CARDIOVASCULAR BENEFITS OF OMEGA-3 POLYUNSATURATED FATTY ACIDS
Solvay Pharmaceuticals Conferences Series Editors Werner Cautreels, Claus Steinborn and Lechoslaw Turski
Volume 7 Previously published in this series Vol. 6 Vol. 5 Vol. 4 Vol. 3 Vol. 2 Vol. 1
B. Testa and L. Turski (Eds.), Virtual ADMET Assessment in Target Selection and Maturation C.G. Kruse, H.Y. Meltzer, C. Sennef and S.V. van de Witte (Eds.), Thinking About Cognition: Concepts, Targets and Therapeutics J. Antel, N. Finer, D. Heal and G. Krause (Eds.), Obesity and Metabolic Disorders G. Krause, J.R. Malagelada and U. Preuschoff (Eds.), Functional Disorders of the Gastrointestinal Tract J.G. Papp, M. Straub and D. Ziegler (Eds.), Atrial Fibrillation: New Therapeutic Concepts E. Ronken and G.J.M. van Scharrenburg (Eds.), Parkinson’s Disease
ISSN 1566-7685
Cardiovascular Benefits of Omega-3 Polyunsaturated Fatty Acids
Edited by
B. Maisch Philipps University of Marburg, Marburg, Germany
and
R. Oelze Solvay Pharmaceuticals, Hannover, Germany
Amsterdam • Berlin • Oxford • Tokyo • Washington, DC
© 2006 The authors. All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without prior written permission from the publisher. ISBN 978-1-58603-707-9 Library of Congress Control Number: 2006939183 Publisher IOS Press Nieuwe Hemweg 6B 1013 BG Amsterdam Netherlands fax: +31 20 687 0019 e-mail:
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Cardiovascular Benefits of Omega-3 Polyunsaturated Fatty Acids B. Maisch and R. Oelze (Eds.) IOS Press, 2006 © 2006 The authors. All rights reserved.
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Preface “The Solvay Pharmaceutical Conferences: where industry meets academia in a search for novel therapies”
Therapy for Sudden Death Still Awaited During the last decades progress has been made in the treatment of patients who survived myocardial infarction. The implementation of coronary care units and evolution of public education to encourage rapid response, development of catheter-based revascularization techniques, greater emphasis on cardiac rehabilitation, and improved therapy have contributed to improvement of prognosis for patients with myocardial infarction. The introduction of aspirin, thrombolytics, ß-blockers, ACE-inhibitors and statins led to reduction in both short-term and immediate mortality rates among patients suffering from myocardial infarction. Nevertheless, patients who survive an acute myocardial infarction are at high risk, with life expectancy half that of their peers who have not experienced similar events, and with increased risk for subsequent cardiovascular events and death. The risk of sudden death increases with severity of systolic dysfunction after myocardial infarction. Sudden death has proved to be more difficult to treat than coronary disease. In recent years, it has become clear that in addition to risk factors such as overweight, lack of exercise, smoking, hypertension and hypercholesterolemia, psychosocial factors play a key role for prognosis in patients with myocardial infarction. Depression, anxiety, perceived social support and social desirability may have an effect on mortality and morbidity in such patients. Therefore, there is high medical need for drugs which lower the incidence of sudden death and have an effect on other risk factors such as depression. A pharmaceutical preparation of highly purified and concentrated :-3 polyunsaturated acids, OMACOR®, may represent such a drug. It lowers the incidence of sudden death in patients with myocardial infarction and decreases depression. This volume summarizes lectures delivered during the symposium entitled “Effect of :-3 polyunsaturated fatty acids on different risk factors in patients with cardiovascular disease” presented during the European Cardiology Society Congress in Stockholm (Sweden) in 2005. In addition, aspects of prevention of cardiovascular disease, risk factors, and pharmacokinetics of :-3 fatty acids ethyl esters have been considered. W. Cautreels C. Steinborn L. Turski
