Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease characterized by sudden death in young people and featured by fibro-adipose myocardium replacement, malignant arrhythmias, and heart failure. To date, no etiological therapies are available. Mutations in desmosomal genes cause abnormal mechanical coupling, trigger pro-apoptotic signaling pathways, and induce fibro-adipose replacement. Here, we discuss the hypothesis that the ACM causative mechanism involves a defect in the expression and/or activity of the cardiac Ca handling machinery, focusing on the available data supporting this hypothesis. The Ca toolkit is heavily remodeled in cardiomyocytes derived from a mouse model of ACM defective of the desmosomal protein plakophilin-2. Furthermore, ACM-related mutations were found in genes encoding for proteins involved in excitation‒contraction coupling, e.g., type 2 ryanodine receptor and phospholamban. As a consequence, the sarcoplasmic reticulum becomes more eager to release Ca, thereby inducing delayed afterdepolarizations and impairing cardiac contractility. These data are supported by preliminary observations from patient induced pluripotent stem-cell-derived cardiomyocytes. Assessing the involvement of Ca signaling in the pathogenesis of ACM could be beneficial in the treatment of this life-threatening disease.

BACKGROUND:Previous studies suggested that genetic status affects the clinical course of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) patients. The aim of this study was to compare the outcome of desmoglein-2 (DSG2) mutation carriers to those who carry the plakophilin-2 (PKP2) mutation, the most common ARVC/D-associated gene. METHODS AND RESULTS:Consecutive ARVC/D patients carrying a pathogenic mutation in PKP2 or DSG2 were selected from a national ARVC/D registry. The cumulative freedom from sustained ventricular arrhythmia and cardiac transplantation/death from heart failure (HF) during follow-up was assessed, compared between PKP2 and DSG2, and predictors for ventricular arrhythmia and HF events determined. Overall, 118 patients from 78 families were included: 27 (23%) carried a DSG2 mutation and 91 (77%) a PKP2 mutation. There were no significant differences between DSG2 and PKP2 mutation carriers concerning gender, proband status, age at diagnosis, T-wave inversion, or right ventricular dysfunction at baseline. DSG2 patients displayed more frequent epsilon wave (37% vs. 17%, P = 0.048) and left ventricular dysfunction at diagnosis (54% vs. 10%, P < 0.001). During a median follow-up of 5.6 years (2.5-16), DSG2 and PKP2 mutation carriers displayed a similar risk of sustained ventricular arrhythmia (log-rank P = 0.20), but DSG2 mutation carriers were at higher risk of transplantation/HF-related death (log-rank P < 0.001). The presence of a DSG2 mutation vs. PKP2 mutation was a predictor of transplantation/HF-related death in univariate Cox analysis (P = 0.0005). CONCLUSIONS:In this multicentre cohort, DSG2 mutation carriers were found to be at high risk of end-stage HF compared to PKP2 mutation carriers, supporting careful haemodynamic monitoring of these patients. The benefit of early HF treatment needs to be assessed in DSG2 carriers.

Aims:The Cardiomyopathy Registry of the EURObservational Research Programme is a prospective, observational, and multinational registry of consecutive patients with four cardiomyopathy subtypes: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), and restrictive cardiomyopathy (RCM). We report the baseline characteristics and management of adults enrolled in the registry. Methods and results:A total of 3208 patients were enrolled by 69 centres in 18 countries [HCM (n = 1739); DCM (n = 1260); ARVC (n = 143); and RCM (n = 66)]. Differences between cardiomyopathy subtypes (P < 0.001) were observed for age at diagnosis, history of familial disease, history of sustained ventricular arrhythmia, use of magnetic resonance imaging or genetic testing, and implantation of defibrillators. When compared with probands, relatives had a lower age at diagnosis (P < 0.001), but a similar rate of symptoms and defibrillators. When compared with the Long-Term phase, patients of the Pilot phase (enrolled in more expert centres) had a more frequent rate of familial disease (P < 0.001), were more frequently diagnosed with a rare underlying disease (P < 0.001), and more frequently implanted with a defibrillator (P = 0.023). Comparing four geographical areas, patients from Southern Europe had a familial disease more frequently (P < 0.001), were more frequently diagnosed in the context of a family screening (P < 0.001), and more frequently diagnosed with a rare underlying disease (P < 0.001). Conclusion:By providing contemporary observational data on characteristics and management of patients with cardiomyopathies, the registry provides a platform for the evaluation of guideline implementation. Potential gaps with existing recommendations are discussed as well as some suggestions for improvement of health care provision in Europe.

