Current Opinion in Cardiology MAY 2009

Editorial introductions Current Opinion in Cardiology was launched in 1985. It is part of a successful series of review...

Author: William J. McKenna | William T. Abraham | David Feldman

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Editorial introductions

Current Opinion in Cardiology was launched in 1985. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of cardiology is divided into 14 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue.

Section Editors William J. McKenna

Dr William McKenna is Professor of Cardiology, at University College London, UK and Clinical Director of The Heart Hospital, University College London Hospitals Trust. He was born in Montreal, Canada and completed a Bachelor of Arts Degree at Yale University before graduating from McGill University Medical School. He completed Internal Medicine Training in at the Royal Victoria Hospital in Montreal and in 1976 moved to the Hammersmith Hospital Royal Postgraduate Medical School in London to train in cardiology. In 1988 he took up a post as Sugden Senior Lecturer in the Division of Cardiological Sciences at St George’s Hospital Medical School and in 1993 was made professor of cardiac medicine. In October 2000 he was appointed British Heart Foundation (BHF) Professor of Molecular Cardiology and in July 2003 moved to University College London (UCL) as Professor of Cardiology and was appointed Clinical Director of The Heart Hospital, University College London Hospital (UCLH) NHS Trust from September 2004. In August 2008 he was appointed Acting Director (West) of the Institute of Cardiovascular Science, UCL/UCLH Trust. His main interests have been in clinical and basic research of the cardiomyopathies. His recent work has contributed to the identification of disease-causing genes in hypertrophic, dilated and arrhythmogenic right ventricular cardiomyopathy, to

the establishment of new diagnostic criteria within the context of familial disease, and to the establishment of algorithms to identify patients at high risk of sudden death. William T. Abraham

William T. Abraham, M.D., F.A.C.P., F.A.C.C. is Professor of Internal Medicine and Chief of the Division of Cardiovascular Medicine at The Ohio State University College of Medicine, USA. He also serves as Deputy Director of the Dorothy M. Davis Heart and Lung Research Institute. Dr Abraham earned his medical degree from Harvard Medical School in Boston, Massachusetts, following which he completed his residency in internal medicine and fellowships in cardiology and heart failure/cardiac transplantation at the University of Colorado Health Sciences Center. He previously held faculty appointments at the University of Colorado, the University of Cincinnati, and the University of Kentucky. He is board certified in Internal Medicine and in Cardiovascular Diseases. Dr Abraham’s research interests include the role of the kidney in heart failure, neurohormonal mechanisms in heart failure, sleep disordered breathing in heart failure, and clinical drug and device trials in heart failure and cardiac transplantation. Dr Abraham has received grants from the National Institutes of Health, the American College of Cardiology, and the Aetna Quality Care Foundation and has participated as Principal Investigator in more than 100 multicenter clinical drug and device trials. In addition to authoring more than 600 original papers, abstracts, book chapters, and review articles, Dr Abraham has co-edited a leading textbook on heart failure entitled Heart Failure: A Practical Approach to Treatment. Dr Abraham serves on the editorial boards of several major journals including Congestive Heart Failure and Journal Watch Cardiology. He is also a scientific reviewer for such publications as Circulation, the European Heart Journal, and the Journal of the American College of Cardiology. Dr Abraham has been recognized as one of the ‘‘Best Doctors in America’’ for six consecutive years.

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Editorial introductions

David Feldman

Dr Feldman MD, PhD, FACC, FAHA is the Director of Heart Failure and Cardiac Transplant at The Ohio State University (OSU), USA. Dr Feldman is also the director of the heart failure fellowship program at OSU. He has appointments in the Departments of Cardiovascular Medicine, Physiology and Cell Biology as well as in the school of Pharmacy.

Dr Feldman’s research interests include the study of Gprotein coupled receptors, mechanisms of heart failure, genomic-mediated developmental changes and cardiac transplantation. He is currently funded by multiple National Institute of Health grants and the Heart failure Society of America. His research endeavors have included both basic and clinical research as he has extensive publications in both clinical and basic science. Despite his research, Dr Feldman continues to have a busy clinical practice. His clinical focus is cardiac transplant, end-stage disease management, and critical care.


Lamin A/C deficiency as a cause of familial dilated cardiomyopathy Rohit Malhotra and Pamela K. Mason University of Virginia Health System, Charlottesville, Virginia, USA Correspondence to Pamela K. Mason, Assistant Professor of Medicine, PO Box 800158, University of Virginia Health System, Charlottesville, VA 22908-0158, USA Tel: +1 434 924 2465; fax: +1 434 924 2581; e-mail: [email protected] Current Opinion in Cardiology 2009, 24:203–208

Purpose of review Familial dilated cardiomyopathy is an underrecognized form of dilated cardiomyopathy. Lamin A/C deficiency is probably the most common cause of familial dilated cardiomyopathy. This review will focus on the emerging knowledge of epidemiology, diagnosis, and treatment of patients with lamin A/C deficiency, as well as possible disease mechanisms. Recent findings Screening of patients with dilated cardiomyopathy continues to indicate that lamin A/C deficiency is a significant cause. Multiple novel mutations have been found, suggesting that many mutations are limited to individuals or families. It is unknown how mutations cause the syndrome, although an animal model has shown that lamin A/C insufficiency causes apoptosis, particularly in the conduction system. Inheritance is predominantly autosomal dominant, but penetrance is variable. For symptomatic patients, the course is malignant, with conduction system disease, atrial fibrillation, heart failure, and sudden cardiac death. The data are contradictory, and currently, there is no clear marker for when a lamin A/C-deficient patient is at risk for sudden death. Summary Lamin A/C deficiency is an important cause of dilated cardiomyopathy, and diagnosis requires that clinicians have a high index of suspicion. Our knowledge of the mechanisms, diagnosis, and treatment of lamin A/C deficiency is incomplete. It is clear that patients with this condition have a malignant course and need to be followed aggressively. Keywords familial dilated cardiomyopathy, lamin A/C deficiency, sudden cardiac death Curr Opin Cardiol 24:203–208 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 0268-4705

Introduction Dilated cardiomyopathy (DCM) accounts for approximately 60% of all cardiomyopathies [1]. DCM is a major source of morbidity and mortality, causing congestive heart failure (CHF) and sudden cardiac death (SCD). This is a clinically heterogeneous disease and can be caused by ischemia, valvular disease, virus exposure, toxin exposure, or infiltrative disease. When no overt cause of DCM is found, it is termed idiopathic dilated cardiomyopathy (IDC). Over the last several decades, it has become increasingly clear that the cause of many ‘idiopathic’ dilated cardiomyopathies is genetic. Familial dilated cardiomyopathy (FDC) is now thought to account for up to 50% of IDC patients, whereas in the early 1980s the reported incidence of FDC was 2–6.5% [2–5]. Most of these cases (>90%) are thought to show autosomal dominant inheritance, although X-linked and autosomal recessive forms have been identified [6]. There are many factors that 0268-4705 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins

have hindered the diagnosis of FDC. Identifying patients with possible FDC requires there be sufficient family history to find that there are at least two first-degree family members with IDC. Many patients do not know their family histories or have small families. In addition, this disease has variable and age-dependent penetrance even within families [5,7,8,9,10]. Patients who have FDC may have other causes of DCM, such as coronary artery disease or valvular heart disease, which confound the true diagnosis. The challenges in recognizing FDC families clinically have made identifying culprit genes difficult. Even when FDC families are identified, only a small number of patients are available. Most research has evaluated candidate genes. More than 20 different genes have been identified in patients with FDC (Table 1). These include genes that affect sarcomeric proteins, cytoskeletal proteins, nuclear proteins, ion channel proteins, and mitochondria [1,11,12,13]. Many of these mutations have been found in few patients, and, indeed, may only DOI:10.1097/HCO.0b013e32832a11c6


204 Molecular genetics

Table 1 Genes that have been implicated in the development of dilated cardiomyopathy Locus

Gene

1p1-q21 1q32 1q42-q43 2q31 2q35 3p21 3p22-p25 5q33 6q22.1 10q22-q23 11p11 11p15 12p12 12q22 14q12 15q14 15q22 17q12 19q13

Lamin A/C Troponin T a-Actinin Titin Desmin Troponin C SCN5A d-Sarcoglycan Phospholamban Metavinculin Myosin-binding protein-C Cardiac muscle LIM protein SUR2A Thymopoietin b-Myosin heavy chain Cardiac actin a-Tropomyosin Telethonin Troponin I

Table adapted from [1,11,12].

account for FDC within single patients or families. Although up to 50% of patients with IDC may have FDC by history, a genetic test may identify the cause in only a small minority of patients. The exception to this is lamin A/C mutation. Lamin A/C mutations are thought to be the cause in up to 10% of FDC cases [14]. Multiple different mutations have been found in the lamin A/C gene (LMNA) and testing is available at several centers. The diagnosis of lamin A/C deficiency denotes important prognostic information [8,15–19]. These patients often have a particularly malignant course and the penetrance for some mutations approaches 100% as patients age. In this review, we will focus on the recent advances in the epidemiology, diagnosis, and treatment of lamin A/C deficiency as a cause of isolated cardiomyopathy. Many of the other mutations described above cause concomitant skeletal muscle disease or other forms of cardiomyopathy such as hypertrophic cardiomyopathy and will be covered in other sections.

Lamin A and C Lamin A and C are type V intermediate filament proteins found in the nuclear membrane or lamina [20,21]. LMNA is found on chromosome 1q21.2-q21.3. Lamin A and C are created by alternative splicing. They are expressed in terminally differentiated somatic cells and found in multiple different tissues, including skeletal and cardiac muscle. The protein is composed of a conserved rod domain with a globular head and tail region. The functions of lamin A and C are incompletely understood, but it is thought that they are important in maintaining nuclear architecture, DNA replication, RNA

transcription, cell cycle regulation, cell differentiation, and apoptosis. Recent in-vitro data suggest various mutations in the gene may each lead to different alterations in protein function [22]. This could lead to dramatically different physiologic consequences for distinct mutations.

Laminopathies There are over 200 mutations described in LMNA, which can cause over 20 different phenotypes. This constellation of syndromes is known as the laminopathies. It is unknown how the mutations cause the syndromes, and up to 25% of patients with LMNA mutation may remain asymptomatic [23]. Many laminopathies have a multisystem phenotype, and virtually all symptomatic patients have some form of cardiac involvement. Emery–Dreifuss muscular dystrophy causes muscular dystrophy and DCM. Hutchinson–Gilford progeria syndrome causes accelerated aging. Other phenotypes cause partial lipodystrophy or neuropathy. When patients have multisystem phenotypes, it is easier to recognize a probable familial cause for their cardiomyopathy. However, there are a significant number of patients with lamin A/C mutation who have only cardiac manifestations. These patients often remain undiagnosed.

Cardiac manifestations of lamin A/C deficiency The earliest cardiac finding in patients with lamin A/C deficiency is usually conduction system disease. In a meta-analysis of 299 carriers of a lamin A/C mutation, 18% of patients less than 10 years of age had evidence of delayed intracardiac conduction. In patients over 30 years of age, 92% had conduction system disease, with 44% requiring pacemaker placement [14]. In early stages, patients have a characteristic electrocardiogram with low amplitude P waves, prolonged PR interval, but a relatively normal QRS complex (Fig. 1). Patients subsequently develop atrial fibrillation and DCM. A high incidence of thromboembolic events has been noted in lamin A/C-deficient patients (30%), but whether this is related to undiagnosed atrial dysrhythmias or factors specific to lamin A/C deficiency is unknown [24]. By age 50, over 60% of patients have symptoms of CHF [14]. A recent animal model of lamin A/C haploinsufficiency has suggested a mechanism for the clinical cardiac findings [25]. The earliest finding in mice with one abnormal LMNA allele was programmed cell death of atrioventricular nodal myocytes. Subsequently, the mice developed worsening electrophysiologic disease. Ultimately, the nonconducting myocytes also experienced apoptosis, leading to DCM.


