodipine accounts for its apparent long duration of action [69–71]. This subclass produces antihypertensive effect with gradual onset but sustained duration over a 24-hour dosing interval during maintenance treatment [71].

Relevance of different formulations to recent retrospective reviews The clinical relevance of the different pharmacodynamic profiles of the rapidly absorbed agents and the more recently introduced slow-release formulations, and their disparate cardioacceleratory and neurohormonal


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effects, is implicit. The study of Psaty et al [14] encompassed a period of observation from 1986 to 1993 at a time when the slow-release formulations were not readily available or, in some instances, had not yet been introduced. Indeed, the trial routinely used three short-acting prototype calcium antagonists (nifedipine, verapamil, and diltiazem) two of which (nifedipine and diltiazem) were not indicated for the treatment of hypertension by the Food and Drug Administration. Consequently, it is reasonable to assume that these short-acting formulations were precisely the ones previously documented to cause wide fluctuations in drug concentrations and vasodilatory effects during apparent steady-state treatment, with resultant cardioacceleration and recurring sympathetic activation [55,58].

Data from recent prospective studies To date, much of the controversy has centered on the limitations of metaanalyses and retrospective studies. Although such analyses are helpful and suggestive, they are no substitute for randomized, prospective studies with hard end points. The important report of the Systolic Hypertension in Europe (Syst-Eur) study lends strong support to the safety of calcium antagonists [72]. The Syst-Eur investigated whether antihypertensive treatment could decrease the risk of cardiovascular complications in elderly patients with isolated systolic hypertension. Patients greater than or equal to 60 years were randomly assigned to treatment with the dihydropyridine calcium antagonist nitrendipine (N = 2398), with addition of enalapril and hydrochlorothiazide if needed, or to matching placebo (N = 2297). Active treatment decreased the total incidence of stroke (the primary end point) by 42% (P = .003); of all cardiac end points by 26% (P = .03); and of all cardiovascular end points combined by 31% (P \ .001). Per protocol analysis largely confirmed the intent-to-treat results. In view of concerns about the use of calcium antagonists as first-line antihypertensive therapy, the demonstration by the Syst-Eur of an almost 50% reduction (P .004) in all types of end points, including total and cardiovascular mortality in patients receiving nitrendipine monotherapy, should allay these concerns. Both the recently reported ALLHAT study and the analysis of cardiovascular results in the IDNT study provide compelling data to support the safety of slow-release long-acting calcium antagonists. In the IDNT trial, although irbesartan had more favorable effects on end-stage renal disease than did amlodipine, there were no significant differences between the two treatment groups in the rates of death from any cause, or in the cardiovascular composite end point [48]. The publication of the results of the ALLHAT study was literally front-page news. This very large, powered clinical outcomes trial in hypertension compared the diuretic chlorthalidone with newer agents, the ACE inhibitor lisinopril and the

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calcium antagonist (CCB) amlodipine [49]. Although the conclusion of the report that the diuretic was superior to the other drugs in preventing major cardiovascular events has generated much controversy, the results for the calcium antagonist amlodipine are clear-cut. Amlodipine performed well in ALLHAT. Although the heart failure findings need further clarification, it was notable that amlodipine not only equaled chlorthalidone for the primary coronary end point, but actually seemed to have a small advantage (albeit not significant) for both mortality and stroke prevention. In concert with the Syst-Eur study, the HOT Study, and the STOP 2 study, both IDNT and ALLHAT provide compelling support for the safety of the newer generation long-acting calcium antagonists. Do calcium antagonists enhance the risk of apoptosis? Apoptosis, a regulated form of cell death, may contribute significantly to cardiac myocyte loss in such conditions as heart failure and myocardial ischemia [73]. The recent controversy surrounding the safety of calcium antagonists was centered, in part, on these concerns [69,11,74]. Calcium and calcium-dependent processes play a major role in apoptosis and in other forms of catastrophic cell damage. The prominence of this role has led several investigators to raise concerns about the use of calcium antagonists in hypertension and heart disease. Specifically, they have expressed concern that these powerful agents may interfere with essential processes of cell growth control and promote the formation of tumors or that they may induce apoptosis in vulnerable tissues, such as the myocardium. The recent controversy surrounding the safety of calcium antagonists was centered, in part, on these concerns. Bishopric et al [73] have recently reviewed this topic in-depth and have concluded that calcium antagonists are not effective in initiating or promoting tumor growth. End-stage renal disease Among patients with end-stage renal disease, the annual mortality rate is nearly 25%. Cardiovascular diseases are the leading cause of death in patients receiving maintenance hemodialysis, especially in the first year of treatment [75]. A history of long-lasting arterial hypertension is associated with an increase in cardiovascular deaths in these patients [76]. Controlled studies are not available on the beneficial effect of antihypertensive therapy on patients in hemodialysis. There is unanimity, however, that maintaining a controlled blood pressure is of great importance for long-term survival [77,78]. Hypertension is the single most important predictor of coronary artery disease in uremic patients, even more so than cigarette smoking and hypertriglyceridemia [79]. There is a paucity of studies comparing different antihypertensive regimens in this patient population, and in


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clinical practice most nephrologists need to extrapolate results obtained from patients with relatively normal kidney function to patients with advanced kidney disease. A recent study supports the safety of calcium antagonists in hemodialysis patients. Tepel et al [81] have retrospectively studied the association of CCBs and mortality in 188 hemodialysis patients. After a follow-up of 30 months, 51 patients (27%) had died, and 72% of those died of cardiovascular causes. In the deceased group, age was significantly higher, smoking was more frequent, and body mass index was lower compared with the group that survived. The percentage of patients taking CCBs was significantly higher in the survival group than in the group of patients that died. Among patients assigned to CCB therapy, there was a significant reduction in mortality of 67% (P \ .001). Because of the retrospective nature of this study, a cause-effect relationship between CCB use and mortality cannot be established with certainty; however, at the very least the study suggests that use of CCBs in hemodialysis patients may be considered safe. Pleiotropic effects Several classes of drugs that are prescribed for the treatment of vascular disease, including statins and angiotensin-converting–enzyme inhibitors, have well described pleiotropic effects that have been accepted as contributing to their benefit. It is not as widely appreciated, however, that calcium antagonists potentially have similar beneficial effects that are related to their noncalcium–related pleiotropic actions. Mason et al [80] have recently viewed data demonstrating that at least one of the calcium antagonists, amlodipine, can regulate membrane fluidity and cholesterol deposition, stimulate NO production to recruit its biologic actions, act as an antioxidant, and regulate matrix deposition. Recognition of these ancillary actions of amlodipine is important for determination of the rational use of this and similar agents in the treatment of cardiovascular disease. Antiatherosclerotic properties As detailed in a recent review [82], changes in calcium transport mechanisms contribute to cellular changes in atherogenesis. Consequently, it has been proposed that pharmacologic calcium antagonists may be effective in slowing the progression of coronary artery disease. Recent studies have shown significant clinical benefits with the long-acting calcium antagonist amlodipine compared with placebo, including a marked reduction in cardiovascular morbidity. Amlodipine therapy also was associated with a significant slowing in the progression of carotid atherosclerosis, a strong surrogate marker for coronary artery disease, independently of blood pressure changes. The findings from PREVENT [83]

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were consistent with the recently reported results of CAPARES [84], in which amlodipine reduced the incidence of percutaneous transluminal coronary angioplasty (PTCA) and clinical events after PTCA without a reduction in luminal loss. A reduction in carotid atherosclerosis has recently been reported with lacidipine in the ELSA study [78]. These beneficial effects of the long-acting calcium antagonists in coronary artery disease may be attributed to distinct antiatherosclerotic properties related to its strong lipophilicity. Furthermore, the distinct ability of certain longacting calcium antagonists to interfere with mechanisms of lipid oxidative modification may represent an important antiatherogenic mechanism of action. Evidence in support of these hypotheses indicates a potentially new therapeutic role for long-acting calcium antagonist in the treatment of coronary artery disease. Of interest, the results from PREVENT and ELSA, induced the authors of the European Hypertension Guidelines to include carotid atherosclerosis as a possible indication for selecting a calcium antagonist [86]. Future perspectives It is important to note that several major studies are either ongoing or have recently been reported including ASCOT, VALUE, PREDICT, ACCOMPLISH, and CAMELOT/NORMALIZE [85]. We anticipate that these studies will further elucidate the attributes of calcium antagonists and their niche in the therapeutic armamentarium. Summary What, if anything, should physicians make of these apparently disparate hazards in a group of drugs that they prescribe so widely? The authors, and many of our colleagues, still believe that most patients clearly benefit from the judicious use of calcium antagonists. Reports of several large, powered prospective, randomized outcome studies including ALLHAT commend the use of long-acting calcium antagonists that, by virtue of their ability to attain more gradual and sustained plasma levels, do not evoke reactive sympathetic activation and consequently are safe. Concomitantly, such formulations should promote increased patient compliance and thereby favorably influence hypertensionrelated morbidity and mortality. Acknowledgments The authors wish to thank Dr. Jan Buch for his critical review of the manuscript and Elsa V. Reina for her secretarial assistance.


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Med Clin N Am 88 (2004) 167–187

Continued importance of diuretics and b-adrenergic blockers in the management of hypertension Marvin Moser, MD*, John Setaro, MD Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, Box 208017, New Haven, CT 06520–8017, USA

Thiazide diuretics were introduced in 1957 and became widely accepted as an effective, inexpensive, and generally well-tolerated antihypertensive treatment [1]. b-Blockers became available in the 1960s and were initially used in the therapy of angina pectoris, but soon found widespread application in treating high blood pressure [2]. Numerous large randomized clinical trials have subsequently demonstrated the effectiveness of these compounds in reducing morbidity and mortality in the hypertensive patient. This article reviews the actions of diuretics and b-blockers in blood pressure regulation; surveys early clinical trial evidence that firmly established their position in the modern antihypertensive armamentarium; and presents data from recent trials and guidelines that reaffirm the principal roles to be played by these medications in the prevention of cardiovascular and renal disease in the hypertension population, now numbering nearly 60 million in the United States.

Physiology and pharmacology Diuretics Available diuretic agents fall into four classes. Thiazide-type diuretics (including hydrochlorothiazide, chlorthalidone, methyclothiazide, and metolazone) interfere with renal sodium reabsorption in the early distal tubule (Fig. 1) [3]. These compounds are best used as antihypertensive

* Corresponding author. 13 Murray Hill Road, Scarsdale, NY 10583, USA. E-mail address: [email protected] (M. Moser) 0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/S0025-7125(03)00121-4

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Fig. 1. Site of action of various diuretic agents. Those that act proximally (ie, loop diuretics) act more rapidly but are less effective as antihypertensive agents. 1, loop diuretics; 2, thiazides; 3, potassium-sparing agents. (From Moser M. Clinical management of hypertension. 6th edition. Caddo, OK: Professional Communications; 2002; with permission.)

agents in patients who have normal or near normal serum creatinine values (1–2 mg/dL), with the exception of metolazone, which retains its diuretic properties despite the presence of renal impairment. Indoline derivatives (including indapamide) may also exert some diuretic action through inhibition of calcium influx into vascular smooth muscle cells. Loop diuretics (including furosemide, bumetanide, torsemide, and ethacrynic acid) are potent, rapidly acting compounds that exert their effects proximally and interrupt sodium reabsorption in the loop of Henle. These agents are effective in patients with renal impairment. Potassium-sparing diuretics (including amiloride, triamterene, spironolactone, and eplerenone) act in the distal tubule, preventing in part the exchange of sodium for potassium that occurs in this section of the tubule. Amiloride and triamterene directly inhibit potassium secretion and are effective in maintaining potassium balance, but both compounds are weak diuretics alone; they are frequently used with hydrochlorothiazide in combined preparations. Spironolactone and eplerenone inhibit aldosterone by competitive or direct blockade of the aldosterone receptor, respectively; both medications exhibit significant potassium-conserving and antihypertensive properties. The antihypertensive mechanism of diuretics comprises several phases. Initially, plasma volume decreases, with a decrease in cardiac output and systemic blood pressure [4]. Later, plasma volume returns toward normal, but blood pressure remains low with reduced peripheral vascular resistance (Fig. 2). This may be related to direct vasorelaxation mediated by effects on ion flux across arterial smooth muscle cells [5]. In contrast to higher doses previously used (50–200 mg hydrochlorothiazide), the use of as little as 12.5 mg results in significant blood pressure lowering in many patients. In the Systolic Hypertension in the Elderly Program (SHEP), low-dose chlortha-


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Fig. 2. Physiologic effects of diuretics. Initially plasma volume (a) and cardiac output (b) are decreased. Plasma volume gradually returns toward normal and cardiac output returns to normal after several weeks. The ultimate result of diuretic therapy is reduction of arterial resistance and blood pressure. A continuing increase in the activity of the renin-angiotensin system, however, is noted. This does not, in most cases, negate the blood pressure response, but can be counteracted in nonresponsive patients by the addition of small doses of an angiotensin converting enzyme inhibitor, a b-blocker, or an angiotensin II receptor blocker. (From Moser M. Clinical management of hypertension. 6th edition. Caddo, OK: Professional Communications; 2002; with permission.)

lidone (12.5 mg) lowered blood pressure to goal levels in nearly half of the study patients [6]. In patients who are responsive to diuretics, blood pressure is reduced in almost two-thirds of patients with 12.5 mg hydrochlorothiazide; an additional 15% respond to 25 mg. Up to 90% may respond to 50 mg daily; above this dose level side effects may be troublesome in certain patients. Compared with placebo, diuretics lower blood pressure by almost 10 to 15/5 to 10 mm Hg, showing a preferential effect on systolic blood pressure, an important consideration in caring for older patients who have isolated systolic hypertension [6]. Overall, in a randomized, nonselected population, diuretics reduce blood pressure to goal levels in about 50% to 60% of patients, a percentage as high as or higher than other antihypertensive medications. Black and elderly patients are more responsive to diuretics than younger or white individuals.

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Low-dose diuretics are also highly effective in lowering blood pressure when used with other agents, such as b-blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and calcium channel blockers. Using such combinations may result in normotensive levels in up to 80% of patients, whereas any type of monotherapy in the general hypertensive population may only be effective in 40% to 50% of patients. The mechanism for this beneficial effect of combination therapy may relate to the fact that diuretics may stimulate the renin-angiotensinaldosterone system because of the decrease in plasma volume that persists. Opposing the activation of this system through use of b-blockers, ACE inhibitors, and angiotensin receptor blockers augments blood pressure reduction [7]. b-Blockers b-Adrenergic receptor blockers, or b-blockers, inhibit the effects of badrenergic stimulation in various organs and body systems. b-Adrenergic stimulation leads to renin release; vasodilation; bronchodilation; increased heart rate and cardiac output; and an increase in insulin secretion, glycogenolysis, and gluconeogenesis in liver and peripheral muscle [8]. Blocking these effects tends to lower blood pressure, primarily by decreasing renin release and reducing cardiac output. b-Receptor selectivity is an important characteristic of b-blocking agents. Nonselective b-blockers (having peripheral and bronchial and cardiac effects) lower blood pressure by decreasing heart rate, cardiac output, myocardial oxygen demand, cardiac contractility, renin release, and the production of angiotensin II and aldosterone but may induce vasoconstriction and bronchoconstriction. Nonselective agents should be avoided or used with care in those patients with asthma or peripheral arterial obstructive disease. b1 selective agents, which have more of an effect on cardiac than peripheral b receptors, may be used in these patients but dosages should be kept in a range where selectivity is maintained. Nonselective agents may be difficult to use in insulindependent diabetic patients because of a theoretical concern that peripheral manifestations of hypoglycemia as part of an insulin reaction are masked and compensatory mechanisms that raise blood glucose levels are blunted. b1 selective blocking agents include acebutolol, atenolol, betaxolol, bisoprolol, and metoprolol. Propranolol, the first b-blocker to be extensively used, is nonselective, as are pindolol and nadolol. In addition to selectivity, b-blockers can be characterized by lipid solubility, and whether or not they possess intrinsic sympathomimetic activity (ISA). Lipid-soluble agents, such as propranolol and metoprolol, cross the blood-brain barrier. Their use may result in central nervous system side effects; they are activated more rapidly in the liver. Non–lipid-soluble agents, such as atenolol and nadolol, may have fewer central nervous system side effects, and are excreted more slowly by the kidney. Pindolol and


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acebutolol manifest ISA, a b2 agonist property that permits blood pressure lowering without significantly diminishing heart rate and cardiac output. This is a potentially useful characteristic in patients with borderline bradycardia, but the evidence that these agents are as effective in treating hypertension as the b-blockers without ISA is limited. Two agents, carvedilol and labetalol, have both b and a blocking (vasodilatory) capabilities. b-Blockers are particularly useful in hypertension for the treatment of young, white patients in whom the first physiologic manifestation of an elevated blood pressure may be an increase in heart rate and cardiac output. These agents are indicated in patients with resting tachycardias, angina, and post–myocardial infarction. A reduction of more than 20% to 30% in mortality and sudden death is noted in post–myocardial infarction patients when a b-blocker is given. In addition, these agents are useful in various arrhythmias and congestive heart failure once euvolemia and vasodilation have been achieved with diuretics, an ACE inhibitor, or an angiotensin receptor blocker. Recent clinical trial evidence indicates that carvedilol, bisoprolol, and metoprolol are effective as add-on therapy in congestive heart failure. Small doses of b-blocker–diuretic combination antihypertensive agents have been found to be as or more effective in reducing blood pressure than other antihypertensive agents in moderate dosages.

