Pathologic evidence of extensive left ventricular involvement in arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (also known as arrhythmogenic right ventricular dysplasia) is characterized by adipose or fibroadipose tissue replacement of the right ventricular myocardium, whereas the left ventricle is substantively spared. Two cases of the disease with evidence of extensive left ventricular involvement at pathologic examination are described. Hearts from two patients who died suddenly showed full-thickness right ventricular fatty infiltration associated with extensive left ventricular involvement (greater than 50% of myocardial thickness). These findings might explain the reported clinical features of left ventricle dysfunction in a subset of patients with arrhythmogenic right ventricular cardiomyopathy. In view of the biventricular involvement of the disease, it should simply be termed "arrhythmogenic cardiomyopathy."     

Arrhythmogenic right ventricular cardiomyopathy: clinicopathologic correlation based on a revised definition of pathologic patterns.

Different morphologic features of arrhythmogenic right ventricular cardiomyopathy (ARVC) have been described. However, it is still unclear whether they correspond to distinct forms of the same disease. A pathologic study was performed on a series of ARVC (15 from heart transplant and 12 from autopsy) from 2 Italian referral university hospitals. Based on both myocellular features and the nature of myocardial replacement, hearts were divided into 2 groups: infiltrative, with a lacelike pattern of transmural fatty infiltration and strands of normal residual cardiomyocytes (n = 11); and cardiomyopathic, with massive myocardial replacement by fibro fatty tissue and cardiomyopathic changes (such as hypertrophy and myofibril loss) of residual cardiomyocytes (n = 16). Hearts from the infiltrative group were mostly obtained at autopsy of patients who died suddenly. Fatty substitution was limited almost exclusively to the right ventricle. Mitral valve dysplasia (prolapse or cleft) was frequently present. Hearts from the cardiomyopathic group came mainly from heart transplants for congestive heart failure. Fibro fatty replacement was more extensive, usually biventricular. Active myocarditis and features suggestive of myocardial transdifferentiation were also observed. Despite these differences in clinical outcome and morphologic features, patients from the 2 groups showed similar mean age, sex distribution, occurrence of threatening ventricular arrhythmias, and prevalence of family history of sudden death, arrhythmias, or cardiomyopathy. Infiltrative and cardiomyopathic patterns represent different clinical and pathologic subsets of ARVC. Myocellular features are an important clue in the distinction between the two entities. The differentiation between the 2 patterns is feasible on endomyocardial biopsy and could give important prognostic information.     

Sudden unexpected death in a 31-year-old man caused by arrhythmogenic right ventricular cardiomyopathy

A 31-year-old white man collapsed suddenly at a graduation ceremony and was pronounced dead after attempted resuscitation. He had no pertinent medical or familial history. Postmortem toxicologic studies showed negative results. A complete autopsy revealed a cardiac cause of death. Grossly, the right ventricular chamber was moderately to markedly dilated, and its free wall showed extensive myocardial adiposity. Microscopically, the right ventricular free wall consisted predominantly of adipose tissue, with only small subendocardial islands of hypertrophied myocytes and interstitial fibrosis. These features are characteristic of arrhythmogenic right ventricular cardiomyopathy. Moreover, Purkinje-like cells were observed among right ventricular myocytes and may have increased the likelihood of developing an arrhythmia. To our knowledge, this finding has not been previously emphasized. Because arrhythmogenic right ventricular cardiomyopathy accounts for 10% of cases of sudden unexpected cardiac death, recognition of this disease by pathologists is important, especially in cases of otherwise unexplained death in young persons.     

心肌扩张型心脏病的病理形态特征及其临床意义

目的探讨单纯心壁病损造成的心脏扩张者的病理形态特征及其意义。方法收集2004年6月至2006年8月中国医学科学院北京协和医学院阜外心血管病医院60例心脏移植的受体心脏在离体后立即进行了肉眼观察、测量和摄影记录,并进行了全面的组织病理学观察。以其中40例单纯心壁病损造成的心脏扩张者进行临床-病理对照分析,并观察其形态特点。结果40例单纯心壁病损造成的心脏扩张者中21例（52．5％）为原发性扩张型心肌病,9例（22．5％）为致心律失常性右心室心肌病,6例（15．0％）为缺血性心肌病,其余的4例（10．0％）为局灶性心肌致密化不全、巨细胞性心肌炎和特异性心肌病中的酒精性心肌病和高血压性心肌病。40例中临床诊断与病理诊断不符15例（37．5％）,不相符率较高的依次为致心律失常性右心室心肌病（7／9）、缺血性心肌病（5／6）和巨细胞性心肌炎（1／1）。不相符的这几种病的原临床和影像学诊断都是扩张型心肌病。致心律失常性右心室心肌病、缺血性心肌病、心肌致密化不全和巨细胞性心肌炎都有特征性的病理形态表现,酒精性心肌病和高血压性心肌病等的病理诊断需要参考临床病史。该组病例没有观察到慢性心肌炎样病变发展成扩张型心肌病的形态学迹象。结论进行心脏移植病例受体心脏的病理学检查有利于提高心脏病的临床和影像诊断的正确率,病理形态检查是不可忽视的重要手段。     