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List of Contributors Alter, P. Molecular Cardiology Laboratory, Department of Internal Medicine and Cardiology, Philipps University of Marburg, Karl-von-Frisch-Strasse 1, D-35033 Marburg, Germany Annemans, L. HEDM-IMS, Rue De Crayer 6, 1000 Brussels, Belgium Ghent University, Sint-Pietersnieuwstraat 25, 9000 Ghent, Belgium Cautreels, W. Solvay Pharmaceuticals, Brussels, Belgium Connolly, S.J Faculty of Health Sciences, McMaster University, 237 Barton Street E., Hamilton, Ontario L8L 2X2, Canada Frasure-Smith, N. Centre Hospitalier de l’Université de Montréal, Hôpital Notre-Dame, Recherche Psychiatrie, Pavillon L-C Simard, 1560 rue Sherbrooke Est, Montréal, Québec, Canada H2L 4M1 Healey, J.S. Faculty of Health Sciences, McMaster University, 237 Barton Street E., Hamilton, Ontario L8L 2X2, Canada Huber, G. 1st Medical Department, SMZ-Ost/Danube Hospital, Langobardenstrasse 122, A-1220 Vienna, Austria Kawalec, P. HTA Center, Nuszkiewicza Street 13/19, Krakow, Poland Institute of Public Health, Collegium Medium, Jagiellonian University, Grzegorzecka Street 20, Krakow, Poland Lamotte, M. HEDM-IMS, Rue De Crayer 6, 1000 Brussels, Belgium Lespérance, F. Centre Hospitalier de l’Université de Montréal, Hôpital Notre-Dame, Recherche Psychiatrie, Pavillon L-C Simard, 1560 rue Sherbrooke Est, Montréal, Québec, Canada H2L 4M1
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Maisch, B. Molecular Cardiology Laboratory, Department of Internal Medicine and Cardiology, Philipps University of Marburg, Baldingerstrasse, D-35043 Marburg, Germany Rupp, H. Molecular Cardiology Laboratory, Department of Internal Medicine and Cardiology, Philipps University of Marburg, Karl-von-Frisch-Strasse 1, D-35033 Marburg, Germany Rupp, T.P. Molecular Cardiology Laboratory, Department of Internal Medicine and Cardiology, Philipps University of Marburg, Karl-von-Frisch-Strasse 1, D-35033 Marburg, Germany Selimi, D. 1st Medical Department, SMZ-Ost/Danube Hospital, Langobardenstrasse 122, A-1220 Vienna, Austria Severus, W.E. Ludwig-Maximilians-University, Department of Psychiatry, Nußbaumstrasse 7, 80336 Munich, Germany Steinborn, C. Solvay Pharmaceuticals, Hannover, Germany Turski, L. Solvay Pharmaceuticals, Weesp, The Netherlands Verboom, C.N. Solvay Pharmaceuticals, Hannover, Germany Vik, H. Pronova Biocare, P.O. Box 420, N-1327 Lysaker, Norway Vinereanu, D. University of Medicine and Pharmacy Carol Davila, Cardiology, University Hospital of Bucharest, Splaiul Independentei 169, Bucharest, 05098, Romania Wagner, D. Molecular Cardiology Laboratory, Department of Internal Medicine and Cardiology, Philipps University of Marburg, Karl-von-Frisch-Strasse 1, D-35033 Marburg, Germany Weber, H.S. 1st Medical Department, SMZ-Ost/Danube Hospital, Langobardenstrasse 122, A-1220 Vienna, Austria Zoellner, Y. Solvay Pharmaceuticals GmbH, Global Health Economics, P.O. Box 220, D-30002 Hannover, Germany
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Contents Preface W. Cautreels, C. Steinborn and L. Turski List of Contributors
v vii
Conference Preface Bernhard Maisch
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Keynote Lecture – Risk Factors for Atherosclerotic Disease: Present and Future Dragos Vinereanu
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Microdetermination of Fatty Acids by Gas Chromatography and Cardiovascular Risk Stratification by the “EPA+DHA Level” Heinz Rupp, Thomas P. Rupp, Daniela Wagner, Peter Alter and Bernhard Maisch Highly Purified Omega-3 Polyunsaturated Fatty Acids Are Effective as Adjunct Therapy for Secondary Prevention of Myocardial Infarction: Critical Analysis of GISSI-Prevenzione Trial Cees N. Verboom Prevention of Cardiovascular Diseases and Highly Concentrated n-3 Polyunsaturated Fatty Acids (PUFAs) Heinz S. Weber, Dzevair Selimi and Gustav Huber Omega-3 Fatty Acids and Sudden Arrhythmic Death Stuart J. Connolly and Jeffrey S. Healey Depression and Coronary Artery Disease: Epidemiology and Potential Mechanisms Nancy Frasure-Smith and François Lespérance Effects of Omega-3 Polyunsaturated Fatty Acids on Depression W. Emanuel Severus A Multi-Country Health-Economic Evaluation of Highly Concentrated n-3 Polyunsaturated Fatty Acids (PUFAs) in the Secondary Prevention After Myocardial Infarction (MI) Mark Lamotte, Lieven Annemans, Pawel Kawalec and York Zoellner
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81
99 111
121 129
139
OMACOR® in Clinical Development: A Survey of Current Trials Hogne Vik
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Author Index
185
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Conference Preface and Keynote Lecture
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Cardiovascular Benefits of Omega-3 Polyunsaturated Fatty Acids B. Maisch and R. Oelze (Eds.) IOS Press, 2006 © 2006 The authors. All rights reserved.
