Distribution of biventricular disease in arrhythmogenic cardiomyopathy: an autopsy study

doi:10.1016/j.humpath.2011.06.014

Human Pathology

Volume 43, Issue 4, April 2012, Pages 592-596

https://doi.org/10.1016/j.humpath.2011.06.014 Get rights and content

Summary

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.

Introduction

Arrhythmogenic cardiomyopathy (AC) or its synonym arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare heart muscle disease in which the right ventricle is “replaced” by fibrofatty tissue [1]. ARVC is clinically characterized by ventricular tachyarrhythmias originating from the right ventricle and by syncopal episodes and sudden death, which are often triggered by exercise. Pathologically, AC is characterized by fibrofatty replacement of the myocardium, accompanied by vacuolated myocytes and interstitial fibrosis. Inflammatory infiltrates have been reported in several cases, raising the possibility that AC is a form of healed myocarditis [1], [2], [3], [4], [5]. Although right ventricular disease formed the basis for the initial reports of AC, left ventricular involvement has been reported with increased frequency, and in some individuals, there may be a global dilated cardiomyopathy [6]. Recently, ARVC has been classified based on magnetic resonance imaging as classic (right ventricular predominant) in 39%, biventricular in 56%, and left dominant disease in 5% of patients [7]. There have been several autopsy studies of ARVC [4], [8], [9], [10], [11], one of which emphasized left ventricular involvement [8]. We herein characterize a series of ARVC from a single medical examiner's office to study the ventricular distribution of ARVC and correlate ventricular distribution with clinicopathologic parameters.

Section snippets

Materials and methods

Fifty cases of sudden cardiac death with the diagnosis of ARVC were retrospectively studied. The disease was defined as subepicardial or right ventricular fibrofatty change surrounding altered degenerating cardiomyocytes. All cases were autopsied at the Office of the Chief Medical Examiner, Baltimore, MD, and were seen in consultation by cardiovascular pathologist and examined in a similar fashion. In all cases, autopsy reports were available, and full autopsy disclosed no other causes of

Results

The mean age of the 50 subjects at the time of sudden death was 35.2 ± 15.7 years (Table 1). There were 23 whites (44%), 25 blacks (50%), and 2 Asians (4%). Death was exertional in 28 cases (56%). In only 3 cases did the autopsy report mention familial cardiac sudden death or cardiomyopathy. One patient had thyroiditis clinically and substantiated at autopsy, and one had a history of Alport syndrome.

Heart weight was increased in 52% of the cases (range, 144-820 g; mean, 438 g) with no

Discussion

The current study shows that the left ventricle is more frequently involved than the right in autopsy cases of AC. This finding has implications in the autopsy diagnosis of AC, in that medical examiners and pathologists who typically encounter sudden cardiac death need to be aware that left ventricular disease is not only common but may also be the only manifestation of AC. Only slightly more than half of hearts shows gross findings in the right ventricle. There may have been a selection bias

References (24)

S. Sen-Chowdhry et al.
Left-dominant arrhythmogenic cardiomyopathy: an under-recognized clinical entity
J Am Coll Cardiol
(2008)
S. Sen-Chowdhry et al.
Arrhythmogenic right ventricular cardiomyopathy: clinical presentation, diagnosis, and management
Am J Med
(2004)
G. d'Amati et al.
Arrhythmogenic right ventricular cardiomyopathy: clinicopathologic correlation based on a revised definition of pathologic patterns
Hum Pathol
(2001)
D.W. Kitzman et al.
Age-related changes in normal human hearts during the first 10 decades of life. Part II (maturity): a quantitative anatomic study of 765 specimens from subjects 20 to 99 years old
Mayo Clin Proc
(1988)
P. Gallo et al.
Pathologic evidence of extensive left ventricular involvement in arrhythmogenic right ventricular cardiomyopathy
Hum Pathol
(1992)
J.G. Webb et al.
Left ventricular abnormalities in arrhythmogenic right ventricular dysplasia
Am J Cardiol
(1986)
M.A. Fogel et al.
Usefulness of magnetic resonance imaging for the diagnosis of right ventricular dysplasia in children
Am J Cardiol
(2006)
G. Thiene et al.
Arrhythmogenic right ventricular cardiomyopathy/dysplasia
Orphanet J Rare Dis
(2007)
H. Suzuki et al.
Arrhythmogenic right ventricular cardiomyopathy with an initial manifestation of severe left ventricular impairment and normal contraction of the right ventricle
Jpn Circ J
(2000)
A.P. Burke et al.
Arrhythmogenic right ventricular cardiomyopathy and fatty replacement of the right ventricular myocardium: are they different diseases?
Circulation
(1998)

D.D. Sugrue et al.