Early clinical trial evidence Most hypertension trials published before 1995 evaluated the use of diuretics and b-blockers. In some cases, centrally acting agents or vasodilators were added to achieve blood pressure goals. A meta-analysis of 17 placebo-controlled studies showed that patients treated with a diuretic or a diuretic and b-blocker–based treatment program achieved a 52% lower incidence of congestive heart failure, 38% decrease in stroke morbidity and mortality, 35% lower occurrence of ventricular hypertrophy, 21% less cardiovascular disease (CVD) mortality, and a 16% decrease in coronary events compared with placebo (Fig. 3) [9]. The natural progression to more severe levels of hypertension was dramatically reduced [9]. A similar analysis confirmed the favorable impact of a diuretic or b-blocker–based treatment program on stroke in 18 trials, with a lesser impact on coronary events [10]. Early trials included the Veterans Administration Study, which demonstrated a marked reduction in strokes using diuretics and other agents in moderately severe and severe hypertensive patients, with a trend toward improved coronary event outcomes [11]. The Hypertension Detection and Follow-up Program (HDFP), which was a diuretic-based trial, reported a 45% reduction in stroke mortality and a 20% reduction in coronary heart disease (CHD) mortality in the more intensively treated

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Fig. 3. Results of therapy. Effect of antihypertensive drug treatment on cardiovascular events (decrease in events, treated with compared controls). Combined results from 17 randomized, placebo-controlled treatment trials (48,000) subjects diuretic or b-blocker based.

group compared with a less aggressively treated group of patients [12]. The SHEP study compared diuretics (and b-blockers, if necessary) with a placebo group and reported a 54% reduction in heart failure, 30% fewer myocardial infarctions, 37% reduction in stroke, and a 25% lower rate of transient ischemic neurologic attacks in the treated compared with the placebo group [6]. Although b-blockers have been shown to reduce events in post– myocardial infarction patients, their role in preventing CHD events in hypertensive patients has not been as consistent as that of diuretics, although they have been protective against stroke when used as initial therapy in high blood pressure [6,13,14]. One trial reported that b-blockers were more protective against coronary events than diuretics in hypertensive patients [15], but the results of this study have been questioned. Most investigations have reported that diuretics are more effective, especially in the elderly. The First and Second Joint National Committees (JNC) on Detection, Evaluation and Treatment of High Blood Pressure in 1977 and 1980 [16,17] recommended diuretics as initial therapy as part of a stepped-care regimen. Beginning with the Third JNC in 1984, national guidelines indicated that diuretics and b-blockers were preferred agents for the initiation of antihypertensive treatment in most patients [18–20]. In the elderly the JNC VI recommended diuretics or diuretics in combination with b-blockers as preferred therapy, based on reduction of morbidity and mortality data from clinical trials where these medications were used [21]. JNC VII has recently recommended diuretics as initial therapy for most patients with bblockers as a possible alternative treatment or for use in special situations (angina, post–myocardial infarction, congestive heart failure, and so forth)


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[22]. These agents have stood the test of time and the results of comparative trials over the past 30 years have justified these recommendations (Table 1).

The question of tolerability and possible metabolic changes with diuretics and b-blockers Diuretics In general, diuretics are well tolerated. Two large double-blinded randomized controlled series reported that only 3% of diuretic-treated subjects withdrew because of side effects [23,24]. Yet important questions regarding treatment with these medications were raised by the observation that, in large clinical trials, antihypertensive therapy had resulted in major reductions in direct pressure-related complications (stroke, heart failure, renal dysfunction, and ventricular hypertrophy) but less impressive benefits for coronary artery disease end points (angina and fatal and nonfatal myocardial infarction). According to one viewpoint, atherosclerotic coronary artery disease is a complex, multifactorial, longitudinal process, the outcome of which may not be altered easily by a limited course of treatment aimed at only a single risk factor, hypertension. An alternate perspective held that the metabolic side effects of thiazide diuretics (electrolyte, lipid, and glucose changes) may negate favorable effects of blood pressure reduction. These criticisms have been addressed in some detail [9,25]. It is possible that the short duration of the diuretic-based treatment trials compared with the longer duration of epidemiologic followup accounted for the so-called short fall in benefit with CHD events. For example, a 12/4 to 5 mm Hg decrease in blood pressure should result in a decrease of about 20% to 25% in CHD events over a 10-year or more period of time. In the 3- to 5-year clinical trials, a blood pressure decrease of this degree only resulted in a 16% decrease. Did this represent a shortfall or just a shorter duration of follow-up [26]? Some data suggest that a longerterm reduction in blood pressure reduced CHD events to a greater degree than in the shorter-term trials. In addition, several recent thiazide diureticbased trials, especially in the elderly, have reported that CHD events are reduced to levels predicted by epidemiologic studies, and in a large comparative trial [27] the use of these medications reduced CHD events to the same degree as an ACE inhibitor or a calcium channel blocker despite some differences in lipids and blood glucose levels among the drugs. It is of interest to explore some of the metabolic abnormalities arguments as they relate to diuretics. Electrolytes Hypokalemia as a result of thiazide diuretics is dose related. Up to one third of patients experience a decrease in serum potassium in the range of 0.5 to 0.8 mEq/L on high doses of hydrochlorothiazide (50–100 mg daily). Less

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Table 1 Evolution of the recommendations of the Joint National Committees on Detection, Evaluation and Treatment of High Blood Pressure JNC II (1980) stepped-care [17]

JNC III (1984) stepped-care [18]

JNC IV (1988) individualized stepped-care [19]

JNC V (1993) modified stepped-care [20]

JNC VI (1977) [21]

JNC VII (2003) [22]

Diuretic or b-blocker

Uncomplicated hypertension:

Thiazide diuretics for most: may consider ACE-I, ARB, b-blocker, or combination

Alternative therapy: ACE inhibitor, CCB, a-b-blocker, or a1-blocker

Diuretic, b-blocker

Step 1

Diuretics

Diuretics

Less than full dose of diuretic b-blocker

Diuretic, b-blocker, calcium antagonist, or ACE inhibitor

Low-dose combination may be appropriate initial therapy Step 2 Add methyl dopa, reserpine or propranolol

Adrenergic inhibiting agents clonidine, methyldopa, b-blocking drugs, a1-blocker, rauwolfia

Add small dose of adrenergic inhibiting agent or thiazide-type diuretic

Add second drug of different class; increase dose of first drug or substitute a drug of a different class

Increase dose or substitute another drug, or add a second agent from a different class

Low-dose combinations in stage II patients

Specific Indications for ARB, ACE1, a-b-blocker, b-blocker, CCB and diuretic

Abbreviations: ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; JNC, Joint National Committees.


JNC I (1977) stepped-care [16]


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hypokalemia is observed at a dose of 25 mg hydrochlorothiazide (serum potassium a decrease of 0.3–0.4 mEq/L), and even less is noted at 12.5 mg/d of hydrochlorothiazide. Potassium-sparing diuretics can be recommended in patients who are particularly sensitive to hypokalemia, especially elderly individuals, those receiving digitalis preparations, or diabetic patients whose insulin use may be influenced by hypokalemia. A logical approach to thiazideinduced hypokalemia indicates the use of combination agents, such as spironolactone-thiazide or ACE inhibitor or ARB-thiazide. In each case the potassium-elevating tendency of the former component serves to offset any hypokalemia induced by the latter, but are the changes in potassium levels of clinical significance? Initial reports suggested that hypokalemia induced by thiazide diuretics could lead to increased ventricular ectopy, including ventricular tachycardia and sudden death [28]. In addition, in what was likely a statistical aberration, subjects with abnormal electrocardiograms in the special-care higher-dose diuretic group in the Multiple Risk Factor Intervention Trial were reported to experience a higher CHD mortality compared with usual-care patients who received smaller doses of the diuretics [29]. These results have been questioned, based on a careful analysis of the Multiple Risk Factor Intervention Trial data [30]. Nonrandomized prospective case-control studies also raised the possibility of increased sudden death in diuretictreated patients. Treatment groups were not adequately matched in these studies [31,32]. In carefully controlled 24- and 48-hour Holter monitoring studies using high doses (100 mg) of hydrochlorothiazide, however, no significant increase in simple or complex ventricular ectopy was noted, despite some degree of hypokalemia (Table 2) [33]. Ectopy was not significant before or after exercise in patients with or without left ventricular hypertrophy [6,24,33]. There had also been some question about the ability of diuretics to reduce left ventricular hypertrophy. Data have established that the lowering of blood pressure with a thiazide diuretic results in regression of left ventricular hypertrophy, itself a risk factor for ventricular ectopy [34]. With regard to the low serum potassium levels noted in diuretic-treated patients who experience a cardiac arrest, this can be explained as a consequence of endogenously released or exogenously administered epinephrine at the time of the cardiac event. This tends to drive potassium into cells, thereby lowering its serum concentration. Finally, more recent large trials using diuretics compared with placebo and diuretics compared with ACE inhibitors or calcium channel blockers showed no greater incidence of sudden cardiac death in the diuretic-treated groups [6,27]. In any case, concerns regarding treatment-related hypokalemia have decreased given the lower doses of diuretic therapy that are presently being used. Lipid changes Within the first year of treatment, thiazide diuretics may increase total and low-density lipoprotein cholesterol by about 5% to 7%, without alteration in

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Table 2 Ventricular Ectopy in patients with or without left ventricular hypertrophy before and after hydrochlorothiazide (50 to 100 mg/d for 4 w) LVH (N = 28)

LVPWT PK (mEq/L) PVC/h Total couplets Total VT episodes

No LVH (N = 16)

Baseline

Diuretic

Baseline

Diuretic

1.39 4.06 16.6 123 5

— 3.39 10.1 15 3

1.03 4.10 2.1 6 2

— 3.33 3 3 0

No increase in ectopy following high-dose diuretic therapy in subjects with or without LVH. Abbreviations: LVH, left ventricular hypertrophy; LVPWT, left ventricular posterior wall thickness; PK, plasma potassium; PVC, premature ventricular contractions; VT, ventricular tachycardia. Data from Papademetriou V, Burris JF, Notargiacomo A, Fletcher RD, Freis ED. Thiazide therapy is not a cause of arrhythmia in patients with systemic hypertension. Arch Intern Med 1988;148:1272–6.

high-density lipoprotein cholesterol concentration. Two small trials suggested that diuretics elevate lipids significantly [35,36], but these trials were not controlled or randomized. Large long-term clinical trials using diuretics, however, report no change or even a decrease in total cholesterol in the thiazide-treated groups [37]. Studies that showed no effect on lipids include the Medical Research Council Study [13], the Medical Research Council Study in the Elderly [14], the Metoprolol Atherosclerosis Prevention in Hypertension Study [15], and the Heart Attack Primary Prevention in Hypertension Study [38]. Other investigations have actually demonstrated improved lipid status in diuretic treatment study arms. For example, subjects in the HDFP experienced an overall decrease in total cholesterol (232–223 mg/dL) in the active diuretic treatment (special care) group [39], as did diuretic-treated patients in several other large prospective trials. These studies include the Multiple Risk factor Intervention Trial [29], the European Working Party on High Blood Pressure in the Elderly Study [40], the Treatment of Mild Hypertension Study [24], the Anti-hypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) [27], and the Verapamil in Hypertension Atherosclerosis Study [41]. In the latter 2-year study changes in lipids were similar in the lipid-neutral calcium channel blocker and diuretic arms of the trial. It should be noted, however, that a significant number of ALLHAT subjects were taking statin agents by the end of the trial as part of the study protocol. Despite a slightly higher average cholesterol concentration in the diuretic compared with the lisinopril or amlodipine groups at the conclusion of ALLHAT, coronary disease rates were similar among study arms [27]. In SHEP and HDFP, cardiovascular morbidity and mortality were reduced by the use of diuretics irrespective of whether participants had high or low baseline serum cholesterol values [6,39].


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On the basis of these observations, it can be concluded that the long-term effects of thiazide diuretics on lipid levels are minimal and probably are of limited clinical significance [42,43]. Patients can be treated safely with thiazide diuretics whatever their lipid status, particularly in light of the availability of statin lipid modifying drugs. Glucose and insulin metabolism Thiazide diuretics may exert unfavorable influences on insulin sensitivity and glucose utilization, but evidence of adverse clinical effects in large clinical trials is lacking [44]. This is an important issue given the cardiovascular risks inherent in insulin resistance and abnormal glucose tolerance, particularly in light of the rising prevalence of obesity and type 2 diabetes in the United States. In multiple trials involving diuretics, fasting glucose changes are minimal, and when data are pooled, diabetes is increased by only 0.6% above placebo [6,13,38–40,45]. Given the older population who usually has been studied in the clinical trials and who, in all probability, had a degree of increased insulin resistance, for several or many years prior to entering a trial a higher rate of overt diabetes would have been anticipated over the trial period if diuretics were indeed causative factors in diabetes. Although hypertensive patients tend to develop diabetes more frequently than normotensive patients, those treated with diuretics do not require antidiabetic therapy any more often than those receiving other blood pressure–lowering agents (Fig. 4) [46].

Fig. 4. Risk of hyperglycemia with use of antihypertensive drugs. Risk for development of hyperglycemia requiring treatment with antidiabetic drugs in users of antihypertensive drugs relative to nonusers. Note increased risk overall in hypertensive subjects compared with nonhypertensives, but no difference between drugs. (From Gurwitz JH, Bohn RL, Glynn RJ, Monane M, Mogun H, Avorn J. Antihypertensive drug therapy and the initiation of treatment for diabetes mellitus. Ann Intern Med 1993;118:273–8; with permission.)

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The ALLHAT study confirmed a small rise in serum glucose and an absolute increase of 3.5% in new-onset diabetes in the diuretic compared with the lisinopril group (11.6% compared with 8.1%), but this finding did not translate into a greater frequency of adverse cardiovascular outcomes in the thiazide diuretic group [27]. In diabetic subjects in ALLHAT, patients receiving diuretics achieved the same CHD outcomes as with the ACE inhibitor or calcium channel blocker and had fewer strokes and episodes of heart failure compared with lisinopril. Heart failure was less in both diabetic and nondiabetic groups in the thiazide-treated patients compared with the amlodipine group [27]. In the Controlled Onset Verapamil Investigation of Cardiovascular End Points Trial, diabetic subjects fared equally well in terms of cardiovascular end points whether they were assigned to verapamil, a diuretic, or a b-blocker [47]. In most trials diabetic patients treated with diuretics achieved fewer cardiovascular events than nondiabetics, illustrating the safety and efficacy of diuretics in these patients [48]. Fig. 5 depicts data with diabetic and nondiabetic subjects from the SHEP trial [6]. The need to lower blood pressure aggressively using effective agents in type 2 diabetics was underscored in the United Kingdom Prospective Diabetes Study Group trial [49], in which tighter versus less strict blood pressure control was linked to better cardiovascular outcomes. A difference of ÿ10/ÿ5 mm Hg between the two groups resulted in a dramatic decrease in both microvascular and macrovascular events. There was no difference in outcome between an ACE inhibitor and a diuretic and b-blocker–based treatment group [49]. A summary of the possible metabolic changes resulting from the use of diuretics is noted in Table 3 and reviewed in detail in other publications [50].