Arrhythmogenic right ventricular cardiomyopathy versus fatty replacement of the right ventricle. An autopsy case report

We report an autopsy case of a cardiomyopathy characterized by fatty replacement of the right ventricular myocardium and compare its clinical and histologic characteristics with those of the arrhythmogenic right ventricular cardiomyopathy. A 39-year old male died suddenly in a hospital room. He had an alcoholic cirrhosis with ascitis, but the clinical examination and the biology showed no abnormalities explaining the death. Histologically, in the right ventricle, large areas of cardiomyocytes were replaced by fat, but there was no fibrosis. In contrast, fibrosis is present in association with fat in arrhythmogenic right ventricular cardiomyopathy. Fatty replacement of the right ventricle is likely to be a distinct entity. Right ventricular failure has been shown to be a possible complication. Sudden death is probably rare and is likely to occur when other arrhythmogenic factors are associated.     

Arrhythmogenic right ventricular cardiomyopathy: new insights into mechanisms of disease

Arrhythmogenic right ventricular cardiomyopathy is a primary heart muscle disorder characterized by the early occurrence of arrhythmias often out of proportion to the extent of structural remodeling and contractile derangement. Approximately 40% of patients with arrhythmogenic right ventricular cardiomyopathy have one or more mutations in genes encoding proteins in desmosomes, intercellular adhesion junctions which, in cardiac myocytes, reside within intercalated disks. Some desmosomal proteins fulfill roles both as structural proteins in cell–cell adhesion junctions and as signaling molecules in pathways mediated by Wnt ligands. Evidence is increasing that mutations in desmosomal proteins can perturb the normal balance of critical proteins in junctions and the cytosol which, in turn, could alter gene expression by circumventing normal Wnt signaling pathways. This review highlights recent advances in understanding the pathogenesis of arrhythmogenic right ventricular cardiomyopathy and presents evidence suggesting that the disease is caused by a combination of altered cellular biomechanical behavior and altered signaling.     

Histopathology of familial versus nonfamilial dilated cardiomyopathy

Idiopathic dilated cardiomyopathy is most likely a heterogenous group of diseases characterized by ventricular dilatation and dysfunction. Approximately 20% of patients with idiopathic dilated cardiomyopathy have familial disease, which may be inapparent by review of the family history alone. It has been suggested that histopathologic features, particularly the presence of bizarrely shaped mitochondria, may be useful in distinguishing familial from nonfamilial disease.

We investigated 57 patients with dilated cardiomyopathy, 13 familial and 43nonfamilial or indeterminate. Pathologic examination of right endomyocardial biopsy specimens showed no significant differences between the familial, nonfamilial, or indeterminate groups by light microscopy or electron microscopy. We conclude that the distinction between familial and nonfamilial dilated cardiomyopathy cannot be made by histopathologic examination in most cases.     

Histological assessment of apoptotic cell death in cardiomyopathies

Apoptosis in the myocardium is complex and often difficult to recognise. Myocyte apoptosis is scattered across the myocardial wall and is restricted to individual cells. In the present study, we describe the amount of apoptosis in 50 endomyocardial biopsies taken from 50 patients with dilated cardiomyopathy, in 14 hearts with hypertrophic cardiomyopathy and in five hearts with arrhythmogenic dysplasia of the right ventricle. As a control group, 15 endomyocardial biopsies from 15 transplanted hearts (of live patients) were used. Apoptosis was immunohistochemically determined in paraffin sections with the TUNEL method. In each specimen the TUNEL index was calculated as the percentage of TUNEL-positive nuclei among a total number of 200 counted nuclei. Cellular morphology was assessed in conjunction with TUNEL staining. The mean percentage of TUNEL-positive myocardial cells varied from 4% for dilated cardiomyopathy to 17.5% for arrhythmogenic right ventricle dysplasia and 18.5% for hypertrophic cardiomyopathy, whereas no signs of apoptotic myocardial cell death were found in normal subjects. The numbers of apoptotic cells in dilated cardiomyopathy specimens were significantly lower by comparison with both those of hypertrophic cardiomyopathy and those of arrhythmogenic right ventricular dysplasia specimens. It is evident that apoptosis constitutes a major biological phenomenon in the development of at least some heart diseases, but its role in their pathophysiology has yet to be delineated.     