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Conference Preface Omega-3 Polyunsaturated Fatty Acids: When Nature Writes the Draft to Evidence-Based Medicine It still happens that nature writes the draft for a fundamental contribution to medical textbooks: such a classic example is the observation that Greenland Eskimos eating a diet high in omega-3 polyunsaturated fatty acids (PUFAs) from fish and sea mammals [1,2] had an unexpectedly low cardiac mortality. Coming from such observational evidence, the next logical step in medical research is to go to evidence-based medicine or truly to the heart of the matter: the US Physicians’ Health Study [3] demonstrated in the 4th quartile of enroled individuals a 50% reduction of sudden cardiac death, if at least one fish meal per day was consumed. Three randomized trials demonstrated a reduction in the risk of sudden death by dietary changes and supplementation of the daily diet increasing omega-3 PUFA intake [4-6]. GISSI-Prevenzione [6] has been the landmark trial with 11324 patients enroled to show a reduction of sudden cardiac death by 45% in post-myocardial infarction patients, which was attributed to the EPA and DHA ethyl esters. In addition, Mozaffarian et al [7] analysed the risk of 5201 men and women older than 65 years from the Medicare eligibility list and found that consumption of tuna or broiled or baked fish was associated with a lower incidence of atrial fibrillation. Similarly, Calo et al [8] reported a reduction of postoperative atrial fibrillation by 54.4% in 160 randomized patients after CABG. As pointed out by Weber et al in their contribution to this book [9], this clear evidence was reflected in the European Society of Cardiology guidelines for the prevention of sudden death [10,11]: omega-3 fatty acids (EPA & DHA) were rated as a class IIa, level of evidence B recommendation for the secondary prevention of sudden death after myocardial infarction. Remarkably, the relative risk reduction (RR) for total mortality was 0.7 for EPA/DHA, 0.83 for ACE-inhibitors and 0.77 for beta-blockers. For sudden cardiac death it was an impressive relative risk reduction of 0.55 for EPA/DHA, whereas it was only 0.8 for ACE-inhibitors and 0.74 for beta-blockers. Rupp et al [12] established a gaschromatic micromethod for analyzing EPA and DHA levels on a routine basis and could show that the supplementation of 1 g/day of highly purified EPA and DHA ethyl esters (OMACOR®) increased EPA from 0.6 to 1.4% and DHA from 2.9 to 4.3%. He suggests, also in his book-chapter, an EPA/arachidonic acid ratio as diagnostic parameter for the identification and reduction of pro-inflammatory eicosanoids and cytokines and recommends 1 g/day of EPA and DHA in CAD patients to reach the level of nPUFAs in the GISSI-Prevention study, which prevented sudden cardiac death.
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B. Maisch / Conference Preface
Atherosclerosis is the leading cause of death worldwide. 3.8 million men and 3.4 million women die each year from coronary artery disease alone. In Germany, death by cardiovascular disease has for the last three decades accounted for roughly 50% of all deaths, more than twice the incidence of neoplastic disease. Cardiovascular disease accounts for 11.8% in men and 10.5% in women of all disability-adjusted life-years lost. But as pointed out by Vinereanu in his contribution to this book [13], the age and gender standardised trends in cardiovascular mortality show different directions in Europe: whereas cardiovascular morbity and mortality are still increasing in Eastern Europe they are decreasing in Western Europe and in the USA. This decrease in Western Europe occurs despite the alarming increase of diabetes, metabolic syndrome and overweight even in adolescents. Over all in the worldwide survey of people aged 15-59 years, coronary artery disease is already the second largest group of deaths. Major risk factors for atherosclerosis have been clearly identified in the last century and categorized as conventional and new risk factors. Their number has been increasing ever since the beginning of the Framingham Heart Study in 1948. Remarkably, the hierarchy of risk factors for different types of atherosclerotic diseases was best evaluated in the INTERHEART study. By multivariate analysis, current smoking and a raised ApoB/ApoA1 ratio were the strongest risk factors, followed by a history of diabetes, hypertension, and psychosocial factors. Lifestyle modifications which are beneficial are the daily consumption of fruits or vegetables and regular physical activity. In carotid atherosclerosis, which is responsible of more than 20% of all strokes in the Framingham Heart Study, the most powerful risk factors were age followed by smoking, hypertension, and raised blood lipids. For peripheral arterial atherosclerotic disease, hypertension, smoking, and diabetes are the most important risk factors. The preventive benefit of n-3 PUFAs in patients with coronary artery disease has historically been attributed to direct interference with lipid metabolism. Presently we know much better, that it is hardly this influence on cholesterol, LDL and HDL-levels but the benefit comes from more complicated and more specific modes of action: Rupp and coworkers summarize in their contribution [14] the pathophysiological and pharmacological basis for interfering of n-3 PUFAs with the electrical instability of the remodelled or ischaemic heart. It has been shown by Xiao and Leaf [15] that the free fatty acids of EPA and DHA but not other fatty acids inhibit the Na+ channel activity which occurs rapidly and can be washed out. In addition, the cardiac Na+-Ca2+ exchanger [16] and the L-type Ca2+ channel [17], which has been inferred particularly in after-depolarisations, were