Srijita Sen-Chowdhry

Clinical and Genetic Characterization of Families With Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Provides Novel Insights Into Patterns of Disease Expression

Background— According to clinical-pathological correlation studies, the natural history of arrhythmogenic right ventricular dysplasia/cardiomyopathy is purported to progress from localized to global right ventricular dysfunction, followed by left ventricular (LV) involvement and biventricular pump failure. The inevitable focus on sudden death victims and transplant recipients may, however, have created a skewed perspective of a genetic disease. We hypothesized that unbiased representation of the spectrum of disease expression in arrhythmogenic right ventricular dysplasia/cardiomyopathy would require in vivo assessment of families in a genetically heterogeneous population. Methods and Results— A cohort of 200 probands and relatives satisfying task force or modified diagnostic criteria for arrhythmogenic right ventricular dysplasia/cardiomyopathy underwent comprehensive clinical evaluation. Desmosomal mutations were identified in 39 individuals from 20 different families. Indices of structural severity correlated with advancing age and were increased in long-term endurance athletes. Fulfillment of modified criteria indicated phenotypically mild disease, whereas asymptomatic status did not. In >80%, ECG, rhythm monitoring, and/or gadolinium-enhanced cardiovascular magnetic resonance were suggestive of LV involvement, the extent of which often was marked among individuals with chain-termination mutations and/or desmoplakin disease. Three patterns of disease expression were identified: (1) classic, with isolated right ventricular disease or LV involvement in association with significant right ventricular impairment; (2) left dominant, with early and prominent LV manifestations and relatively mild right-sided disease; and (3) biventricular, characterized by parallel involvement of both ventricles. Conclusions— LV involvement in arrhythmogenic right ventricular dysplasia/cardiomyopathy may precede the onset of significant right ventricular dysfunction. Recognition of disease variants with early and/or predominant LV involvement supports adoption of the broader term arrhythmogenic cardiomyopathy.

Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Associated with Mutations in the Desmosomal Gene Desmocollin-2

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited myocardial disorder associated with arrhythmias, heart failure, and sudden death. To date, mutations in four genes encoding major desmosomal proteins (plakoglobin, desmoplakin, plakophilin-2, and desmoglein-2) have been implicated in the pathogenesis of ARVD/C. We screened 77 probands with ARVD/C for mutations in desmocollin-2 (DSC2), a gene coding for a desmosomal cadherin. Two heterozygous mutations--a deletion and an insertion--were identified in four probands. Both mutations result in frameshifts and premature truncation of the desmocollin-2 protein. For the first time, we have identified mutations in desmocollin-2 in patients with ARVD/C, a finding that is consistent with the hypothesis that ARVD/C is a disease of the desmosome.

Novel Mutation in Desmoplakin Causes Arrhythmogenic Left Ventricular Cardiomyopathy

Background—Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial heart muscle disease characterized by structural, electrical, and pathological abnormalities of the right ventricle (RV). Several disease loci have been identified. Mutations in desmoplakin have recently been isolated in both autosomal-dominant and autosomal-recessive forms of ARVC. Primary left ventricular (LV) variants of the disease are increasingly recognized. We report on a large family with autosomal-dominant left-sided ARVC. Methods and Results—The proband presented with sudden cardiac death and fibrofatty replacement of the LV myocardium. The family was evaluated. Diagnosis was based on modified diagnostic criteria for ARVC. Seven had inferior and/or lateral T-wave inversion on ECG, LV dilatation, and ventricular arrhythmia, predominantly extrasystoles of LV origin. Three had sustained ventricular tachycardia; 7 had late potentials on signal-averaged ECG. Cardiovascular magnetic resonance imaging in 4 patients revealed wall-motion abnormalities of the RV and patchy, late gadolinium enhancement in the LV, suggestive of fibrosis. Linkage confirmed cosegregation to the desmoplakin intragenic marker D6S2975. A heterozygous, single adenine insertion (2034insA) in the desmoplakin gene was identified in affected individuals only. A frameshift introducing a premature stop codon with truncation of the rod and carboxy terminus of desmoplakin was confirmed by Western blot analysis. Conclusions—We have described a new dominant mutation in desmoplakin that causes left-sided ARVC, with arrhythmias of LV origin, lateral T-wave inversion, and late gadolinium enhancement in the LV on magnetic resonance images. Truncation of the carboxy terminus of desmoplakin and consequent disruption of intermediate filament binding may account for the predominant LV phenotype.

