Arrhythmogenic right ventricular cardiomyopathy: use of a left ventricular assist device as a bridge to transplantation?

The principal characteristic of arrhythmogenic right ventricular cardiomyopathy (ARVC) is the tendency for ventricular arrhythmia and sudden death to occur without overt ventricular dysfunction. Current recommendations for management of patients with ARVC include insertion of an automated implantable cardioverter–defibrillator (AICD) to prevent sudden cardiac death. However, despite the use of AICD and/or anti-arrhythmic drugs some patients suffer recurrent ventricular arrhythmias unresponsive to optimum medical management. We present two cases of ARVC with refractory recurrent ventricular arrhythmias that were successfully managed by left ventricular assist device (LVAD) implantation, as a bridge to transplant (BTT). These two cases are unconventional examples of use of LVAD, given the predominant right ventricular pathology of ARVC and the arrhythmogenic nature of their presentation. The novelty of these cases should be taken in the context of increasing pressure to standardize indications for use of mechanical circulatory support.     

Fat in the right ventricle of the normal heart

AIMS: Fibrofatty replacement of the right ventricle wall, often with associated inflammation, is the hallmark of arrhythmogenic right ventricular cardiomyopathy (ARVC), a rare but established cause of sudden cardiac death in young adults. Fatty infiltration of the right ventricle alone without fibrosis may also occur but its relation to sudden death is not well established. In this study we assessed the amount of epicardial and intramyocardial fat in the right ventricle of 'normal' hearts from subjects who had died of non-cardiac causes. METHODS AND RESULTS: Hearts (n = 148) were examined from 81 males and 67 females, with an age range of 6 months to 68 years, who had died of non-cardiac causes. The extent and distribution of right ventricular epicardial and intramyocardial fat was assessed macro- and microscopically, respectively. The majority of hearts (85%) contained at least some intramyocardial fat with significantly more fat replacement noted in the right ventricles of older subjects and in females than in males. There was no significant fibrosis or inflammation in any of the 148 cases. CONCLUSION: Variable amounts of intramyocardial fat may be seen in the right ventricle of subjects dying of non-cardiac related causes. Care should be taken not to confuse this relatively common simple fatty infiltration with ARVC.     

‘It had to be done’: genetic testing decisions for arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable disease of the heart muscle, causing life‐threatening ventricular arrhythmias, sudden cardiac death and/or biventricular heart failure. Little research examines ARVC genetic test decisions, despite the gravity of the condition. This qualitative study used semi‐structured interviews to explore the testing decisions of 21 individuals across 15 families segregating a well‐studied, particularly lethal form of ARVC caused by a p.S358L TMEM43 mutation. Genetic testing decisions were rarely described as ‘decisions’ per se, but rather ‘something that had to be done’. This perception was attributed to personality type or personal suspicion of carrying the TMEM43 mutation, but most often was described in the context of testing for other family members, usually children. Participants related a strong need to rule out risk, more for children than for themselves, but lingering doubts remained about personal and children's risk for ARVC, even when gene test results were negative. Study findings highlight the interdependent nature of genetic test decisions and suggest that an individualistic conception of autonomy in genetic services may not meet the needs of affected families. Findings also suggest the need for follow‐up support of families affected by ARVC, including for those individuals testing negative for the family mutation.     

Naxos disease and Carvajal syndrome: cardiocutaneous disorders that highlight the pathogenesis and broaden the spectrum of arrhythmogenic right ventricular cardiomyopathy.