inhibited. Further clinical support for anti-arrhythmogenic effects of omega-3 fatty acids was provided in the study of Calo et al [8]. But pathophysiologically coherent conclusions may not always be so coherent in everyday reality. Three recently published smaller ICD trials , in a situation different from acute post-MI situation in GISSI-Prevenzione, examined patients who had a defibrillator implanted for the incidence of arrhythmic events. Raitt et al [18], in a possibly underpowered study of 200 randomized patients, could not demonstrate a reduction of incidences of ventricular tachycardia and only a trend for less episodes of ventricular fibrillation. Leaf et al [19] could show in a secondary outcome analysis that fish oil prevented ventricular arrhythmic events more effectively than olive oil but missed this point in the primary outcome analysis. The SOFA-trial by Brouwer et al [20], when comparing fish oil vs. placebo in a similar ICD setting with 273 patients, only showed a trend but not a significant benefit. Remarkably, Burr et al (2003) in recent study examining the effect of the advice to increase fish oil consumption in patients with angina, showed a lack of benefit under these circumstances [5]. All these latter quasi-neutral studies share the following common deficiencies: they lack the measurement of EPA and DHA in the trial population. So in the
B. Maisch / Conference Preface
5
case of the last mentioned study by Burr et al. [5] we do not know whether patients really followed the advice to increase fish oil consumption or not, since compliance was not measured. And in the 3 ICD studies one should be aware of the fact that they involved only 4 percent of the study population of the GISSI-Prevention trial in a situation not analogous to the acute post-MI situation. For this reason they may be considered as “convenience” trials. Rupp et al [12,14] hypothesize that this may be due to the fact that in acute infarction free EPA and DHA are raised in advance to levels required for their anti-arrhythmogenic action by the event and sympathetic drive, whereas the ICD is expected to terminate re-entrant ventricular tachycardias or ventricular fibrillation before a marked sympathetic activation and release of EPA and DHA occurs. An additional intriguing possibility is the observation that the process of adverse dilatation of the heart could be attenuated by EPA and DHA as shown in the pressure overloaded rat heart. Connolly and Healy [21], when reviewing the data on the protective effect of n-3 PUFAs on cardiovascular deaths in their chapter, underline the recommendations of the American Heart Association and the European Society of Cardiology and come to the conclusion that the benefit of secondary and probably also of primary prevention by n-3 PUFAs is based primarily on avoiding episodes of sudden cardiac death. That the costs for secondary prevention after acute myocardial infarction by n-3 PUFAs are well worthwhile and can be calculated in life-years gained (LYG) as the price to be paid is pointed out by Lamotte, Annemans, Kawalec and Zoellner in their chapter [22] on the socio-economic impact of this treatment. But the society must be willing to pay a threshold of about 20 000 EUR/LYG. The OMACOR authors in this book [23] describe the avenue of newly planned and carried out clinical trials to expand the spectrum of application of EPA and DHA: ASCEND will evaluate serious (cardio)vascular events in a randomized clinical trial (RCT) which is four-armed and enroles 10 000 patients with diabetes mellitus. Treatment options are OMACOR® 1 g/day both in combination with 100 mg aspirin and without vs. placebo. AFORRD is also directed to type-2 diabetes patients but in a dose of 2 g/day. Beyond the effect on coronary artery disease and sudden cardiac death omega-3 supplementation has a clearly warranted effect on the reduction of post-infarction depression and, remarkably, also on depressive patients not suffering from CAD, as shown by FrasureSmith and Lespérance in their own scientific work [24] represented here and by Severus in his overview on depression and n-3 PUFAs in this book [25]. These interesting data may expand the therapeutic spectrum of OMACOR® considerably in the near future. In summary, this book on omega-3 fatty acids gives an up to date reappraisal for the use of n-3 PUFAs in different fields of medicine. It has been both a privilege and a distinct pleasure to orchestrate the authors in this “concert” of various but related topics. Bernhard Maisch
References [1] [2]
H.O. Bang, J. Dyerberg, A.B. Nielsen. Plasma lipid and lipoprotein pattern in Greenlandic West-coast Eskimos. Lancet 1 (1971) 1143-1145. N. Kromann and A. Green. Epidemiological studies in the Upernavik district, Greenland. Incidence of some chronic diseases 1950-1974. Acta Med. Scand. 208 (1980) 401-406.
6 [3] [4] [5] [6]
[7] [8]
[9] [10] [11] [12]
[13] [14] [15] [16] [17]
[18]
[19] [20]
[21] [22]
[23] [24] [25]