Fig. 5. Reduction in morbidity and mortality in diabetic and nondiabetic subjects in the SHEP study. The SHEP study: low-dose diuretic as initial therapy; b-blocker added if necessary. CABG, coronary artery bypass surgery; MI, myocardial infarction; SCD, sudden cardiac death; SHEP, Systolic Hypertension in the Elderly Program Cooperative Research Group. Open bars represent the diabetic therapy group (283 subjects) and placebo group (300 subjects). Filled bars represent the nondiabetic therapy group (2080 subjects) and placebo group (2069 subjects).


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Table 3 Potential metabolic changes with diuretic use Metabolic change

Comments

Hypokalemia

Less marked with lower dosages; avoid if possible, especially in diabetics and patients receiving digitalis Short term: an increase of 5% to 7% in total cholesterol and low-density lipoproteins (may be less with smaller doses); no effect on high-density lipoproteins. Long term: little effect; cardiovascular events reduced to the same degree in subjects with hyperlipidemia or normal cholesterol levels Insulin resistance increased, but only slight increase in blood glucose levels in long-term trials in diuretic-treated compared with placebo subjects. Overall cardiovascular mortality reduced to same or greater degree in diabetics than in nondiabetics Gout in less than 3% of patients; if diuretic essential to management, allopurinol can be given May be advantage in treatment of osteoporosis and prevention of fractures

Hyperlipidemia

Increased insulin resistance

Hyperuricemia Hypercalcemia

Modified from Moser M. Diuretics in the management of hypertension. Med Clin North Am 1987;71:935–46; with permission.

Angiotensin receptor blockers have been shown to slow or reverse the progression of nephropathy in type 2 diabetic patients and prevent the occurrence of end-stage renal disease. They are clearly indicated in these patients [51–53]. Yet because many diabetic patients are sodium sensitive and volume expanded, a thiazide diuretic is usually a necessary part of multidrug therapy if blood pressure goals (130/80 mm Hg) are to be achieved [22,54]. Indeed, almost every trial in the past 30 or more years has been a multidrug trial and a thiazide diuretic has most often been part of the regimen. Several trials have demonstrated prevention of new-onset type 2 diabetes with pharmacologic inhibitors of the renin-angiotensin-aldosterone system. These include captopril in the Captopril Prevention Project, ramipril in the Heart Outcomes Prevention Evaluation study, and losartan in the Losartan Intervention for Endpoint reduction in hypertension study [55–57]. A significant proportion of patients in these studies also required diuretic therapy to attain blood pressure goals; in patients who are obese or who have a family history of diabetes, it may be logical to commence antihypertensive therapy with a combination diuretic and ACE inhibitor or diuretic and angiotensin receptor blocker. b-Blockers Although fatigue is sometimes noted as a b-blocker side effect, it is not clear whether it is related to reduced cardiac output or central nervous system effects. Using modest doses of non–lipid soluble preparations may be

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helpful. It should be noted, however, that in randomized studies of bblockers, diuretics, and ACE inhibitors, selective b-blockers demonstrated similar quality of life measures, and in the Treatment of Mild Hypertension Study, b-blockers and diuretics were associated with improved quality of life compared with other agents [24]. The long-term use of b-blockers may result in elevated triglyceride levels and slightly reduced high-density lipoprotein cholesterol levels [58], effects that are less prominent with agents that are selective or that possess ISA. Nonetheless, b-blockers have demonstrated highly significant benefits in reducing morbidity and mortality post–myocardial infarction, and in a 9year study showed significant cardiovascular benefits in a type 2 diabetic population [49]. A major trial in the elderly [14] that reported less benefit on CHD events with a b-blocker compared with a diuretic was unblinded. Results are difficult to assess based on the large number of patients who were lost to follow-up or discontinued therapy. Nevertheless, as noted, these agents are generally less effective in lowering blood pressure in the elderly than diuretics and, as recommended by the JNC VI, may best be used in combination for effective therapy. In JNC VII, they are specifically indicated in patients post–myocardial infarction, with angina, and so forth.

Recent trials and an update on recommendations Recent studies have reaffirmed the role of diuretics as initial therapy for most high blood pressure patients [22]. The benefit of b-blockers is also not in dispute as an add-on agent or in combination with a diuretic as initial therapy. For other patients, including those with resistant hypertension, diabetes, or renal impairment (where goals are now lower than previously set [130/80 mm Hg]), diuretics and in many cases b-blockers may still be used as part of a multidrug regimen [22,54,59,60]. Frequently in these situations the use of a diuretic with an ACE inhibitor or an ARB and in some cases a calcium channel blocker is indicated. In many recent and older controlled prospective trials, the importance of diuretics as part of a treatment program has been validated. In several of these trials b-blockers were also used. The following points are noted: (1) In diabetic hypertensive patients, a regimen of b-blockers and diuretics and the achievement of tight blood pressure control produced favorable cardiovascular outcomes over an 8.5-year period (Table 4) [49]; (2) In the Controlled Onset Verapamil Investigation of Cardiovascular End Points Trial, the use of a calcium channel blocker did not prove to be superior to either b-blocker or thiazide diuretic in preventing adverse cardiovascular events [47]; (3) In the Perindopril Protection Against Recurrent Stroke Study investigation, the ACE inhibitor perindopril required the addition of the diuretic indapamide before significant benefit could be demonstrated in reducing stroke and


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Table 4 Comparative study of ACE inhibitor and b-blocker–based treatment program in UKPDS Number of patients in study (non–insulin dependent diabetics): 1148 Tight blood pressure control; achieved blood pressure of 144/82 mm Hg compared with group with blood pressures of 154/87 mm Hg d Reduction in cardiovascular risk – tight: less effective blood pressure control d % Reduction in events Strokes 44 Heart failure 56 Deaths related to diabetes 32 Microvascular disease 37 Myocardial infarction and sudden death (not significant) 21 No difference in outcome between different treatment groups; difference in achieved blood pressure accounted for difference in outcome. d d

From United Kingdom Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: (UKPDS). BMJ 1998;317:703–13.

transient ischemic neurologic attacks in hypertensive patients who had suffered a stroke [61]; (4) The Multicentre Isradipine Diuretic Atherosclerosis Study found fewer cardiovascular events in a diuretic group compared with a short-acting dihydropyrimidine calcium channel blocker [62]; (5) In the Verapamil in Hypertension and Atherosclerosis Study, there was no difference in cardiovascular event outcome between long-acting verapamil and diuretic therapy [41]; (6) In the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment there was no overall difference in cardiovascular events with long-acting nifedipine compared with a diuretic and potassium-sparing combination. Although the numbers were small, the diuretic group experienced fewer fatal myocardial infarction and heart failure events [63]; (7) In the NORDIC Diltiazem trial there was no overall difference in primary end points between a diltiazem and a b-blocker–diuretic combination. There were fewer strokes, however, in the diltiazem group but a trend toward higher rates of Mis, cardiovascular deaths, and congestive heart failure in the calcium channel blocker group [64]; (8) The Swedish Trial in Old Patients with Hypertension-2 also failed to demonstrate a difference in outcomes among older hypertension patients treated with diuretics and b-blockers, calcium channel blockers, or ACE inhibitors [65]. None of these trials have demonstrated a long-term mortality-morbidity benefit of the newer agents (ie, ACE inhibitors or calcium channel blocker) when compared with a diuretic or a diuretic and b-blocker combination. The Anti-hypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Some details of the most recent trial, the ALLHAT [27], which was published in late 2002, are of interest. Thirty-three thousand hypertensive

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patients were studied over a 5-year period. It was designed to assess differences in cardiovascular outcomes among patients treated with a diuretic (low-moderate dose of chlorthalidone); a calcium channel blocker (amlodipine); or an ACE inhibitor (lisinopril). An earlier a-adrenergic blocker arm of the study (doxazosin) had been discontinued when it became clear to investigators that there was a significant excess in congestive heart failure events in the doxazosin group compared with the diuretic group. To reach goal blood pressure in ALLHAT, b-blockers, reserpine, clonidine, or hydralazine could be added as second- or third-line agents. The study participants averaged 67 years of age and represented a high-risk group for cardiovascular outcomes. Thirty-five percent were black and 36% were diabetic. At the end of 5 years there were no differences in the primary outcome of coronary events or CHD deaths among the three drugs. There were, however, fewer overall cardiovascular events in the diuretic group. For example, compared with lisinopril-treated patients, the diuretic cohort had fewer strokes and heart failure events, particularly in black patients. Compared with amlodipine-treated patients, the diuretic group had a reduced occurrence of severe heart failure events leading to death or hospitalization. Some of the differences may be explained by overall blood pressure differences among the groups. There was a 4 mm Hg lower average systolic blood pressure in blacks who were treated with diuretics compared with lisinopril and a 3 mm Hg lower systolic blood pressure in patients over 65 years of age. The ALLHAT study has been criticized because of protocol limitations but on balance the data are consistent with other trials. Previous clinical and investigator experience indicate that hypertensive patients respond as well or better to diuretic agents compared with other compounds. In addition, combination therapies that contain a diuretic have been shown to be more effective than those that do not include a diuretic. The equivalent primary outcome results and the more favorable secondary end point results for the diuretic-treated group in ALLHAT tend to counter arguments that metabolic effects of diuretic drugs detract from their potential to reduce cardiovascular events compared with other agents [66]. Because more than half of the ALLHAT study participants did not reach goal blood pressure on monotherapy, multidrug treatment was required; the study findings suggest that at least one of the drugs should be a diuretic. Based on ALLHAT and the previous trials, the JNC VII affirmed that diuretics be considered as first-step therapy in most patients, acknowledging that many if not most patients require a multidrug program [22]. The committee recognized compelling or specific reasons for using other agents (b-blockers, ACE inhibitors, angiotensin receptor blockers, or calcium channel blockers). These indications include heart failure, diabetes, diabetic nephropathy, and so forth or in some instances possibly to prevent diabetes


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in individuals at risk. Most patients who are given these medications also require a diuretic in some form to achieve goal blood pressures. Perhaps more important than the question of how one begins therapy is the question of how one ends it. For most hypertension patients that ending consists of a multidrug program. The Australian National Blood Pressure-2 trial The recently reported Australian National Blood Pressure study noted a marginally significant benefit in reducing CVD events from ACE inhibitor–based therapy compared with a diuretic-based regimen [67]. Benefit was noted only in men. Less than two thirds of patients remained on the original study drug and the demographics of this trial were different from those of ALLHAT. The results of this study do not negate previous data but indicate that ACE inhibitor–based therapy is also highly effective in reducing the complications of hypertension. Summary The use of thiazide diuretics as one of the preferred antihypertensive medications has stood the test of time. Since the introduction of orally effective agents in 1957 to 1958, these drugs have continued to prove their usefulness. Numerous clinical trials have confirmed that these medications are as or more effective in reducing blood pressure and cardiovascular events than any of the other effective antihypertensive agents. Although some metabolic changes may occur with higher dosages of these medications, they seem to be of limited clinical significance. In addition to being well tolerated and effective, thiazide-type diuretics are less expensive than other agents. This should be considered in view of the fact that quality of care is not compromised when the less expensive medication is used. b-Blockers should also be considered as a major drug class in the management of hypertensive patients. There are few studies directly comparing these drugs with other agents. Although some data suggest that they are less effective in reducing CHD events in the elderly, there are numerous situations where b-blockers are clearly indicated. Combination therapy with a b-blocker and diuretic has been shown to be highly effective in reducing cardiovascular events in both diabetic and nondiabetic patients. References [1] Moser M, Macaulay AI. Chlorothiazide as an adjunct in the treatment of essential hypertension. Am J Cardiol 1959;3:214. [2] Prichard BNC, Gillam PMS. Use of propranolol in the treatment of hypertension. BMJ 1964;2:725–7. [3] Moser M. Clinical management of hypertension. 6th edition. Caddo, OK: Professional Communications; 2002.

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[46] Gurwitz JH, Bohn RL, Glynn RJ, Monane M, Mogun H, Avorn J. Antihypertensive drug therapy and the initiation of treatment for diabetes mellitus. Ann Intern Med 1993; 118:273–8. [47] Black HR, Elliott WJ, Grandits G, et al, for the Research Group. Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular Endpoints () Trial. JAMA 2003;289:2073–82. [48] Curb JD, Pressel SL, Cutler JA, et al. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. JAMA 1996;276:1886–92. [49] United Kingdom Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: (UKPDS). BMJ 1998;317:703–13. [50] Moser M. Diuretics in the management of hypertension. Med Clin North Am 1987;71: 935–46. [51] Brenner BM, Cooper ME, DeZeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861–9. [52] Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851–60. [53] Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P, et al, for the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345:870–8. [54] Bakris GL. A practical approach to achieving recommended blood pressure goals in diabetic patients. Arch Intern Med 2001;161:2661–7. [55] Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin converting enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomized trial. Lancet 1999;353:611–6. [56] Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of an angiotensin converting enzyme inhibitor, ramipril, on cardiovascular events in high risk patients. N Engl J Med 2000;342:145–53. [57] Dahlof B, Devereux RB, Kjeldsen SE, et al, for the LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet 2002;359:995–1003. [58] Weir MR, Moser M. Diuretics and b-blockers: Is there a risk for dyslipidemia? Am Heart J 2000;139:174–84. [59] Yakovlevitch M, Black HR. Resistant hypertension in a tertiary care clinic. Arch Intern Med 1991;151:1786–92. [60] Setaro JF, Black HR. Refractory hypertension. N Engl J Med 1992;327:543–7. [61] PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood pressure lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet 2001;358:1033–41. [62] Borhani NO, Mercuri M, Borhani PA, et al. Final outcome results of the Multicentre Isradapine Diuretic Atherosclerosis Study (MIDAS): a randomized controlled trial. JAMA 1996;276:785–91. [63] Brown MJ, Palmer CR, Cataigne A, et al, for the INSIGHT Study Group. Morbidity and mortality in patients randomized to double blind treatment with a long acting calcium channel blocker or diuretic in the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet 2000;356:366–72. [64] Hansson L, Hedner T, Lund-Johansen P, et al, for the NORDIL Study Group. Randomised trial of effects of calcium antagonists compared with diuretics and beta-


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blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem Study. Lancet 2000;356:359–65. [65] Hansson L, Lindholm LH, Ekbom T, et al. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity in the Swedish Trial of Old Patients with Hypertension-2 Study (STOP-2). Lancet 1999;354: 1751–6. [66] Moser M. Results of ALLHAT: Is this the final answer regarding initial antihypertensive drug therapy? Arch Intern Med 2003;163:1269–73. [67] Wing LMH, Reifel CM, Ryan P, et al. A comparison of outcomes with angiotensin converting enzyme inhibitors and diuretics for hypertension in the elderly. Australian National Blood Pressure Study 2. N Engl J Med 2003;348:583–92.