Histologic abnormalities of the left ventricle in a patient with arrhythmogenic right ventricular dysplasia

Heart Vessels

(1985)

S. Sen-Chowdhry et al.

Clinical and genetic characterization of families with arrhythmogenic right ventricular dysplasia/cardiomyopathy provides novel insights into patterns of disease expression

Circulation

(2007)

Cited by (28)

Arrhythmogenic Right Ventricular Cardiomyopathy
2022, JACC: Clinical Electrophysiology
Arrhythmogenic right ventricular cardiomyopathy (ARVC) encompasses a group of conditions characterized by right ventricular fibrofatty infiltration, with a predominant arrhythmic presentation. First described in the late 1970s and early 1980s, it is now frequently recognized to have biventricular involvement. The prevalence is ∼1:2,000 to 1:5,000, depending on geographic location, and it has a slight male predominance. The diagnosis of ARVC is determined on the basis of fulfillment of task force criteria incorporating electrophysiological parameters, cardiac imaging findings, genetic factors, and histopathologic features. Risk stratification of patients with ARVC aims to identify those who are at increased risk of sudden cardiac death or sustained ventricular tachycardia. Factors including age, sex, electrophysiological features, and cardiac imaging investigations all contribute to risk stratification. The current management of ARVC includes exercise restriction, β-blocker therapy, consideration for implantable cardioverter-defibrillator insertion, and catheter ablation. This review summarizes our current understanding of ARVC and provides clinicians with a practical approach to diagnosis and management.
Phenotypic expression of ARVC: How 12 lead ECG can predict left or right ventricle involvement. A familiar case series and a review of literature
2017, International Journal of Cardiology
Citation Excerpt :
The three cases we presented showed epsilon waves on the right precordial leads, however Case 2 developed epsilon waves also in the left precordial leads and in DI-aVL (Fig. 2b, Appendix Table 2), reflecting the extended LV involvement by the fibro-fatty tissue substitution. This ECG evolution is not usually described in LV dominant or biventricular forms: Sen-Chowdhry et al., in a cohort of 200 probands (82% with LV involvement), reported epsilon waves in lateral leads only in 2 patients [4]; other reports described epsilon wave in V1-V3, and characteristic negative T wave in left precordial leads [3,4,7,14,27–34]. Epsilon wave detection in left precordial leads may be underestimated.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart-muscle disease primarily affecting the right ventricle (RV) and potentially causing sudden death in young people. The natural history of the disease is firstly characterized by a concealed form progressing over a biventricular involvement. Three different cases coming from the same family are presented together with a review of the literature.
Multi-parameter analysis including imaging and electrocardiographic analysis is presented since the first medical referral with follow-up ranging from 11 to 38 years. Case 1 presented a typical RV involvement in agreement with the ECG pattern. Case 2 presented a prevalent left ventricular involvement leading from the beginning to a pattern of dilated cardiomyopathy in agreement with his ECG evolution over the years. On the other side, Case 3 came to observation with a typical RV involvement (similar to Case 1) but with ECG evolution of typical left ventricle involvement (similar to Case 2). The genetic analysis showed a mutation in desmoglein-2 (DSG2) gene: p. Arg49His. Comparison between size and localization of ventricular dyskinesia at cardiovascular imaging and the surface 12 lead electrocardiography are proposed.
ARVC may lead to an extreme phenotypic variability in clinical manifestations even within patients coming from the same family in which ARVC is caused by the same genetic mutation. ECG progression over time reflects disease evolution and in particular cases may anticipate wall motion abnormalities by years.
Nonischemic left ventricular scar and cardiac sudden death in the young
2016, Human Pathology
Citation Excerpt :
Findings of left ventricular myocardial replacement consistent with NLVS and often associated with RV involvement are also increasingly reported at autopsy. In this setting, this morphologic pattern is usually defined as ARVC/D, although genetic confirmation of the disease is not provided in the majority of cases [9,18,21,22]. In this study, we provided a detailed description of gross and histologic features of NLVS.