B. Maisch / Conference Preface C.M. Albert, C.H. Hennekens, C.J. O’Donnell et al. Fish consumption and risk of sudden cardiac death. The US Physicians’ Health Study. JAMA 279 (1998) 23-28. M. de Lorgeril, S. Renaud, N. Mamelle et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 343 (1994) 1454-1459. M.L. Burr, A.M. Fehily, J.F. Gilbert et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet 2 (1989) 757-761. R. Marchioli, F. Barzi, E. Bomba et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione. Circulation 105 (2002) 1897-1903. D. Mozaffarian, B.M. Psaty, E.B. Rimm et al. Fish intake and risk of incident atrial fibrillation. Circulation 110 (2004) 368-373. L. Calo, L. Bianconi, F. Colivicchi et al. N-3 fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a randomized, controlled trial. J. Am. Coll. Cardiol. 45 (2005) 17231728. H. Weber, D. Selimi, G. Huber. Prevention of cardiovascular diseases and highly concentrated n-3 polyunsaturated fatty acids (PUFAs) (2006). In this book, chapter 4. S.G. Priori, E. Aliot, C. Blomstrom-Lundqvist et al. Task force on sudden cardiac death of the European Society of Cardiology. Eur. Heart J. 22 (2001) 1374-1450. S.G. Priori, E. Aliot, C. Blomstrom-Lundqvist et al. Update of the guidelines on sudden cardiac death of the European Society of Cardiology. Eur. Heart J. 24 (2003) 13-15. H. Rupp, D. Wagner, T. Rupp et al. Risk stratification by the “EPA+DHA Level” and the “EPA/AA ratio” focus on anti-inflammatory and antiarrhythmogenic effects of long-chain omega-3 fatty acids. Herz 29 (2004) 673-685. D. Vinereanu. Risk factors for atherosclerotic disease: present and future (2006). In this book, chapter 1. H. Rupp, T.P. Rupp, D. Wagern et al. Microdetermination of fatty acids by gas chromatography and cardiovascular risk stratification by the “EPA+DEHA level” (2006). In this book, chapter 2. Y.F. Xiao, J.X. Kang, J.P. Morgan et al. Blocking effects of polyunsaturated fatty acids on Na+ channels of neonatal rat ventricular myocytes. Proc. Natl. Acad. Sci. U.S.A. 92 (1995) 11000-11004. Y.F. Xiao, Q. Ke, Y. Chen et al. Inhibitory effect of n-3 fish oil fatty acids on cardiac Na+/Ca2+ exchange currents in HEK293t cells. Biochem. Biophys. Res. Commun. 321 (2004) 116-123. Y.F. Xiao, A.M. Gomez, J.P. Morgan et al. Suppression of voltage-gated L-type Ca2+ currents by polyunsaturated fatty acids in adult and neonatal rat ventricular myocytes. Proc. Natl. Acad. Sci. U.S.A. 94 (1997) 4182-4187. M.H. Raitt, W.E. Connor, C. Morris et al. Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators: a randomized controlled trial. JAMA 293 (2005) 2884-2891. A. Leaf, C.M. Albert, M. Josephson et al. Prevention of fatal arrhythmias in high-risk subjects by fish oil n-3 fatty acid intake. Circulation 112 (2005) 2762-2768. I.A. Brouwer, P.L. Zock, A.J. Camm et al. Effect of fish oil on ventricular tachyarrhythmia and death in patients with implantable cardioverter defibrillators: the Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA) randomized trial. JAMA 295 (2006) 2613-2619. S.J. Connolly and J.S. Healey. Omega-3 fatty acids and sudden arrhythmic death (2006). In this book, chapter 5. M. Lamotte, L. Annemans, P. Kawalec et al. A multi-country health economic evaluation of highly concentrated n-3 polyunsaturated fatty acids (PUFAs) in the secondary prevention after myocardial infraction (MI) (2006). In this book, chapter 8. OMACOR-authors. OMACOR® in clinical development: a survey of current trials (2006). In this book, chapter 9. N. Frasure-Smith and F. Lespérance. Depression and coronary artery disease: epidemiology and potential mechanisms (2006). In this book, chapter 6. W.E. Severus. Effects of omega - 3 polyunsaturated fatty acids on depression (2006). In this book, chapter 7.
Cardiovascular Benefits of Omega-3 Polyunsaturated Fatty Acids B. Maisch and R. Oelze (Eds.) IOS Press, 2006 © 2006 The authors. All rights reserved.
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Risk Factors for Atherosclerotic Disease: Present and Future Dragos Vinereanu University of Medicine and Pharmacy Carol Davila, Cardiology, University Hospital of Bucharest, Splaiul Independentei 169, Bucharest, 05098, Romania Abstract. Atherosclerotic disease is considered to be the leading cause of death and loss of disability-adjusted life-years worldwide. Major differences are between different countries, mainly because of the variation of risk factors for atherosclerosis between populations. Over 300 risk factors have been associated with atherosclerosis and its major complications, coronary heart disease and stroke. However, between 70% and 90% of the risk of atherosclerotic disease can be explained by different associations between conventional risk factors, such as smoking, abnormal lipids, hypertension, diabetes, obesity, psychosocial factors, unhealthy diet, and lack of physical activity. Because risk factors can have multiplicative effects, their assessment in an individual subject needs application of different models for total risk estimation. Effective cardiovascular prevention needs a global strategy, based on knowledge of the importance of different risk factors, conventional and newly-described, and of the best model that can be applied to assess risk for atherosclerotic disease in an individual subject. Keywords. Risk factors, atherosclerosis, coronary heart disease, myocardial infarction
Epidemiology Cardiovascular diseases are the major cause of death in adults in the world, accounting for about 50% of all death and for 30% of all death before the age of 65 years. One in 8 men and one in 17 women die from cardiovascular disease before the age of 65 years [1]. There are still major differences in cardiovascular mortality between different European countries, with high mortality rates in Central and Eastern Europe (ranging from 5 per 1000 inhabitants in Poland to 9 per 1000 inhabitants in Ukraine and Bulgaria), and relatively low mortality rates in Northern, Western and Southern Europe (ranging from 2 to 4 per 1000 inhabitants). Trends of age and gender standardised cardiovascular mortality during the 19802002 period show a similar pattern to all-cause mortality: up sloping curves in Central and Eastern Europe (e.g. Ukraine, Bulgaria, and Romania), and down sloping curves in the Northern, Western and Southern Europe (except Greece) (Figure 1) [2]. It should be noted, however, that while standardised mortality rates continue to decline, the crude, non-standardised mortality rates remain stable or even increase (e.g. Ukraine, Bulgaria, and Romania), due to the ageing of the population.