Med Clin N Am 88 (2004) 189–207

What have we learned from the current trials? Kevin C. Abbott, MDa,b, George L. Bakris, MDc,* a

Nephrology Service, Walter Reed Army Medical Center, 6900 Georgia Avenue, Building 2, Ward 48, Washington, DC 20307–5001, USA b Department of Medicine, Uniformed Services University of the Health Sciences, Washington, DC, USA c Clinical Research Center, Department of Preventive Medicine, Rush University Medical Center, 1700 West Van Buren Street, Suite 470, Chicago, IL 60612, USA

The twenty-first century has opened with an explosion of landmark randomized clinical trials assessing the impact of therapeutic agents on outcomes in hypertensive patients. The trials discussed in this article are in the opinion of the authors the most significant studies of the new century in several categories: (1) assessment of the impact of agents on incident cardiovascular disease in high-risk patients in the general population (ie, in patients at high risk for but not exclusively those with known prevalent disease) [1–3]; (2) progression of renal disease in patients with type II diabetes [4–6]; and (3) outcomes in high-risk ethnic subgroups (ie, African Americans) [7,8]. Agents featured include diuretics versus angiotensinconverting enzyme (ACE) inhibitors or calcium channel blockers (CCBs) for de novo events, angiotensin receptor blockers (ARB) for progression of diabetic renal disease, and ACE inhibitors versus CCBs in African Americans with hypertensive nephropathy. The demographic makeup, follow-up time, interventions, and outcomes of these trials are summarized in Table 1. It should be noted that early termination occurred in three of these trials: (1) in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT) trial [1], the a-blocker arm (represented by doxazosin) was terminated early because of a relative excess rate of hospitalized congestive heart failure; (2) the Controlled Onset Verapamil Investigation of Cardiovascular Endpoints trial [3] was halted early for commercial reasons; and (3) in the AASK trial [7], the amlodipine arm was

* Corresponding author. E-mail address: [email protected] (G.L. Bakris). 0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/S0025-7125(03)00129-9

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Table 1 Summary of Cardiovascular and Kidney Outcome Trials from 2001 to the present

De novo CVD ALLHAT [1]

ANBP2 [2]

Population

North American patients Mean age: 67 age 55 with HTN 47% female and at least one other 35% black cardiac risk factor. 19% Hispanic 36% diabetes Excluded patients with known CHF and serum creatinine 2 mg/dL Mean age 72 Age 65–84, with HTN, 49% male absence of CV events in 100% white or past 6 mo; excluded serum Australian creatinine 2.5 mg/dL Aborigines 7% diabetes

CONVINCE [3] Age 55 with HTN and at least one other risk factor Renal disease progression in type II diabetes RENAAL [4] Type II diabetes age 31–70 with nephropathy

Man Age 65 56% female 6.9% black 19.9% diabetes

N

Mean SBP Follow-up, achieved, 1 mean years year, mm Hg

33,357 4.9 1.4

6083 4.1

Mean SBP achieved, end of study, mm Hg

GFR

Outcomes

133.9 Chlorthalidone 134.7 group: 136.9 Amlodipine: 138.5 135.9 Lisinopril: 140

70.0a 75.1* 70.7

CHDb 11.5 11.3 11.4

ACEc: 147 Diureticd: 146

Not given

All CVD events and death from any causee 56.1* 59.8 (significant reduction in CVD events for males only) MI, stroke, of CV death: 4.94% 4.73% Outcomes in #/100 person years

16,602 3

ACE: 141 Diuretic: 142

Verapamil: 136.5 Atenolol or HCTZ: 136.6

SBP at study end, mm Hg

Mean age 60 36.8% female 15.2% black

1513 3.4

Losartan: 146 Placebo: 150

140 142

Doubling of serum creatinine, ESRD, or death 15.9* 18.1

K.C. Abbott, G.L. Bakris / Med Clin N Am 88 (2004) 189–207

Study

Baseline demographics

IDNT [5]

Type II diabetes age 30–70, HTN and proteinuria

Mean age 58 68.7% male 2.6% nonwhite

1715 2.6

590 2

Irbesartan: 141 Amlodipine: 142 Placebo: 144

Doubling of serum creatinine, ESRD, or death 32.6%* 41.1% 39% UAE 200 mg/min 9.7% 5.2%* 14.9%

Irbesartan 150 mg: 143 Irbesartan 300 mg: 141 Placebo: 144

Rates for death and ESRD per 100 person years

Mean age 54.5 38.5% female

1094

Ramipril: 135 Amlodipine: 133 Metropolol: 135

D GFRf Ramipril 0.34 vs amlodipine Ramipril þ 0.61 vs metropolol* Metropolo þ 1.08 vs amlodipine*

ESRD: Ramipril 3* Amlodipine 4.3 Death: ramipril 1.1* Amlodipine 1.6

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Abbreviations: CHD, coronary heart disease; CHF, congestive heart failure; CVD, cardiovascular disease; ESRD, end-stage renal disease requiring dialysis or kidney transplantation; GFR, glomerular filtration rate; HTN, hypertension; UAE, urinary albumin excretion in an overnight urine collection. * P \ .001 vs other medication groups in study. a mL/min/1.73 m2 by MDRD formula. b Composite coronary heart disease, 6-year rate per 100 persons. c Initially enalapril, but could be changed by primary provider. d Initially hydrochlorothiazide, but could be changed by primary provider. e Rate per 1000 person years. f Assessed by iothalamate clearance, mL/min/1.73 m2 per year.


Irbesartan in Type II diabetes and microalbuminuria patients with type 2 diabetes and microalbumrinuria study [6] Renal disease progression in African Americans with hypertensive nephropathy AASK [7,8] African Americans age 18–70 with hypertensive renal disease

Mean age 59 66% male 13.3% black

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terminated early because of a relative excess rate of end-stage renal failure and death in comparison with ramipril. Cardiovascular disease In the field of hypertension the ALLHAT trial was the largest ever completed with more than 42,000 participants. Because of its potential impact and size, the release of the Seventh Joint National Committee recommendations for the treatment of hypertension was delayed pending its publication [9]. A summary of the study’s composition, objectives, and outcome findings is shown in Table 1. ALLHAT was a large multicenter trial of older hypertensive patients with additional risk factors for heart disease including previous myocardial infarction or stroke occurring more than 6 months before the study start, or other documentation of atherosclerotic heart disease. Patients with known heart failure or poor left ventricular systolic function were excluded from the study, similar to the HOPE trial [10]. The stated objectives of the ALLHAT study were to determine ‘‘whether the occurrence of fatal [coronary heart disease] or non-fatal myocardial infarction is lower for high-risk patients treated with a calcium channel blocker [amlodipine], an angiotensin converting enzyme inhibitor [lisinopril] or an alpha blocker [doxazosin], each compared with diuretic treatment [chlorthalidone].’’ The choice of agents for each arm, from today’s perspective, seems somewhat curious. In particular, the choice of chlorthalidone as the diuretic agent in this trial was somewhat controversial because, among thiazide diuretics, chlorthalidone is used less commonly than hydrochlorothiazide (HCTZ) in the United States, and consequently many providers are less familiar with it than with HCTZ. It was chosen, however, because in other clinical trials it reduced cardiovascular mortality. The choice of lisinopril was logical, because at the time the trial started it was the most commonly used once-daily ACE inhibitor. Since then, however, the most convincing evidence of a benefit of ACE inhibitors on reducing cardiovascular events comes from higher doses of ACE inhibitors, such as 40 mg lisinopril or 10 mg ramipril, used in concert with thiazide diuretics not b-blockers as was generally the case in ALLHAT [10]. Lisinopril is known to reduce early postmyocardial infarction mortality in diabetic patients at an average dose above 30 mg per day [11]. The choice of amlodipine, a dihydropyridine (DHP) CCB, was also somewhat controversial, given initial reports of significantly higher rates of fatal and nonfatal myocardial infarction among patients receiving the DHP CCB nisoldipine than among those assigned to receive the ACE inhibitor enalapril [12], although a late effect on mortality with long-acting DHP CCB was not replicated in later studies [13]. Similar controversy did not exist for the use of non-DHP CCB, such as diltiazem or verapamil, although these agents had not been directly compared with ACE inhibitors [14,15]. The a-blocker arm had to be discontinued early because of a high incidence of heart failure and


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accompanying increases in morbidity. Add-on therapy consisted of atenolol, clonidine, and reserpine, with hydralazine if necessary. Combination ACE and diuretic (9.3% in the chlorthalidone arm and 15.7% in the lisinopril arm) and CCB and diuretic (5.8% in the chlorthalidone arm and 16.6% in the amlodipine arm) did occur by 5 years. This may have been a major factor to explain the overall 5 mm Hg per year systolic blood difference, until the final year, between the ACE inhibitor and diuretic group, an effect that probably contributed to the final outcome. Aside from the choice of medications, the treatment arms were remarkably well matched for all major characteristics, and medication adherence, followup time, and cross-overs. The study was well-powered and appropriately designed to assess equivalence [16]. Because of the large size of the cohort these differences, although statistically significant, were of modest clinical significance when assed in the final year of the trial (2 mm Hg for the difference between chlorthalidone and lisinopril at 5 years [Fig. 1]). The study found no differences in the 6-year rate of the primary outcome, defined as fatal coronary heart disease or nonfatal myocardial infarction combined (Fig. 2). Among secondary outcomes, the lisinopril arm had a significantly adjusted higher rate of stroke and combined cardiovascular disease compared with chlorthalidone, whereas amlodipine did not. Both amlodipine and lisinopril had significantly higher adjusted rates of heart failure compared with chlorthalidone, whereas lisinopril had a higher adjusted rate of angina compared with chlorthalidone. Interestingly, the event rates for lisinopril and amlodipine for each of these outcomes were

Fig. 1. Achieved blood pressure for various treatment arms in the ALLHAT study. The chlorthalidone arm achieved a statistically significant lower blood pressure in comparison with lisinopril over the course of the study, with an absolute difference in systolic blood pressure of 2 mm Hg. (From ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensinconverting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981–97; with permission.)

194 K.C. Abbott, G.L. Bakris / Med Clin N Am 88 (2004) 189–207

Fig. 2. Time to primary outcomes for the ALLHAT study by treatment arm. As shown, there were no significant differences between groups. (From ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensinconverting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981–97; with permission.)


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identical; however, in multivariable analysis, lisinopril, but not amlodipine, was statistically significant. The actual difference in 6-year event rates between lisinopril and chlorthalidone in each case was 0.1 per 100 persons. Although numbers needed to harm were not given in the study, this difference equals 10 patients (95% confidence interval, 9 to 11) who would need to be treated with lisinopril or amlodipine over 6 years, respectively, in comparison with chlorthalidone, to result in one additional case of heart failure. In timeto-event analysis, both amlodipine and lisinopril had higher risk than chlorthalidone from the beginning of the study. After 3 to 4 years, however, the rate of heart failure seemed to be higher for amlodipine than for lisinopril (Fig. 3). Differences for these outcomes were fairly uniform among subgroups, including differences by age, gender, race, and diabetic status. Among other outcomes, angioedema was significantly most common for users of lisinopril, as expected. Among metabolic complications, hypercholesterolemia, hyperglycemia, and hypokalemia were all significantly more common among users of chlorthalidone than either the amlodipine or lisinopril group. The mean serum potassium for the chlorthalidone group at the end of 5 years was 4.1 (0.7) mEq/L, however, and 8.5% of patients had serum potassium of less than 3.5 mEq/L compared with 1.9% for amlodipine and 0.8% for lisinopril. The authors noted no significantly increased risk of bleeding or cancer associated with use of amlodipine. The findings of Psaty et al [17], which indicated an increased risk of myocardial infarction associated with use of short-acting nifedipine, and an increased risk of gastrointestinal hemorrhage associated with CCB use [18], were not replicated in this large, prospective, randomized trial. Although the mean serum creatinine for the cohort was 1 mg/dL, some patients did reach end-stage renal disease and a glomerular filtration rate (GFR) slope was plotted for all patients. Results of this subgroup analysis will be published later. From a renal standpoint, proteinuria was not measured, so whether lisinopril or amlodipine had different effectiveness compared with chlorthalidone in patients with proteinuria cannot be answered by the ALLHAT study. The authors concluded that use of chlorthalidone in hypertensive, high cardiovascular risk patients was associated with a similar risk of cardiovascular events equivalent to that of CCB and ACE (and perhaps superior for outcomes, such as heart failure) and in general was well tolerated. The Angiotensin Converting Enzyme Inhibitors and Diuretics for Hypertension in the Elderly (ANBP2) trial [2] has been cited as contradicting the results of the ALLHAT trial (see Table 1). Using both a different ACE inhibitor (ramipril) and diuretic (HCTZ) than the ALLHAT trial, the study also found a statistically significant difference (P ¼ .05) between the two agents in its primary outcome, defined as the combination of all cardiovascular events or death from any cause, and myocardial infarction. In subgroup analysis, these differences were observed only in male subjects. Add-on therapy consisted of b-blockers, CCBs, and a-blockers.

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Fig. 3. Time to heart failure, a secondary outcome for the different treatment arms in the ALLHAT study. The risk for chlorthalidone was consistently less than for either amlodipine or lisinopril; however, the risk for amlodipine and lisinopril seemed to differentiate between 3 and 4 years, although this was not statistically significant. (From ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981–97; with permission.)

The percentage of patients who were on combination therapy, specifically combined ACE-CCB therapy, which has been associated with improved tolerability and stabilization of proteinuria in diabetic nephropathy [19], was not specified. Table 1 illustrates substantial differences between the two studies: the ANBP2 cohort was smaller, older, with fewer diabetics and blacks, and also had a higher serum creatinine level for exclusion. Detailed


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information on patient renal function was not given. Aside from differences in the medications used, however, perhaps the most important difference between the ANBP2 trial and ALLHAT was the achieved systolic blood pressures. Recent studies have shown that intensive blood pressure control (defined as mean systolic blood pressure 128 mm Hg versus 137 mm Hg) was associated with a significantly lower risk of cardiovascular events even in patients with established peripheral vascular disease [20], but with no difference between an ACE inhibitor and a CCB. The ANBP2 cohort may also have contained a higher proportion of patients with a serum creatinine greater than or equal to 1.4 mg/dL, a group that specifically benefited from the use of ramipril in a reanalysis of the HOPE trial [21]. The Controlled Onset Verapamil Investigation of Cardiovascular Endpoints trial [3] was designed to assess equivalence between controlled-onset extended-release verapamil with a physicians’ choice of either atenolol or hydrochlorothiazide in preventing cardiovascular disease. Unfortunately, the trial was ended early for commercial, nonscientific reasons before optimal accrual and follow-up occurred. Although no differences in primary outcomes were statistically significant (hazard ratio for primary outcome of cardiovascular death, stroke, or myocardial infarction for verapamil was 1.02), the confidence intervals (0.88, 1.18) were wider than the study authors’ target to establish equivalence (upper 95% confidence interval limit, 1.16). Among secondary outcomes, verapamil use was associated with significantly higher rates of heart failure and bleeding than the atenolol or HCTZ group. Taken together with the results of the ALLHAT trial, the effectiveness of CCB in reducing cardiovascular disease may be similar to but not better than diuretic or b-blocker treatment. The higher rates of bleeding associated with verapamil are in contrast to that seen with amlodipine, and may reflect a true class difference in these agents.

Progression of nephropathy in patients with type II diabetes The September 20, 2001, issue of the New England Journal of Medicine published a trio of randomized clinical trials assessing the effectiveness of ARBs on different outcomes in patients with type II diabetes and established nephropathy. Two of these, the RENAAL [4] and Irbesartan Diabetic Nephropathy Trial (IDNT) [5] trials, assessed hard outcomes, such as doubling of serum creatinine, end-stage renal failure, or death, and are featured in Table 1. Both trials have been subject to criticism for not using ACE inhibitors as a comparison arm. The rationale and ethics for this decision were thoroughly discussed in the accompanying editorial [22]. Some evidence already did exist, however, that ACE might be associated with improved renal outcomes in patients with type II diabetes [23,24]. The decision to use DHP CCB in such a large proportion of placebo patients, much less as a separate arm in the IDNT trial, was certainly controversial.