Naxos disease is a recessive association of arrhythmogenic right ventricular cardiomyopathy (ARVC) with wooly hair and palmoplantar keratoderma or similar skin disorder. The clinical and histopathological spectrum of heart disease, molecular genetics and genotype-phenotype correlation are reviewed in 22 affected families with this cardiocutaneous syndrome reported in the literature from Greece, Italy, India, Ecuador, Israel and Turkey. All patients had the hair and skin phenotype from infancy and developed ARVC by adolescence. Mutations in genes encoding the cell adhesion proteins piakoglobin and desmoplakin that truncate the proteins at the C-terminal domains were identified to underlie this syndrome. A particular mutation in Ecuadorian families that truncates the intermediate filament-binding site of desmoplakin results in a variant of Naxos disease with predominantly left ventricular involvement, early morbidity and clinical overlapping with dilated cardiomyopathy (Carvajal syndrome). A lethal autosomal recessive cardiocutaneous syndrome of Poll Hereford calves has been reported in Australia sharing similarities with the human syndrome reviewed here with respect to hair and cardiac phenotype. The cardiomyopathy in Naxos cardiocutaneous syndromes presents with increased arrhythmogenicity and variable left ventricular involovement and is characterized histologically by myocardial loss with fibrofatty or fibrous replacement at subepicardial and mediomural layers. The clinical heterogeneity and tissue characteristics in this cell-adhesion cardiomyopathy might be mutation specific and leads to consideration that the spectrum of ARVC should be broadened.     

Discordance between pre and post cardiac transplant diagnosis: implications for pre- and postoperative decision making.

A correct clinical diagnosis in end-stage patients undergoing cardiac transplantation may have important prognostic and therapeutic implications. A retrospective clinico-pathologic study was carried out in 257 patients who had undergone cardiac transplantation at the University of Padua. A discrepancy between clinical and pathological diagnosis was found in 20 cases (8%). Among 126 patients with the clinical diagnosis of dilated cardiomyopathy, seven were found eventually to have ischemic heart disease (IHD), five myocarditis, one arrhythmogenic right ventricular cardiomyopathy (ARVC), and one non-compacted myocardium. Among the 87 patients with clinical diagnosis of IHD, three turned out to be dilated cardiomyopathy and one granulomatous myocarditis. Among the 10 patients with the clinical diagnosis of hypertrophic-restrictive cardiomyopathy, one had ARVC and one had cardiac fibroma. Altogether, only 24.5% underwent endomyocardial biopsy (EMB) and 75% coronary angiography before transplantation. Missed diagnosis of myocarditis occurred in patients in whom EMB was not carried out. EMB and coronary angiography might be indicated routinely in patients with apparent dilated cardiomyopathy, before proceeding to cardiectomy.     

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.     

Clinical usefulness of immunohistochemistry for plakoglobin,N-cadherin,and connexin-43 in the diagnosis of arrhythmogenic right ventricular cardiomyopathy

Diagnosing arrhythmogenic right ventricular cardiomyopathy (ARVC) is often challenging because no single diagnostic tool is available to detect the disease. We evaluated whether analysis of plakoglobin, N-cadherin, and connexin-43 immunoreactivity can be used as a significant test in diagnosis of ARVC. We selected subjects with suspicion of ARVC (n=22) in patients who underwent endomyocardial biopsy (EMB) in Kyungpook National University Hospital (n=1326). The patients (n=22) were classified into definite ARVC patients (n=17) and borderline ARVC (n=5). We selected control subjects (n=20) who were autopsied and died of non-cardiac disease. Hematoxylin-eosin, Masson’s trichrome, and immunohistochemical stains for plakoglobin, N-cadherin, and connexin-43 were used for all specimens. Reduced immunoreactivity of plakoglobin was observed in 13 (76%) of the 17 patients with a definite ARVC and in 4 (80%) of the 5 patients with a borderline ARVC. All subjects displayed no significant reduction of the immunoreactivity for connexin-43 as well as for N-cadherin. Our investigation revealed that the immunohistochemical analysis for plakoglobin had an accuracy of 81%, 76% sensitivity, and 84% specificity in diagnosis of ARVC. Results of our study showed that the immunohistochemical analysis of plakoglobin had a relatively high sensitivity and specificity in ARVC, but immunohistochemistry for plakoglobin alone could not be relied upon as a diagnostic test for ARVC. We confirmed that N-cadherin and connexin-43 had no diagnostic value in ARVC.     