Clinical Expression of Plakophilin-2 Mutations in Familial Arrhythmogenic Right Ventricular Cardiomyopathy

Background— Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disorder characterized by loss of cardiomyocytes and their replacement by adipose and fibrous tissue. It is considered a disease of cell adhesion because mutations in desmosomal genes, desmoplakin and plakoglobin, have been implicated in the pathogenesis of ARVC. In a recent report, mutations in plakophilin-2, a gene highly expressed in cardiac desmosomes, have been shown to cause ARVC. Methods and Results— We investigated 100 white patients with ARVC for mutations in plakophilin-2. Nine different mutations were identified by direct sequencing in 11 cases. Five of these mutations are novel (A733fsX740, L586fsX658, V570fsX576, R413X, and P533fsX561) and predicted to cause a premature truncation of the plakophilin-2 protein. Family studies showed incomplete disease expression in mutation carriers and identified a number of individuals who would be misdiagnosed with the existing International Task Force and modified diagnostic criteria for ARVC. Conclusions— In this study, we provide new evidence that mutations in the desmosomal plakophilin-2 gene can cause ARVC. A systematic clinical evaluation of mutation carriers within families demonstrated variable phenotypic expression, even among individuals with the same mutation, and highlighted the need for a more accurate set of diagnostic criteria for ARVC.

Genetics of Right Ventricular Cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease that may result in arrhythmia, heart failure, and sudden death. The hallmark pathological findings are progressive myocyte loss and fibrofatty replacement, with a predilection for the right ventricle. However, variants of ARVC that preferentially affect the left ventricle are increasingly recognized. ARVC is distinguished from dilated cardiomyopathy by a propensity toward ventricular arrhythmia and sudden death in the absence of significant ventricular dysfunction.

Familial Evaluation in Arrhythmogenic Right Ventricular Cardiomyopathy Impact of Genetics and Revised Task Force Criteria

Background— With recognition of disease-causing genes in arrhythmogenic right ventricular cardiomyopathy, mutation analysis is being applied. Methods and Results— The role of genotyping in familial assessment for arrhythmogenic right ventricular cardiomyopathy was investigated, including the prevalence of mutations in known causal genes, the penetrance and expressivity in genotyped families, and the utility of the 2010 Task Force criteria in clinical diagnosis. Clinical and molecular genetic evaluation was performed in 210 first-degree and 45 second-degree relatives from 100 families. In 51 families, the proband was deceased. The living probands had a high prevalence of ECG abnormalities (89%) and ventricular arrhythmia (78%) and evidence of more severe disease than relatives. Definite or probable causal mutations were found in 58% of families and 73% of living probands, of whom 28% had an additional desmosomal variant (ie, mutation or polymorphism). Ninety-three relatives had a causal mutation; 33% fulfilled the 2010 criteria, whereas only 19% satisfied the 1994 version ( P =0.03). An additional desmosomal gene variant was found in 10% and was associated with a 5-fold increased risk of developing penetrant disease (odds ratio, 4.7; 95% confidence interval, 1.1 to 20.4; P =0.04). Conclusions— Arrhythmogenic right ventricular cardiomyopathy is a genetically complex disease characterized by marked intrafamilial phenotype diversity. Penetrance is definition dependent and is greater with the 2010 criteria compared with the 1994 criteria. Relatives harboring >1 genetic variant had significantly increased risk of developing clinical disease, potentially an important determinant of the phenotypic heterogeneity seen within families with arrhythmogenic right ventricular cardiomyopathy. # Clinical Perspective {#article-title-19}Background— With recognition of disease-causing genes in arrhythmogenic right ventricular cardiomyopathy, mutation analysis is being applied. Methods and Results— The role of genotyping in familial assessment for arrhythmogenic right ventricular cardiomyopathy was investigated, including the prevalence of mutations in known causal genes, the penetrance and expressivity in genotyped families, and the utility of the 2010 Task Force criteria in clinical diagnosis. Clinical and molecular genetic evaluation was performed in 210 first-degree and 45 second-degree relatives from 100 families. In 51 families, the proband was deceased. The living probands had a high prevalence of ECG abnormalities (89%) and ventricular arrhythmia (78%) and evidence of more severe disease than relatives. Definite or probable causal mutations were found in 58% of families and 73% of living probands, of whom 28% had an additional desmosomal variant (ie, mutation or polymorphism). Ninety-three relatives had a causal mutation; 33% fulfilled the 2010 criteria, whereas only 19% satisfied the 1994 version (P=0.03). An additional desmosomal gene variant was found in 10% and was associated with a 5-fold increased risk of developing penetrant disease (odds ratio, 4.7; 95% confidence interval, 1.1 to 20.4; P=0.04). Conclusions— Arrhythmogenic right ventricular cardiomyopathy is a genetically complex disease characterized by marked intrafamilial phenotype diversity. Penetrance is definition dependent and is greater with the 2010 criteria compared with the 1994 criteria. Relatives harboring >1 genetic variant had significantly increased risk of developing clinical disease, potentially an important determinant of the phenotypic heterogeneity seen within families with arrhythmogenic right ventricular cardiomyopathy.