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Early reports had indicated that DHP CCBs, particularly nifedipine, were associated with increases in albuminuria even in comparison with placebo in diabetic patients with microalbuminuria [25–28]. Although later reports did not necessarily indicate a worsening of proteinuria associated with DHP CCB use, most evidence certainly indicated ACEs were superior to DHP CCBs for diabetic nephropathy [29–34]. This is in contrast to non-DHP CCBs, such as verapamil and diltiazem, for which data suggested a beneficial effect of combination therapy with ACE on proteinuria in diabetic patients [35]. Primary end points for the two studies were identical: doubling of serum creatinine, end-stage renal disease, or death (Fig. 4). Inclusion and exclusion criteria were slightly different between the two studies. Although both limited study patients to patients with a clinical diagnosis of type II diabetes, age 30 or 31 to 70, the RENAAL trial defined serum creatinine level from 1.3 to 3 mg/dL for both men and women, whereas the IDNT used from 1 to 3 mg/dL for women and from 1.2 to 3 mg/dL for men. Proteinuria was also defined differently: the RENAAL trial used a urine albumin/creatinine ratio of greater than or equal to 300, further stratifying patients by a ratio of greater than or equal to 2000 or less, whereas the IDNT trial used 900 mg urinary protein in 24 hours. Intervention arms were defined quite differently: the RENAAL trial used losartan (titrated to 100 mg orally every day as needed to achieve target blood pressure less than 140/90 mm Hg) or placebo (essentially any antihypertensive medication except for ARB or ACE). During study treatment, approximately 80% of patients in both treatment arms were treated with a CCB (about 60% each with a DHP CCB), and over 80% of patients in each arm were treated with diuretics. For all intents and purposes, the RENAAL study actually studied the effectiveness of ARB use in combination with diuretic therapy. The IDNT treatment groups consisted of irbesartan (titrated to 300 mg orally each day as needed to a slightly lower target systolic blood pressure, 135 mm Hg); amlodipine; or placebo (consisting of all medications except ARB, ACE, or CCB). The percentage of patients in each arm who were on diuretics was not specified. Achieved blood pressure was significantly lower in the ARB arm compared with placebo in both studies, requiring adjustment in final analysis. The IDNT trial did not give outcome rates in person years; however, comparison of outcome rates can be seen in Figs. 4 and 5. At 36 months in the RENAAL trial, the event rate for the losartan group was approximately 35% compared with approximately 45% in the placebo group. At 36 months in the IDNT trial, the event rate for the irbesartan group was approximately 30% compared with approximately 40% for both the placebo and amlodipine group. The lower event rates in the IDNT trial may c Fig. 4. Primary outcomes for the RENAAL trial. The solid horizontal line indicates losartan, the hatched line indicates placebo. (From Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861–9; with permission.)


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200



201

be a consequence of the lower achieved blood pressure, but rates are otherwise comparable. The adjusted relative risks of primary outcomes compared with placebo for losartan (16% risk reduction, and 22% for those who continued to receive their assigned study treatment, P ¼ .02) and irbesartan (19%, P ¼ .03) were also comparable. In the IDNT trial, irbesartan had a more significant difference in comparison with amlodipine (relative risk reduction 24%, P ¼ .005) than in comparison with placebo. There was no significant difference in the risk of death for the ARB group versus placebo in either study. In fact, in the RENAAL study, a higher percentage of patients died in the losartan group (21%) than in the placebo group (20.3%), although this was not statistically significant. This was not seen in the IDNT trial, where the irbesartan group had the lowest percentage of deaths, although this was also not statistically significant. A variety of secondary outcomes were also assessed. Neither study found a significant difference in composite cardiovascular outcomes. The RENAAL trial, however, found that ARB use was associated with a significantly lower rate of hospitalized heart failure than placebo (risk reduction 32%, P ¼ .005). This specific outcome was not reported in the IDNT trial; however, irbesartan had a significantly lower risk of doubling of serum creatinine compared with both placebo (relative risk reduction 29%, P ¼ .009) and amlodipine (relative risk reduction 39%, P \ .001). Hyperkalemia leading to discontinuation of medication was significantly more common in the ARB group (1.9%) compared with placebo (0.5%). This was not reported for the RENAAL trial. The RENAAL trial reported a significantly greater reduction in proteinuria for the losartan group than for the placebo group, as expected. This was not reported in the IDNT trial; however, the accompanying study by Parving et al [6] showed irbesartan had comparable effects on albuminuria. Progression of renal disease in African Americans The AASK trial assessed the effectiveness of three different agents on the progression of renal disease in African Americans with hypertension, GFR 20 to 65 mL/min/1.73 m2, and no other identifiable cause of renal insufficiency. Those with a urine protein-creatinine ratio of greater than or equal to 2.5 were excluded. The agents studied were ACE (ramipril), CCB (amlodipine), and bblocker metropolol. As indicated previously, the amlodipine arm was halted prematurely after analysis indicated a relative excess rate of end-stage renal failure and death in comparison with ramipril. A summary of the outcomes is shown in Table 1. In summary, lower than usual blood pressure control b Fig. 5. Primary outcomes for the IDNT trial. The solid horizontal line indicates irbesartan, the hatched line indicates placebo or amlodipine. (From Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851–60; with permission.)

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Fig. 6. Change in serial GFR over time, AASK trial by treatment arm stratified by proteinuric status. Although achieved blood pressure showed less of a difference in outcomes for patients with baseline proteinuria greater than 0.22 (urine spot protein per creatinine ratio), amlodipine was significantly associated with a steeper slope of change of GFR over time in patients with proteinuria. (From Wright JT Jr, Bakris G, Greene T, Agodoa LY, Appel LJ, Charleston J, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA 2002;288:2421–31; with permission.)

(mean systolic blood pressure of 128 mm Hg versus 141 mm Hg in the ‘‘usual’’ group) did not slow progression of renal disease. Further, in this group, ACE (ramipril) was more effective at slowing progression of renal disease than either b-blockers (metropolol) or CCB (amlodipine). The difference between amlodipine and other agents was most dramatic for patients who had detectable proteinuria (defined as a urine protein-creatinine ratio of greater than or equal to 0.22, still considered a relatively low amount of proteinuria by most clinicians) (Fig. 6). As shown, among patients without significant proteinuria, amlodipine transiently raised GFR early, consistent with its known hemodynamic effects. In patients with proteinuria, however, the effect on GFR was consistently adverse. No benefit of more intensive blood pressure control on change in GFR was seen for proteinuric versus less proteinuric patients. In addition to the evidence that DHP CCBs were inferior to ACE in diabetic nephropathy, some studies also documented a potential disadvantage of DHP CCB in comparison with ACE in nondiabetic nephropathy [36]. In this light, the results of amlodipine group in the AASK trial were hardly surprising. The benefits of ACE in African Americans, however, were perhaps unexpected by some. In contrast to the belief that African Americans have a higher prevalence of low-renin hypertension and might be resistant to ACE, previous studies had documented that renin levels did not predict antihypertensive response in this group [37]. In fact, even salt intake was not predictive, but instead diuretic use was the most effective means of achieving target blood pressure with use of ACE or ARB in African Americans [38]. Higher doses of ACE or ARB may be required to achieve


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desired blood pressure levels in African Americans than other groups, but this should not lead to the avoidance of this therapy in African Americans [39]. Summary Even well-conducted randomized controlled trials can only reduce uncertainty, not eliminate it. The trials presented in this article all have gaps, and like many studies, some raise more questions than answers. A summary of the current trials, however, can be presented as follows. For patients with essential hypertension who are at high risk for cardiovascular disease, the use of diuretic therapy (excluding simultaneous use of ACE or CCB) resulted in outcomes at least equivalent to the use of either ACE or CCB without diuretics. Naturally, the dilemma for clinicians is that these drugs are most often used in combination with thiazide diuretics, as indicated by the RENAAL trial where 80% of ARB were used with diuretics in patients with type II diabetes and known nephropathy. The increased risk of heart failure observed with ACE and CCB in that trial may be relevant only to patients in whom diuretics were not also used. The study does raise important awareness, however, that ACE or CCB use without diuretic therapy is no better than diuretic therapy, and may be associated with higher risk of certain outcomes. A substantial number of patients with essential hypertension might achieve adequate blood pressure control with diuretic monotherapy. If so, that certainly has important implications for the cost of medical care in this country. For African Americans with essential hypertension, ACE may have advantages as a component of therapy in comparison with CCBs or b-blockers, although diuretics should probably be the cornerstone of therapy for them and supported by the Seventh Joint National Committee. For patients with proteinuric renal disease, whether associated with diabetes or hypertension, it should be considered inappropriate to use DHP CCB as monotherapy in any setting, whether as part of a clinical trial or in clinical practice. These drugs should not be considered as ethical placebo arms in trials, most especially in diabetic nephropathy, nor should they be used without an ACE or ARB in patients with proteinuric renal disease in the absence of documented contraindications or intolerance to ACE, ARB, or non-DHP CCB (which are now considered second-line agents for proteinuric renal disease, and are acceptable placebo or comparison arms in clinical trials) [40–42]. For patients with type I diabetes, ACE remain the cornerstone of therapy. Because of recent RENAAL and IDNT trial results, the greatest benefit for slowing progression of renal disease in type II diabetic nephropathy now belongs to ARBs. In contrast, however, the HOPE trial showed that ACE, specifically ramipril, had the greatest evidence for prevention of cardiovascular outcomes in patients with renal insufficiency, regardless of diabetic status. Cardiovascular outcomes were secondary end points in the RENAAL

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and IDNT trials, and with the exception of heart failure for losartan, no benefits on cardiovascular outcomes were statistically significant [43]. Progression of renal disease has only been studied in a relatively small cohort of Israeli patients comparing enalapril with nifedipine [23]. These gaps lead to a classic dilemma in medical decision-making. Because evidence has shown that patients with elevated serum creatinine (greater than or equal to 1.4 mg/dL) are just as likely to die from cardiovascular disease as they are to reach end-stage renal disease [44], which outcome should be the focus for clinicians, or for researchers? Using a strictly evidence-based approach, this question can only be answered by yet another large, long, randomized, controlled trial. Given the similarity of actions between the ARB and ACE, it is likely there is considerable overlap of both benefits and side-effects between the two, although ARB may have a lower incidence of cough [45] and hyperkalemia [46]. The decision of which antihypertensive agents to use will have to be tailored carefully to the needs of the patient and careful consideration of both medical and economic factors. Regardless of the choice between an ACE or ARB, however, post hoc analysis of clinical trials [21,47] and observational data [48,49] clearly indicate that patients with chronic kidney disease, even if considered mild (ie, serum creatinine greater than or equal to 1.4 mg/dL) are at significantly greater risk of cardiovascular morbidity and mortality compared with those with better kidney function. As stated in a recent review by the authors of the HOPE trial [50], ‘‘the frequent practice of withholding ACE [or ARB] in patients with mild renal insufficiency is unwarranted,’’ because not only are these patients precisely those who might benefit most from their use, but safety and tolerability are generally excellent. Based on the results of the AASK trial, the authors add the same for the use of ACE inhibitors in African Americans.

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[23] Ravid M, Brosh D, Levi Z, Bar-Dayan Y, Ravid D, Rachmani R. Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus: a randomized, controlled trial. Ann Intern Med 1998;128(12 pt 1):982–8. [24] Ravid M, Savin H, Jutrin I, Bental T, Katz B, Lishner M. Long-term stabilizing effect of angiotensin-converting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type II diabetic patients. Ann Intern Med 1993;118:577–81. [25] Mimran A, Insua A, Ribstein J, Bringer J, Monnier L. Comparative effect of captopril and nifedipine in normotensive patients with incipient diabetic nephropathy. Diabetes Care 1988;11:850–3. [26] Romanelli G, Giustina A, Bossoni S, Caldonazzo A, Cimino A, Cravarezza P, et al. Shortterm administration of captopril and nifedipine and exercise-induced albuminuria in normotensive diabetic patients with early-stage nephropathy. Diabetes 1990;39:1333–8. [27] Demarie BK, Bakris GL. Effects of different calcium antagonists on proteinuria associated with diabetes mellitus. Ann Intern Med 1990;113:987–8. [28] Bilo H, Kluitman E, van Ballegooie E, Potter van Loon BJ, Bakker K, Michels B, et al. Long term use of captopril or nifedipine in normotensive microalbuminuric patients with insulin-dependent diabetes mellitus. Diabetes Res 1993;23:115–22. [29] Giordano M, Sanders LR, Castellino P, Canessa ML, DeFronzo RA. Effect of alphaadrenergic blockers, ACE inhibitors, and calcium channel antagonists on renal function in hypertensive non-insulin-dependent diabetic patients. Nephron 1996;72:447–53. [30] Abbott K, Smith A, Bakris GL. Effects of dihydropyridine calcium antagonists on albuminuria in patients with diabetes. J Clin Pharmacol 1996;36:274–9. [31] Yokoyama H, Tomonaga O, Hirayama M, Ishii A, Takeda M, Babazono T, et al. Predictors of the progression of diabetic nephropathy and the beneficial effect of angiotensin-converting enzyme inhibitors in NIDDM patients. Diabetologia 1997;40: 405–11. [32] Crepaldi G, Carta Q, Deferrari G, Mangili R, Navalesi R, Santeusanio F, et al. Effects of lisinopril and nifedipine on the progression to overt albuminuria in IDDM patients with incipient nephropathy and normal blood pressure: the Italian Microalbuminuria Study Group in IDDM. Diabetes Care 1998;21:104–10. [33] Smith AC, Toto R, Bakris GL. Differential effects of calcium channel blockers on size selectivity of proteinuria in diabetic glomerulopathy. Kidney Int 1998;54:889–96. [34] Abbott KC, Sanders LR, Bakris GL. Microalbuminuria in non-insulin-dependent diabetes mellitus: implications for renal survival. Arch Intern Med 1994;154:146–53. [35] Bakris GL, Weir MR, DeQuattro V, McMahon FG. Effects of an ACE inhibitor/calcium antagonist combination on proteinuria in diabetic nephropathy. Kidney Int 1998;54: 1283–9. [36] Ruggenenti P, Perna A, Benini R, Remuzzi G. Effects of dihydropyridine calcium channel blockers, angiotensin-converting enzyme inhibition, and blood pressure control on chronic, nondiabetic nephropathies. Gruppo Italiano di Studi Epidemiologici in Nefrologia (GISEN). J Am Soc Nephrol 1998;9:2096–101. [37] Weir MR, Saunders E. Renin status does not predict the anti-hypertensive response to angiotensin-converting enzyme inhibition in African-Americans. Trandolapril Multicenter Study Group. J Hum Hypertens 1998;12:189–94. [38] Weir MR, Smith DH, Neutel JM, Bedigian MP. Valsartan alone or with a diuretic or ACE inhibitor as treatment for African American hypertensives: relation to salt intake. Am J Hypertens 2001;14(7 pt 1):665–71. [39] Flack JM, Mensah GA, Ferrario CM. Using angiotensin converting enzyme inhibitors in African-American hypertensives: a new approach to treating hypertension and preventing target-organ damage. Curr Med Res Opin 2000;16:66–79. [40] Bakris GL, Copley JB, Vicknair N, Sadler R, Leurgans S. Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM associated nephropathy. Kidney Int 1996;50:1641–50.


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[41] Tarif N, Bakris GL. Preservation of renal function: the spectrum of effects by calciumchannel blockers. Nephrol Dial Transplant 1997;12:2244–50. [42] Griffin KA, Picken MM, Bakris GL, Bidani AK. Class differences in the effects of calcium channel blockers in the rat remnant kidney model. Kidney Int 1999;55:1849–60. [43] Berl T, Hunsicker LG, Lewis JB, Pfeffer MA, Porush JG, Rouleau JL, et al. Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and overt nephropathy. Ann Intern Med 2003;138:542–9. [44] Thomas MC, Cooper ME, Shahinfar S, Brenner BM. Dialysis delayed is death prevented: a clinical perspective on the RENAAL study. Kidney Int 2003;63:1577–9. [45] Sica DA, Gehr TW. The pharmacokinetics and pharmacodynamics of angiotensin-receptor blockers in end-stage renal disease. J Renin Angiotensin Aldosterone Syst 2002;3:247–54. [46] Bakris GL, Siomos M, Richardson D, Janssen I, Bolton WK, Hebert L, et al. ACE inhibition or angiotensin receptor blockade: impact on potassium in renal failure. VAL-K Study Group. Kidney Int 2000;58:2084–92. [47] Mann JF, Gerstein HC, Yi QL, Lonn EM, Hoogwerf BJ, Rashkow A, et al. Development of renal disease in people at high cardiovascular risk: results of the HOPE Randomized Study. J Am Soc Nephrol 2003;14:641–7. [48] Manjunath G, Tighiouart H, Coresh J, Macleod B, Salem DN, Griffith JL, et al. Level of kidney function as a risk factor for cardiovascular outcomes in the elderly. Kidney Int 2003;63:1121–9. [49] Manjunath G, Tighiouart H, Ibrahim H, Macleod B, Salem DN, Griffith JL, et al. Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community. J Am Coll Cardiol 2003;41:47–55. [50] Mann JF, Gerstein HC, Dulau-Florea I, Lonn E. Cardiovascular risk in patients with mild renal insufficiency. Kidney Int Suppl 2003;84:192–196.