Autosomal‐dominant biventricular arrhythmogenic cardiomyopathy in a large family with a novel in‐frame DSP nonsense mutation

A novel autosomal‐dominant in‐frame deletion resulting in a nonsense mutation in the desmoplakin (DSP) gene was identified in association with biventricular arrhythmogenic cardiomyopathy across three generations of a large Caucasian family. Mutations that disrupt the function and structure of desmosomal proteins, including desmoplakin, have been extensively linked to familial arrhythmogenic right ventricular cardiomyopathy (ARVC). Analysis of data from 51 individuals demonstrated the previously undescribed variant p.Cys81Stop (c.243_251delCTTGATGCG) in DSP segregates with a pathogenic phenotype exhibiting variable penetrance and expressivity. The mutation's pathogenicity was first established due to two sudden cardiac deaths (SCDs), each with a biventricular cardiomyopathy identified on autopsy. Of the individuals who underwent genetic screening, 27 of 51 were heterozygous for the DSP mutation (29 total with two obligate carriers). Six of these were subsequently diagnosed with arrhythmogenic cardiomyopathy. An additional nine family members have a conduction disorder and/or myocardial structural changes characteristic of an evolving condition. Previous reports from both human patients and mouse studies proposed DSP mutations with a premature stop codon impart mild to no clinical symptoms. Loss of expression from the abnormal allele via the nonsense‐mediated mRNA decay pathway has been implicated to explain these findings. We identified an autosomal‐dominant DSP nonsense mutation in a large family that led to SCD and phenotypic expression of arrhythmogenic cardiomyopathy involving both ventricles. This evidence demonstrates the pathogenic significance of this type of desmosomal mutation and provides insight into potential clinical manifestations.     

X-linked dilated cardiomyopathy

To study the inheritance of idiopathic dilated cardiomyopathy, we investigated a large kindred in which 11 young male members had definite or possible evidence of the disorder. The five affected males for whom we had complete clinical data survived for 5 to 12 months after the onset of symptoms, which occurred early in life (ages 15 to 21 years). In six other males, clinical data were incomplete but suggested possible cardiomyopathy. Three mothers of affected males were given a diagnosis of definite, and two of possible, late-onset dilated cardiomyopathy. These women presented in their 40s with atypical chest pain, and progressive congestive heart failure developed gradually over a period of 10 or more years. X-linked inheritance of dilated cardiomyopathy is suggested in this family by the early onset in males, late onset in females, and no evidence of male-to-male transmission. The late onset of the disease in females, in contrast to the early onset in hemizygous males, is compatible with heterozygosity for the mutant allele. Since most cases of genetically lethal X-linked syndromes appear to be sporadic, for every case of "idiopathic" dilated cardiomyopathy in which X-linked inheritance can be confirmed from family information, it is possible that there are several nonfamilial cases due to a mutation at the same locus.     

Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy 7 is caused by a DES mutation

Using exome sequencing we searched for the genetic cause of autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy (ARVC) in a Swedish family. A heterozygous C-to-T transition, c.1255C>T, p.Pro419Ser in the desmin gene on chromosome 2q35, was identified. Previous studies had demonstrated linkage to chromosome 10q22.3, but no causative mutation had been found in that region. Sanger sequencing of DNA from 17 family members confirmed the heterozygous c.1255C>T desmin mutation in seven out of ten family members that had been classified as affected in the previous study. Our new results demonstrate the usefulness of next-generation sequencing, and the diagnostic difficulties with some forms of dominantly inherited muscle diseases as they can display a wide clinical and morphological variability even within a given family.     

R298Q mutation of p63 gene in autosomal dominant ectodermal dysplasia associated with arrhythmogenic right ventricular cardiomyopathy

Mutations in the p63 gene have been identified in five types of syndromic ectodermal dysplasias (EDs) with overlapping phenotypes: Ectrodactyly-Ectodermal dysplasia-Clefting (EEC syndrome, MIM 604292), Ankyloblepharon-Ectodermal dysplasia-Clefting (AEC syndrome, MIM 106260) [3], Acro-Dermato-Ungueal-Lacrimal-Tooth (ADULT syndrome, MIM 103285), Rapp-Hodgkin (RHS syndrome, MIM 129400) and Limb-Mammary (LMS syndrome, MIM 603543) [2]. In all those conditions congenital heart defects have been only occasionally found and to date, arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) has never been observed in patients affected by p63-related ectodermal dysplasia [9]. Here we describe for the first time this association.     