AIMS:Arrhythmogenic right ventricular (RV) cardiomyopathy (ARVC) is associated with ventricular arrhythmias, even without RV structural disease. We aimed to characterize the RV substrate using electroanatomical mapping and to define outcomes following ventricular tachycardia (VT) ablation in patients with and without RV structural abnormalities. METHODS AND RESULTS:Twenty-nine patients with definite or suspected ARVC undergoing VT ablation were classified as 'electrical' and 'structural' cardiomyopathy based on the absence or presence of major structural criteria. Right ventricular (RV) endocardial and epicardial mapping with assessment of bipolar and unipolar voltages, distribution of late potentials (LPs), and inducible VT morphologies were performed. The endpoints for VT ablation were VT non-inducibility and LP abolition. Fourteen patients were categorized as electrical RV cardiomyopathy and 15 were categorized as structural RV cardiomyopathy. In patients with electrical cardiomyopathy, scar was limited to the epicardial surface (epicardium 13 cm2vs. endocardium 1 cm2, P < 0.05), primarily in the outflow tract, whereas patients with structural disease had greater involvement of the endocardium. During a mean follow-up of 22 ± 11 months, the VT recurrence rate was 27%, with LP abolition being a predictor of VT-free survival (HR 0.075 (0.008-0.661), P = 0.020). There was a trend towards higher recurrence rates in structural RV cardiomyopathy (40%) compared with the electrical cardiomyopathy (15%, P = 0.17). CONCLUSION:The development of RV structural disease in patients with ARVC is associated with extensive epicardial and endocardial scar. Conversely those patients without RV structural disease have identifiable epicardial scar limited to the RV outflow tract. Ventricular tachycardia (VT) ablation in both groups targeting LP abolition is effective in preventing VT recurrence.

BACKGROUND:Arrhythmogenic cardiomyopathy/arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease characterized by fibrofatty replacement of the myocardium, resulting in heart failure and sudden cardiac death. The most aggressive arrhythmogenic cardiomyopathy/ARVC subtype is ARVC type 5 (ARVC5), caused by a p.S358L mutation in TMEM43 (transmembrane protein 43). The function and localization of TMEM43 are unknown, as is the mechanism by which the p.S358L mutation causes the disease. Here, we report the characterization of the first transgenic mouse model of ARVC5. METHODS:We generated transgenic mice overexpressing TMEM43 in either its wild-type or p.S358L mutant (TMEM43-S358L) form in postnatal cardiomyocytes under the control of the α-myosin heavy chain promoter. RESULTS:We found that mice expressing TMEM43-S358L recapitulate the human disease and die at a young age. Mutant TMEM43 causes cardiomyocyte death and severe fibrofatty replacement. We also demonstrate that TMEM43 localizes at the nuclear membrane and interacts with emerin and β-actin. TMEM43-S358L shows partial delocalization to the cytoplasm, reduced interaction with emerin and β-actin, and activation of glycogen synthase kinase-3β (GSK3β). Furthermore, we show that targeting cardiac fibrosis has no beneficial effect, whereas overexpression of the calcineurin splice variant calcineurin Aβ1 results in GSK3β inhibition and improved cardiac function and survival. Similarly, treatment of TMEM43 mutant mice with a GSK3β inhibitor improves cardiac function. Finally, human induced pluripotent stem cells bearing the p.S358L mutation also showed contractile dysfunction that was partially restored after GSK3β inhibition. CONCLUSIONS:Our data provide evidence that TMEM43-S358L leads to sustained cardiomyocyte death and fibrofatty replacement. Overexpression of calcineurin Aβ1 in TMEM43 mutant mice or chemical GSK3β inhibition improves cardiac function and increases mice life span. Our results pave the way toward new therapeutic approaches for ARVC5.