Distribution of biventricular disease in arrhythmogenic cardiomyopathy: an autopsy study

Arrhythmogenic cardiomyopathy is a rare cardiomyopathy characterized by fibrofatty replacement primarily of the right ventricular myocardium. It is a major cause of sudden death in the young and in athletes. There are few autopsy studies of the ventricular distribution of the disease. Fifty cases of sudden cardiac death with fibrofatty replacement in either ventricle from a single medical examiner's office were studied. Distribution of disease as determined grossly and microscopically was correlated with activity at time of death, race, and presence of inflammation. Extent of disease was right ventricular in 6 cases (12%; age, 25 ± 5 years), biventricular in 25 (50%; age, 36 ± 3 years), and left ventricular in 19 (38%; age, 37 ± 3 years) (P = .13). Inflammation was present in 44% of biventricular arrhythmogenic cardiomyopathy versus 74% of left ventricular arrhythmogenic cardiomyopathy and 83% of right ventricular arrhythmogenic cardiomyopathy (P = .06). Arrhythmogenic cardiomyopathy, when presenting with sudden death, is usually biventricular. There is a trend that univentricular involvement occurs at an earlier age and that right ventricular involvement shows more inflammation, suggesting different stages of disease.     

遗传性心肌病的临床实践指南

心肌病是一组异质性心肌疾病,可由各种原因(常为遗传因素)引起,能够导致心力衰竭、心律失常和猝死。原发性心肌病包括遗传性肥厚型心肌病、致心律失常右室心肌病、线粒体心肌病、混合性(遗传性及获得性)扩张型心肌病和限制型心肌病、左心室致密化不全以及其他未分类的心肌病。借助基因组学技术,在人群中发现的一些常见突变与疾病的关联已被鉴定。这些突变的体内和体外功能研究为疾病的发生机制和治疗提供了有用的线索。本指南在参考国内外本领域的基础研究、临床研究和其他国家的相关指南共识的基础上,对不同类型遗传型心肌病的表型、诊断、治疗及遗传咨询进行了总结,期望有助于患者临床管理的规范化。     

Genetic testing for inherited heart diseases: longitudinal impact on health-related quality of life

PurposeA genetic diagnosis is an extremely useful tool in the management and care of families with inherited heart diseases, particularly in allowing clarification of risk status of asymptomatic family members. The psychosocial consequences of genetic testing in this group are poorly understood. This longitudinal pilot study sought to determine changes in health-related quality of life in patients and asymptomatic family members undergoing genetic testing for inherited heart diseases.MethodsIndividuals attending two specialized multidisciplinary cardiac genetic clinics in Australia were invited to participate. Patients undergoing proband or predictive genetic testing for an inherited cardiomyopathy or primary arrhythmogenic disorder were eligible. The Medical Outcomes Short Form-36 (version 2) was administered before the genetic result was given, and follow-up surveys were completed 1–3, 6, and 12 months after the result was given.ResultsA total of 54 individuals with hypertrophic cardiomyopathy, familial dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, and long QT syndrome completed baseline and at least one follow-up survey, including 33 probands and 21 asymptomatic relatives. Physical and mental component scores analyzed at baseline and 1–3 months were found to be unchanged in all groups. Furthermore, no significant differences were observed up to 12 months after result.ConclusionIn this longitudinal pilot study, no change in health-related quality of life was observed up to 12 months after the result was given in patients and their asymptomatic family members undergoing genetic testing for an inherited heart disease.Genet Med 2012:14(8):749–752.     

Adipositas cordis, fatty infiltration of the right ventricle, and arrhythmogenic right ventricular cardiomyopathy. Just a matter of fat?

Whether fatty infiltration of the right ventricle has to be considered "per se" a sufficient morphologic hallmark of arrhythmogenic right ventricular cardiomyopathy (ARVC) is still a source of controversy; ARVC should be kept distinct from both fatty infiltration of the right ventricle and adipositas cordis. In fact, it is well known that a certain amount of intramyocardial fat is present in the right ventricular antero-lateral and apical regions even in the normal heart and that the epicardial fat increases with increasing body weight. However, both the fibro-fatty and fatty variants of ARVC show, besides fatty replacement of the right ventricular myocardium, degenerative changes of the myocytes and interstitial fibrosis, with or without extensive replacement-type fibrosis. The need to adopt strict diagnostic criteria is warranted not only in the clinical setting but also in the forensic and general pathology arena. When dealing with a case of sudden death, in which the only morphologic finding consists of an increased amount of epicardial or intramyocardial fat, a more convincing arrhythmogenic source such as myocardial inflammatory infiltrates, fibrosis, anomalous pathways, and ion channel disease should always be searched for, in order to avoid an over-diagnosis of ARVC cases.     