Sudden Cardiac Death in the Young: A Strategy for Prevention by Targeted Evaluation

The annual incidence of sudden cardiac death (SCD) in the general population is estimated as 1 in a 1,000. Since survival rates from out-of-hospital cardiac arrests are poor, primary prevention is key to reducing the burden of SCD in the community. Prominent causes of SCD include ischaemic heart disease, anomalous coronary arteries, and the primary myocardial diseases: hypertrophic cardiomyopathy, dilated cardiomyopathy, and ar rhythmogenic right ventricular cardiomyopathy (ARVC). In 4% of sudden deaths in the 16–64 age group, post-mortem examination fails to identify a cause, yielding a default diagnosis of sudden arrhythmic death syndrome (SADS). The inherited arrhythmia syndromes (long QT, short QT, and Brugada syndromes, and familial catecholaminergic polymorphic ventricular tachycardia) may be implicated in SADS, owing to their propensity for producing ventricular tachyarrhythmia in the structurally normal heart. Monogenic disorders therefore predominate as causes of SCD in the young. The advent of effective therapies for these diseases, particularly implantable cardioverter defibrillators, has prompted calls for universal screening to enable timely diagnosis of occult cardiac disease. Since prospective cardiac assessment of the general population is not feasible, the solution may be to target high-risk subgroups, namely, patients with cardiac symptoms, relatives of SCD victims, and competitive athletes. The recommended preliminary work-up includes a 12-lead ECG, signal-averaged ECG, transthoracic echocardiogram, exercise test, and ambulatory ECG monitoring. Cardiovascular magnetic resonance is a useful adjunct in patients with suspected ARVC or anomalous coronary arteries. Provocative challenge with a sodium challenge blocker may be of value in unmasking the Brugada syndrome. Identification of disease-causing mutations in affected individuals facilitates cascade screening of families.

Left ventricular noncompaction and cardiomyopathy: cause, contributor, or epiphenomenon?