AIMS:Arrhythmogenic cardiomyopathy (AC) shows large heterogeneity in its clinical, genetic, and pathological presentation. This study aims to provide a comprehensive atlas of end-stage AC and illustrate the relationships among clinical characteristics, genotype, and pathological profiles of patients with this disease. METHODS AND RESULTS:We collected 60 explanted AC hearts and performed standard pathology examinations. The clinical characteristics of patients, their genotype and cardiac magnetic resonance imaging findings were assessed along with pathological characteristics. Masson staining of six representative sections of each heart were performed. Digital pathology combined with image segmentation was developed to calculate distribution of myocardium, fibrosis, and adipose tissue. An unsupervised clustering based on fibrofatty distribution containing four subtypes was constructed. Patients in Cluster 1 mainly carried desmosomal mutations (except for desmoplakin) and were subjected to transplantation at early age; this group was consistent with classical 'desmosomal cardiomyopathy'. Cluster 2 mostly had non-desmosomal mutations and showed regional fibrofatty replacement in right ventricle. Patients in Cluster 3 showed parallel progression, and included patients with desmoplakin mutations. Cluster 4 is typical left-dominant AC, although the genetic background of these patients is not yet clear. Multivariate regression analysis revealed precordial QRS voltage as an independent indicator of the residual myocardium of right ventricle, which was validated in predicting death and transplant events in the validation cohort (n = 92). CONCLUSION:This study provides a novel classification of AC with distinct genetic backgrounds indicating different potential pathogenesis. Cluster 1 is distinct in genotype and clinicopathology and can be defined as 'desmosomal cardiomyopathy'. Precordial QRS amplitude is an independent indicator reflecting the right ventricular remodelling, which may be able to predict transplant/death events for AC patients.

BACKGROUND:Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disease that affects predominantly the right ventricle and is part of the spectrum of arrythmogenic cardiomyopathies (ACMs). ARVC is a genetic condition; however, a pathogenic gene variant is found in only half of patients. OBJECTIVE:Filamin C gene truncations () have recently been identified in dilated cardiomyopathy with ventricular arrhythmia and sudden cardiac death, a phenotype partially overlapping with ARVC and part of the ACM spectrum. We hypothesised that could be a novel gene associated with ARVC. METHODS:One hundred fifty-six patients meeting 2010 ARVC Task Force Criteria and lacking variants in known ARVC genes were evaluated for variants. Available family members were tested for cosegregation. RESULTS:We identified two unique variants in two families (c.6565 G>T, p.Glu2189Ter and c.8107delG, p.Asp2703ThrfsTer69), with phenotypes of dominant RV disease fulfilling 'definite' diagnosis of ARVC according to the 2010 Task Force Criteria. Variants in other cardiomyopathy genes were excluded in both kindreds, and segregation analysis revealed that p.Asp2703ThrfsTer69 was a de novo variant. In both families, the disease phenotype was characterised by prominent ventricular arrhythmias and sudden cardiac arrest. CONCLUSION:The identification of as a novel cause of ARVC in two unrelated families expands the spectrum of ARVC disease genes for this disorder. Our findings should prompt inclusion of genetic testing in ARVC to improve diagnostic yield and testing of at-risk relatives in ARVC.