Lamin A/C deficiency as a cause of FDC Malhotra and Mason 205 Figure 1 Characteristic electrocardiogram from an asymptomatic patient with lamin A/C deficiency

Conduction system disease is generally the earliest finding in patients with lamin A/C deficiency. Patients demonstrate low amplitude P waves, prolonged PR intervals, but narrow QRS complexes.

Lamin A/C-deficient patients are at high risk of SCD, probably at significantly higher risk than patients with other forms of DCM [26]. In one Dutch kindred, there was a precipitous decline in survival after age 40, and by age 65 no family members were alive [27]. Meune et al. [15] found that, in a small cohort of patients with known lamin A/C defects, 42% of patients experienced SCD. The approximate mean age and mean ejection fraction in this cohort were 42 years and 58%, indicating that this group experienced SCD at young age and with relatively preserved ejection fraction. Other recent studies have also found that risk of SCD precedes left ventricular dysfunction [28]. Further, in the meta-analysis described above, the need for a pacemaker or the presence of a pacemaker did not seem to be predictive of SCD [14]. A more recent study by Pasotti et al. [29] also found that patients with lamin A/C defects experienced a malignant course. By examining 94 patients derived from a genetic analysis of 27 families with DCM, they were able to identify risk factors for SCD. Univariate analysis indicated that New York Heart Association class III or IV, clinical manifestation of LMNA deficiency, conduction system disease, left ventricular ejection fraction (LVEF) less than 35%, left ventricular end-diastolic volume more than 180 ml, and history of competitive athleticism were predictive of death, CHF, heart transplant, or SCD. Multivariate analysis identified only function class III or IV and history of competitive sports as independent predictors of an event. SCD occurred in 6.3 per 100 person years among affected individuals. Both competi-

tive sports for greater than 10 years and genotype were predictive on multivariate analysis of risk of SCD. In contradiction to previous data, those who did not manifest disease did not have clinical events. However, by age 60, all patients with a mutation manifested disease, indicating 100% penetrance over time.

Genetic screening Several mutations in LMNA were identified in five families with DCM with conduction system disease by Fatkin et al. in 1999 [19]. The location of the mutation within the gene altered the phenotype. Since then, multiple familial studies [23,30,31,32] have identified a number of other novel mutations in exons as well as splicing sites. These mutations generate missense, splice site, nonsense, and deletion mutations. The recent genetic study by Parks et al. [30] of 324 unrelated DCM patients identified 11 novel LMNA mutations. This study identified a prevalence of LMNA mutations of 5.9% in the FDC and DCM patients evaluated. Several family members of the probands enrolled in this study carried pathogenic LMNA mutations without disease manifestations, demonstrating a variable penetrance of the disease process. In contrast, there were kindreds in which only some of the family members who had DCM had LMNA mutations. This study demonstrates the difficulty in developing a screening examination that does not involve sequencing the entire genetic locus for LMNA, including introns. However, novel mutations may not alter protein structure or function, thus



confounding results of these sequencing tests. No repository to maintain a correlation between identified genetic mutations and clinical manifestations exists. Genetic screening is most useful in identified FDC families. The probands have usually already developed clinical disease, although some known mutations do have a more malignant course, which can help with prognosis and therapy. Unfortunately, many newly diagnosed lamin A/C-deficient families are found to have novel mutations. However, identifying a specific genetic mutation within a family can be important for family planning and directing follow-up for the family members. Family members of probands should undergo genetic counseling. Although up to 10% of the IDC patients may have lamin A/C defects, generalized screening of the DCM population is not performed. There are too many unidentified mutations and comprehensive screening is insensitive [33]. There are also substantial resource and financial barriers to this kind of testing. We are likely many years from being able to comprehensively screen patients genetically for FDC.

Clinical screening Identifying new lamin A/C-deficient families requires a high index of suspicion. Patients with IDC and at least one other first-degree relative with IDC should be considered for genetic screening. Most patients with lamin A/C deficiency do have conduction system disease as one of the first features, and up to 30% of patients with DCM and conduction system disease are thought to have lamin A/C deficiency [2–5]. Finally, while lamin A/C deficiency causes isolated cardiomyopathies, it often causes DCM in conjunction with other clinical findings, particularly skeletal muscle abnormalities. Careful history, physical examination, and laboratory testing in patients can often identify evidence of mild limb-girdle muscular dystrophies or neuropathies in them or their family members. At this time, there is no consensus on the frequency or type of screening that patients with known mutations and no clinical phenotype should undergo. Recommendations have been made to screen family members of affected patients every 3–5 years with physical examination, electrocardiogram, and echocardiogram, but it is unknown whether the frequency of screening should increase as patients get older, given that penetrance increases as patients age [12]. In addition, the particular genotype alters the rate of disease progression and it is unknown how this should affect the screening process. Several studies have suggested that left ventricular enlargement may be one of the earliest findings in asymptomatic patients who go on to develop symptomatic FDC [4,34]. Left bundle branch block (LBBB) has also been

implicated as an early warning sign [12]. These findings warrant more frequent and aggressive follow-up. Of particular concern in the lamin A/C-deficient population is the accelerated risk of SCD. The data are conflicting, but there is evidence that these patients are at risk prior to the development of the usual markers for SCD that are used for other forms of DCM, particularly left ventricular dysfunction and CHF symptoms. There is currently no clear marker that can be identified by physical examination, laboratory work, or imaging study that indicates that a patient with lamin A/C deficiency is now at risk for SCD. MRI has been evaluated as a modality to diagnose subclinical disease in asymptomatic patients with lamin A/C deficiency [35,36,37]. One recent study [35] evaluated the use of MRI to diagnose cardiac involvement in 12 patients with one mutated allele and no disease manifestations. MRI studies demonstrated differences in these patients when compared with 14 control patients. There was no single parameter that identified patients at risk, but an amalgam of parameters calculated from MRI measurements was different in carriers when compared with normals, suggesting that MRI may identify patients who are predisposed to disease. These patients will need to be followed up to determine whether they will manifest symptoms in order to determine the true predictive capacity of MRI in these patients. Should all of these patients develop conduction system disease or CHF, a cardiac MRI may predict who will require more aggressive therapy.

Therapy There is little data to guide therapy for patients with lamin A/C deficiency. Standard medical therapies for CHF are employed when patients develop left ventricular dysfunction [33]. It is unknown whether these patients benefit from being started on angiotensin-converting enzyme inhibitors or b-blockers prior to the development of CHF. It is also unknown whether the use of b-blockers will exacerbate or reveal underlying conduction system disease. Patients do often progress to end-stage CHF, and transplantation has been described for this population [17]. There is a substantial role for device therapy in this population. Many of these patients will require pacemakers due to severe conduction system disease. The optimal timing of implantable cardioverter defibrillator (ICD) placement remains undefined. Meune et al. [15] placed ICDs in 19 patients who had lamin A/C mutations and indications for pacemakers, but had no traditional indications for ICDs. Eight of these patients (42%) received appropriate shocks. It has been suggested that


Lamin A/C deficiency as a cause of FDC Malhotra and Mason 207

the development of conduction system disease may be a marker of fibrosis, which also puts the patient at risk for SCD. The use of electrophysiology studies has also been recommended as a screening tool. However, other data indicate that the need for or presence of a pacemaker does not affect SCD risk [14]. A recent study [29] did not find that asymptomatic patients were at risk of SCD. In the absence of conclusive data, there should be a low threshold to place ICDs in these patients. It is clear that lamin A/C-deficient patients have a malignant course and are at high risk for SCD. Knowledge of the patient’s family history of SCD can help guide timing as well. The fact that competitive sports may be a risk marker for poor prognosis in patients with lamin A/C deficiency suggests that these patients may not fit into a standard cardiac paradigm [29]. Earlier screening may be necessary if athleticism is detrimental in order to prevent asymptomatic individuals from being too athletic. However, data are limited and we would refrain at this time from limiting activity based upon a potential risk rather than confirmed causality.

Conclusion FDC accounts for a larger proportion of IDC than has been recognized by the clinical cardiology community. There are multiple different genes that have been identified as causes of FDC in a limited number of patients, but lamin A/C deficiency is one of the most prevalent of the genetic causes of IDC. Our knowledge of appropriate diagnosis and treatment of patients with lamin A/C deficiency is incomplete. However, symptomatic patients can have a very malignant course with severe CHF and ventricular dysrhythmias. Clinicians should have high index of suspicion for the diagnosis of FDC and particularly lamin A/C deficiency. Further, they should have a low threshold to treat patients for left ventricular dysfunction and ventricular dysrhythmias.

References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 260). 1 Karkkainen S, Peuhkurinen K. Genetics of dilated cardiomyopathy. Ann Med 2007; 39:91–107. A comprehensive review of the known genetic mutations that have been shown to cause FDC.

5

Grunig E, Tasman JA, Kucherer H. Frequency and phenotypes of familial dilated cardiomyopathy. J Am Coll Cardiol 1998; 31:186–194.

6

Mestroni L, Rocco C, Gregori D, et al. Familial dilated cardiomyopathy: evidence for genetic and phenotypic heterogeneity. J Am Coll Cardiol 1999; 34:181–190.

7

Jakobs PM, Hanson E, Crispell KA, et al. Novel lamin A/C mutations in two families with dilated cardiomyopathy and conduction system disease. J Card Fail 2001; 7:249–256.

8

Hershberger RE, Hanson E, Jakobs PM, et al. Novel lamin A/C mutation in a family with dilated cardiomyopathy, prominent conduction system disease, and need for permanent pacemaker implantation. Am Heart J 2002; 144:1081–1086.

van Spaendonck-Zwarts KY, van den Berg MP, van Tintelen JP. DNA analysis in inherited cardiomyopathies: current status and clinical relevance. Pacing Clin Electrophysiol 2008; 31:S46–S49. A review of the use of genetic testing in the evaluation, diagnosis, and treatment of patients with forms of inherited cardiomyopathy.

9

10 Rankin J, Auer-Grumbach M, Bagg W, et al. Extreme phenotypic diversity and nonpenetrance in families with LMNA gene mutation R644C. Am J Med Genet 2008; 146A:1530–1542. A series of patients with the same missense mutation. This study highlights the variability in penetrance and phenotype for lamin A/C deficiency. 11 Hershberger RE. Familial dilated cardiomyopathy. Prog Ped Cardiol 2005; 20:161–168. 12 Crispell KA, Hanson EL, Coates K, et al. Periodic rescreening is indicated for family members at risk of developing familial dilated cardiomyopathy. J Am Coll Cardiol 2002; 39:1503–1507. 13 Burkett EL, Hershberger RE. Clinical and genetic issues in familial dilated cardiomyopathy. J Am Coll Cardiol 2005; 45:969–981. 14 van Berlo JH, deVoogt WG, van der Kooi AJ, et al. Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations: do lamin A/C mutations portend a high risk of sudden death? J Mol Med 2005; 83:79–83. 15 Meune C, van Berlo J, Anselme F, et al. Primary prevention of sudden death in patients with lamin A/C gene mutations. N Engl J Med 2006; 354:209–210. 16 Taylor MR, Fain PR, Sinagra G, et al. Natural history of dilated cardiomyopathy due to lamin A/C gene mutations. J Am Coll Cardiol 2003; 41:771–780. 17 Sylvius N, Bilinska ZT, Veinot JP, et al. In vivo and in vitro examination of the functional significances of novel lamin gene mutations in heart failure patients. J Med Genet 2005; 42:639–647. 18 Arbustini E, Pilotto A, Repetto A, et al. Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease. J Am Coll Cardiol 2002; 39:981–990. 19 Fatkin D, MacRae C, Sasaki T, et al. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conductionsystem disease. N Engl J Med 1999; 341:1715–1724. 20 Gruenbaum Y, Goldman RD, Meyuhas R, et al. The nuclear lamina and its functions in the nucleus. Int Rev Cytol 2006; 226:1–62. 21 Shumaker DK, Kuczmarski ER, Goldman RD. The nucleoskeleton: lamins and actin are major players in essential nuclear functions. Curr Opin Cell Biol 2003; 15:358–366. 22 Sylvius N, Hathaway A, Boudreau E, et al. Specific contribution of lamin A and lamin C in the development of laminopathies. Exp Cell Res 2008; 314:2362– 2375. In-vitro study evaluating the effects of lamin A and C overexpression in COS7 cells. The results suggested that different mutations in lamin A and C may cause differential effects on cellular function. 23 Sylvius N, Tesson F. Lamin A/C and cardiac diseases. Curr Opin Cardiol 2006; 21:159–165. 24 van Tintelen JP, Hofstra RMW, Katerberg H, et al. High yield of LMNA mutations in patients with dilated cardiomyopathy and/or conduction disease referred to cardiogenetics outpatient clinics. Am Heart J 2007; 154:1130– 1139. A series of patients with FDC who were screened for lamin A/C deficiency. This study found several different mutations that resulted in different clinical courses.