Med Clin N Am 88 (2004) 209–221

Target organ involvement in hypertension: a realistic promise of prevention and reversal Edward D. Frohlich, MD, MACP, FACC Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA 70121, USA

Substantial gains have been achieved in reducing hypertension-related morbidity and mortality over the past 45 years with antihypertensive therapy. Reductions in mortality from stroke and coronary heart disease of 70% and 55%, respectively, have been achieved, and hypertensive emergencies have become infrequent [1,2]. The responsiveness of the cerebral circulation to antihypertensive therapy, a circulation highly responsive to pressure changes, is directly related to the consistent reductions in stroke mortality as shown in prospective, double-blind, placebo-controlled studies [1,3]. Although a significant reduction in coronary heart disease (CHD) mortality has been realized since the early multicenter trials, reduction in the increasing prevalence of cardiac failure and end-stage renal disease (ESRD) has not yet been seen [1]. A putative atherogenic effect of diuretics, originally thought to be related to elevated blood lipid levels, was considered responsible for the lower than expected, albeit significant, reduction in CHD mortality [3]. The projected 26% reduction in CHD mortality [3] was clearly demonstrated when substantially lower doses of the thiazide diuretics were recommended and used (from 100 to 150 mg to 12.5 to 25 mg daily) [4]. The benefit of diuretic and b-adrenergic receptor blocking antihypertensive therapy to prevent stroke and CHD continues to be recommended by the major hypertension advisory panels [1,2,5]. Notwithstanding, national and world public health projections for patients with hypertension have been met with less success [1]. In 1972, when national efforts for education and blood pressure control began in the United States, the number of treated and controlled patients began to increase. Today, as compared with a decade ago, fewer hypertensive patients are detected, evaluated, treated, and controlled. Moreover, the number of

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hypertensive patients who progress to ESRD or congestive heart failure (CHF) maintains a steady and disturbing increase despite the continued reduction in stroke and CHD mortality [1–5]. Importantly, patients with hypertension, diabetes, or who are black comprise the three most common groups of patients who develop ESRD; it must be emphasized that the coexistence of diabetes and hypertension (and patients who are black) is exceedingly common. Furthermore, hypertension continues to remain the most common cause of CHF and hospitalization in the elderly [1,2,6,7]. In this regard, it is most important to point out that the manifestations of CHF have become very different since the advent of antihypertensive therapy. In the years before antihypertensive therapy, systolic dysfunction was the predominant mechanism because of the persistent pressure overload on the left ventricle (LV) [8]. Today, CHF is more frequently associated with diastolic dysfunction [6,7,9,10]. Experimental work from the author’s laboratory and others using elderly (73-week-old) and younger (23-week-old) adult spontaneously hypertensive rats (SHRs) with cardiac involvement and exacerbated ESRD continues to be confirmed by recent clinical reports, and data from large multicenter clinical trials show promising and exciting new information highlighted in this article. The message of this article is that newer benefits are being achieved using more specific antihypertensive therapy on heart and kidney, two target organs of essential hypertension that have been resistant to conventional antihypertensive therapy. ESRD can be retarded and prevented; the ischemia, fibrosis, and apoptosis associated with cardiac involvement and the progression of left ventricular hypertrophy (LVH) also can be retarded, reversed, and prevented. Hypertensive heart disease A constellation of structural, functional, and endothelial pathophysiologic mechanisms that effect coronary hemodynamics and ventricular function explain the clinical outcomes caused by hypertensive heart disease. Structural alterations associated with hypertension that directly impact on coronary blood flow include vascular compression by the hypertrophied LV, increased wall thickening of the coronary arterioles that increase the wall:lumen ratio, and luminal obstruction from atherosclerotic plaque formation in the epicardial coronary vessels [9]. Additionally, reduced vascularity (or rarefaction) of the vessels of the enlarged LV wall in hypertension has also been demonstrated [11]. Hypertrophy of LV myocytes and intramural and extramural deposition by protein and collagen in the extracellular matrix of the ventricular wall are also responsible for the increased ventricular mass [9,12,13]. In the setting of hypertension, functional alterations of the LV include reduced resting coronary blood flow and, even more significant, diminished coronary blood flow reserve, which can now be assessed using physiologic and pharmacologic interventions that include exercise testing or


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systemic infusion of pharmacologic agents (eg, dipyridamole, adenosine) that induce maximal coronary vasodilation [9,14]. The demand for increased coronary flow caused by these interventions, whether physiologic or pharmacologic, diminishes the already increased resting coronary vascular resistance, and this is expressed as increased minimal coronary vascular resistance. The clinical value of obtaining these hemodynamic actions was first demonstrated experimentally by Marcus et al [14], and these changes have been found repeatedly to be useful clinically [15–19]. Additionally, coronary arteriolar and endothelial dysfunctions of the coronary circulation now seem to be reversible with appropriate antihypertensive treatment [20–25]. The potential causes of coronary arterial insufficiency and the mechanisms for associated ischemic heart disease in patients with hypertension include the increased oxygen demands associated with LVH, hypertensive arteriolar disease, and endothelial dysfunction of the arterioles and capillaries, all of which are exacerbated by concomitant obstructive atherosclerotic epicardial disease. Moreover, these vascular alterations are exacerbated by hyperlipidemia, diabetes mellitus, exogenous obesity, and other comorbid diseases that affect the endothelium [9]. In this regard it is extremely important to emphasize that this ischemia frequently occurs without occlusive atherosclerotic disease in hypertension with LV enlargement and is associated with collagen deposition not only in the ventricular extracellular matrix but also with perivascular fibrosis. Coexistent atherosclerosis of the epicardial coronary arteries only exacerbates the ischemia further. Ischemic heart disease, symptomatic or asymptomatic, sudden cardiac death, lethal cardiac dysrhythmias, angina pectoris, and CHF are end points directly related to hypertension and hypertensive heart disease per se. These events can be attributable to the LV enlargement, collagen deposition, arteriolar constriction, and endothelial dysfunction and can be explained by their underlying mechanisms. Furthermore, recent reports have additionally demonstrated an increase in programmed myocardial cell death (ie, apoptosis), which provides yet another mechanism of cardiac involvement in hypertension [26–28]. An improved understanding of the coronary arterial insufficiency and ventricular functional impairment in hypertension has been provided by experimental studies from the author’s and other laboratories involving the SHR and in patients with essential hypertension. Most importantly, clinical observations that support these experimental observations have, only recently, provided further insight into these abnormalities in hypertensive heart disease in the presence or absence of concomitant ischemic atherosclerotic disease.

Effects of hypertension on the heart Until recently, the only major cardiac involvement in hypertension that was considered in any depth clinically was LVH [29]. Indeed, LVH is

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considered an extremely important epidemiologic risk factor that underlies CHD, even more than the height of arterial pressure [9,30,31]. The precise mechanisms associated with this increased risk now seem to be appearing [9,28]; but whether the risk of LVH per se is diminished by the antihypertensive therapy that reduces ventricular mass associated with LVH remains to be determined more precisely [9,32]. It seems that if risk reduction is related to the reduced left ventricular mass per se, which is corrected by pharmacologic treatment, it should be disassociated form the reduction in arterial pressure, improved coronary hemodynamics, the direct antiarrhythmic effect, or any other effect produced by the antihypertensive agent [32]. Studies that demonstrate reduced risk with antihypertensive therapy must also identify the precise mechanisms for this risk reduction (eg, pressure reduction, reduced ventricular muscle mass, reduced collagen and perivascular fibrosis, the drug’s antiarrhythmic or other effects, improved ventricular performance, reduced apoptosis, and so forth). The range of hemodynamic and nonhemodynamic factors involved with the development of LVH, as shown in clinical and experimental studies, include pressure (or volume) overload; hormonal or humoral agents; vascular and other growth factors; gender; race; age; pharmacologic therapy; and additional comorbidities, such as atherosclerosis, obesity, and diabetes mellitus. Ventricular ischemia with altered coronary flow reserve, increased collagen deposition in the extracellular LV matrix and perivascularly, and apoptosis have been important factors recently demonstrated experimentally and clinically that strongly suggest underlying mechanisms, which account for risk, at least in part [9,28].

Effects of aging on hypertension Perhaps the most striking alterations involving left and right ventricular hemodynamics changes with age were demonstrated in the author’s experimental SHR studies involving 20- to 65-week-old SHRs with ischemia of the hypertrophied LV and the nonhypertrophied right ventricle. Moreover, it was of particular interest that the ischemic changes of both ventricles also occurred in normotensive age- and gender-matched WKY rats [33]. Specifically, in that study, the author demonstrated reduced left and right ventricular coronary blood flow and flow reserve, and increased coronary vascular resistance and minimal vascular resistance of the hypertrophied LV and right ventricle in the SHR. Notably, the 65-weekold normotensive WKY rats also demonstrated similar profound hemodynamic alterations in both ventricles [33]. Compounding these ischemic alterations, hydroxyproline deposition also increased with aging and myocyte hypertrophy in the SHRs [33]. This increased collagen deposition also occurring in the walls of the left and right ventricles of both normotensive and hypertensive rats was strengthened by


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its confirmation in patients with essential hypertension who demonstrated a progressive increase in fibrosis with increasing myocyte hypertrophy [34]. Clearly, myocyte hypertrophy associated with concomitant coronary flow reserve reductions are clearly complicated by ventricular fibrosis in patients with essential hypertension, thereby confirming the findings in the SHR with naturally occurring hypertension [9,15–18]. Age-related factors of ventricular ischemia and fibrosis occur in the normotensive or hypertensive patient and in the SHR, an excellent experimental model of essential hypertension.

Apoptosis Still more recently, a relatively new pathophysiologic phenomenon has been related to the problem of hypertensive heart disease: the alteration of programmed cellular death or apoptosis of the ventricle [26–28]. Programmed cellular death is in striking contrast to the cellular death achieved by sudden ischemia, such as that produced by acute vascular occlusion with myocardial infarction. The process of apoptosis seems to be initiated when a locally produced agent (eg, angiotensin) initiates the progression of cellular death [28]. In this circumstance it has been suggested that this disappearance of functioning cardiac myocytes reduces functional ventricular muscle mass thereby enhancing the development of cardiac failure. It is of particular interest that this process of cell death can be reduced and, perhaps, even reversed by the inhibition or block of the offending agent (such as angiotensin). One recent report, dealing with patients with essential hypertension, has demonstrated a reduction in apoptosis with an angiotensin II type I receptor antagonist, but not with a calcium antagonist [27]. Clearly, this new concept is in its early stages of translational research, but the findings clearly complement existing knowledge of therapeutic reversal of ischemia and fibrosis. Future reports of investigation in this area are eagerly anticipated.

Therapeutic intervention Adverse changes in coronary hemodynamics have been related to progressive hypertensive disease and aging, and are manifested by normal or reduced resting blood flow and increased vascular resistance and impaired coronary flow reserve [14–19,33]. In addition to LVH, important other structural and functional coronary vascular changes occur in hypertension. These include a thickened arteriolar wall of hypertensive vascular disease clearly manifested in the coronary arterioles by a reduced luminal diameter and increased vascular resistance [35]. In addition, hypertensive vascular disease is also complicated by endothelial dysfunction. These changes compromise coronary flow reserve, even when resting coronary hemodynamics seem normal [15–19,36]. Aging further aggravates

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the changes in coronary hemodynamics, and these changes are exacerbated by ventricular fibrosis [33]. Functionally, these alterations individually, but especially in combination, account for impaired ventricular function (including diastolic dysfunction) in pure hypertensive heart disease. In the SHR, the angiotensin converting enzyme inhibitor (ACE-I), angiotensin II type 1 (AT1-) receptor antagonist, or a calcium antagonist have markedly improved the impaired coronary ischemia and fibrosis associated with hypertension [37]. This has also been shown in patients with essential hypertension with an ACE-I [38,39] and a receptor antagonist [26,28,40–42]. Notably, the author has found that the combination of an ACE-I and an AT1-receptor antagonist improved left and right ventricular hemodynamics [41,42]; when combined with an AT2-receptor, the fibrosis was shown to be mediated most likely through the AT2 receptor [42]. Calcium antagonists also improved coronary hemodynamics (ie, increased ventricular flow reserve and reduced minimal coronary resistance) and decreased left ventricular hydroxyproline content [37,43]. In the SHR, left ventricular hydroxyproline content decreased with each of the calcium antagonists that the author has studied over the years but it increased in right ventricle. When an ACE inhibitor was added to the calcium antagonist, however, the right ventricular hydroxyproline increase induced by the calcium antagonist was prevented [44–45]. The author also observed this echocardiographically in patients with hypertension; right ventricular wall thickness was increased with each of the calcium antagonists investigated [46].

Endothelial dysfunction in hypertension Endothelial dysfunction complicates hypertension-related hemodynamic changes [19–25]. This alteration is distinctly different from the classical abnormality of hypertensive arteriolar disease. It also occurs in a number of other clinical conditions (eg, aging, menopause, tobacco smoking, hypertension, diabetes mellitus, obesity, atherosclerosis, hyperlipidemia, hyperhomocysteinemia, and cardiac failure). Moreover, a number of differing but disease-specific therapies have been shown to be effective in addressing the underlying endothelial dysfunction of these conditions (eg, estrogen, tobacco-cessation, antihypertensive agents, hypoglycemic agents, stroke, and so forth). These clinical observations suggest a multifactorial causation of the endothelial dysfunction of nitric oxide synthesis. A spectrum of endothelial dysfunctional cardiovascular states, initiated by a variety of specific biologic alterations of the endothelium, seem to impair the production of nitric oxide and are responsible for the impaired regulation of local coronary and other organ blood flows. Interestingly, additional hypertension-related changes in hemodynamics and fibrosis have been improved by the administration of the nitric oxide amino acid precursor


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L-arginine

alone [47,48]. It was also of great interest to find that prolonged administration of an ACE-I together with L-arginine also resulted in an additional improvement in systemic and coronary hemodynamics and ventricular fibrosis in 2-year-old WKY rats with isolated systolic hypertension [49]. Apoptosis of the cardiac myocytes and noncardiac myocytic elements (experimentally and in patients) has been improved with angiotensin II (type 1) antagonists [27,28].