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D. Vinereanu / Risk Factors for Atherosclerotic Disease: Present and Future
Figure 1. Age and gender standardised cardiovascular mortality per 1000 inhabitants [2] (copyright ESC: reproduced with permission).
Of the cardiovascular deaths, more than 70% are due to the complications of atherosclerosis (nearly 50% results from coronary artery disease and another 20% from stroke). Coronary heart disease is now the leading cause of death worldwide, 3.8 million men and 3.4 million women dying each year from this disease (Figure 2 and 3). Stroke is the third leading cause of death and the principal cause of long-term disability. Moreover, coronary heart disease and stroke account for 11.8% and 10.5% of all disability-adjusted life-years (DALY’s) lost in men and women, respectively [3].
Figure 2. Number of deaths (thousands) worldwide of people aged 15 to 59 years [3].
D. Vinereanu / Risk Factors for Atherosclerotic Disease: Present and Future
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Figure 3. Number of deaths (thousands) worldwide of people aged 60 years and above [3]. COPD = chronic obstructive pulmonary disease
The main cause of mortality from coronary artery disease is represented by the acute coronary syndromes. Their clinical classification is presented in Figure 4 [4]. Of the patients enrolled into the Euro Heart Survey on Acute Coronary Syndromes, 57% presented with no ST elevation and 47% with ST elevation. Of patients with no ST elevation, 64% were discharged with a diagnosis of unstable angina, 13% with non-Q-wave myocardial infarction, and only 9% with Q-wave myocardial infarction. Of patients with ST elevation, 65% were discharged with a diagnosis of Q-wave myocardial infarction [5].
Figure 4. Clinical classification of acute coronary syndromes. NQMI = non-Q-wave myocardial infarction; NSTEMI = non-ST elevation myocardial infarction; QwMI = Q-wave myocardial infarction; ST = ST segment of ECG tracing [4].
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D. Vinereanu / Risk Factors for Atherosclerotic Disease: Present and Future
In-hospital mortality rates were 1.0% for patients with unstable angina, 5.8% for non-Qwave myocardial infarction, and 9.3% for Q-wave myocardial infarction. At 30 days, mortality rates were 1.7%, 7.4%, and 11.1%, respectively [6], with rather high differences between different European countries (Figure 5) [2].
Figure 5. 30-day mortality in acute coronary syndromes admitted without (left) and with (right) ST elevation [2] (copyright ESC: reproduced with permission).
The likelihood of a person to develop a cardiovascular event due to atherosclerosis over a definite period of time (usually 10 years) defines a risk factor. There are two basic categories of risk factors for atherosclerosis: conventional, well-demonstrated, incorporated already into different risk prediction models, and newly-described risk factors (Table 1) [7]. From a historical perspective, all major risk factors were initially described by the Framingham Heart Study (Table 2) (www.framingham.com/heart/timeline.htm). Table 1. Risk factors for atherosclerosis Category Conventional risk factors Predisposing factors Risk-modifying behaviours Metabolic risk factors New risk factors Markers of inflammation Metabolic risk factors Thrombogenic factors Markers of sub-clinical atherosclerosis
Risk factors Age, sex, family history, genes Smoking, nutrition, physical activity, psychosocial factors Dyslipidaemia, hypertension, diabetes, obesity, metabolic syndrome C-reactive protein and other markers Homocysteine, lipoprotein(a) Fibrinogen, fibrin D-dimer, markers of fibrinolytic function, other risk factors for arterial thrombosis Markers of endothelial dysfunction, arterial stiffness, intima-media thickness, ankle-brachial index, calcium score
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Table 2. A timeline of milestones from the Framingham Heart Study Year 1948 1960 1961 1967 1974 1978 1981 1990 1994 1998
Milestone Start of the Framingham Heart Study Smoking found to increase the risk of heart disease Cholesterol level and blood pressure found to increase the risk of heart disease Physical activity found to reduce the risk of heart disease Obesity found to increase the risk of heart disease Diabetes found to increase the risk of heart disease Psychosocial factors found to increase the risk of heart diseases Major report issued on relationship of diet and heart disease Homocysteine suggested to be a possible risk factor for heart disease Lipoprotein(a) suggested to be a possible risk factor for heart disease New risk prediction model described to calculate risk of a subject for developing coronary disease
Conventional Risk Factors 1. Predisposing Factors 1.1. Age and Sex Coronary heart disease is related strongly to age. Europe has the oldest population in the world, with a projection of one in three Europeans aged 65 and over by 2050 [1,4]. Therefore, the prevalence of patients who are at risk is on the increase and the overall burden of coronary heart disease is anticipated to increase in the forthcoming decades. Female gender is considered as a protection against coronary heart disease. The agespecific incidence rates are 3-6 times lower in women compared to men, but this difference attenuates at older age [8]. Moreover, in younger patients with acute coronary syndromes, women were less likely than men to present with ST elevation, however, in older patients there were no differences [9]. The onset of coronary heart disease events may be delayed by some 10 years in women, but when they are affected by the disease their prognosis is worse [1]. 1.2. Family History and Genetic Factors The importance of a family history as a risk factor for coronary heart disease has been established: (1) when an individual is a first degree relative of a family member who has developed coronary heart disease; (2) when the percentage of family members with coronary heart disease is increased; (3) when family members developed coronary heart disease at young ages [1]. Lifestyle advice and, where appropriate, therapeutic management of the other risk factors should be used for members of families where coronary heart disease is highly prevalent. A large number of genes have been investigated in relation to the risk of coronary heart disease. Apart from some well-defined genetic disorders, such as familial hypercholesterolaemia and familial combined hyperlipidaemia, which are strongly related to severe atherosclerosis and premature coronary heart disease, there is also evidence of a relatively important genetic contribution to some of the major risk factors of atherosclerosis. This genetic contribution is usually estimated by “heritability”. And indeed, for apolipoproteins and lipid traits heritability varies between 40-60% [10], and for plasma