致心律失常右室心肌病的临床和心电图特点分析

目的 分析致心律失常右室心肌病（ARVC）患者临床特征与心电图的特点。方法 选取2016年1月~2019年1月在我院治疗的52例ATVC患者临床资料为研究对象,分析其临床及心电图特点。结果 52例患者中18例室性心律失常,占34.61%;右心力衰竭9例,占17.30%;无症状者25例,占48.07%;无症状占比高于室性心律失常和右心力衰竭,差异有统计学意义（P＜0.05）。26例伴有晕厥发作史,占50.00%;22例电图检查出现V1~V3导联Epsilon波,占42.31%,20例在右侧胸导联发现T波倒置,占38.46%;V1~V3导联QRS1值为0.1~0.22 s,平均（0.13±0.03）s,V4~V6导联QRS2值0.08~0.18 s,平均（0.11±0.02）s,QRS1平均值高于QRS2平均值,统计学意义显著（P＜0.01）;其中QRS1≥0.13s者19例,占35.53%（P＞0.05）;QRS1/ QRS2≥1.2者32例,占61.53%（P＞0.05）;20例V1~V3导联出现T波倒置,占38.46%,与未出T波倒置者比较,差异有统计学意义（P＜0.05）,其中8例肢体导联低电压,6例完全性的右束支传导阻滞,2例室内阻滞,2例类右束支阻滞,2例左后分支阻滞,2例左前分支阻滞,2例aVF导联出现T波电交替现象。结论 ARVC患者主要表现为无症状和心律失常型,其心电图检测主要表现为右胸导联与Epsilon波QRS间期的延长。熟悉了解ARVC患者心电图特点,对临床诊治ARVC具有重要的意义。     

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.     

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.     

Identification of a PKP2 gene deletion in a family with arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary heart muscle disease characterized by progressive myocardial loss, with fibro-fatty replacement, and high frequency of ventricular arrhythmias that can lead to sudden cardiac death. ARVC is a genetically determined disorder, usually caused by point mutations in components of the cardiac desmosome. Conventional mutation screening of ARVC genes fails to detect causative mutations in about 50% of index cases, suggesting a further genetic heterogeneity. We performed a genome-wide linkage study and a copy number variations (CNVs) analysis, using high−density SNP arrays, in an ARVC family showing no mutations in any of the desmosomal genes. The CNVs analysis identified a heterozygous deletion of about 122 kb on chromosome 12p11.21, including the entire plakophilin-2 gene and shared by all affected family members. It was not listed on any of available public CNVs databases and was confirmed by quantitative real-time PCR. This is the first SNP array-based genome-wide study leading to the identification of a CNV segregating with the disease phenotype in an ARVC family. This result underscores the importance of performing additional analysis for possible genomic deletions/duplications in ARVC patients without point mutations in known disease genes.     

A mutation in the Z‐line Cypher/ZASP protein is associated with arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an important cause of malignant arrhythmia and sudden death particularly in young people. Although it is considered a desmosomal disease, mutations in non‐desmosomal genes have also been identified. We report on a family where a mutation in LDB3 is associated with this condition. The index case and first and second degree relatives underwent a complete clinical evaluation: physical examination, electrocardiography (ECG), signal‐averaged ECG, 2D echocardiogram, cardiac magnetic resonance and 24‐h monitoring. After ruling out mutations in the five desmosomal genes, genetic testing by means of Next Generation Sequencing was carried out on the proband. A heterozygous missense mutation in LDB3 c.1051A>G was identified. This result was confirmed by subsequent Sanger DNA sequencing. Another six carriers were identified amongst her relatives. Three subjects fulfilled the criteria for a definitive diagnosis of ARVC and one reached a borderline diagnosis. In conclusion, this is the first family with ARVC where a mutation in LDB3 is associated with ARVC. Next generation sequencing arises as a particular useful tool to point to new causative genes in ARVC.     