Nonischemic left ventricular scar (NLVS) is a pattern of myocardial injury characterized by midventricular and/or subepicardial gadolinium hyperenhancement at cardiac magnetic resonance, in absence of significant coronary artery disease. We aimed to evaluate the prevalence of NLVS in juvenile sudden cardiac death and to ascertain its etiology at autopsy. We examined 281 consecutive cases of sudden death of subjects aged 1 to 35 years. NLVS was defined as a thin, gray rim of subepicardial and/or midmyocardial scar in the left ventricular free wall and/or the septum, in absence of significant stenosis of coronary arteries. NLVS was the most frequent finding (25%) in sudden deaths occurring during sports. Myocardial scar was localized most frequently within the left ventricular posterior wall and affected the subepicardial myocardium, often extending to the midventricular layer. On histology, it consisted of fibrous or fibroadipose tissue. Right ventricular involvement was always present. Patchy lymphocytic infiltrates were frequent. Genetic and molecular analyses clarified the etiology of NLVS in a subset of cases. Electrocardiographic (ECG) recordings were available in more than half of subjects. The most frequent abnormality was the presence of low QRS voltages (<0.5 mV) in limb leads. In serial ECG tracings, the decrease in QRS voltages appeared, in some way, progressive. NLVS is the most frequent morphologic substrate of juvenile cardiac sudden death in sports. It can be suspected based on ECG findings. Autopsy study and clinical screening of family members are required to differentiate between arrhythmogenic right ventricular cardiomyopathy/dysplasia and chronic acquired myocarditis.
Sudden Natural Death: Cardiovascular
2015, Encyclopedia of Forensic and Legal Medicine: Second Edition
Sudden cardiovascular death includes sudden arrhythmic death, and other cardiovascular events that result in abrupt circulatory compromise. Typical substrates predisposing to arrhythmias include epicardial coronary thrombosis, coronary atherosclerosis in the absence of thrombosis, non-atherosclerotic coronary disease, cardiomyopathies, secondary causes of cardiac enlargement, cardiac scarring, inflammatory conditions, valve disease, and cardiac tumors. Because most cardiac arrhythmias arise in the setting of chronic underlying heart disease, exclusion of other natural and nonnatural conditions is essential in forensic evaluation of unexpected deaths.
Mutations of desmoglein-2 in sudden death from arrhythmogenic right ventricular cardiomyopathy and sudden unexplained death
2015, Forensic Science International
Citation Excerpt :
Although ARVC has been considered primarily as a right-sided cardiomyopathy, the growing evidence supporting a concomitant or independent left ventricular (LV) involvement in these patients. [24–29] A previous study examined 50 cases of SCD with ARVC, found that 50% involve both ventricles, 38% predominantly left ventricles involved [30], similar to the clinical reports by Sen-Chowdhry et al. [24,29]. SCD is one of the most common causes of death, with many attributable to cardiac/coronary abnormalities evident at autopsy.
Desmoglein-2 (DSG2), a member of the desmosomal cadherin superfamily, has been linked to arrhythmogenic right ventricular cardiomyopathy (ARVC)which may cause life-threatening ventricular arrhythmias and sudden death. Fatal arrhythmias resulting in sudden death also occur in the absence of morphologic cardiac abnormalities at autopsy. We sequenced all 15 exons of DSG2 in DNA extracted from post-mortem heart tissues of 25 patients dying with ARVC and 25 from sudden unexplained death (SUD). The primers were designed using the Primer Express 3.0 software. Direct sequencing for both sense and antisense strands was performed with a BigDye Terminator DNA sequencing kit on a 3130 xl Genetic Analyzer. Mutation damage prediction was made using Mutation Taster, Polyphen and SIFT software. 2 DSG2 mutations (p. S1026Q fsX12, p. G678R)in two ARVC samples and 2 DSG2 mutations(p. E 896K, p. A858 V) in two SUD samples were identified, all the mutations were novel. We concluded that DSG2 mutations may not specific for ARVC and may be related to the fatal arrhythmic events even in patients with a morphological normal heart.
Arrhythomgenic right ventricular dysplasia and sudden death: An autopsy and histological study
2015, Annales de Cardiologie et d'Angeiologie