Chronic right-sided myocarditis mimicking arrhythmogenic right ventricular dysplasia

Arrhythmogenic right ventricular dysplasia (ARVD) is a cause of right ventricular heart failure and has been implicated in some cases of sudden death in young adults. It is well known that a large majority of patients with ARVD have histological evidence suggestive of inflammation. Here we report a unique case of chronic myocarditis limited to the right ventricle and right side of the interventricular septum which presented clinically as ARVD. The fact that right sided myocarditis can clinically mimic the genetic disease of classic arrhythmogenic right ventricular dysplasia has therapeutic implications for the patient and relatives.     

Cardiac sarcoidosis and sudden death. The heart may look normal or mimic other cardiomyopathies

Cardiac sarcoidosis has been known to give rise to heart failure, arrhythmias and sudden cardiac death. We have a large database of sudden cardiac death cases at the CRY Centre for Cardiac Pathology at Imperial College, London, UK in which we found 17 of 1,720 cases with a diagnosis of cardiac sarcoid. Macroscopic examination showed a variety of findings including left ventricular hypertrophy, a dilated thin-walled left ventricle ,areas of fibrosis, changes resembling arrhythmogenic right ventricular cardiomyopathy and in some cases, no gross abnormalities. Histological examination revealed large areas of fibrosis and focal lymphocytic inflammation mimicking infarction/myocarditis. Careful search had to be made for non-necrotizing granulomata, since the lymphocytic foci, fibrosis and granulation tissue often predominated throughout the heart. The conduction tissue is often not sampled at autopsy despite the history of heart block. The heterogeneous nature of the macroscopic appearance and histological findings means that widespread sampling of the heart and the conduction system is essential in cases of sudden death in order that a diagnosis of myocardial sarcoidosis is not missed.     

Role of genetic testing in arrhythmogenic right ventricular cardiomyopathy/dysplasia

Barahona-Dussault C, Benito B, Campuzano O, Iglesias A, Leung TL, Robb L, Talajic M, Brugada R. Role of genetic testing in arrhythmogenic right ventricular cardiomyopathy/dysplasia.
In a cohort of patients with confirmed or suspected arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), genetic testing is useful in confirming the diagnosis, particularly in individuals who do not completely fulfil Task Force criteria for the disease, thereby also enabling the adoption of preventive measures in family members. Due to the high percentage of novel mutations that are expected to be identified in ARVC/D, the use of genetic screening technology based on the identification of known mutations seems to have very restricted value. Our results support that the presence of certain genetic variations could play a role in the final phenotype of patients with ARVC/D, where single and compound mutation carriers would have more symptomatic forms of the disease and the polymorphism P366L could be associated to a more benign phenotype.     

Cardiomyopathy in neurological disorders

According to the American Heart Association, cardiomyopathies are classified as primary (solely or predominantly confined to heart muscle), secondary (those showing pathological myocardial involvement as part of a neuromuscular disorder) and those in which cardiomyopathy is the first/predominant manifestation of a neuromuscular disorder. Cardiomyopathies may be further classified as hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, or unclassified cardiomyopathy (noncompaction, Takotsubo-cardiomyopathy). This review focuses on secondary cardiomyopathies and those in which cardiomyopathy is the predominant manifestation of a myopathy. Any of them may cause neurological disease, and any of them may be a manifestation of a neurological disorder. Neurological disease most frequently caused by cardiomyopathies is ischemic stroke, followed by transitory ischemic attack, syncope, or vertigo. Neurological disease, which most frequently manifests with cardiomyopathies are the neuromuscular disorders. Most commonly associated with cardiomyopathies are muscular dystrophies, myofibrillar myopathies, congenital myopathies and metabolic myopathies. Management of neurological disease caused by cardiomyopathies is not at variance from the same neurological disorders due to other causes. Management of secondary cardiomyopathies is not different from that of cardiomyopathies due to other causes either. Patients with neuromuscular disorders require early cardiologic investigations and close follow-ups, patients with cardiomyopathies require neurological investigation and avoidance of muscle toxic medication if a neuromuscular disorder is diagnosed. Which patients with cardiomyopathy profit most from primary stroke prevention is unsolved and requires further investigations.     

Twenty years of progress and beckoning frontiers in cardiovascular pathology: cardiomyopathies.