AIMS:Plakophilin-2 (PKP2) is the most prevalent mutant gene causing arrhythmogenic cardiomyopathy (ACM) and PKP2 carriers are prone to develop ventricular arrhythmic events. The objective of this study is to use integrated analysis of whole genome sequencing (WGS) and transcriptome sequencing (RNAseq) to identify deep intronic and/or coding variants that cause aberrant splicing events in ACM patients, and hence, to test the hypothesis that recessive variants in PKP2 may lead to early-onset ACM with severe heart failure. METHODS AND RESULTS:We performed WGS and RNAseq in 27 heart transplanted ACM patients. By integrated analysis of WGS/RNAseq, we discovered that two patients with PKP2 variants were affected in recessive pattern. One patient had aberrant splicing arising from two intronic variants that led to exon skipping and exon retention. We screened three additional recessive PKP2 variants in 47 non-heart transplanted ACM patients. We compared the clinical characteristics of recessive PKP2 (n = 5) and heterozygous PKP2 carriers (n = 18), and found that recessive PKP2 variant carriers all had early-onset ACM with left ventricular dysfunction. We examined truncating PKP2 variants in explanted hearts and confirmed that truncated PKP2 was not translated. Moreover, the morphology of intercalated disc in recessive PKP2 variants carriers was similar to normal heart suggesting little intercalated disc remodelling. CONCLUSION:By using combined implementation of WGS RNAseq, we were able to demonstrate that recessive variants in PKP2 may contribute to early-onset ACM with severe heart failure. These findings may play a role in risk stratification of ACM based on genetic testing in clinical practice.

BACKGROUND:Inflammation is a prominent feature of arrhythmogenic cardiomyopathy (ACM), but whether it contributes to the disease phenotype is not known. METHODS:To define the role of inflammation in the pathogenesis of ACM, we characterized nuclear factor-κB signaling in ACM models in vitro and in vivo and in cardiac myocytes from patient induced pluripotent stem cells. RESULTS:Activation of nuclear factor-κB signaling, indicated by increased expression and nuclear accumulation of phospho-RelA/p65, occurred in both an in vitro model of ACM (expression of in neonatal rat ventricular myocytes) and a robust murine model of ACM (homozygous knock-in of mutant desmoglein-2 []) that recapitulates the cardiac manifestations seen in patients with ACM. Bay 11-7082, a small-molecule inhibitor of nuclear factor-κB signaling, prevented the development of ACM disease features in vitro (abnormal redistribution of intercalated disk proteins, myocyte apoptosis, release of inflammatory cytokines) and in vivo (myocardial necrosis and fibrosis, left ventricular contractile dysfunction, electrocardiographic abnormalities). Hearts of mice expressed markedly increased levels of inflammatory cytokines and chemotactic molecules that were attenuated by Bay 11-7082. Salutary effects of Bay 11-7082 correlated with the extent to which production of selected cytokines had been blocked. Nuclear factor-κB signaling was also activated in cardiac myocytes derived from a patient with ACM. These cells produced and secreted abundant inflammatory cytokines under basal conditions, and this was also greatly reduced by Bay 11-7082. CONCLUSIONS:Inflammatory signaling is activated in ACM and drives key features of the disease. Targeting inflammatory pathways may be an effective new mechanism-based therapy for ACM.

BACKGROUND:Mutations in desmoplakin (), the primary force transducer between cardiac desmosomes and intermediate filaments, cause an arrhythmogenic form of cardiomyopathy that has been variably associated with arrhythmogenic right ventricular cardiomyopathy. Clinical correlates of cardiomyopathy have been limited to small case series. METHODS:Clinical and genetic data were collected on 107 patients with pathogenic mutations and 81 patients with pathogenic plakophilin 2 () mutations as a comparison cohort. A composite outcome of severe ventricular arrhythmia was assessed. RESULTS: and cohorts included similar proportions of probands (41% versus 42%) and patients with truncating mutations (98% versus 100%). Left ventricular (LV) predominant cardiomyopathy was exclusively present among patients with (55% versus 0% for , <0.001), whereas right ventricular cardiomyopathy was present in only 14% of patients with versus 40% for (<0.001). Arrhythmogenic right ventricular cardiomyopathy diagnostic criteria had poor sensitivity for cardiomyopathy. LV late gadolinium enhancement was present in a primarily subepicardial distribution in 40% of patients with (23/57 with magnetic resonance images). LV late gadolinium enhancement occurred with normal LV systolic function in 35% (8/23) of patients with . Episodes of acute myocardial injury (chest pain with troponin elevation and normal coronary angiography) occurred in 15% of patients with and were strongly associated with LV late gadolinium enhancement (90%), even in cases of acute myocardial injury with normal ventricular function (4/5, 80% with late gadolinium enhancement). In 4 cases with 18F-fluorodeoxyglucose positron emission tomography scans, acute LV myocardial injury was associated with myocardial inflammation misdiagnosed initially as cardiac sarcoidosis or myocarditis. Left ventricle ejection fraction <55% was strongly associated with severe ventricular arrhythmias for cases (<0.001, sensitivity 85%, specificity 53%). Right ventricular ejection fraction <45% was associated with severe arrhythmias for cases (<0.001) but was poorly associated for cases (=0.8). Frequent premature ventricular contractions were common among patients with severe arrhythmias for both (80%) and (91%) groups (=non-significant). CONCLUSIONS: cardiomyopathy is a distinct form of arrhythmogenic cardiomyopathy characterized by episodic myocardial injury, left ventricular fibrosis that precedes systolic dysfunction, and a high incidence of ventricular arrhythmias. A genotype-specific approach for diagnosis and risk stratification should be used.

Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disorder, predisposing to malignant ventricular arrhythmias leading to sudden cardiac death, particularly in young and athletic patients. Pathological features include a progressive loss of myocardium with fibrous or fibro-fatty substitution. During the last few decades, different clinical aspects of ACM have been well investigated but still little is known about the molecular mechanisms that underlie ACM pathogenesis, leading to these phenotypes. In about 50% of ACM patients, a genetic mutation, predominantly in genes that encode for desmosomal proteins, has been identified. However, the mutation-associated mechanisms, causing the observed cardiac phenotype are not always clear. Until now, the attention has been principally focused on the study of molecular mechanisms that lead to a prominent myocardium adipose substitution, an uncommon marker for a cardiac disease, thus often recognized as hallmark of ACM. Nonetheless, based on Task Force Criteria for the diagnosis of ACM, cardiomyocytes death associated with fibrous replacement of the ventricular free wall must be considered the main tissue feature in ACM patients. For this reason, it urges to investigate ACM cardiac fibrosis. In this review, we give an overview on the cellular effectors, possible triggers, and molecular mechanisms that could be responsible for the ventricular fibrotic remodeling in ACM patients.

Background It has been suggested that endocardial and epicardial ablation of ventricular tachycardia ( VT ) improves outcome in arrhythmogenic right ventricular cardiomyopathy/dysplasia. We investigated our sequential approach for VT ablation in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia in a single center. Methods and Results We included 47 patients (44±16 years) with definite (81%) or borderline (19%) arrhythmogenic right ventricular cardiomyopathy/dysplasia between 1998 and 2016. Our ablation strategy was to target the endocardial substrate. Epicardial ablation was performed in case of acute ablation failure or lack of an endocardial substrate. Single and multiple procedural 1- and 5-year outcome data for the first occurrence of the study end points (sustained VT /ventricular fibrillation, heart transplant, and death after the index procedure, and sustained VT /ventricular fibrillation for multiple procedures) are reported. Eighty-one radiofrequency ablation procedures were performed (mean 1.7 per patient, range 1-4). Forty-five (56%) ablation procedures were performed via an endocardial, 11 (13%) via an epicardial, and 25 (31%) via a combined endo- and epicardial approach. Complete acute success was achieved in 65 (80%) procedures, and partial success in 13 (16%). After a median follow-up of 50.8 (interquartile range, [18.6; 99.2]) months after the index procedure, 17 (36%) patients were free from the primary end point. After multiple procedures, freedom from sustained VT /ventricular fibrillation was 63% (95% CI , 52-75) at 1 year, and 45% (95% CI , 34-61) at 5 years, with 36% of patients receiving only endocardial radiofrequency ablation. A trend (log rank P=0.058) towards an improved outcome using a combined endo-/epicardial approach was observed after multiple procedures. Conclusion Endocardial ablation can be effective in a considerable number of arrhythmogenic right ventricular cardiomyopathy/dysplasia patients with VT , potentially obviating the need for an epicardial approach.