Renal involvement in hypertension End-stage renal disease also continues to increase in patients with essential hypertension, particularly in black patients and in patients with diabetes mellitus. Because hypertension is exceedingly common in diabetes, hypertension should be considered as the major contributor to the development of ESRD [50]. The renal and glomerular hemodynamic changes characteristic of ESRD include afferent arteriolar constriction that diminishes total renal blood flow and blood flow to the glomerulus and efferent glomerular arteriolar constriction that increases intraglomerular hydrostatic pressure, which promotes the glomerular ultrafiltration of protein and the development of glomerulosclerosis [51,52]. Hyaline deposition and glomerulosclerosis results from the transcapillary movement of protein and other large molecules into the mesangium of the glomerulus. These systemic and local renin-angiotensin systems play a major role in the foregoing intrarenal hemodynamic alterations and the pathogenesis of ESRD. Recent experimental and clinical studies have shown that rigorous blood pressure control [53] and inhibition of systemic and renal ACE inhibitors and angiotensin II (type 1) antagonists retards, and most likely also reverses, early and established ESRD [54–60]. Each of those multicenter clinical trials has shown that the increasing incidence of ESRD may be reduced with ACE-I therapy. Blood pressure reduction to levels less than 130 and 80 mm Hg systolic and diastolic, respectively, also has been demonstrated to improve outcomes in patients with diabetes mellitus [53]. ACE-inhibition (ACE-I) or angiotensin II (type 1)–inhibition (ARB) therapy for patients with high or high-normal blood pressure has also been recommended by national and international guidelines based on the results of these large multicenter clinical trials [1,2,5,61]. Experimental studies The ability of the ACE inhibitors and angiotensin II (type 1) receptor blockers to reduce the development and progression of ESRD and even reverse disease-associated lesions has been demonstrated in several experimental studies in the author’s laboratory and others. The author’s studies reported both prevention and reversal of the systemic and renal

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hemodynamic, glomerular dynamic, histologic, and general clinical responses in elderly SHRs (72 weeks of age) [62] with naturally occurring ESRD and in young adult SHRs (23-week-old) with ESRD provoked by prolonged (3-week) administration of the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) [63]. The pathophysiologic and clinical changes associated with ESRD in hypertension develop naturally in elderly SHRs at 72 weeks of age [62]. Each of these changes included development of elevated arterial pressure, reduced renal blood flow and elevated renal vascular resistance, increased afferent and efferent glomerular arteriolar resistance, glomerular hydrostatic pressure, reduced glomerular filtration rate, increased filtration coefficient, proteinuria, and all of the histopathologic lesions of the glomeruli and renal arterioles that characterize severe nephrosclerosis [63]. Most importantly, ACE inhibitor therapy for 3 weeks reversed or normalized all of these pathophysiologic dysfunctions. Total peripheral resistance was reduced and cardiac output and heart rate were normalized with blood pressure reduction (albeit in the SHR suboptimally). Also reduced was the renal vascular resistance and afferent and efferent glomerular arteriolar resistances. Renal and glomerular flow rates were increased, filtration fraction reduced, glomerular hydrostatic pressure reduced, and the proteinuria was markedly reduced to the levels of age-matched (73-week-old) normotensive WKY rats. ESRD can be demonstrated in the naturally developing hypertension of the SHR at 73 weeks or with nitric oxide synthase inhibition in younger adult SHRs without the need to extirpate up to seven-eighths of renal mass, salt-loading, steroids and salt, or nephrotoxic chemicals. In 23-week-old SHRs given L-NAME for 3 weeks, nitric oxide synthase inhibition produced the same nephrosclerotic pathophysiology as seen in the 72-week-old SHRs [63]. Impaired renal flow and function had not been shown in earlier studies of 23-week-old SHRs indicating that the endothelial dysfunction produced by L-NAME mimicked all of the age-related changes of nephrosclerosis [64,65]. It was of further interest that, in this model of accelerated SHR/L-NAME–induced nephrosclerosis, co-administration of the ACE inhibitor with L-NAME prevented the development of the expected pathophysiologic structural and functional lesions; these pathophysiologic changes demonstrated reversal when the L-NAME administration was followed by a 3-week course of the ACE-I [66]. Moreover, it was noteworthy that co-administration of hydrochlorothiazide and L-NAME exacerbated the pathologic and functional lesions, suggesting that the thiazide-induced stimulation of the local intrarenal renin-angiotensin system (RAS) exacerbated pathophysiologic changes [67]. These findings were repeated in additional studies using another ACE-I [68]; an AT1-receptor antagonist [69]; and with the amino acid precursor of nitric oxide, L-arginine [48]. Coadministration of bradykinin receptor antagonist icataban (HOE-140) with the ACE-I enalapril produced similar intrarenal hemodynamic and glomerulodynamic changes and remission of


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the pathologic lesions to what was observed with the ACE inhibitor alone, suggesting that the reversal of the renal disease with the ACE inhibitor was not dependent on bradykinin [68]. The author has also demonstrated that the calcium antagonists felodipine, amlodipine, mibefradil, and cilnidipine improved systemic and renal hemodynamics, and the glomerular dynamic changes produced by L-NAME in the 23-week-old SHRs [68,70]. Moreover, the intrarenal glomerular and arteriolar histologic lesions were also prevented and reversed with the calcium antagonists [68,70]. Pharmacotherapy with ACE-inhibitors, an AT1-receptor antagonist, and certain calcium antagonists has been shown to prevent and reverse nephrosclerosis in experimental studies of naturally developing nephrosclerosis of old (72 weeks) SHRs and in L-NAME–induced or exacerbated nephrosclerosis in young (23 weeks) SHRs. Further, the antihypertensive therapy used in these studies provided those benefits without drastic reductions of arterial pressure, although pressure was normalized with the AT1-receptor blocker. Reversal of nephrosclerotic changes did not occur with all antihypertensive agents, as shown by the exacerbation of the L-NAME–induced nephrosclerotic changes with hydrochlorothiazide. In light of these findings, the author envisions that the ability of the newer antihypertensive agents that were nephroprotective in the SHR will continue to be confirmed by clinical multicenter studies and, it is hoped, will be reflected epidemiologically.

Summary The major message from this discussion is that the end points from hypertensive disease (stroke, CHD, and hypertensive emergencies) are now preventable. Cardiac failure and ESRD, however, two exceedingly common end points from long-standing hypertension, remain as major disabilities and causes of death. The former is the most common cause of hospitalization in industrialized societies; hypertension and diabetes mellitus are the most common causes of the latter. The mechanisms of risk of these target organ diseases is not LVH per se, or the elevated arterial pressure alone in the kidney, but the coronary and renal ischemia, organ fibrosis, and, perhaps, apoptosis. Present day therapy now can effectively reverse these costly (economically and by human suffering) complications. Recent experimental studies suggest that, when used early enough, these newer pharmacologic agents may even prevent their occurrences and consequences. The very practical lesson from these experiences is that early detection and treatment of hypertension, effective control of arterial pressure, and the suppression of the underlying disease mechanisms markedly reduce the now increasing prevalence of both cardiac and renal failure.

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Med Clin N Am 88 (2004) 223–238

Primary prevention of essential hypertension Marie A. Krousel-Wood, MD, MSPHa,b,c,*, Paul Muntner, PhDb,c, Jiang He, MD, PhDb,c, Paul K. Whelton, MD, MScb,c a

Clinical/Outcomes Research, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA 70121, USA b Department of Epidemiology, Tulane School of Public Health and Tropical Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA c Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA

Despite progress in recent years in prevention, detection, and treatment of high blood pressure, hypertension remains an important public health challenge. It affects approximately 50 million persons in the United States and about 1 billion individuals worldwide [1]. In 2002, hypertension was the most common primary diagnosis reported in the outpatient setting in the United States, accounting for more than 35 million office visits [2]. The direct and indirect costs related to treatment and management of hypertension continue to rise with approximately $50 billion estimated to be spent in 2003 [3]. High blood pressure is associated with an increased risk of mortality and morbidity from stroke, coronary heart disease, congestive heart failure, and end-stage renal disease [4–6]. In addition, a diagnosis of hypertension has also been reported to have a negative impact on patient-reported quality of life [7–9]. Primary prevention of hypertension provides an avenue to interrupt and prevent the continuing costly cycle of managing this disease and its complications [10,11]. This article reviews the new recommendations for classification of hypertension, updated information on the incidence of hypertension, and lifestyle interventions for primary prevention of this chronic disease.

* Corresponding author. E-mail address: [email protected] (M.A. Krousel-Wood). 0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/S0025-7125(03)00126-3

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M.A. Krousel-Wood et al / Med Clin N Am 88 (2004) 223–238

Classification of hypertension The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII report) recommended a new classification system for hypertension (Table 1) [1]. According to this report, individuals can be classified based on the mean of two or more properly measured seated blood pressure readings on each of two or more office visits. The JNC VII report added a new category designated as ‘‘prehypertension’’ for patients with a systolic blood pressure between 120 and 139 mm Hg or a diastolic blood pressure between 80 and 90 mm Hg. This change in classification is based on the findings from the Framingham Heart study that patients with high normal (according to JNC VI classification: systolic blood pressure of 130 to 139 mm Hg or diastolic blood pressure of 85 to 89 mm Hg) and normal blood pressure (JNC VI classification: systolic blood pressure of 120 to 129 mm Hg or diastolic blood pressure of 80 to 84 mm Hg) were at increased risk for progression to hypertension. The JNC VII report recommends individuals with prehypertension engage in health-promoting lifestyle modifications to prevent the development of hypertension and cardiovascular disease. Hypertension is defined as a confirmed elevation of systolic or diastolic blood pressure (greater than or equal to 140 mm Hg or greater than or equal to 90 mm Hg, respectively). Hypertension is further characterized into two stages based on the person’s systolic or diastolic blood pressure levels. Stage 1 hypertension, the most common form of hypertension, includes systolic blood pressure range of 140 to 159 mm Hg or diastolic blood pressure range of 90 to 99. Stage 2 hypertension includes patients with systolic blood pressure greater than or equal to 160 mm Hg or diastolic blood pressure greater than or equal to 100 mm Hg. (Stage 2 hypertension in the JNC VII report represents Table 1 Classification of blood pressure for adults 18 years or older Category

Systolic BP (mm Hg)

Diastolic BP (mm Hg)

Normal Prehypertension Hypertension Stage 1 Stage 2

\120 120–139

and or

\80 80–90

140–159 160

or or

90–99 110

Based on the average of two or more readings taken at each of two or more visits in individuals not taking antihypertensive drugs and not acutely ill. When systolic and diastolic BP fall into different categories, the higher category should be selected to classify the individual’s BP status. Isolated systolic hypertension is defined as systolic BP 140 mm Hg and diastolic BP \ 90 mm Hg and staged appropriately. Based on the recommendations of Seventh Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Abbreviation: BP, blood pressure. Data from Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, And Treatment of High Blood Pressure. The JNC 7 report. JAMA 2003;289:2560–72.


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the collapsing of stage 2 and 3 from the JNC VI report; stage 4 from the JNC VI report has been omitted from the JNC VII report). Although the focus of this article is lifestyle modifications in the context of preventing hypertension, they are also recommended as concurrent treatment for patients diagnosed with hypertension.

Incidence of hypertension Vasan et al [12] recently estimated the lifetime residual risk for developing hypertension in middle-aged women and men from 1298 participants enrolled in the Framingham Heart Study. According to this study, the residual lifetime risk for incident hypertension (greater than or equal to 140/ 90 mm Hg) was 90% for both 55- and 65-year-old subjects. The lifetime probability of receiving blood pressure-lowering medication was 60%. Although the risk for women was unchanged between 1976 to 1998 and 1952 to 1975, the risk for men was about 60% higher in the later 1976 to 1998 period compared with the earlier 1952 to 1975 period. This study is somewhat limited in its generalizability to race-ethnic groups because the Framingham Heart Study included only whites. In the Atherosclerosis Risk in Communities (ARIC) study, Pereira et al [13] reported incident hypertension in 7459 black and white adults who participated in a populationbased prospective study in four United States clinic centers. The incidence of hypertension was substantially higher among blacks compared with whites in this study. Specifically, the cumulative incidence of hypertension was 16.7% and 25.8% among white and black men and 15% and 28.9% among white and black women [13]. The incidence of hypertension in the San Antonio Heart Study, however, was similar for Mexican-Americans and non-Hispanic whites over 8 years of follow-up [14].

Primary prevention of hypertension To achieve the Healthy People 2010 goal of reducing the proportion of adults with high blood pressure from 28% to 16% [15], concerted efforts must be undertaken not only in earlier detection and treatment of this chronic disease, but also in implementation of primary prevention strategies. The goal of primary prevention is to preserve health by removing the precipitating causes and determinants of poor health; epidemiologically speaking, the aim of primary prevention is to reduce the incidence of disease [16]. Two strategies for the prevention of essential hypertension have been recommended: a population-based strategy and an intensive targeted strategy directed at those with increased risk of developing hypertension [10,11]. The population-based approach is aimed at achieving a downward shift in the distribution of blood pressure in the general population. Based on results from the Framingham Heart Study, Cook et al [17] reported that

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a 2 mm Hg reduction in the population average of diastolic blood pressure for white United States residents aged 35 to 64 years would result in a 17% reduction in the prevalence of hypertension, a 14% decrease in the risk of stroke and transient ischemic attacks, and a 6% reduction in the risk of coronary heart disease. Some examples of population-based approaches to primary prevention may include decreasing sodium content or caloric density in processed food and providing safe and convenient opportunities for exercise [1,11]. Complementary to the population-based approach to prevention is the more intensive targeted approach where interventions are aimed at persons at high risk for developing hypertension. Those at high risk include persons with prehypertension, family history of hypertension, African American ethnicity, overweight, excess consumption of sodium or alcohol, and physical inactivity. There are a number of interventions for which there is documented efficacy: reduced intake of dietary sodium, potassium supplementation, weight loss, moderation of alcohol consumption, increased physical exercise, and modification of eating patterns [11]. The following sections review the evidence for each of these approaches.

Interventions with documented efficacy Dietary sodium reduction Over the last several decades, results from animal experiments, observational studies across and within populations, migration studies, and randomized controlled clinical trials have provided considerable support for a causal relationship between dietary sodium intake and elevated blood pressure [18]. The most compelling evidence for a causal relationship comes from properly conducted randomized controlled clinical trials. In the last 10 years there have been at least four meta-analyses of randomized controlled trials that address the efficacy of decreased sodium intake in lowering blood pressure [19–22]. Although the meta-analyses conducted differed in methodology, inclusion-exclusion criteria, and statistical analysis, each of these studies found significant reductions in blood pressure among those assigned to sodium reduction versus usual care. Midgley et al [19] reported on 28 trials conducted in hypertensive patients and 28 trials conducted in normotensive patients. Among normotensive participants, the mean reductions (treatment versus control) in daily urinary excretion, a proxy measure of dietary sodium intake, was 125 mmol (95% CI, 95 to 156 mmol). Compared with the control group, the mean reduction in blood pressure (95% CI) was 1.6 mm Hg (range 2.4 to 0.9 mm Hg) for systolic and 0.5 mm Hg (range 1.2 to 0.1) for diastolic in normotensives. Despite the small differences in the trials that they reviewed, a significant dose-response relationship between net change in urinary sodium and net change in systolic blood pressure was detected [19]. Cutler et al [20]

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conducted a meta-analysis of 12 randomized controlled clinical trials conducted in 1689 normotensive participants. It was estimated that an average reduction of 77 mmol/d in dietary intake of sodium resulted in a 1.9 mm Hg (95% CI, 1.2 to 2.6 mm Hg) decrement in systolic blood pressure and a 1.1 mm Hg (95% CI, 0.6 to1.6 mm Hg) decline in diastolic blood pressure. The most recently published meta-analysis was by He and MacGregor [22]. Among the 11 trials of persons without hypertension they identified, the median participant age was 47 years and the study duration ranged from 4 weeks to 3 years. The median net reduction in urinary sodium excretion was 74 mmol/d among those randomized to sodium reduction versus their counterparts randomized to usual care. The pooled estimates (95% CI) of systolic and diastolic blood pressure reductions among those randomized to the sodium reduction intervention were 2.03 (95% CI, 2.56 to 1.50) and 0.97 (95% CI, 1.39 to 0.55) mm Hg, respectively [22]. Table 2 shows the reductions in systolic and diastolic blood pressure in the four meta-analysis studies standardized to reflect a reduction in sodium intake of 100 mmol/d. In a more recent randomized controlled feeding trial, the Dietary Approaches to Stop Hypertension (DASH)-Sodium Trial [23], 412 persons with an average systolic blood pressure of 120 to 159 mm Hg and an average diastolic blood pressure of 80 to 95 mm Hg were randomized to either a diet high in fruits, vegetables, and low-fat dairy (DASH) or the usual American diet (control) and were also assigned to spend 30 days receiving each of the three levels of sodium intake in random order based on use of a standard crossover design. A change in sodium intake from a higher level (mean urinary sodium excretion, 142 mmol/d) to an intermediate level (mean urinary sodium excretion, 107 mmol/d) reduced systolic blood pressure by 2.1 mm Hg (P \ .001) during consumption of a usual American control diet and by 1.3 mm Hg (P ¼ .03) during consumption of a DASH diet. Further reductions in sodium intake from the intermediate to a lower level (mean urinary sodium excretion, 65 mmol/d) resulted in an additional decrement in systolic and diastolic blood pressures of 4.6 and 2.4 mm Hg during consumption of the control diet (P \ .001) and 1.7 and 1 mm Hg reduction during consumption of the DASH diet (P \ .05) [23]. The evidence from these and other studies has led to the National High Blood Pressure Education Program Coordinating Committee [11] recommending reducing Table 2 Reduction in systolic and diastolic blood pressure associated with a 100 mmol/d reduction in sodium intake from four meta-analyses Study

SBP, mm Hg

DBP, mm Hg

Midgely (1996) [19] Cutler (1997) [20] Graudal (1998) [21] He (2002) [22]

1 2.3 0.75 3.57

0.1 1.4 0.16 1.66

Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure.