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lipoprotein(a) heritability is reported to be >90% [11]. So far, however, DNA-based tests do not add significantly to the assessment of overall risk of atherosclerosis [1]. 2. Risk-Modifying Behaviours 2.1. Smoking Smoking is the most important modifiable risk factor for coronary heart disease. A strong and graded relation was found between dose (number of cigarettes smoked) and risk of myocardial infarction, with the risk increasing at every increment, so that subjects smoking more than 40 cigarettes per day had an OR of 9.16 (99% CI 6.18-13.58) (Figure 6) [12]. The risk is particularly high if smoking starts before the age of 16 years [3]. Smoking acts synergistically with the other risk factors, and also with oral contraceptive agents, placing smoking women taking this medication at even higher risk [1]. There are now nearly 1 billion individuals smoking worldwide [3]. Within Europe, the impact of smoking has been found to be smaller in Mediterranean populations than in Northern European populations [1]. Even non-smokers exposed to environmental smoke have also a relative risk of coronary heart disease of 1.25 (95% CI 1.17-1.32), as compared with non-smokers not exposed to smoke [13]. Smoking increases the risk of atherosclerosis by several mechanisms: (1) decreases myocardial oxygen supply; (2) has acute unfavourable effects on blood pressure; (3) enhances oxidation of LDL cholesterol; (4) impairs endothelial function; and (5) has adverse inflammatory and thrombotic effects [7]. Smoking cessation reduced coronary heart disease mortality by 36% as compared with mortality in subjects who continued smoking, an effect that was consistent regardless of age, sex, or country of origin [14].
Figure 6. Odds ratio of myocardial infarction according to number of cigarettes smoked [12].
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2.2. Nutrition Nutrition, as a risk factor for atherosclerosis, includes the effects of saturated fatty acids and cholesterol, and the protective effects of polyunsaturated fatty acids (PUFAs), fruits and vegetables, and alcohol. Food lipids are made up of 3 major classes of fatty acids: saturated, monounsaturated, and polyunsaturated, classification based on the number of double bonds between carbon atoms. In food, these fatty acids are mixed together, making the study of the effects of specific classes considerably complex. It has been demonstrated that only the saturated fatty acids increases the concentration of LDL cholesterol and are related to coronary mortality. The source of saturated fatty acids in human diet are mainly derived from animal products, oils used for cooking or ready-cooked meals from the food industry (i.e. coconut and palm oils), and some home cooking fats (lard, hard margarines) [1]. The effect of replacing dietary saturated fats with polyunsaturated fats consists of a decrease of total cholesterol by 0.39 mmol/l and a decrease of LDL cholesterol by 0.29 mmol/l [15]. The effects of monounsaturated fatty acids on coronary heart disease are not wellestablished yet. On the contrary, the protective effects of some of the polyunsaturated fatty acids (PUFAs) are clearly demonstrated. And indeed, both groups of omega-3 PUFAs, of vegetable origin (D-linolenic acid) and fish oils (eicosapentaenoic acid, EPA, and docosahexaenoic acid, DHA), were shown to decrease coronary mortality and all-cause mortality. Thus, in secondary prevention, a reduction of 65% and 56% in coronary and all-causes mortality was achieved after 3.8 years, among patients randomly assigned to a Mediterranean diet, enriched in omega-3 PUFAs, compared to a control diet [16]. Moreover, in myocardial infarction, the DART study showed a reduction of 32% and 29% in coronary and all-cause mortality after 2 years follow-up, in patients eating fish twice a week [17]. Trans fatty acids are isomers, derived from meat, dairy products, margarines and readycooked meals, whose conformation has been modified during the digestion of ruminants or by industrial hydrogenation processes. They increase LDL cholesterol and, to a lesser extent, reduce HDL cholesterol. Epidemiological studies have found significant association between the intake of trans fatty acids and cardiovascular morbidity and mortality [1]. Fruits and vegetables are significant sources of antioxidant vitamins (vitamin E and A) and fibre. Cohort studies have shown negative correlations between the consumption of fruits and vegetables and the occurrence of coronary events or stroke. Thus, a 15% reduction in relative risk of coronary heart disease was found between the 10th and the 90th centile of fruit and vegetable consumption (indicating a 4-fold difference in fruit and a 2-fold difference in vegetable consumption) [18]. However, intervention trials of antioxidant vitamin supplements have failed to show any beneficial effects on total or coronary mortality [1,7]. Epidemiological studies showed that non-alcohol drinkers have a slightly higher risk of coronary heart disease than moderate drinkers. Indeed, in the INTERHEART study, moderate consumption of alcohol was associated with a reduced risk of myocardial infarction (OR 0.91, 99% CI 0.82-1.02) [12]. It is considered that the optimum consumption of alcohol ranges between 10 and 30 g per day (about 150 ml of wine, 250 ml of beer, or 30 to 50 ml of spirits), lower for women than for men because of enzymatic differences in the alcohol metabolism in women [19]. Alcohol has several protective effects, such as: (1) increases HDL cholesterol; (2) reduces concentrations of fibrinogen, antithrombin III, and increases concentrations of
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plasminogen and of the tissue factor activator, thus modifying favourably the haemostatic balance [1]. 2.3. Physical Activity Lack of physical activity is a risk factor for atherosclerotic disease whereas regular physical exercise has a protective effect. Prospective epidemiological studies have shown that a sedentary life is associated with a doubling of the risk of premature death and with an increased risk of atherosclerotic disease [1,3].