2

Fuster B, Gersh BJ, Guiliani ER, et al. The natural history of idiopathic dilated cardiomyopathy. Am J Cardiol 1981; 47:525–531.

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Michels VV, Driscoll DJ, Miller FA. Familial aggregation of idiopathic dilated cardiomyopathy. Am J Cardiol 1985; 55:1232–1233.

25 Wolf CM, Wang L, Alcalai R, et al. Lamin A/C haploinsufficiency causes dilated cardiomyopathy and apoptosis-triggered cardiac conduction system disease. J Mol Cell Cardiol 2008; 44:293–303. This mouse model study demonstrated a possible mechanism for the clinical presentation of lamin A/C deficiency. Lamin A/C-deficient myocytes demonstrated apoptosis, particularly in conducting cells.

4

Baig MK, Goldman JH, Caforio AP, et al. Familial dilated cardiomyopathy: cardiac abnormalities are common in asymptomatic relatives and may represent early disease. J Am Coll Cardiol 1998; 31:195–201.

26 Becane HM, Bonne G, Varnous S, et al. High incidence of sudden death with conduction system and myocardial disease due to lamins A and C gene mutation. Pacing Clin Electrophysiol 2000; 23:1661–1666.


208 Molecular genetics 27 van Tintelen JP, Tio RA, Kerstjens-Frederikse WS, et al. Severe myocardial fibrosis caused by a deletion of the 50 end of the lamin A/C gene. J Am Coll Cardiol 2007; 49:2430–2439. A family study demonstrating the malignant course that many patients with lamin A/C deficiency experience. The patients were at high risk for CHF and sudden death. 28 de Backer J, van Beeumen K, Loeys B, Duytschaever M. Expanding the phenotype of sudden cardiac death – an unusual presentation of a family with a lamin A/C mutation. Int J Cardiol 2008. [Epub ahead of print] A family study that demonstrated that the risk of SCD preceded the development of left ventricular dysfunction. 29 Pasotti M, Klersy C, Pilotto A, et al. Long-term outcome and risk stratification in dilated cardiolaminopathies. J Am Coll Cardiol 2008; 52:1250–1260. A large series of 164 patients in 27 families with lamin A/C deficiency. These patients had a malignant course. The authors were able to identify several markers for risk of sudden death, including CHF, which is in contrast to previous studies. Athleticism was also a risk factor for sudden death. 30 Parks SB, Kushner JD, Nauman D, et al. Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy. Am Heart J 2008; 156:161–169. A large series of patients who were found to have lamin A/C deficiency. Multiple different mutations were found with multiple different phenotypes. Not all affected family members were found to have the mutation, suggesting that not all lamin A/C defects cause disease. 31 Perrot A, Hussein S, Ruppert V, et al. Identification of mutational hot spots in LMNA encoding lamin A/C in patients with familial dilated cardiomyopathy. Basic Res Cardiol 2009; 104:90–99. A series of patients with FDC who were found to have lamin A/C deficiency. Two novel mutations were found and mutational hot spots were identified.

32 Rudenskaya GE, Polyakov AV, Tverskaya SM, et al. Laminopathies in Russian families. Clin Genet 2008; 74:127–133. A series of patients with lamin A/C deficiency who were genetically screened. Several novel mutations were discovered and mutational hot spots were identified. 33 Crispell K, Wray A, Ni H, et al. Clinical profiles of four large pedigrees with familial dilated cardiomyopathy: preliminary recommendations for clinical practice. J Am Coll Cardiol 1999; 34:837–847. 34 Michels VV, Moll PP, Miller FA, et al. The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy. N Engl J Med 1992; 326:77–82. 35 Koikkalainen JR, Antila M, Lotjonen JMP, et al. Early familial dilated cardiomyo pathy: identification with determination of disease state parameter from cine MR image data. Radiology 2008; 249:88–96. MRI was used to screen for preclinical findings in a series of patients with lamin A/C mutations who did not have clinical disease. 36 Jerosch-Herold M, Sheridan DC, Kushner JD, et al. Cardiac magnetic reso nance imaging of myocardial contrast uptake and blood flow in patients affected with idiopathic or familial dilated cardiomyopathy. Am J Physiol Heart Circ Physiol 2008; 295:H1234–H1242. MRI was used to evaluate alterations in blood flow in a series of patients with IDC or FDC. 37 Carboni N, Mura M, Marrosu G, et al. Muscle MRI findings in patients with an apparently exclusive cardiac phenotype due to a novel LMNA gene mutation. Neuromuscul Disord 2008; 18:291–298.


Left ventricular noncompaction Antonios A. Pantazis and Perry M. Elliott The Heart Hospital, University College London/ University College London Hospital, London, UK Correspondence to Dr P. Elliott, The Heart Hospital, 16–18 Westmoreland Street, London W1G 8PH, UK Tel: +44 207 573 8888; fax: +44 207 573 8838; e-mail: [email protected] Current Opinion in Cardiology 2009, 24:209–213

Purpose of review Isolated left ventricular noncompaction (LVNC) is a myocardial disorder characterized by excessive and prominent trabeculations of the left ventricle, associated with progressive systolic failure, stroke and arrhythmia. Until quite recently, LVNC was thought to be extremely rare, but, with greater awareness of the disease and improvements in echocardiographic technology, there has been a dramatic increase in the frequency of diagnosis. Recent studies suggest that the frequency of LVNC is determined in part by the diagnostic criteria used. Recent findings Up to 50% of adult patients with LVNC have mutations in genes encoding proteins of the cardiac sarcomere, suggesting that LVNC might represent a new disease paradigm in which mutations that more typically cause dilated and hypertrophic cardiomyopathies result in abnormal ventricular morphogenesis. Summary In this review, we briefly summarize current clinical literature on LVNC, with a particular focus on the limitations of current diagnostic criteria and emerging data on the genetics of the disorder. Keywords cardiomyopathies, left ventricular noncompaction, sarcomeric proteins Curr Opin Cardiol 24:209–213 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 0268-4705

Introduction Left ventricular noncompaction (LVNC) is a myocardial disorder defined by the presence of prominent trabeculations on the luminal surface of the ventricle, associated with deep intertrabecular recesses that extend into the ventricular wall (Fig. 1). Histological findings are nonspecific, with areas of fibrosis interspersed with normal myocytes [1,2]. LVNC frequently occurs in association with other congenital heart abnormalities, including atrial and ventricular septal defects, congenital aortic stenosis and coarctation of the aorta [3–7]. LVNC in the absence of such lesions was, until quite recently, thought to be an extremely rare phenomenon with a prevalence between 0.05 and 0.24% [8,9], but, with improvements in diagnostic imaging, the frequency of diagnosis has dramatically increased in children and adults [10].

Pathogenesis Several hypotheses have been proposed to explain LVNC, but there is an emerging consensus that most cases of LVNC are the result of abnormal ventricular morphogenesis. Trabeculations in the embryonic murine heart are evident from day 10.5 (equivalent to the fourth 0268-4705 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins

gestational week in humans) when endocardium evaginates through the cardiac jelly to contact the adjacent myocardium [11]. Myocardial trabeculations at this early stage appear as projections of myocardium protruding into the ventricular lumen. Later, these undergo a process of compaction that results in a reduced inner layer of trabeculations, with the compacted layer forming the ventricular walls and conduction system; LVNC is thought to represent a failure of this process that results in an increase in the thickness of the trabecular layer relative to the compact layer of the ventricular walls.

Genetics of left ventricular noncompaction Some unconfirmed reports have suggested that the phenotype for isolated ventricular noncompaction may appear during adult life in patients with muscular dystrophy [12] or as a transient phenomenon during myocarditis [13]. At present, it would seem more appropriate to label such cases as ‘hypertrabeculation’ rather than noncompaction, although without serial echocardiographic data it may be impossible to distinguish the two. A number of studies suggest that many cases of LVNC are caused by inheritable genetic variants. The fact that DOI:10.1097/HCO.0b013e32832a11e7


210 Molecular genetics Figure 1 Typical echocardiographic pictures of left ventricular noncompaction in apical four-chamber view (a) and short axis view (b)

Apical echocardiographic view of a noncompacted left ventricle with extended and prominent trabeculations in the apical region and in the lateral wall. Two-layered appearance of the myocardium in a short axis view of the left ventricle.

LVNC is compatible with survival into adulthood suggests that it is caused by defective maturation of the ventricle rather than its initial specification. Very few mutations of genes encoding the transcription factors and signaling molecules involved in left ventricular development are known disease alleles. One explanation might be that mutations in these genes are not compatible with survival. As inherited disease alleles, by definition, have to allow formation of the left ventricle (LV), it is more likely that the molecular defect in most cases of LVNC affects maturation of the ventricle. This distinction between ventricular maturation and ventricular specification is important as it questions the relevance of most published mouse ‘knock-out’ studies to human cardiac disease.

Several disease loci have been identified in humans: (1) G4.5 Mutations in G4.5 gene located at Xq28 are associated with Barth syndrome, an X-linked disorder that presents in infant males with dilated cardiomyopathy (DCM), LVNC, neutropenia, abnormal cholesterol metabolism, lactic acidosis, elevated 3-methylglutaconic acid and 2-ethylhydracrylic acid and cardiolipin abnormalities [14]. G4.5 encodes members of the tafazzin (TAZ) group of proteins, which are expressed primarily in heart and muscle cells and are thought to have acyltransferase functions within mitochondria. (2) ZASP ZASP is a cardiac and skeletal muscle Z-line protein that is expressed in the cytoplasm. The protein localizes together with actin and interacts with the C-terminus of a-actinin-2 via a PDZ domain. The PDZ domain-containing proteins interact with each other in the cytoskeletal structure and contribute to the assembly of membrane proteins. Thus, ZASP has an important role in the maintenance of the normal architecture of the myocytes. It is not surprising, therefore, that mutations in ZASP are responsible for DCM. The exact mechanism by which mutations result in LVNC is unclear [15]. (3) a-dystrobrevin a-dystrobrevin (DTNA) is a cytoskeletal protein component of the dystrophin-associated glycoprotein complex (DAPC), which is composed of three subcomplexes: the dystroglycan complex, the sarcoglycan complex and the cytoplasmic complex, which includes the syntrophins and dystrobrevins. These groups of proteins link the extracellular matrix to the dystrophin cytoskeleton of the muscle fibre. A mutation in the DTNA gene has been associated with LVNC [16], but, as in other genetic cardiomyopathies, there is significant variability in disease phenotype and severity. (4) Lamin A/C Lamins are major protein components of the nuclear lamina, the meshwork underlying the inner nuclear membrane. Mutations in the lamin A/C gene have been causally linked to different diseases [17] such as DCM with conduction system disease, limb girdle muscular dystrophy (LGMD), autosomal dominant variant of Emery–Dreifuss muscular dystrophy (EDMD) and partial lipodystrophy. The identification of isolated LVNC in a carrier of the lamin A/C mutation [18] does not explain the role of this protein in the pathogenesis of the disorder. (5) Sarcomeric protein genes Mutations in the genes encoding the thick and thin filaments of the cardiac sarcomere can cause hypertrophic cardiomyopathy (HCM) and DCM. Recent data from case reports and a large series of


Left ventricular noncompaction Pantazis and Elliott 211

patients suggest that mutations in the same genes may be associated with an LVNC phenotype. Actin proteins are essential for the generation and maintenance of cell morphology and polarity. LVNC is described in association with an actin reported to cause apical hypertrophy. The same gene defect was also associated with an interatrial septal defect [19], an observation suggestive of the role of ACTC in cardiac morphogenesis. In a study of 63 patients [20] exhibiting features of LVNC, seven disease-causing mutations were found in b-myosin heavy chain (MYH7) and one in cardiac troponin T [troponin T type 2 (TNNT2)]. It is interesting, and may be of pathogenetic significance, that different phenotypes related to MYH7 mutations are caused by mutations clustering in specific areas of the gene, although some are more evenly spread. Although assessment of family members was limited, the penetrance of the mutations (defined by the presence of LVNC) was 100%.