Arrhythmogenic cardiomyopathy has been clinically defined since the 1980s and causes right or biventricular cardiomyopathy associated with ventricular arrhythmia. Although it is a rare cardiac disease, it is responsible for a significant proportion of sudden cardiac deaths, especially in athletes. The majority of patients with arrhythmogenic cardiomyopathy carry one or more genetic variants in desmosomal genes. In the 1990s, several knockout mouse models of genes encoding for desmosomal proteins involved in cell-cell adhesion revealed for the first time embryonic lethality due to cardiac defects. Influenced by these initial discoveries in mice, arrhythmogenic cardiomyopathy received an increasing interest in human cardiovascular genetics, leading to the discovery of mutations initially in desmosomal genes and later on in more than 25 different genes. Of note, even in the clinic, routine genetic diagnostics are important for risk prediction of patients and their relatives with arrhythmogenic cardiomyopathy. Based on improvements in genetic animal engineering, different transgenic, knock-in, or cardiac-specific knockout animal models for desmosomal and nondesmosomal proteins have been generated, leading to important discoveries in this field. Here, we present an overview about the existing animal models of arrhythmogenic cardiomyopathy with a focus on the underlying pathomechanism and its importance for understanding of this disease. Prospectively, novel mechanistic insights gained from the whole animal, organ, tissue, cellular, and molecular levels will lead to the development of efficient personalized therapies for treatment of arrhythmogenic cardiomyopathy.

It is 35 years since the first description of arrhythmogenic right ventricular cardiomyopathy (ARVC) and more than 20 years since the first reports establishing desmosomal gene mutations as a major cause of the disease. Early advances in the understanding of the clinical, pathological and genetic architecture of ARVC resulted in consensus diagnostic criteria, which proved to be sensitive but not entirely specific for the disease. In more recent years, clinical and genetic data from families and the recognition of a much broader spectrum of structural disorders affecting both ventricles and associated with a propensity to ventricular arrhythmia have raised many questions about pathogenesis, disease terminology and clinical management. In this paper, we present the conclusions of an expert round table that aimed to summarise the current state of the art in arrhythmogenic cardiomyopathies and to define future research priorities.

BACKGROUND:Arrhythmogenic cardiomyopathy (AC) is one of the leading causes for sudden cardiac death (SCD). Recent studies have identified mutations in cardiac desmosomes as key players in the pathogenesis of AC. However, the specific etiology in individual families remains largely unknown. METHODS:A 4-generation family presenting with syncope, lethal ventricular arrhythmia and SCD was recruited. Targeted next generation sequencing (NGS) was performed and validated by Sanger sequencing. Plasmids containing the mutation and wild type (WT) were constructed. Real-time PCR, western-blot and immunofluorescence were performed to detect the functional change due to the mutation. RESULTS:The proband, a 56-year-old female, presented with recurrent palpitations and syncope. An ICD was implanted due to her family history of SCD/ aborted SCD. NGS revealed a novel heterozygous frame-shift variant (c.832delG) in Desmoplakin (DSP) among 5 family members. The variant led to frame-shift and premature termination, producing a truncated protein. Cardiac magnetic resonance (CMR) of the family members carrying the same variant shown myocardium thinning and fatty infiltration in the right ventricular, positive bi-ventricular late gadolinium enhancement and severe RV dysfunction, fulfilling the diagnostic criteria of AC. HEK293T cells transfected with mutant plasmids expressed truncated DSP mRNA and protein, upregulation of nuclear junction plakoglobin (JUP) and downregulation of β-catenin, when compared with WT. CONCLUSION:We infer that the novel c.832delG variant in DSP was associated with AC in this family, likely through Wnt/β-catenin signaling pathway.