Figure 7. Age-adjusted relative risks of cardiovascular disease according to quintile of total energy expenditure due to physical exercise, measured in metabolic equivalents (MET score), in subgroups defined by age and body-mass index. The reference category is the lowest quintile of MET score (modified from [7] and [20]).
On the contrary, walking briskly for 30 minutes five times per week was associated with a 30% reduction in vascular events over a 3.5 years follow-up, irrespective of age or body-mass index, prolonged vigorous exercise being not needed for risk reduction (Figure 7) [20].
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Moreover, INTERHEART study has shown that moderate physical exercise was associated with a reduced risk of myocardial infarction (OR 0.86, 99% CI 0.76-0.97) [12]. Different physical activities that have a similar benefit to atherosclerotic disease are presented in Table 3 [3]. A potential problem with a modest physical activity is that it may not be adequate to reduce weight in obese subjects. Therefore, it is now accepted that long-term weight reduction requires more vigorous exercise. Table 3. Physical activities with similar benefits to atherosclerotic disease (modified from [3]) The following activities have similar benefits to atherosclerotic disease: Walking 3 km in 30 minutes Playing volleyball for 45 minutes Bicycling 8 km in 30 minutes Swimming for 20 minutes Playing basketball for 15-20 minutes Washing and waxing a car for 45-60 minutes Washing windows or floors for 45-60 minutes
Regular physical activity has multiple protective effects: (1) it decreases LDL cholesterol and triglycerides, increasing thereby HDL cholesterol; (2) it reduces overweight; (3) it decreases blood pressure levels; (4) it improves insulin sensitivity and glycaemic control; (5) it improves endothelial function, plasma rheology, and vascular inflammation [1,7]. 2.4. Psychosocial Factors Psychosocial factors, such as low socio-economic status, social isolation, stress at work and in family life, and negative emotions including depression and hostility, have been shown to contribute independently to the risk of coronary heart disease. Thus, socio-economic status was related inversely to coronary heart disease morbidity and mortality, with a fourfold difference between the highest and lowest occupational categories. Subjects who are isolated socially are also at increased risk of dying prematurely from coronary heart disease [1]. Stress at work, such as work at night, was shown to have a 50% increased risk of coronary heart disease [21]. Clinical depression also is associated with a significantly increased relative risk of developing coronary heart disease (2.69, 95% CI 1.63-4.43) [22]. In the recent published subanalysis of the INTERHEART study, psychosocial factors were the third most important risk factor for myocardial infarction (OR 2.67, 99% CI 2.21-3.22), after smoking and hyperlipidaemia [12,23]. Subjects with high stress were younger, heavier, more often smokers, and were less likely to have a low income and a low education [23]. The mechanisms by which psychosocial factors increase the risk of coronary heart disease are complex, involving activation of the sympato-adreno-medullary system and disturbances of the hypothalamic pituitary adrenocortical axis, which affect multiple metabolic, inflammatory, and haemostatic processes [1,7,23]. Psychosocial intervention strategies and medical treatment of depression have been demonstrated to have the potential of reducing cardiac mortality and morbidity. And indeed, patients who did not receive psychosocial treatment showed greater mortality and cardiac recurrence rates during the first 2 years of follow-up, with log-adjusted odds ratios of 1.70 for mortality (95% CI 1.09-2.64) and 1.84 for recurrence (95% CI 1.12-2.99) [24].
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3. Metabolic Risk Factors 3.1. Dyslipidaemia Types of dyslipidaemia associated with atherosclerotic disease are: (1) increased LDL cholesterol; (2) decreased HDL cholesterol; and (3) increased triglycerides. LDL transports most of the cholesterol in blood plasma, and has a strong positive association with the risk of atherosclerotic disease. LDLs are heterogeneous. Small, dense LDLs appear in plasma when triglycerides concentrations exceed 1.4 mmol/l (130 mg/dl), and they seem to be more atherogenic than larger forms of LDLs. They are associated with premature coronary artery disease, particularly in young and middle-aged people [25]. LDLs enter into the artery wall, where they are modified by oxidation, and they activate the atherosclerosis cascade. Decrease of LDL cholesterol by HMG-CoA reductase inhibitors reduces coronary events by up to 30% over a 5-year period. The goal of therapy is represented by an LDL cholesterol