Natural history Presentation with symptoms of heart failure and arrhythmia is described at all ages. Several studies [9,21,22] have suggested that afflicted patients have poor left ventricular function, with a high incidence of ventricular arrhythmias and systemic thromboembolism. Recent studies [10,23], nonetheless, report a much lower incidence of death, stroke or documented sustained ventricular arrhythmia, probably reflecting the identification of preclinical or mild cases.

Clinical diagnosis of left ventricular noncompaction Fine trabeculations are a feature of the normal LV, but it is only quite recently that technical advances such as harmonic imaging, contrast echocardiography and cardiac MRI have facilitated their visualization. A number of echocardiographic definitions for the diagnosis of LVNC have been proposed. Two are based on an analysis of fewer than 45 patients with a common phenotype [1,24]; the third is extrapolated from a postmortem study [25]. Although all definitions describe the morphology of the condition, they differ substantially in their approach. The method proposed originally by Chin et al. [24] compares the length of trabeculae with the thickness of the compacted wall in different echocardiographic views and at different levels of the LV in end diastole. Jenni et al. [1] have proposed a criterion that relies on the detection of two myocardial layers in short axis views of the LV in end systole. LVNC, in this instance, is defined by a ratio between the two layers. The third definition, proposed by Sto¨llberger et al. [25], determines the number of promi-

nent trabeculations visible in apical views of the LV in diastole. Cardiac magnetic resonance (CMR) imaging is also being used to detect LVNC. CMR has the advantage of good spatial resolution at the apex and lateral wall of the LV and, in a recent study [26], has been used to quantify the ratio of noncompacted and compacted layers in patients with LVNC and in normal controls. However, CMR studies have used an adapted version of existing echo criteria with all the same limitations. Moreover, direct comparison with echo is not always possible as the detection of the noncompact layer using CMR is performed in diastole, whereas the echocardiographic definition applies to systole (in the case of the criteria of Jenni et al. [1]).

Limitations of current diagnostic criteria Evidence from developmental studies, case reports and small clinical series supports the concept of LVNC as a genuine disease entity that may in some cases have an association with other cardiac and somatic abnormalities. However, a study from our own group [27] has recently shown that a high proportion of patients with systolic heart failure fulfill current diagnostic criteria for LVNC, at least when the criteria are applied retrospectively. This might be explained by a genuine congenital abnormality or an exaggeration of normal trabeculation patterns, but the fact that 8.3% of normal controls also fulfilled LVNC criteria suggests that prominent trabeculations in patients with heart failure could be no more than an incidental finding. This may be particularly true in black individuals, who have a higher incidence of trabeculation patterns fulfilling current diagnostic criteria, irrespective of the presence of left ventricular disease. Furthermore, the variable patterns of noncompacted hearts pose an additional difficulty in the characterization and quantification of the observed features (Figs. 1 and 2).

Clinical management Limited evidence is available about the management of LVNC. Specific treatment for the primary disorder is lacking, and the aim is to prevent the complications or manage the symptoms using treatment protocols extrapolated from the experience with other cardiomyopathies. The main clinical issues in this disease are thromboembolism, arrhythmia and heart failure [9]. Given that the risk of thromboembolism is probably lower than previously believed, anticoagulation is reserved for those patients who present with dilated LV and reduced systolic function with ejection fraction less than 40% or history of thromboembolism [23]. At earlier stages of the disease, aspirin can be used instead. The management of the systolic dysfunction is no different from that in DCM.



Figure 2 The diagnostic criteria are not applicable in all cases

tion is a genuine clinical entity. The fact that it coexists with a range of abnormalities in left ventricular morphology and function suggests that it may be better to consider it as a marker of underlying myocardial disease rather than a discrete cardiomyopathy.

References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 260).

Diffuse pattern of trabeculation at the apex of the left ventricle in an echocardiographic short axis of the left ventricle. This is a case in which the diagnostic criteria could not be applied.

In the case of symptomatic ventricular arrhythmia and in the context of impaired systolic function, prevention of a sustained and potentially lethal arrhythmic event is indicated using antiarrhythmic agents or implantable cardiac defibrillators in accordance with international guidelines.

Challenges for the future The emergence of LVNC as a new diagnosis in clinical cardiology presents clinicians with many diagnostic and therapeutic dilemmas. First, the limitations of current diagnostic criteria mean that it is important to consider family history, symptoms, left ventricular function and possibly ethnicity before making the diagnosis. Overdiagnosis of the condition may have social and financial and psychological ramifications for the individual and the family members. Once a diagnosis is made, the fact that isolated ventricular noncompaction is often a genetic disease means that it is important to counsel family members on their chance of having the same disease or an overlapping phenotype such as dilated or HCM. Finally, treatment should be patient-specific, focusing on the mechanism of symptoms and where appropriate the prevention of long-term complications. Clinical, genetic and basic research is ongoing, and it is anticipated that it will shed some light on the mechanisms of pathogenesis of noncompaction cardiomyopathy, the factors that can influence this and any disease-specific features that aid diagnosis and management.

Conclusion Although the diagnostic criteria for LVNC are imperfect, there is good evidence that pathological hypertrabecula-

1

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Nugent AW, Daubeney PE, Chondros P, et al., National Australian Childhood Cardiomyopathy Study. The epidemiology of childhood cardiomyopathy in Australia. N Engl J Med 2003; 348:1639–1646.

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Stollberger C, Finsterer J. Left ventricular hypertrabeculation/noncompaction. J Am Soc Echocardiogr 2004; 17:91–100.

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Bellet S, Gouley BA. Congenital heart disease with multiple cardiac abnormalities: report of a case showing aortic atresia, fibrous scar in myocardium and embryonal sinusoidal remains. Am J Med Sci 1932; 183:458–465.

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Lauer RM, Fink HP, Petry EL, et al. Angiographic demonstration of intramyocardial sinusoids in pulmonary-valve atresia with intact ventricular septum and hypoplastic right ventricle. N Engl J Med 1964; 271:68–72.

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Dusek J, Ostadal B, Duskova M. Postnatal persistence of spongy myocardium with embryonic blood supply. Arch Pathol 1975; 99:312–317.

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Ritter M, Oechslin E, Su¨tsch G, et al. Isolated noncompaction of the myocardium in adults. Mayo Clin Proc 1997; 72:26–31.

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Oechslin EN, Attenhofer Jost CH, Rojas JR, et al. Long-term follow-up of 34 adults with isolated left ventricular noncompaction: a distinct cardiomyopathy with poor prognosis. J Am Coll Cardiol 2000; 36:493–500.

10 Pignatelli RH, McMahon CJ, Dreyer WJ, et al. Clinical characterization of left ventricular noncompaction in children: a relatively common form of cardiomyopathy. Circulation 2003; 108:2672–2678. 11 Sedmera D, Pexieder T, Vuillemin M, et al. Developmental patterning of the myocardium. Anat Rec 2000; 258:319–337. 12 Finsterer J, Sto¨llberger C, Gaismayer K, Janssen B. Acquired noncompaction in Duchenne muscular dystrophy. Int J Cardiol 2006; 106:420–421. 13 Pfammatter JP, Paul T, Flik J, et al. Q-fever associated myocarditis in a 14-yearold boy. Z Kardiol 1995; 84:947–950. 14 Ichida F, Tsubata S, Bowles KR, et al. Novel gene mutations in patients with left ventricular noncompaction or Barth syndrome. Circulation 2001; 103: 1256–1263. 15 Vatta M, Mohapatra B, Jimenez S, et al. Mutations in cypher/ZASP in patients with dilated cardiomyopathy and left ventricular noncompaction. J Am Coll Cardiol 2003; 42:2014–2027. 16 Kenton AB, Sanchez X, Coveler KJ, et al. Isolated left ventricular noncompaction is rarely caused by mutations in G4.5, a-dystrobrevin and FK binding protein-12. Mol Genet Metab 2004; 82:162–166. 17 Worman HJ, Bonne G. ‘Laminopathies’: a wide spectrum of human diseases. Exp Cell Res 2007; 313:2121–2133. 18 Hermida-Prieto M, Monserrat L, Castro-Beiras A, et al. Familial dilated cardiomyopathy and isolated left ventricular noncompaction associated with lamin A/C gene mutations. Am J Cardiol 2004; 94:50–54. 19 Monserrat L, Hermida-Prieto M, Fernandez X, et al. Mutation in the alphacardiac actin gene associated with apical hypertrophic cardiomyopathy, left ventricular noncompaction, and septal defects. Eur Heart J 2007; 28:1953– 1961. 20 Klaassen S, Probst S, Oechslin E, et al. Mutations in sarcomere protein genes in left ventricular noncompaction. Circulation 2008; 117:2893– 2901. A study that suggests that sarcomeric protein gene mutations are a common cause of LVNC.


Left ventricular noncompaction Pantazis and Elliott 213 21 Ichida F, Hamamichi Y, Miyawaki T, et al. Clinical features of isolated noncompaction of the ventricular myocardium: long-term clinical course, hemodynamic properties, and genetic background. J Am Coll Cardiol 1999; 34:233–240. 22 Rigopoulos A, Rizos IK, Aggeli C, et al. Isolated left ventricular noncompaction: an unclassified cardiomyopathy with severe prognosis in adults. Cardiology 2002; 98:25–32. 23 Murphy RT, Thaman R, Blanes JG, et al. Natural history and familial characteristics of isolated left ventricular noncompaction. Eur Heart J 2005; 26:187–192. 24 Chin TK, Perloff JK, Williams RG, et al. Isolated noncompaction of left ventricular myocardium. A study of eight cases. Circulation 1990; 82:507–513.

25 Sto¨llberger C, Finsterer J, Blazek G. Left ventricular hypertrabeculation, noncompaction and association with additional cardiac abnormalities and neuromuscular disorders. Am J Cardiol 2002; 90:899–902. 26 Petersen SE, Selvanayagam JB, Wiesmann F, et al. Left ventricular noncompaction: insights from cardiovascular magnetic resonance imaging. J Am Coll Cardiol 2005; 46:101–105. 27 Kohli SK, Pantazis AA, Shah JS, et al. Diagnosis of left-ventricular noncompaction in patients with left-ventricular systolic dysfunction: time for a reappraisal of diagnostic criteria? Eur Heart J 2008; 29: 89–95. A study that compares the published diagnostic criteria for LVNC and reveals their limitations.