BACKGROUND:Data characterizing structural changes of arrhythmogenic right ventricular (RV) cardiomyopathy are limited. METHODS:Patients presenting with left bundle branch block ventricular tachycardia in the setting of arrhythmogenic RV cardiomyopathy with procedures separated by at least 9 months were included. RESULTS:Nineteen consecutive patients (84% males; mean age 39±15 years [range, 20-76 years]) were included. All 19 patients underwent 2 detailed sinus rhythm electroanatomic endocardial voltage maps (average 385±177 points per map; range, 93-847 points). Time interval between the initial and repeat ablation procedures was mean 50±37 months (range, 9-162). No significant progression of voltage was observed (bipolar: 38 cm [interquartile range (IQR), 25-54] versus 53 cm [IQR, 25-65], =0.09; unipolar: 116 cm [IQR, 61-209] versus 159 cm [IQR, 73-204], =0.36) for the entire study group. There was a significant increase in RV volumes (percentage increase, 28%; 206 mL [IQR, 170-253] versus 263 mL [IQR, 204-294], <0.001) for the entire study population. Larger scars at baseline but not changes over time were associated with a significant increase in RV volume (bipolar: Spearman ρ, 0.6965, =0.006; unipolar: Spearman ρ, 0.5743, =0.03). Most patients with progressive RV dilatation (8/14, 57%) had moderate (2 patients) or severe (6 patients) tricuspid regurgitation recorded at either initial or repeat ablation procedure. CONCLUSIONS:In patients with arrhythmogenic RV cardiomyopathy presenting with recurrent ventricular tachycardia, >10% increase in RV endocardial surface area of bipolar voltage consistent with scar is uncommon during the intermediate term. Most recurrent ventricular tachycardias are localized to regions of prior defined scar. Voltage indexed scar area at baseline but not changes in scar over time is associated with progressive increase in RV size and is consistent with adverse remodeling but not scar progression. Marked tricuspid regurgitation is frequently present in patients with arrhythmogenic RV cardiomyopathy who have progressive RV dilation.

Arrhythmogenic cardiomyopathy is a genetic disorder characterized by the risk of life-threatening arrhythmias, myocardial dysfunction and fibrofatty replacement of myocardial tissue. Mutations in genes that encode components of desmosomes, the adhesive junctions that connect cardiomyocytes, are the predominant cause of arrhythmogenic cardiomyopathy and can be identified in about half of patients with the condition. However, the molecular mechanisms leading to myocardial destruction, remodelling and arrhythmic predisposition remain poorly understood. Through the development of animal, induced pluripotent stem cell and other models of disease, advances in our understanding of the pathogenic mechanisms of arrhythmogenic cardiomyopathy over the past decade have brought several signalling pathways into focus. These pathways include canonical and non-canonical WNT signalling, the Hippo-Yes-associated protein (YAP) pathway and transforming growth factor-β signalling. These studies have begun to identify potential therapeutic targets whose modulation has shown promise in preclinical models. In this Review, we summarize and discuss the reported molecular mechanisms underlying the pathogenesis of arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is an arrhythmogenic disorder of the myocardium not secondary to ischemic, hypertensive, or valvular heart disease. ACM incorporates a broad spectrum of genetic, systemic, infectious, and inflammatory disorders. This designation includes, but is not limited to, arrhythmogenic right/left ventricular cardiomyopathy, cardiac amyloidosis, sarcoidosis, Chagas disease, and left ventricular noncompaction. The ACM phenotype overlaps with other cardiomyopathies, particularly dilated cardiomyopathy with arrhythmia presentation that may be associated with ventricular dilatation and/or impaired systolic function. This expert consensus statement provides the clinician with guidance on evaluation and management of ACM and includes clinically relevant information on genetics and disease mechanisms. PICO questions were utilized to evaluate contemporary evidence and provide clinical guidance related to exercise in arrhythmogenic right ventricular cardiomyopathy. Recommendations were developed and approved by an expert writing group, after a systematic literature search with evidence tables, and discussion of their own clinical experience, to present the current knowledge in the field. Each recommendation is presented using the Class of Recommendation and Level of Evidence system formulated by the American College of Cardiology and the American Heart Association and is accompanied by references and explanatory text to provide essential context. The ongoing recognition of the genetic basis of ACM provides the opportunity to examine the diverse triggers and potential common pathway for the development of disease and arrhythmia.