La dysplasie arythmogène du ventricule droit (DAVD) est une cardiomyopathie où le tissu normal du myocarde est remplacé par du tissu fibro-adipeux. L’examen histologique réalisé sur des biopsies myocardiques ou sur des prélèvements autopsiques permettent d’affirmer le diagnostic. Cependant, dans plusieurs cas, la certitude diagnostique ne peut pas se faire sur une simple étude macroscopique et histologique et nécessite une étude génétique et de biologie moléculaire. Dans ce travail, nous nous proposons de décrire les principales constatations macroscopiques et histologiques de la DAVD à travers l’étude d’une série autopsique. Nous rapportons 12 cas autopsiques de mort subite par DAVD colligés dans le service de médecine légale de l’hôpital universitaire Fattouma Bourguiba de Monastir (Tunisie) sur une période de 20 ans. L’examen microscopique a été réalisé sur des coupes histologiques de 5 microns d’épaisseur. Toutes les lames ont été relues par deux observateurs en double insu (médecin anatomopathologiste, médecin légiste) et chacun a précisé le pourcentage du tissu adipeux, de la fibrose et du myocarde au niveau du ventricule droit, ventricule gauche et septum interventriculaire, la présence ou pas d’infiltrat inflammatoire, la présence ou pas de signes de dégénérescence des myocytes. La DAVD était retrouvée dans 12 cas (soit 1,8 % des MS cardiovasculaires). L’âge était compris entre 13 et 67 ans (âge moyen est de 45,3 ans). Le décès est survenu dans la moitié des cas pendant un exercice physique. L’examen macroscopique du ventricule droit (VD) a montré la présence d’un amincissement de la paroi (épaisseur < 3 mm) dans 9 cas dont deux comportant une infiltration adipeuse macroscopique associée. L’étude histologique a permis de mettre en évidence une infiltration adipeuse du VD dans tous les cas avec un pourcentage variant entre 15 % et 60 %, des lésions de fibrose ont été notées seulement dans 9 cas avec un pourcentage moyen de 10,25 % et des signes de dégénérescence de myocytes ont été notés dans 10 cas. En concordance par rapport à ce qui a été rapporté dans la littérature, il n’y a pas encore de consensus en ce qui concerne les critères à adopter pour poser avec certitude le diagnostic de DAVD et la présence d’un tissu adipeux reste le critère le plus suggestif.
Arrhythmogenic right ventricular dysplasia (ARVD) is cardiomyopathy where normal myocardial tissue is replaced with fibrofatty tissue. Histological examination performed on myocardial biopsy or on autopsy samples are used to confirm the diagnosis. However, in many cases, the diagnosis cannot be made on a simple macroscopic and histological study and requires genetic analysis and molecular biology. In this work, we propose to describe the main macroscopic and histological findings of ARVD through the study of an autopsy series. We report 12 autopsy cases of sudden death in ARVD collected in the Department of Forensic Medicine of the University Hospital Fattouma Bourguiba Monastir (Tunisia) during a period of 20 years. Microscopic examination was performed on 5 microns thick histological sections. All slides were reviewed by two operators in a double blind (physician pathologist, pathologist) and in each, the percentage of adipose tissue, fibrosis and infarction in the right ventricle, left ventricle and interventricular septum, the presence or absence of inflammatory infiltrate, the presence or absence of signs of degeneration of myocytes were noticed. ARVD was found in 12 cases (1.8% of sudden cardiac death). The age ranged between 13 and 67 years (mean age: 45.3 years). The death occurred in half of the cases during exercise. Macroscopic examination of the RV showed the presence of a wall thinning (thickness < 3 mm) in 9 cases. Histological study highlight RV adipose infiltration in all cases with a percentage between 15% and 60%, fibrotic lesions were observed in only 9 cases with an average percentage of 10.25% and signs of degeneration of myocytes were noted in 10 cases. In concordance with what has been reported in the literature, there is still no consensus regarding the criteria to be adopted to pose with certainty the diagnosis of ARVD and the presence of adipose tissue remains the criterion more suggestive.

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Original contributionDistribution of biventricular disease in arrhythmogenic cardiomyopathy: an autopsy study

Summary

Introduction

Section snippets

Materials and methods

Results

Discussion

J Am Coll Cardiol

Am J Med

Hum Pathol

Mayo Clin Proc

Hum Pathol

Am J Cardiol

Am J Cardiol

Arrhythmogenic right ventricular cardiomyopathy/dysplasia

Orphanet J Rare Dis

Arrhythmogenic right ventricular cardiomyopathy with an initial manifestation of severe left ventricular impairment and normal contraction of the right ventricle

Jpn Circ J

Arrhythmogenic right ventricular cardiomyopathy and fatty replacement of the right ventricular myocardium: are they different diseases?

Circulation

Histologic abnormalities of the left ventricle in a patient with arrhythmogenic right ventricular dysplasia

Heart Vessels

Clinical and genetic characterization of families with arrhythmogenic right ventricular dysplasia/cardiomyopathy provides novel insights into patterns of disease expression

Circulation

Original contribution
Distribution of biventricular disease in arrhythmogenic cardiomyopathy: an autopsy study