Restrictive cardiomyopathy Jens Mogensena and Eloisa Arbustinib a Department of Cardiology, Skejby University Hospital, Brendstrupgaardsvej, Aarhus N, Denmark and b Academic Hospital, IRCCS Foundation Policlinico San Matteo, Pavia, Italy

Correspondence to Jens Mogensen, MD, PhD, Department of Cardiology, Skejby University Hospital, Brendstrupgaardsvej, 8200 Aarhus N, Denmark Tel: +45 89 49 61 99; fax: +45 89 49 60 02; e-mail: [email protected] Current Opinion in Cardiology 2009, 24:214–220

Purpose of review Restrictive cardiomyopathy (RCM) is an uncommon myocardial disease characterized by impaired filling of the ventricles in the presence of normal wall thickness and systolic function. Most affected individuals have severe signs and symptoms of heart failure. A large number die shortly after diagnosis unless they receive a cardiac transplant. Controversy has existed about the exact definition of the condition and diagnostic criteria that will be discussed along with an update on recent findings. Recent findings Previously, RCM was believed to be of idiopathic origin unless otherwise associated with inflammatory, infiltrative or systemic disease. Recent investigations have shown that the condition may be caused by mutations in sarcomeric disease genes and even may coexist with hypertrophic cardiomyopathy in the same family. However, most sarcomeric RCM mutations appear to be de novo and associated with a severe disease expression and an early onset. Summary Recent reports suggest that mutations in sarcomeric contractile protein genes are not uncommon in RCM. These findings imply that RCM may be hereditary, and that clinical assessment of relatives should be considered in addition to genetic investigations when systemic disease has been excluded. Identification and risk stratification of affected relatives is important to avoid adverse disease complications and diminish the rate of sudden death. Keywords genetic investigations, inheritance, restrictive cardiomyopathy Curr Opin Cardiol 24:214–220 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 0268-4705

Introduction Restrictive cardiomyopathy (RCM) is characterized by increased stiffness of the ventricles leading to compromised diastolic filling with preserved systolic function. These changes may develop in association with local inflammatory or systemic, infiltrative or storage disease (Fig. 1) [1]. Usually, patients develop severe symptoms of heart failure over a short period of time, and the majority die within a few years following diagnosis unless they receive a cardiac transplant [2]. The results of recent molecular genetic investigations have revealed that a substantial proportion of RCM without associated systemic disease is caused by mutations in sarcomeric disease genes that have been associated with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and noncompaction cardiomyopathy [3–5,6]. Controversy exists on how to define the condition because restrictive filling patterns of the ventricles occur in a wide range of different diseases [7–9]. It is the purpose of this review to demonstrate that a variety of 0268-4705 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins

myocardial and systemic diseases are associated with RCM. Therefore, the definition of RCM should be descriptive rather than categorical and reflect that many conditions may ultimately lead to RCM.

Clinical characteristics Adult RCM patients present with dyspnea, fatigue and limited exercise capacity. They may experience palpitation accompanied by dizziness due to supraventricular arrhythmia (SVT). Thromboembolic complications are common and may be the initial presentation of the condition. In children, RCM may present with failure to thrive, fatigue and even syncope [8,9]. In advanced cases, patients develop raised jugular venous pressures, peripheral edema, liver enlargement and ascites. Chest radiograph usually shows a normal-sized heart with enlarged atria and variable degrees of pulmonary congestion. The ECG exhibits large P waves indicating biatrial enlargement accompanied by various ST segment and T wave abnormalities (Fig. 2b). Echocardiography typically reveals biatrial enlargement, a normal or slightly DOI:10.1097/HCO.0b013e32832a1d2e


Restrictive cardiomyopathy Mogensen and Arbustini 215 Figure 1 Restrictive cardiomyopathy

Restrictive cardiomyopathy

Inflammatory

Infiltrative

Storage

Idiopathic

Endomyocardial fibrosis

Amyloidosis

Hemochromatosis

Loeffler cardiomyopathy

Sarcoidosis

Glycogen storage disease

Postirradiation therapy

Fabry disease

Patients need to be assessed in relation to familial involvement and the potential genetic basis. Adapted from [1].

impaired systolic function and mitral inflow Doppler velocities indicative of severe diastolic dysfunction (Fig. 2a). These include increased ratio of early diastolic filling to atrial filling, decreased E-deceleration time and decreased isovolumic relaxation time (IVRT) (Fig. 3). Invasive pressure measurements within the ventricles during cardiac catheterization are characterized by an early diastolic dip quickly followed by a plateau, also called the ‘square-root sign’. Usually, the diastolic pressure of both ventricles is elevated with the highest plateau being in the left ventricle [2]. However, when diagnosing RCM, it is important to realize that pressure measurements obtained during cardiac catheterization as well as Doppler velocities vary according to preload, which in turn is highly dependent on the current medication of individual patients. For instance, aggressive diuretic therapy will tend to normalize filling pressures and diastolic volumes. Furthermore, pressures and velocities also vary in response to heart rate and rhythm [7].

Diagnosis

RCM in patients with mild systolic dysfunction or mild left ventricular hypertrophy or both, the specific values for Doppler velocities and diastolic volumes and whether systemic diseases such as amyloidosis and glycogen storage diseases should be classified as RCM [7,10]. Recently, a working group of the European Society of Cardiology (ESC) proposed revised classification of cardiomyopathies reflecting the clinical disease expression of the conditions focusing on ventricular morphology and function and the familial/genetic background [11]. Specifically, the classification characterizes cardiomyopathies in relation to the familial background. In this context, RCM is defined as a condition presenting with restrictive ventricular physiology in the presence of normal or reduced diastolic volumes and normal ventricular wall thickness in the absence of ischemic heart disease, hypertension, valvular heart disease and congenital heart disease. This broad definition should help physicians to identify the condition and consider further diagnostic investigations to reveal the cause that may include cardiac biopsies, family screening and genetic investigations.

It has been difficult to obtain consensus about uniform diagnostic criteria of RCM. From a historical perspective, there has been general agreement that RCM should be considered in patients presenting with heart failure in the presence of a nondilated, nonhypertrophic left ventricle with preserved contractility but abnormal diastolic function. There is uncertainty regarding the diagnosis of

Differentiation of RCM from constrictive pericarditis is important, as patients suffering from the latter condition may recover completely following surgical removal of the fibrotic pericardium. However, the distinction between the two conditions may be difficult. Noninvasive realtime imaging with echo Doppler and respirometry provides


216 Molecular genetics Figure 2 Restrictive cardiomyopathy

Clinical characteristics of restrictive cardiomyopathy in a 19-year-old male who was diagnosed at the age of 16 years following a stroke as previously reported [7]. (a) Apical four-chamber echocardiogram in systole with marked biatrial dilatation, normal-sized ventricles and normal wall thickness. (b) Twelve-lead ECG in sinus rhythm with prominent P waves, T wave inversion and incomplete right bundle branch block. (c) Microscopy of heart tissue obtained postmortem with myocyte hypertrophy, abundant fibrosis and myofibrillar disarray characteristic of the histological findings in HCM (hematoxylin–eosin staining, x40). aVF, augmented vector foot; aVL, augmented vector left; aVR, augmented vector right; HCM, hypertrophic cardiomyopathy. Part (a) adapted from [3]. Parts (b) and (c) reproduced from [3].

the mainstay of diagnosis. Patients with restriction will not have sufficient respiratory variation. Cardiac magnetic resonance and computed tomography (CT) may be useful to assess pericardial thickness, whereas MRI with late enhancement may facilitate diagnosis of infiltrative myocardial disease, for example, amyloidosis. During invasive investigation, it is possible to obtain simultaneous pressure measurements in the ventricles, and both conditions are characterized by rapid early diastolic filling with diastolic dip and plateau waveform. There may be a pressure difference between left ventricular end-diastolic pressure (LVEDP) and right ventricular end-diastolic pressure (RVEDP) in RCM, which is considered significant if diastolic pressure is

more than 5–7 mmHg, in contrast to constrictive pericarditis, in which the pressures tend to be equal in both ventricles. Nonetheless, no technique is totally reliable, and in some patients it is necessary to perform a diagnostic pericardiectomy [2,7,12,13].

Outcome RCM carries a poor prognosis, particularly in children, despite optimal medical treatment. Several studies [14,15] have reported that 66–100% die or receive a cardiac transplant within a few years of diagnosis. In one study of 18 RCM children, five died suddenly without signs of heart failure. However, they had severe angina


Restrictive cardiomyopathy Mogensen and Arbustini 217 Figure 3 Doppler velocities in restrictive cardiomyopathy

Typical restrictive Doppler findings including increased E to A ratio (2.1), decreased E-deceleration time (90 ms) and decreased isovolumetric relaxation time (40 ms). A, atrial filling; E, early diastolic filling.

and ECG evidence of ischemia. Four hearts of children who died suddenly were available for autopsy and revealed acute myocardial infarcts, subendocardial ischemic necrosis or chronic ischemic scarring, despite normal appearance of their coronary arteries. These findings led the authors to suggest that pediatric patients with RCM represent a population of children who are at high risk for ischemiarelated complications and death in addition to heart failure. In adults, two studies [16,17] have reported that 32–44% suffered a cardiovascular-related death within 5 years following diagnosis. The outcome is highly correlated to symptoms and signs of heart failure. Embolic stroke is a common complication as a consequence of large atria and SVT. Therefore, prophylactic anticoagulant therapy should be considered in all RCM patients with enlarged atria even before SVT has developed.

Familial restrictive cardiomyopathy associated with sarcomeric gene mutations In 1992, Feld and Caspi [18] reported a family with a mixed appearance of RCM and HCM. The cardiac morphology of a deceased individual with RCM showed typical features of HCM with myocyte disarray. Angelini et al. [19] reported similar histomorphological features of seven patients with a clinical diagnosis of RCM and suggested that RCM and HCM may represent two different phenotypes of the same basic sarcomeric disease, although no genetic investigations were performed. We investigated a large family in which the proband and two additional individuals were diagnosed with RCM,

nine individuals had clinical features of HCM and 12 individuals died suddenly. Linkage analysis for selected sarcomeric contractile protein genes identified troponin I [troponin I (TNNI3)] as the likely disease gene [3]. Subsequent mutation analysis revealed a missense mutation, which segregated with the disease in the family (lod score: 4.8). To elucidate whether TNNI3 mutations were common in RCM, mutation analysis was performed in nine unrelated RCM patients with unexplained restrictive filling patterns, gross atrial dilatation, normal systolic function and normal wall thickness. Histology of heart tissue from several individuals showed myofibril disarray characteristic of HCM (Fig. 2c). TNNI3 mutations were identified in seven of 10 patients including the index family of the study. Two of the mutations identified in young individuals were de-novo mutations. All mutations were novel missense mutations and appeared in conserved and functionally important domains of the gene. We concluded that mutations in cardiac troponin I were responsible for the development of RCM in a significant proportion of patients diagnosed with RCM. Additional TNNI3 mutations have been reported in RCM, as well as mutations in other sarcomeric genes including troponin T (TNNT2), b-myosin heavy chain (MYH7) and a-cardiac actin (ACTC) [15,20–22]. Most of the mutations reported appeared de novo with a severe disease expression and onset of symptoms in childhood leading to premature death or cardiac transplantation shortly after diagnosis. These findings imply that RCM is part of the clinical expression of hereditary sarcomeric contractile protein disease, and familial evaluation should be


218 Molecular genetics Figure 4 Cardiac amyloidosis

considered whenever an individual has been diagnosed with RCM.

Familial restrictive cardiomyopathy, atrioventricular block and desmin accumulation Desmin-related myopathies are very rare disorders characterized by intracytoplasmatic accumulation of desmin caused by mutations in the gene for either desmin (DES) or a-B-crystallin (CRYAB). Diagnosis requires ultrastructural investigation and immunohistochemistry of cardiac or skeletal muscle biopsy to reveal desmin deposits [23]. The disease expression may involve skeletal muscle only, affect both cardiac and skeletal muscle simultaneously or have an isolated impact on the heart [24–27]. Very few families have been reported with isolated RCM and cardiac-specific accumulation of desmin. In one large four-generation family, no disease gene was identified, whereas another report identified four independent individuals with RCM, atrioventricular block and mutations of the DES gene [23,28]. Genetic investigations and clinical assessment of relatives revealed one de-novo mutation, one mutation with recessive inheritance and two dominant mutations with a total number of three affected relatives. Penetrance was 100%, and all but one had advanced atrioventricular block. Recognizing that this disease expression is extremely rare, the authors suggested that desmin accumulation might be considered in patients presenting with RCM and atrioventricular block.

Cardiac amyloidosis By tradition, cardiac amyloidosis has been classified as a RCM, as deposits of amyloid within the heart typically result in restrictive filling patterns [10,11]. However, this condition is also characterized by increased ventricular wall thickness and impaired systolic function. Echocardiography often reveals a remarkable homogeneous granular sparkling of the myocardium, and valves are often thickened due to amyloid infiltration. In addition, the ECG of patients with cardiac amyloidosis often shows low voltage in standard leads. Cardiac biopsies show typical features of amyloid deposits (Fig. 4a–c). A variety of diseases are associated with sporadic occurrence of Figure 4 (continued)

Clinical characteristics of a 46-year-old male who was diagnosed with cardiac amyloidosis at the age of 42 years because of heart failure symptoms. (a) Apical four-chamber view in systole with biatrial dilatation, normal-sized ventricles and significant thickening of ventricular walls that

appears bright and sparkling. (b) Twelve-lead ECG in sinus rhythm with low voltage in standard leads. (c) Microscopy of cardiac biopsies stained with hematoxylin–eosin showing extensive infiltration of amyloid between myocytes (x40). The small picture inserted shows cardiac tissue from the same patient stained with Congo red, which defines amyloid deposits by its green refringence under polarized light. aVF, augmented vector foot; aVL, augmented vector left; aVR, augmented vector right.