Purpose of review To discuss unresolved issues pertaining to aetiology and diagnosis of isolated left ventricular noncompaction. Recent findings Left ventricular noncompaction may be sporadic or familial and is linked to mutations in mitochondrial, cytoskeletal, Z-line, and sarcomeric proteins. Severe childhood manifestations include fetal hydrops or sudden infant death syndrome. Adults with severe phenotypes have a similarly guarded prognosis due to heart failure, arrhythmia and thromboembolism. Conversely, healthy individuals may fulfil current imaging criteria for diagnosis. Left ventricular noncompaction is also observed in families with hypertrophic or dilated cardiomyopathy, casting doubt on its acceptance as a distinct disease entity. Summary The extent of myocardial compaction may be a continuous trait within the population. Sensitive imaging techniques may detect subtle variations in morphology that fall within the normal range, underscoring the need for more restrictive diagnostic criteria, as in mitral valve prolapse. Conversely, rather than being a root cause of myocardial dysfunction, left ventricular noncompaction may represent a secondary consequence of a genetic alteration, well-tolerated when the heart is otherwise normal. In the presence of a pathogenic mutation, disruption to myocyte function at a molecular level may be the primary disease determinant, with noncompaction arising as a maladaptive remodelling response that compounds the disease process through subendocardial ischaemia and fibrosis.

Sudden Death From Genetic and Acquired Cardiomyopathies

From the Aphorisms of Hippocrates to the sports fields of the twenty-first century, by both the lay public and the medical community, the cardiomyopathies have been recognized as causes of sudden cardiac death (SCD). Prevention of SCD in the cardiomyopathies is a 2-fold challenge. First, and central to clinical practice, is the need for reliable prognostication in individuals with established disease, and effective therapies to prevent or terminate events in those at risk. The second is the need for public health measures to preempt individuals with undiagnosed, asymptomatic disease from presenting with SCD: a not uncommon phenomenon in the cardiomyopathies. This review seeks to address the demographics and burden of SCD due to cardiomyopathy, its underlying mechanisms and determinants, and current approaches to risk prediction and management. Both genetic and acquired cardiomyopathies are discussed, with the former encompassing hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC), all of which demonstrate Mendelian inheritance. By expert consensus, the umbrella term “cardiomyopathy” is not applicable to myocardial dysfunction secondary to ischemic heart disease, valvular dysfunction, or congenital anomalies. Heart muscle disorders resulting from systemic, metabolic, or other identifiable causes are included if arrhythmia and SCD are prominent components of the phenotype.1 ### Burden of SCD From Cardiomyopathy The cardiomyopathies differ in the relative contribution of SCD to overall mortality, with ARVC ranking the highest, followed by HCM and then DCM, in which heart failure is the leading cause of death (Figure).2–7 In evaluating the burden of SCD related to cardiomyopathy, 3 distinct questions need to be addressed. First, what is the annual incidence of SCD among individuals with an established diagnosis of cardiomyopathy? Second, to what extent do cardiomyopathies account for SCD from undiagnosed cardiovascular disease—unexpected SCD—in the general population? A third and more involved issue is whether current medical …

The utility of magnetic resonance imaging in the evaluation of arrhythmogenic right ventricular cardiomyopathy.

Purpose of review Perceptions of the utility of cardiovascular magnetic resonance in the evaluation of arrhythmogenic right ventricular cardiomyopathy have changed considerably in the past decade. This review offers an up-to-date perspective on the diagnostic role of cardiovascular magnetic resonance in the genetics era. Recent findings Originally hailed as a putative gold standard in arrhythmogenic cardiomyopathy, cardiovascular magnetic resonance has received a more guarded reception lately owing to interobserver variability and lack of standardized protocols. Recent studies have nonetheless affirmed its value as an integral component of the diagnostic work-up. Quantitative volume analysis is relatively robust, but visualization of myocardial fat by spin-echo imaging is less reliable. Interpretation of wall motion abnormalities appears reproducible among expert readers. Emerging data suggest a key role for late gadolinium enhancement in detection of left ventricular involvement. Summary Cardiovascular magnetic resonance in arrhythmogenic cardiomyopathy is facilitated by appropriate patient selection and preparation, experienced readers and operators, and a dedicated, comprehensive protocol. Indications for magnetic resonance assessment include proven arrhythmogenic cardiomyopathy in the family, unexplained ventricular arrhythmia, inverted T-waves in the right precordial or lateral leads, and/or family history of sudden cardiac death. Arrhythmia suppression is essential for optimal electrocardiographic triggering and image acquisition.