In the last 20 years, with the advent of cardiac transplantation and the availability of molecular biology techniques, major advancements were achieved in the understanding of cardiomyopathies. Novel cardiomyopathies have been discovered (arrhythmogenic right ventricular, primary restrictive, and noncompacted myocardium) and added in the update of WHO classification. Myocarditis was also included with the name "inflammatory cardiomyopathy." Adenoviruses and parvoviruses were found to be frequent cardiotropic viruses in addition to enteroviruses. The extraordinary progress accomplished in molecular genetics of inherited cardiomyopathies allowed to establish hypertrophic and restrictive cardiomyopathies as sarcomeric ("force generation") diseases, dilated cardiomyopathies as cytoskeleton ("force transmission") disease, and arrhythmogenic right ventricular cardiomyopathy (ARVC) as cell junction disease. If we consider also cardiomyopathy as ion channel disease (long and short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia), because they are diseases of the myocardium associated with electrical dysfunction, then a genomic/postgenomic classification of inherited cardiomyopathies may be put forward: cytoskeletal cardiomyopathy, sarcomeric cardiomyopathy, cell junction cardiomyopathy and ion channel cardiomyopathy.     

A clinical role for right ventricular endomyocardial biopsy

There is considerable uncertainty about the value of endomyocardial biopsy (EMB) in the diagnosis and management of patients with suspected primary myocardial dysfunction. To determine the clinical utility of this procedure in patients referred to our centre, we reviewed the clinical records and biopsy findings of the first 21 consecutive patients in whom we performed right ventricular EMB. Patients were divided into four groups according to the clinical indications for EMB: unexplained congestive cardiac failure and a dilated heart (Group 1: 11 patients); unexplained congestive cardiac failure and a non dilated heart (Group 2: three patients); unexplained cardiomegaly in the absence of cardiac failure (Group 3: one patient); suspected hypertrophic cardiomyopathy (HCM) (Group 4: six patients). Histological examination of EMB tissue obtained from all patients in Group 1 as well as the single patient in Group 3 showed non specific features judged to be compatible with a diagnosis of dilated cardiomyopathy. Accordingly, in all patients in Groups 1 and 3, a potentially treatable cause of primary myocardial dysfunction was excluded. Biopsy examination demonstrated the presence of a specific disease process in two of three patients in Group 2 (one patient had amyloidosis, the other endomyocardial fibrosis). In five of the six patients in Group 4, the biopsy findings were either diagnostic or suggestive of HCM. Our results suggest that EMB is a clinically useful tool in patients presenting with features suggestive of a primary myocardial disorder.     

The investigation of sudden cardiac death

Pathologists are faced with an increasing complexity in the cardiac diseases that cause sudden natural death in the absence of coronary artery disease. A significant proportion of such natural sudden deaths are due to familial heart muscle disease (cardiomyopathy). The phenotypic characteristics of both hypertrophic cardiomyopathy and arrythmogenic right ventricular dysplasia are wider than previously thought and the hearts may be very close to normal on naked eye examination. Detailed histology of the myocardium is needed to identify such cases. Up to 200 sudden deaths a year in England occur in young, apparently fit individuals in whom toxicology and detailed examination of the heart for structural abnormalities is negative. Genetic defects in ion channels (long QT interval) are now known to be one cause of this phenomenon. In investigating a case of sudden death without cause, a study of the family -- if they wish it -- may be helpful in arriving at a cause.     

The natural history of a genetic subtype of arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43

To determine the phenotype and natural history of a founder genetic subtype of autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) caused by a p.S358L mutation in TMEM43. The age of onset of cardiac symptoms, clinical events and test abnormalities were studied in 412 subjects (258 affected and 154 unaffected), all of which occurred in affected males significantly earlier and more often than unaffected males. Affected males were hospitalized four times more often than affected females (p ≤ 0.0001) and died younger (p ≤ 0.001). The temporal sequence from symptoms onset to death was prolonged in affected females by 1–2 decades. The most prevalent electrocardiogram (ECG) manifestation was poor R wave progression (PRWP), with affected males twice as likely to develop PRWP as affected females (p ≤ 0.05). Left ventricular enlargement (LVE) occurred in 43% of affected subjects, with 11% fulfilling criteria for dilated cardiomyopathy. Ventricular ectopy on Holter monitor was common and occurred early: the most diagnostically useful clinical test. No symptom or test could rule out diagnosis. This ARVC subtype is a sex‐influenced lethal arrhythmogenic cardiomyopathy, with a unique ECG finding, LV dilatation, heart failure and early death, where molecular pre‐symptomatic diagnosis has the greatest clinical utility.