Restrictive cardiomyopathy Mogensen and Arbustini 219

cardiac amyloidosis, whereas hereditary appearances most often are caused by mutations in the genes for transthyretin and apolipoprotein A1 [29,30].

Other rare familial diseases associated with restrictive cardiomyopathy Hemochromatosis is an autosomal recessive disorder leading to iron deposition in multiple organs resulting in widespread damage. Although clinical disease expression in many cases is unpredictable, most patients present with a variety of symptoms from different organ systems, whereas only few patients have isolated cardiac manifestations and very rarely RCM [29]. Anderson–Fabry’s disease is an X-linked lysosomal storage disorder caused by mutations in the gene for a-galactosidase A (GLA). Glycosphingolipids accumulate in multiple organs and cause substantial morbidity and mortality, especially in men. In women, isolated affection of the heart is more frequent than in men, and affected women most often present with symptoms late in life. Typical echocardiographic findings include left ventricular hypertrophy, modest diastolic filling abnormalities and thickening of the valves [31–33]. RCM in the context of Fabry’s disease with normal ventricular wall thickness is extremely rare [34]. The same seems to be the case with a variety of rare hereditary glycogen storage diseases exhibiting different modes of transmission.

Nonfamilial restrictive cardiomyopathy Sporadic RCM may be diagnosed in patients affected by systemic diseases including scleroderma and sarcoidosis [29]. Patients who previously have undergone radiotherapy of the chest, as in Hodgkin’s disease, have an increased risk of developing myocardial and endocardial fibrosis many years later leading to RCM. Restrictive ventricular physiology can also be caused by endocardial fibrosis in association with hypereosinophilic syndromes or induced by exposure to various drugs and parasitic infections [30].

Conclusion RCM is an uncommon condition with a poor outcome unless patients receive a cardiac transplant. RCM is generally seen in association with local inflammatory or systemic diseases. The finding of TNNI3 mutations in a substantial proportion of patients fulfilling diagnostic criteria of idiopathic RCM suggested a causal relationship between gene abnormality and disease. This has prompted genetic investigations of other RCM patients and confirmed that RCM in many instances is part of the clinical expression of sarcomeric contractile protein disease. De-novo mutations appear to be prevalent findings especially in children and young adults, suggesting that they are associated with a more severe disease expression

and early onset in comparison with mutations that have been inherited through many generations. As RCM, HCM, DCM and even noncompaction cardiomyopathy may be caused by mutations in the same genes, previous perceptions of cardiomyopathies as separate and distinct clinical and pathophysiological entities are difficult to sustain. It is important to realize that transitional forms of the conditions frequently appear even within the same family affected by the same mutation. Therefore, the diagnosis of any condition likely to be a cardiomyopathy should lead to family screening for a potential hereditary disorder. Identification and risk stratification of affected relatives is important to avoid adverse disease complications and diminish the rate of sudden death.

References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 260–261). 1

Topol EJ, editor. Textbook of cardiovascular medicine. Philadelphia: Lippincott Williams & Wilkins; 2007. p. 430.

2

Benotti JR, Grossman W, Cohn PF. Clinical profile of restrictive cardiomyopathy. Circulation 1980; 61:1206–1212.

3

Mogensen J, Kubo T, Duque M, et al. Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. J Clin Invest 2003; 111:209–216.

4

Kamisago M, Sharma SD, DePalma SR, et al. Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N Engl J Med 2000; 343:1688– 1696.

5

Geisterfer-Lowrance AA, Kass S, Tanigawa G, et al. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell 1990; 62:999–1006.

6

Monserrat L, Hermida-Prieto M, Fernandez X, et al. Mutation in the alphacardiac actin gene associated with apical hypertrophic cardiomyopathy, left ventricular noncompaction, and septal defects. Eur Heart J 2007; 28:1953– 1961.

7

Keren A, Popp RL. Assignment of patients into the classification of cardiomyopathies. Circulation 1992; 86:1622–1633.

8

Chen SC, Balfour IC, Jureidini S. Clinical spectrum of restrictive cardiomyopathy in children. J Heart Lung Transplant 2001; 20:90–92.

9

Russo LM, Webber SA. Idiopathic restrictive cardiomyopathy in children. Heart 2005; 91:1199–1202.

10 Richardson P, McKenna W, Bristow M, et al. Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the definition and classification of cardiomyopathies. Circulation 1996; 93:841–842. 11 Elliott P, Andersson B, Arbustini E, et al. Classification of the cardiomyopa thies: a position statement from the European Society Of Cardiology Working Group on myocardial and pericardial diseases. Eur Heart J 2008; 29:270– 276. An important study discussing and proposing a novel definition of cardiomyopathies. 12 Reuss CS, Wilansky SM, Lester SJ, et al. Using mitral ‘annulus reversus’ to diagnose constrictive pericarditis. Eur J Echocardiogr 2008. [Epub ahead of print] 13 Sengupta PP, Krishnamoorthy VK, Abhayaratna WP, et al. Comparison of usefulness of tissue Doppler imaging versus brain natriuretic peptide for differentiation of constrictive pericardial disease from restrictive cardiomyopathy. Am J Cardiol 2008; 102:357–362. 14 Rivenes SM, Kearney DL, Smith EO, et al. Sudden death and cardiovascular collapse in children with restrictive cardiomyopathy. Circulation 2000; 102:876–882.


220 Molecular genetics 15 Kaski JP, Syrris P, Burch M, et al. Idiopathic restrictive cardiomyopathy in children is caused by mutations in cardiac sarcomere protein genes. Heart 2008; 94:1478–1484. The first genetic study of children with RCM revealing that sarcomeric gene mutations are not an uncommon cause. 16 Kubo T, Gimeno JR, Bahl A, et al. Prevalence, clinical significance, and genetic basis of hypertrophic cardiomyopathy with restrictive phenotype. J Am Coll Cardiol 2007; 49:2419–2426. 17 Ammash NM, Seward JB, Bailey KR, et al. Clinical profile and outcome of idiopathic restrictive cardiomyopathy. Circulation 2000; 101:2490–2496. 18 Feld S, Caspi A. Familial cardiomyopathy with variable hypertrophic and restrictive features and common HLA haplotype. Isr J Med Sci 1992; 28:277–280. 19 Angelini A, Calzolari V, Thiene G, et al. Morphologic spectrum of primary restrictive cardiomyopathy. Am J Cardiol 1997; 80:1046–1050. 20 Karam S, Raboisson MJ, Ducreux C, et al. A de novo mutation of the beta cardiac myosin heavy chain gene in an infantile restrictive cardiomyopathy. Congenit Heart Dis 2008; 3:138–143. 21 Peddy SB, Vricella LA, Crosson JE, et al. Infantile restrictive cardiomyopathy resulting from a mutation in the cardiac troponin T gene. Pediatrics 2006; 117:1830–1833. 22 Gambarin FI, Tagliani M, Arbustini E. Pure restrictive cardiomyopathy associated with cardiac troponin I gene mutation: mismatch between the lack of hypertrophy and the presence of disarray. Heart 2008; 94:1257. 23 Arbustini E, Pasotti M, Pilotto A, et al. Desmin accumulation restrictive cardiomyopathy and atrioventricular block associated with desmin gene defects. Eur J Heart Fail 2006; 8:477–483.

24 Arbustini E, Morbini P, Grasso M, et al. Restrictive cardiomyopathy, atrioventricular block and mild to subclinical myopathy in patients with desminimmunoreactive material deposits. J Am Coll Cardiol 1998; 31:645–653. 25 Bergman JE, Veenstra-Knol HE, van Essen AJ, et al. Two related Dutch families with a clinically variable presentation of cardioskeletal myopathy caused by a novel S13F mutation in the desmin gene. Eur J Med Genet 2007; 50:355–366. 26 Kaminska A, Strelkov SV, Goudeau B, et al. Small deletions disturb desmin architecture leading to breakdown of muscle cells and development of skeletal or cardioskeletal myopathy. Hum Genet 2004; 114:306–313. 27 Li D, Tapscoft T, Gonzalez O, et al. Desmin mutation responsible for idiopathic dilated cardiomyopathy. Circulation 1997; 100:461–464. 28 Zhang J, Kumar A, Stalker HJ, et al. Clinical and molecular studies of a large family with desmin-associated restrictive cardiomyopathy. Clin Genet 2001; 59:248–256. 29 Lubitz SA, Goldbarg SH, Mehta D. Sudden cardiac death in infiltrative cardiomyopathies: sarcoidosis, scleroderma, amyloidosis, hemachromatosis. Prog Cardiovasc Dis 2008; 51:58–73. 30 Kushwaha SS, Fallon JT, Fuster V. Restrictive cardiomyopathy. N Engl J Med 1997; 336:267–276. 31 Zarate YA, Hopkin RJ. Fabry’s disease. Lancet 2008; 372:1427–1435. 32 Clarke JT. Narrative review: Fabry disease. Ann Intern Med 2007; 146:425– 433. 33 Linhart A, Lubanda JC, Palecek T, et al. Cardiac manifestations in Fabry disease. J Inherit Metab Dis 2001; 24 (Suppl 2):75–83. 34 Cantor WJ, Butany J, Iwanochko M, Liu P. Restrictive cardiomyopathy secondary to Fabry’s disease. Circulation 1998; 98:1457–1459.


EDITORIAL COMMENT

Beyond the guidelines: where evidence ends and the frontier begins David S. Feldman The Ohio State University Suite, 200 Davis Heart and Lung Research Institute, Columbus, Ohio, USA Correspondence to David S. Feldman, MD, PhD, The Ohio State University Suite, 200 Davis Heart and Lung Research Institute, 473 West 12th Avenue, Columbus, OH 43210-1252, USA Tel: +1 614 293 4967; fax: +1 614 293 5614; e-mail: [email protected] Current Opinion in Cardiology 2009, 24:221–222

Heart failure continues to be one of the leading causes of death in the western world. Although we have a significant amount of data and multiple sets of guidelines for the management of chronic systolic heart failure, there are many nuances in these management schemes that fall beyond the limits of the guidelines because of a scarcity of data. This group of articles is devoted to areas that are predominantly beyond the boundaries of the current guidelines, purview, leaving the clinicians to rely on best practice methodologies. The first article, by Eapen and Rogers, addresses the relevance of reverse remodeling in systolic heart failure as a surrogate endpoint. These authors make the case that an improvement in ventricular geometry is strongly correlated with improvement in heart failure outcomes observed in large clinical trials. With the current multimodality approach to heart failure therapy (i.e. drugs and devices), discerning the relevance of a new therapy is becoming more difficult and costly. Future clinical trials should consider direct and indirect measures of reverse remodeling as endpoints. This methodology may decrease the ‘n’ value required to achieve relevance by incorporating these metrics into an endpoint strategy, thereby making new drugs trials realistic. This strategy of incorporating changes of reverse remodeling should include functional measures of recovery as well as molecular signaling to increase the granularity of a new therapeutic intervention. Traditionally, the 6-min walk test and echocardiography have been used despite all the misgivings that researchers and the US Food and Drug Administration (FDA) have had regarding these modalities. Less commonly used are cardiac magnetic resonance and VO2 studies. Future studies should also include biomarkers that focus on myocyte and fibroblast signaling as well as global changes in RNA fingerprinting that are consistent with cellular as well as ventricular reverse remodeling. The authors suggest that reverse remodeling may be more than a surrogate marker and perhaps a relevant milestone in the cessation of a progressive disease. 0268-4705 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins

The evaluation of clinical trials and patient outcomes becomes even more difficult when investigators are targeting patients with diastolic dysfunction or patients with heart failure and preserved left ventricular function. The seven diastolic heart failure trials evaluated in this second review article highlight the importance of understanding the underlying pathophysiology and relevance of careful inclusion and exclusion criteria, as any therapeutic intervention intended to modify heart failure outcomes must first identify a target population. This has been more difficult than one may anticipate, as there is a paucity of acceptable animal models to reproduce diastolic disorder. This gap in our current knowledge has slowed the development of effective treatment options for diastolic heart failure, as clinicians and trialists have been left in an interesting position of predominately relying on human data to design the current trials and presumed relevant endpoints. This theme of a limited data set is further continued in the next review on right ventricular heart failure (RVHF). In this section, Drs McDonald and Ross purport that RVHF is becoming a more common entity in clinical practice and is associated with increasingly inferior outcomes. As with diastolic heart failure patients, many of these individuals are followed with an imaging modality; however, the therapy and the ‘point-of-no-return’ for RVHF are predominately based on best clinical practice and a search for underlying reversible causes. With persistently elevated right-sided filling pressures, patients insidiously develop a low cardiac output related, in part, to right ventricle–left ventricle (RV–LV) transport issues leading to end-organ hypoperfusion (e.g. the cardio-renal syndrome). The patient’s clinical status may be further impaired as LV diastolic filling becomes impaired through mechanical ventricular interdependence. With a deficient dataset, clinicians have sought to apply therapies utilized in the past for chronic left-sided systolic heart failure, primary pulmonary hypertension therapies, and more recently the utilization of mechanical therapies. As an emerging therapy modality, ventricular assist devices (VADs) may help treat elevated intracardiac and pulmonary pressures in patients who are recalcitrant to conventional medical therapy. Many of these issues regarding patient selection are addressed in the review by Lietz and Miller. In this article, the authors help clinicians decide how to choose appropriate patients for VAD therapy, as success of this DOI:10.1097/HCO.0b013e32832ad871


222 Cardiac failure

therapy is often determined by the selection of patients and the timing of their operation. In the past, both physicians and patients have underestimated the mortality of a given patient. This review provides some objective criteria and a consensus of expert opinions to optimize the opportunity that these very infirm patients will have the best chance of operative success and returning home. They base their evaluation on clinical severity of heart failure, cardiac and anatomic considerations, other concordant disease pathology or life-limiting illnesses, psychosocial and age-related considerations, and assessment of operative risk. Subsequent to VAD implantation, Drs Mountis and Starling address many of the relevant management considerations, including nutrition, drive-line care, anticoagulation, and others. These authors advocate a multidisciplinary team approach with standardization of care to optimize patient results. Our goal in compiling these studies from different authors and their provocative subjects was to facilitate an exchange of information and to help remind us that we still have a lot of work to do to develop evidence-based algorithms for the treatment of acute decompensated heart failure, rightsided heart failure, diastolic heart failure, and the management and selection of VAD patients. As our field evolves, we believe we must think about all of these patients as part of an overriding heart failure disease management strategy.

These articles are also a call for the medical community to embrace translational science. If we are to adequately address the needs of these patients, it will be done in a piecemeal way by investigating mechanisms of disease and not just endpoints. When we are looking for future therapies, we should not expect to go from ‘nearly terminal’ to running on a treadmill with a single intervention. As we expect to use multiple therapies for stage C and D patients, we should expect different interventions for recovering facets of that disease process. Similarly to cancer, in heart failure we must first slow the disease process that is contributing to the patient’s demise (treat symptoms and relieve suffering). Second, we must arrest the process, similarly to how oncologists comment on neoplasias being in ‘remission’. Third, we must address the root of the disease to ultimately alter mortality. With each patient who presents with new challenges, many do not fit neatly into the guidelines; however, if we focus on three questions, we will provide the best possible care with the data available. These are: why did a given patient get sick? what are we going to do to make them feel better? and how are we going to stop the patient from getting sick again? Although this simple approach is far from ideal, it will be the best we can do until we have more data and perhaps more wisdom.


Strategies to attenuate pathological remodeling in heart failure Zubin Eapena and Joseph G. Rogersa,b a

Division of Cardiology, Department of Medicine and Duke Clinical Research Institute, Duke University, Durham, North Carolina, USA b

Correspondence to Joseph G. Rogers, MD, Associate Professor of Medicine, Duke University Medical Center, Box 3034 DUMC, Durham, NC 27710, USA Tel: +1 919 681 3398; fax: +1 919 681 7755; e-mail: [email protected] Current Opinion in Cardiology 2009, 24:223–229

Purpose of review The incidence of heart failure is increasing due to an aging population and improved management of diseases that are precursors to ventricular dysfunction. The success of therapeutic advances has created a challenge for the next generation of investigational heart failure treatments because the mortality rate has decreased to such a degree that larger trials will be needed to demonstrate mortality advantage. Prior work has linked favorable changes in ventricular geometry to improved survival, suggesting that remodeling may be a suitable surrogate endpoint. Recent findings In addition to the established benefits of neurohormonal blockade, new mechanical and electrical therapies are proving beneficial in heart failure. Passive cardiac support devices and cardiac resynchronization therapy have been recently demonstrated to induce reverse remodeling of the left ventricle and may improve outcomes, including quality of life, functional status, and mortality. Summary Ventricular remodeling is strongly correlated with improvement in other heart failure outcomes. Early phase trials of novel therapeutics should carefully examine remodeling to obtain an efficacy signal. Larger clinical investigations should include remodeling metrics as endpoints and consider their use in a composite primary endpoint to reduce trial size. Keywords cardiac resynchronization therapy, cardiac support device, heart failure, ventricular remodeling Curr Opin Cardiol 24:223–229 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 0268-4705

Introduction Myocardial injury elicits a prototypical response that is central to progressive, chronic heart failure. The cardiac phenotype that accompanies ventricular systolic dysfunction is characterized by variable degrees of dilation of the affected chamber and hypertrophy of the viable segments of myocardium. Fundamental to our understanding of these alterations in cardiac structure and function are pathologic alterations in loading conditions and activation of neurohormonal pathways, both of which serve as targets for therapies demonstrated to improve quality of life and reduce heart failure mortality. The impact of myocardial infarction (MI) on ventricular geometry and function in an animal model of coronary artery ligation was described in 1985 by Pfeffer et al. [1], who demonstrated a strong relationship between the size of the myocardial injury and the degree of left ventricular (LV) remodeling and mortality. The same investigators showed a beneficial reduction in LV end-diastolic volume index in rats treated with the angiotensin-converting 0268-4705 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins

enzyme inhibitor (ACEi) captopril (Fig. 1). Others have confirmed the relationship between myocardial injury, activation of neurohormonal pathways, and the pathologic cardiac phenotype associated with heart failure [2–5]. Further, it has been demonstrated that treatment strategies resulting in reversal of pathologic remodeling typically also reduce heart failure mortality, whereas therapies with adverse impact on survival have minimal or no effect on ventricular remodeling [6–10]. In this review, we will discuss the evidence supporting the beneficial impact of medical therapy targeting neurohormonal inhibition as well as mechanical and electrical therapies that have linked remodeling and mortality in systolic heart failure. Inhibition of angiotensin-converting enzyme and angiotensin receptor blockade

Remodeling and functional impairment of myocardial contractility have been associated with high intramyocardial levels of angiotensin, norepinephrine, and aldosterone [11]. Furthermore, neurohormonal activation DOI:10.1097/HCO.0b013e32832a11ff


224 Cardiac failure Figure 1 Captopril administered to rats for 3 months following myocardial infarction induced by coronary artery ligation

Figure 2 Least squares mean changes (WSEM) from baseline in left ventricular internal diastolic diameter/body surface area (cm/m2)

ml/kg 3.5 Months 4

12

24

3

Last observation

0.05 LSM changes 0 + SEM

2.5 2

--0.05

1.5

--0.1

1

--0.15

0.5

--0.2

(n = 323) P = 0.252

(n = 275) P = 0.311 (n = 138) P = 0.061

(n = 327) P < 0.001

0 Non-MI

Small

Moderate

Large

Extensive

Infarct size Left ventricular end-diastolic volume indices of captopril-treated rats (solid bars) were significantly less than those of untreated rats (open bars). Captopril reduces left ventricular volumes following myocardial infarction. Data from [1].

appears to be integral in the development of myocardial hypertrophy. Thus, it follows that pharmacologic inhibition of dysregulated neurohormonal pathways might play an important role in stabilization or reversal of pathological remodeling and improve clinical outcomes. As noted above, early animal experiments demonstrated that addition of an ACEi following MI attenuated the remodeling process and reduced mortality [12]. These early findings provided the groundwork for human trials focused on renin–angiotensin pathway inhibition. The Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial examined the effects of enalapril on survival in patients with diminished LV function. Patients with clinical heart failure [primarily New York Heart Association (NYHA) class II–III] and an ejection fraction of 0.35 or less were randomized to receive enalapril or placebo in a double-blind fashion [13]. During an average follow-up of 41.4 months, enalapril-treated patients experienced significantly fewer deaths, primarily as a result of reduction in progressive heart failure, and fewer hospitalizations. An echocardiography substudy examining the impact of enalapril on LV function and geometry revealed that patients in the placebo arm had progressive LV dilation, whereas those treated with enalapril had sustained reductions in LV dimensions [14,15]. Similar outcomes have been demonstrated with captopril [16] and ramipril [17], suggesting a causative relationship between ACEi, reverse ventricular remodeling, and mortality reduction. Blockade of the effects of the renin–angiotensin system utilizing angiotensin receptor blockers (ARBs) also

The P values refer to the LSM comparison between the valsartan (solid bars) and placebo (open bars) groups by analysis of covariance. n ¼ total number of patients in the valsartan and placebo treatment groups. Valsartan favorably reduces left ventricular size in patients with chronic heart failure. LSM, Least squares mean. Data from [18].

appears to be linked to reverse ventricular remodeling and mortality benefit. Patients intolerant of ACEi treated with valsartan in the Valsartan-Heart Failure trial (ValHeFT) benefited from reduction in both all-cause mortality and combined mortality and morbidity (17.3 vs. 27.1%, P ¼ 0.017 and 24.9 vs. 42.5%, P < 0.001, respectively) compared with those treated with placebo [18]. Furthermore, patients in the valsartan group demonstrated improvement in remodeling indices with a significantly smaller mean LV internal diastolic dimension index than patients randomized to placebo (Fig. 2) [18]. Similar reductions in morbidity and mortality were seen in the Candesartan in Heart failure - Assessment of Reduction in Mortality and morbidity (CHARM)alternative trial, a study that assessed the benefits of candesartan vs. placebo in patients intolerant of ACEi [19]. b-Adrenergic antagonism

Ventricular remodeling and progression of the heart failure syndrome also result from activation of the sympathetic nervous system, and b-adrenergic antagonists have well characterized beneficial effects on cardiac remodeling and heart failure mortality. The mechanism of these benefits is likely multifactorial and related to negative chronotropy, which reduces myocardial oxygen consumption, reduction of the impact of high intramyocardial norepinephrine levels, and decreased myocardial ischemia and infarction [20]. The effects of b-blockade appear to be independent of ACE inhibition, despite coregulation of these pathways [21]. Post-MI patients with LV dysfunction treated with an ACEi who were subsequently randomized to carvedilol experienced significant reduction in all-cause mortality, cardiovascular