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dietary sodium intake to no more than 100 mmol/d (2.4 g sodium or 6 g sodium chloride). Even lower levels of dietary sodium intake (\70 mmol/d) may result in a greater reduction in blood pressure [23]. Potassium supplementation Over the last several decades, results of observational epidemiologic studies, clinical trials, and meta-analyses indicate that potassium supplementation lowers blood pressure in normotensive and hypertensive individuals. Whelton et al [24,25] conducted a meta-analysis of the results from 12 randomized controlled clinical trials with 1049 normotensive subjects and reported that potassium supplementation (median 75 mmol/d) lowered systolic blood pressure by 1.8 mm Hg (95% CI, 0.6 to 2.9) and diastolic blood pressure by 1 mm Hg (95% CI, 0 to 2.1) (Fig. 1). The blood pressure effects of potassium administration seemed to be greater in those subjects who were concurrently exposed to high sodium intake and in African Americans [24,25]. In a more recent randomized controlled trial of 150 Chinese adults with mild hypertension or high normal blood pressure, Gu et al [26] reported that compared with those randomized to placebo, participants randomized to receive potassium supplements experienced a greater reduction in systolic blood pressure (5 mm Hg, 95% CI, 2.13 to 7.88 mm Hg, P \ .001) during the 12-week intervention. As a result of these findings, maintaining an adequate intake of dietary potassium ([90 mmol [3500 mg] per day) has been recommended for the primary prevention of hypertension by the National High Blood Pressure Education Program Coordinating Committee [11]. Weight loss According to data from the two most recent National Health and Examination Surveys, the age-adjusted prevalence of obesity, defined as a body mass index greater than 30, in the United States has increased from 22.9% in the 1988 to 1994 time period to 30.5% (P \ .001) in 1999 to 2000 [27]. Several large epidemiologic studies and clinical trials of weight reduction have explored the role of obesity in the etiology of hypertension and the effects of weight loss on blood pressure [28–34]. Vasan et al [35] reported that a 5% weight gain over 4 years of follow-up in the Framingham Heart Study was associated with a 20% to 30% increased odds of hypertension. Additionally, in the ARIC study, hazard ratios for hypertension associated with 1 kg weight gain were 1.36 (95% CI, 1.29 to 1.45) and 1.12 (95% CI, 1.03 to 1.21) in white and black women and 1.35 (95% CI, 1.27 to 1.43) and 1.43 (95% CI, 1.27 to 1.61) in white and black men [36]. Data from the Trials of Hypertension Prevention (TOHP)-Phase I and TOHP-II studies revealed that weight loss counseling is an effective approach for the primary prevention of hypertension [31,32]. The TOHP-I weight loss intervention resulted in a 51% decrease (relative risk 0.49; 95%


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Fig. 1. Net change in systolic (circle) and diastolic (square) blood pressure comparing individual interventions from meta-analyses of weight loss, potassium intervention, alcohol reduction, and physical activity. Data from (clockwise from top left) Refs. [38,43,24,52].

CI, 0.29 to 0.83) in the incidence of hypertension over 18 months of followup [31] in men and women with high normal blood pressure. In the TOHP-II trials, compared with their counterparts who received usual care, participants randomized to weight loss counseling experienced a 21% reduction (P ¼ .02) in the incidence of hypertension over 36 months of follow-up [33]. More recently, He et al [37] completed a prospective follow-up of participants at one of the TOHP clinical centers. The initial 18-month weight loss counseling was noted to have a long-lasting effect; over an average follow-up period of 7 years, those assigned to the intervention counseling program experienced 77% decrease (odds ratio 0.23; 95% CI, 0.07 to 0.76, P ¼ .02) in the incidence of hypertension compared with their counterparts who were assigned to usual care [37]. In a meta-analysis of four randomized controlled trials of weight reduction in normotensive adults aged 45 years and older with at least 6 months of follow-up, Ebrahim and Smith [38] reported the net (ie, intervention versus control group) systolic and diastolic blood pressure reductions for normotensive participants was 2.8 mm Hg (3.9 to 1.8) and 2.3 mm Hg (3.2 to 1.4), respectively (see Fig. 1). Given the overwhelming evidence from clinical trials and meta-analyses, weight loss intervention is recommended as a strategy for primary prevention of hypertension.

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Moderation in alcohol consumption A close association between alcohol consumption and hypertension has been established in several epidemiologic investigations and randomized trials [39–44]. A number of cross-sectional and prospective cohort studies have demonstrated that alcohol consumption is one of the most important modifiable risk factors for hypertension among populations from a variety of geographic regions, including North America, Europe, and Asia [44–47]. For example, Fuchs et al [44] analyzed data on 8334 participants, aged 45 to 64 years and free of hypertension and coronary heart disease at baseline, in the ARIC Study. After 6 years of follow-up, there was an increased risk of hypertension in those participants who consumed greater than or equal to 210 g of alcohol per week (approximately three drinks per day). The odds ratio was 1.47 (95% CI, 1.15 to 1.89) after adjustment for race, age, body mass index, education, sport index, and diabetes [44]. In addition, consumption of low to moderate amounts of alcohol also seems to be associated with a higher risk of hypertension in black men. [44]. Xin et al [43] conducted a meta-analysis of randomized controlled trials to assess the effects of alcohol reduction on blood pressure. They reported that reduced alcohol consumption was associated with a decrease in blood pressure, and that the relationship between reduction in mean percentage of alcohol and decline in blood pressure is dose-dependent [43]. In a subgroup analyses of 269 normotensive subjects enrolled in six randomized controlled trials, reduced consumption of alcohol was associated with a 3.56 mm Hg (95% CI, 2.51 to 4.61 mm Hg) and 1.80 mm Hg (95% CI, 0.58 to 3.03) reduction of systolic and diastolic blood pressure, respectively (see Fig. 1) [43]. Reduction in alcohol consumption has been recommended as an important means for primary prevention of hypertension [11]. Physical activity Physical inactivity has been identified as a major risk factor for cardiovascular disease, and persons who are less active and less fit have a 30% to 50% greater risk for developing hypertension [3]. Evidence relating physical activity and blood pressure comes from observational epidemiologic studies and randomized controlled clinical trials [48–53]. Investigators have evaluated various forms of physical activity including occupational or leisure-time physical activity, physical fitness, and aerobic exercise. Results from these prior studies have identified an inverse relationship between physical activity and blood pressure; this relationship has been noted at all ages, in both sexes, in racial subgroups, and has been independent of body weight. Whelton et al [52] reviewed data from 1108 normotensive persons enrolled in 27 clinical trials whose intervention and control groups differed only in aerobic exercise. In the subgroup analysis of 26 clinical trials with normotensive subjects, this meta-analysis identified a 4.04 mm Hg (95% CI, 2.75 to 5.32) decrease in systolic blood pressure in participants assigned to


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aerobic exercise compared with their counterparts in the control group [52]. The analogous reduction in diastolic blood pressure was 2.33 mm Hg (95% CI, 1.51 to 3.14) (see Fig. 1). Regular aerobic physical activity (eg, brisk walking) for at least 30 minutes a day for most days of the week has been recommended for primary prevention of hypertension [11]. Modification of dietary patterns The effect of dietary patterns on blood pressure has been explored in observational epidemiologic studies and randomized controlled clinical trials. In clinical trials of vegetarian diets in which vegetable products have replaced animal products, blood pressure was reduced in normotensive and hypertensive participants [54,55]. The effect of the vegetarian diet on blood pressure reduction is believed to be associated with the increased fiber and mineral content coupled with the low fat content of these diets. Several trials that have tested the blood pressure–lowering effect of these nutrients, however, often given in the form of dietary supplements, have found small and sometimes inconsistent reductions in blood pressure [31,56–58]. More recently, the DASH trial, a multicenter, randomized feeding study that tested the effects of dietary patterns on blood pressure, was conducted [59]. DASH tested the combined effects of nutrients that occur together in food. This trial included participants with a systolic blood pressure of less than 160 mm Hg and a diastolic blood pressure between 80 and 95 mm Hg. Participants were randomly assigned to one of the following dietary interventions: (1) a control diet that was low in fruits, vegetables, and dairy products, with a fat content typical of the average American diet; (2) a fruit and vegetables diet; or (3) a combination diet (ie, the DASH diet), which was rich in fruits, vegetables, and low-fat dairy products but reduced in saturated and total fat [59]. In a subanalysis of the 326 normotensive participants (blood pressure \140/90 mm Hg) in the trial, the DASH diet reduced systolic and diastolic blood pressure by an average of 3.5 mm Hg (95% CI, 5.3 to 1.6) and 2.1 (95% CI, 3.6 to 0.5) mm Hg (each P \ .001), respectively, when compared with the control diet [59]. These results support the recommendation by the National High Blood Pressure Education Program Coordinating Committee for the primary prevention of hypertension: consumption of a diet rich in fruits, vegetables, and low-fat dairy products and reduced in saturated and total fats [11]. Comprehensive lifestyle modification A recent clinical trial assessed the effect of a program of simultaneous weight loss, sodium reduction, increased physical activity, and limited alcohol intake on blood pressure conducted between January 2000 and June 2001 [60]. The PREMIER clinical trial included 810 adults with systolic blood pressure between 120 and 159 mm Hg and diastolic blood pressure

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between 80 and 95 mm Hg. Participants were randomized to one of three interventions: (1) a one-time 30-minute counseling session, (2) a behavioral intervention that implemented established recommendations for each of these lifestyle changes, and (3) the behavioral intervention plus advice on the DASH diet [60]. After 6 months of follow-up, the decline in systolic blood pressure was 3.1 mm Hg greater among the nonhypertensive participants randomized either to the behavioral intervention or the behavioral intervention plus DASH diet compared with their counterparts randomized to advice only (Fig. 2; each P \ .01). The analogous differential reductions in diastolic blood pressure were 1.6 and 2 mm Hg (see Fig. 2; each P \ .01). Additionally, 26%, 17%, and 12% of patients randomized to advice only, behavioral intervention, and behavioral intervention plus DASH diet, respectively, were hypertensive (systolic or diastolic blood pressure 140/90 mm Hg or antihypertensive medication usage) at the 6-month follow-up visit, respectively (P-trend \ .001). This trial demonstrated the feasibility and potential benefits of the adoption of a comprehensive behavioral intervention in the prevention of hypertension [60]. Interventions with uncertain or less proved efficacy Prior observational studies, randomized trials, and meta-analyses have investigated the association of calcium and fish oil supplementation and reduced caffeine consumption with blood pressure and have found the blood pressure-lowering effects minimal [61,62–67]. Griffith et al [68] updated their

Fig. 2. Net reduction in systolic and diastolic blood pressure levels comparing normotensive participants randomized to an established multicomponent behavioral intervention [(filled bars) weight loss, reduced sodium intake, reduce alcohol consumption, and increased physical activity] and established multicomponent intervention plus the DASH diet (open bars) versus advice only. (Data from Appel LJ, Champagne CM, Harsha DW, Cooper LS, Obarzanek E. Related Articles, Writing Group of the PREMIER Collaborative Research Group: effects of comprehensive lifestyle modification on blood pressure control: main results of the PREMIER clinical trial. JAMA 2003;289:2083–93.)


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original meta-analyses [62] of the effect of calcium on blood pressure in nonpregnant adults to include results from newer trials. From the pooled analysis, they reported a significant but small reduction in systolic blood pressure of 1.44 mm Hg (95% CI, 2.20 to 0.68; P \ .001) and in diastolic blood pressure of 0.84 mm Hg (95% CI, 1.44 to 0.24; P \ .001) associated with calcium supplementation. The effect has only been observed, however, in individuals with hypertension. Appel et al [67] performed a pooled analysis of 11 trials comparing fish oil supplementation with placebo among 728 normotensive subjects. They reported that fish oil intake (3.4 g/d) reduced systolic blood pressure by 1 mm Hg (95% CI, 0 to 2) and diastolic blood pressure by 0.5 mm Hg (95% CI, 0.2 to 1.2) [67]. In a meta-analysis of 11 controlled trials of predominately normotensive subjects, the median intake of five cups of caffeinated coffee per day was associated with a 2.4 mm Hg (range, 1 to 3.7) increase in systolic blood pressure and 1.2 mm Hg (range, 0.4 to 2.1) increase in diastolic pressure [66]. Although further research is needed, this analysis supports a relationship between coffee intake and high blood pressure. Although adequate calcium intake, fish oil supplementation, and reduced caffeine intake may be important for general health [69–71], the effect of these lifestyle modifications on blood pressure are too small to support a recommendation for primary prevention of hypertension. Although observational studies have found a strong inverse relationship between dietary protein and fiber intake and blood pressure, clinical trial data are limited [72,73]. In the two randomized trials for which blood pressure has been the primary outcome, significant reductions in systolic blood pressure (P \ .05) were seen for participants randomized to soy protein compared with their counterparts randomized to either carbohydrates or low-protein supplementation [74,75]. Additionally, a small (N ¼ 41) randomized controlled trial found 5.9 (95% CI: 8.1 to 3.7) and 1.4 (95% CI: 3 to 0.2) mm Hg reductions in 24-hour systolic and diastolic blood pressure, respectively, among persons with hypertension randomized to receive dietary fiber supplementation compared with their counterparts randomized to placebo [75]. Further research is needed to explore the impact of these nutrients in reducing the incidence of hypertension.

Summary The best approach to the primary prevention of hypertension is a combination of lifestyle changes: weight loss in overweight persons; increased physical activity; moderation of alcohol intake; and consumption of a diet that is higher in fruits, vegetables, and low-fat dairy products and lower in sodium content than the average American diet (Table 3). Recent randomized controlled trials have demonstrated that these lifestyle changes can be sustained over long periods of time (more than 3 years) and can have blood pressure–lowering effects as large as those seen in drug studies [11].

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Table 3 Lifestyle modifications for primary prevention of hypertension Modification

Recommendation a

Weight reduction Adopt DASH eating plana Dietary sodium reductiona Physical activitya Limit alcohol consumptiona

Dietary potassium maintenance

Maintain normal body weight (BMI, 18.5–24.9) Consume a diet rich in fruits, vegetables, and low-fat dairy products with a reduced content of saturated and total fat Reduce dietary sodium intake to no more than 100 mmol/d (2.4 g sodium or 6 g sodium chloride) Engage in regular aerobic physical activity, such as a brisk walk (at least 30 min/d, most days of the week) Limit consumption to no more than two drinks per day (1 oz or 30 mL ethanol [eg, 24 oz beer, 10 oz wine, or 2 oz of 100 proof whiskey] in most men and no more than one drink per day in women and light-weight persons Maintain adequate intake of dietary potassium (>90 mmol [3500 mg] per day)

a Of note, the recommendations for primary prevention are the same as the lifestyle modifications recommendations for the management of hypertension (JNC VII). Abbreviations: BMI, body mass index calculated as weight in kilograms divided by the square of height in meters; BP, blood pressure; DASH, dietary approaches to stop hypertension. Adapted from Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, And Treatment of High Blood Pressure. The JNC 7 report. JAMA 2003;289:2560– 72; and Whelton PK, He J, Appel LJ, et al. Primary prevention of hypertension: clinical and public health advisory from the National High Blood Pressure Education Program. JAMA 2002;288:1882–8; with permission.

Hypertension is an important preventable risk factor for cardiovascular disease, the leading cause of mortality in the United States [3,76]. To achieve the Healthy People 2010 goal of reducing the proportion of adults with hypertension from 28% to 16% [15], concerted efforts must be directed toward primary prevention strategies. Lifestyle modifications including weight loss, increased physical activity, and dietary changes in individuals have been shown to reduce the incidence of hypertension and should be recommended for all persons and especially those with prehypertension. In addition, timely adoption of prevention strategies to reduce the incidence of hypertension and its subsequent complications in the general population may interrupt the costly cycle of hypertension and prevent the reductions in quality of life associated with this chronic disease.

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