Arrhythmogenic right ventricular cardiomyopathy type 6 (ARVC6): support for the locus assignment, narrowing of the critical region and mutation screening of three candidate genes

Background  

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable disorder characterized by progressive degeneration of right ventricular myocardium, arrhythmias and an increased risk of sudden death at a young age. By linkage analysis, ARVC type 6 was previously mapped to a 10.6 cM region on chromosome 10p12-p14 in a large North American kindred. To date, the genetic defect that causes ARVC6 has not been identified.     

Perceived economic burden associated with an inherited cardiac condition: a qualitative inquiry with families affected by arrhythmogenic right ventricular cardiomyopathy

PurposeSignificant gaps remain in the literature on the economic burden of genetic illness. We explored perceived economic burden associated with one inherited cardiac condition, arrhythmogenic right ventricular cardiomyopathy (ARVC).MethodsSemistructured interviews were held with individuals from families affected by ARVC. Data on the perceived financial and economic impacts of ARVC were used to identify emerging categories and themes using the method of constant comparison.ResultsData analysis revealed four themes that described participants’ perceptions of the economic impact ARVC had on them and their families: (i) economic impact during childhood, (ii) impact on current and future employment, (iii) impact on current and future financial well-being, and (iv) no perceived economic impact.ConclusionsThis study is the first to explore the economic burden of ARVC from the perspective of affected families. It revealed a number of perceived burdens, from employment and career choices to worry about insurance for self and children, decreased household spending, and the need for childhood employment. Findings highlight potential areas of discussion for genetic counseling sessions, as well as areas for future research.     

Restrictive loss of plakoglobin in cardiomyocytes leads to arrhythmogenic cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inheritable myocardial disorder associated with fibrofatty replacement of myocardium and ventricular arrhythmia. A subset of ARVC is categorized as Naxos disease, which is characterized by ARVC and a cutaneous disorder. A homozygous loss-of-function mutation of the Plakoglobin (Jup) gene, which encodes a major component of the desmosome and the adherens junction, had been identified in Naxos patients, although the underlying mechanism remained elusive. We generated Jup mutant mice by ablating Jup in cardiomyocytes. Jup mutant mice largely recapitulated the clinical manifestation of human ARVC: ventricular dilation and aneurysm, cardiac fibrosis, cardiac dysfunction and spontaneous ventricular arrhythmias. Ultra-structural analyses revealed that desmosomes were absent in Jup mutant myocardia, whereas adherens junctions and gap junctions were preserved. We found that ventricular arrhythmias were associated with progressive cardiomyopathy and fibrosis in Jup mutant hearts. Massive cell death contributed to the cardiomyocyte dropout in Jup mutant hearts. Despite the increase of β-catenin at adherens junctions in Jup mutant cardiomyoicytes, the Wnt/β-catenin-mediated signaling was not altered. Transforming growth factor-beta-mediated signaling was found significantly elevated in Jup mutant cardiomyocytes at the early stage of cardiomyopathy, suggesting an important pathogenic pathway for Jup-related ARVC. These findings have provided further insights for the pathogenesis of ARVC and potential therapeutic interventions.     

Unclassifiable arrhythmic cardiomyopathy associated with Emery–Dreifuss caused by a mutation in FHL1

Emery–Dreifuss muscular dystrophy (EDMD) is a heterogeneous genetic disorder characterized by peripheral muscular weakness often associated with dilated cardiomyopathy. We characterize clinically a large family with a mutation in FHL1 gene (p.Cys255Ser). Penetrance was 44%, 100% for males and 18% for females. The heart was the main organ involved. Affected adult males had mild hypertrophy, systolic dysfunction and restriction with non‐dilated ventricles. Carriers had significant QTc prolongation. The proband presented with resuscitated cardiac arrest. There were two transplants. Pathological study of explanted heart showed fibrofatty replacement and scarring consistent with arrhythmogenic cardiomyopathy and prominent left ventricular trabeculations. Myopathic involvement was evident in all males. Females had no significant neuromuscular disease. Mutations in FHL1 cause unclassifiable cardiomyopathy with coexisting EDMD. Prognosis is poor and systolic impairment and arrhythmias are frequent. Thrombopenia and raised creatine phosphokinase should raise suspicion of an FHL‐1 disorder in X‐linked cardiomyopathy.