Strategies to attenuate pathological remodelling in heart failure Eapen and Rogers 225

mortality, and nonfatal recurrent MI [22]. Doughty et al. [23] demonstrated the incremental beneficial effects of carvedilol on LV volumes, function, and wall motion score in patients treated with ACEis. Similarly, the Australia–New Zealand Heart Failure Research Collaborative group showed that the addition of carvedilol in the treatment regimen of patients treated with optimal doses of ACEi resulted in a further reduction in LV volumes at 6 and 12 months compared with those treated with placebo [24]. Other measures of LV remodeling, such as LV mass, cardiac sphericity, and mitral regurgitation, decrease as early as 4 months after the initiation of carvedilol [25]. Similar findings have been shown with metoprolol in patients with mild-to-moderate heart failure and chronic LV dysfunction. The Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) trial demonstrated the benefits of sustained-release metoprolol in patients with NYHA II–IV heart failure, including a 34% relative risk reduction in all-cause mortality at 12 months, reduction in hospitalization for cardiovascular causes, and improvement in NYHA functional class and quality of life measures [26,27]. The magnetic resonance imaging substudy showed that, compared with placebo, metoprololtreated patients had significant reductions in LV enddiastolic volume, LV end-systolic volume, and LV mass as well as improvement in ejection fraction. The Carvedilol and ACE-Inhibitor Remodeling Mild Heart Failure Evaluation (CARMEN) trial randomized 572 patients with chronic heart failure to receive carvedilol, enalapril, or the combination of these two agents. Over an 18-month follow-up period, the LV end-systolic volume index decreased by 5.4 ml/m2 (P ¼ 0.0015) using combination therapy compared with enalapril alone [21]. CARMEN emphasized the importance of simultaneous inhibition of multiple neurohormonal pathways to optimize remodeling outcomes in chronic systolic heart failure and reinforced the recommendations to utilize a multidrug regimen in the care of these patients.

systolic heart failure in the Randomized Aldactone Evaluation Study (RALES) [29]. Patients randomized to spironolactone derived a 30% relative risk reduction in mortality over 36 months compared with placebotreated patients. Some of the benefits of aldosterone antagonism in patients with ischemic heart disease and chronic heart failure appear to be related to remodeling of the cardiac extracellular matrix. The failing heart is histologically characterized by increased interstitial fibrosis, which is postulated to contribute to the diastolic filling abnormalities commonly seen in systolic heart failure. Brilla et al. [30] showed that aldosterone stimulated collagen synthesis in cultured adult rat cardiac fibroblasts. Thus, the impact of aldosterone on myocardial fibrosis may be attenuated by inhibiting the neurohormonal influences of aldosterone. Revascularization

Acute MI results in a well characterized series of molecular and cellular events that result in the ventricular remodeling and contractile dysfunction that accompany diminished survival. Ischemia-induced myocyte necrosis, consequent ventricular stiffness, and diminished contractility lead to adverse loading conditions characterized by elevated cardiac filling pressures [31]. An inflammatory response ensues with migration of monocytes and neutrophils into the infarct zone resulting in additional myocardial injury. Early remodeling occurs as a result of degradation of the myocardial extracellular matrix by matrix metalloproteinases and serine proteases [32]. Remodeling continues resulting from myocyte hypertrophy and the development of collagenous scar. Infarct artery patency favorably influences both early and late ventricular remodeling by salvaging stunned myocardium and limiting the extension of an infarct zone [33]. Patency of infarct-related arteries has independent, long-term prognostic value following thrombolysis for acute MI and correlates with improvement in LV volumes and function [34–36].

Aldosterone antagonism

Aldosterone receptor antagonists represent the third class of agents shown to reduce mortality in systolic heart failure. Two pivotal trials form the basis for the addition of these agents to ACEi/ARB and b-blockers. The Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS) trial randomized patients with a recent MI, depressed LV ejection fraction, mild heart failure symptoms and treatment with ACEi and b-blockers to receive either placebo or eplerenone. Patients treated with eplerenone experienced a 17% risk reduction in cardiovascular mortality (P ¼ 0.005) and a 21% reduction in risk of sudden cardiac death (P ¼ 0.035) [28]. Another aldosterone receptor antagonist, spironolactone, was studied in patients with more symptomatic

Correction of mitral regurgitation

Mitral valve regurgitation commonly accompanies LV remodeling and is caused by a variety of mechanisms, including annular dilatation, papillary muscle displacement, and abnormalities of myocardial contractility that result in ventricular dyssynchrony. Functional mitral regurgitation begets further LV dysfunction and remodeling through chronic volume loading, increased ventricular transmural pressure, and increased wall stress. Moderate-to-severe mitral regurgitation is seen in up to 50% of patients with dilated cardiomyopathy and is an independent prognostic factor for adverse heart failure outcomes [37,38]. Correction of functional mitral regurgitation has been targeted as a means of preventing


226 Cardiac failure Figure 3 Reduction in left ventricular volumes in the Acorn trial

Figure 4 Examples of passive cardiac support devices

(a) Reduction in LV end-diastolic volume - MV surgery stratum Change from 0 baseline (ml) --10 --20 --30 --40 --50 --60 --70

n = 144 P = 0.0001

3

n = 127 P = 0.0001

n = 124 P = 0.0001

6

12

n = 81 P = 0.0001

18

n = 46 P 30 kg/m2, %) SBP (mmHg) DBP (mmHg)

would favor the ACE-I arm. The depressed ejection fraction is the arbitrator and distinguishes heart failurespecific risk. Similarly, and likely more challenging, selecting a true DHF population may demonstrate differences in therapeutic strategies beyond control of comorbidities. Therefore, it is important to recognize that acute control of chronic cardiovascular conditions may result in short-term reductions of heart failure endpoints and strategies to address underlying mechanisms of disease would achieve sustained benefits. Therapeutics should be designed to address comorbidities with treatments that preferentially target underlying mechanisms of disease. It is in the context of this background that clinically relevant data, especially any treatment paradigms pertaining to DHF, must be discussed.

Mean value 73 58 74 32 29 40 146 77

DBP, diastolic blood pressure; SBP, systolic blood pressure. Adapted from [25].

heart failure outcomes must first identify a target population that is at sufficient risk for heart failure endpoints. As an example, a hypertensive population treated with an angiotensin-converting enzyme inhibitor (ACE-I) or calcium channel blocker to the same target blood pressure would have similar outcomes with regard to heart failure, death or hospitalization. However, a hypertensive depressed ejection fraction population, similarly treated,

Lessons learned from current clinic trials Historically, the first trial addressing DHF was the ancillary Digoxin Investigation Group (DIG) [27], designed to determine the impact of chronic digitalis treatment for

Figure 2 European Study Group on Diastolic Heart Failure group paradigm for the diagnosis of diastolic heart failure

Symptoms or signs of heart failure

Normal or mildly reduced left ventricular systolic function LVEF > 50% and LVEDVI < 97 ml/m2

Evidence of abnormal LV relaxation, filling, diastolic distensibility, and diastolic stiffness

Invasive hemodynamic measurements mPCWP > 12 mmHg or > 16 mmHg or τ > 48 ms or b > 0.27

TD EIE’>15

15 > EIE’ >8

Biomarkers NT-proBNP > 220 pg/ml or BNP > 200 pg/ml

Biomarkers NT-proBNP > 220 pg/ml or BNP > 200 pg/ml

Echo -- bloodflow doppler EIE>50yr < 0.5 and DT>50yr < 280 ms or Ard-Ad > 30 ms or LAVI >40 ml/m2 or LVMI > 122 g/m2 (O+): > 149 g/m2 (O+) or Atrial fibrillation

TD EIE’>8

HFNEF

Ard Ad, time difference in atrial wave of pulmonary venous flow and mitral A; b, modulus for compliance; BNP, b-type natriuretic peptide; DT, mitral E-wave deceleration time; E0 , early mitral annular tissue Doppler velocity; E, early mitral inflow velocity; HFNEF, heart failure normal ejection fraction; LVEDVI, left ventricular end-diastolic volume index; LVMI, left ventricular mass index; LVEF, left ventricular ejection fraction; mPCWP, mean pulmonary capillary wedge pressure; NT-proBNP, N-terminal pro b-type natriuretic peptide; TD, tissue Doppler; t, time constant for relaxation. Data from Paulus et al. [26].


Challenges with diastolic heart failure trials Thohan and Patel 233

patients with heart failure. Investigators enrolled patients with a spectrum of ejection fractions and a total of 988 patients with left ventricular ejection fraction (LVEF) of at least 45%. In keeping with contemporary DHF demographics, patients were older and more likely women, and 86% were taking ACE-I. The conclusions in this subpopulation were similar to the overall trial; treatment with digoxin conferred no observed impact on all or causespecific mortality, and a trend toward reduction in heart failure hospitalizations was balanced with an increase in hospitalizations for worsening ischemia. Readmission rates were high; a total of 662 (67%) patients were hospitalized. However, only 197 (19.9%) of these were for CHF and 131 (13.1%) for conventional cardiac causes (myocardial infarction, stroke or revascularization), leaving a full 67% of patients being readmitted for presumably noncardiac causes [27]. Among the 116 deaths, 70% were cardiovascular and 56% of these were not due to heart failure. This investigation conceptually defined heart failure as a clinical syndrome without including ejection fraction as the distinguishing criterion. It also underscores the challenge of identifying a population at sufficient risk for morbidity and mortality endpoints attributable to DHF and not comorbidities or ‘noncardiovascular causes’. Although digoxin may have a role in patients with atrial fibrillation and heart failure, it is not therapy advocated for DHF. Kitzman et al. [28] demonstrated that DHF, as compared with age-matched controls, is associated with upregulation of a variety of neurohormones with levels that are similar to disease-matched SHF cohorts. Similarly, elevations of neurohormones among patients with DHF are associated with disease severity, exercise intolerance and other measures of cardiovascular outcome [20,23,29]. Chronic upregulation of the sympathetic nervous system mediated through interactions of norepinephrine and various adrenergic receptors is well characterized in a number of cardiovascular disease states, including hypertension, left ventricular hypertrophy, ischemic heart disease, atrial fibrillation and SHF. In fact, beta-blockers are the cornerstone for the treatment of each of these comorbidities of DHF and are class I indication for patients with American College of Cardiology (ACC)/American Heart Association (AHA) stage B, C and D heart failure [2,8]. A true large-scale clinical investigation of beta-adrenergic receptor blocker therapy has not been conducted in DHF. The SENIORS trial [30] examined 2128 elderly patients with a prior hospitalization for heart failure (16 s

40%

(C) Destination Therapy Risk Score Patient characteristics Platelet count 148 103/ml Serum albumin 3.3 g/dl International normalization ratio >1.1 Vasodilator therapy Mean pulmonary artery pressures 25 mmHg Aspartate aminotransferase >45 U/ml Hematocrit 34% Blood urea nitrogen >51 U/dl No intravenous inotropes

Weighted Risk Score 7 5 4 4 3 2 2 2 2

Adapted with permission from [7,38,39].

and were largely related to operative complications, such as sepsis, multiorgan failure, bleeding, right ventricular failure and stroke [1–4,7,11]. Several risk factors have been identified to correlate with increased operative risk of LVAD placement, including the markers of right ventricular dysfunction [23,24–31,40], abnormal renal [7,9,40–43], liver [7,12,42] and lung function and history of pulmonary infarct [7,9,42], coagulation and hematologic abnormalities [7,9,38], nutritional deficiency [7], previous cardiac surgeries [38], small body surface area [7], active infection [7,38]. As there is no one predictor that would correlate with LVAD operative outcomes, composite risk scores have been used to help predict the outcomes with device placement, such as the APACHE II score (Acute Physiology and Chronic Health Evaluation) [43] and the Heart Failure Survival Score [21]. In recent years, risk scales have been derived in BTT patients [38,39] and those who underwent destination therapy [7], as shown in Table 1. The Destination Therapy Risk Score used the largest cohort of 222 patients studied to date [7]. It was designed to help clinicians prospectively estimate candidate 90-day probability of in-hospital mortality after LVAD implantation. Patients who were considered to have a lower operative risk (cumulative Destination Therapy Risk Score 16),

Medical therapy 26%

40 20

Weighted Risk Score 4 2 2 1 1

Acceptable operative candidates

60

(B) Columbia University – Cleveland Clinic Revised Risk Scale Patient characteristics

69%

High-risk operative candidates

19% 8%

0 0

4

8

12

16

20

24

Months after LVAD implantation

The graph shows 2-year survival with destination therapy stratified by the operative risk estimated using the Destination Therapy Risk Score in the post-REMATCH population of patients who underwent LVAD implantation as destination therapy in the United States between years 2002 and 2005. High-risk candidates were defined as those with in-hospital mortality risk >50%, which is equivalent to the Destination Therapy Risk Score >16. Adopted with permission from [44].

were more likely to survive surgery and achieved a 1-year survival ranging between 71 and 80%, whereas high-risk operative candidates had poor outcomes (1-year survival

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