Arrhythmogenic right ventricular cardiomyopathy (ARVC), an inherited heart muscle disease, is characterized by a progressive replacement of viable, in its classic form predominantly right ventricular myocardium by fibro-fatty tissue. These pathological alterations may provide the substrate for the occurrence of life-threatening ventricular tachyarrhythmias, heart failure, and sudden cardiac death. The clinical course in this young patient population is highly variable, diagnostic algorithms complex, and individualized treatment strategies yet to be refined. Molecular genetic analyses have revealed both heterozygous and compound mutations in genes encoding for desmosomal proteins that are an integral part of the intercellular architecture. However, its diagnostic and prognostic impact remains to be elucidated. Over time, other genetic (i.e., non-desmosomal) and non-genetic causes (phenocopies) have been identified, and biventricular and left dominant manifestations (ALVC) are known. Based on a qualitative scoring system, initially published in 1994, diagnostic criteria were revised and substantiated by quantitative criteria in 2010 followed by a critical appraisal 9 years later. In 1995, ARVC was included in the classification of cardiomyopathies of the World Health Organization but was recently proposed to be subsumed in a broader concept termed "arrhythmogenic cardiomyopathy" (AC). This review provides an update on the clinical diagnosis and differential diagnoses of ARVC as well as our current understanding of the underlying pathogenesis, and it sheds light on new efforts in risk stratification.

BACKGROUND:Desmin () mutations cause severe skeletal and cardiac muscle disease with heterogeneous phenotypes. Recently, mutations were described in patients with inherited arrhythmogenic right ventricular cardiomyopathy/dysplasia, although their cellular and molecular pathomechanisms are not precisely known. Our aim is to describe clinically and functionally the novel -p.Glu401Asp mutation as a cause of inherited left ventricular arrhythmogenic cardiomyopathy/dysplasia. METHODS:We identified the novel mutation p.Glu401Asp in a large Spanish family with inherited left ventricular arrhythmogenic cardiomyopathy/dysplasia and a high incidence of adverse cardiac events. A full clinical evaluation was performed on all mutation carriers and noncarriers to establish clinical and genetic cosegregation. In addition, desmin, and intercalar disc-related proteins expression were histologically analyzed in explanted cardiac tissue affected by the mutation. Furthermore, mesenchymal stem cells were isolated and cultured from 2 family members with the mutation (1 with mild and 1 with severe symptomatology) and a member without the mutation (control) and differentiated ex vivo to cardiomyocytes. Then, important genes related to cardiac differentiation and function were analyzed by real-time quantitative polymerase chain reaction. Finally, the p.Glu401Asp mutated gene was transfected into cell lines and analyzed by confocal microscopy. RESULTS:Of the 66 family members screened for the -p.Glu401Asp mutation, 23 of them were positive, 6 were obligate carriers, and 2 were likely carriers. One hundred percent of genotype-positive patients presented data consistent with inherited arrhythmogenic cardiomyopathy/dysplasia phenotype with variable disease severity expression, high-incidence of sudden cardiac death, and absence of skeletal myopathy or conduction system disorders. Immunohistochemistry was compatible with inherited arrhythmogenic cardiomyopathy/dysplasia, and the functional study showed an abnormal growth pattern and cellular adhesion, reduced desmin RNA expression, and some other membrane proteins, as well, and desmin aggregates in transfected cells expressing the mutant desmin. CONCLUSIONS:The -p.Glu401Asp mutation causes predominant inherited left ventricular arrhythmogenic cardiomyopathy/dysplasia with a high incidence of adverse clinical events in the absence of skeletal myopathy or conduction system disorders. The pathogenic mechanism probably corresponds to an alteration in desmin dimer and oligomer assembly and its connection with membrane proteins within the intercalated disc.

Sudden cardiac death (SCD) is a devastating possible outcome of all cardiomyopathies. The risk of SCD is increased in patients with structural heart disease and continues to increase as ventricular dysfunction worsens. There is, however, a subset of cardiomyopathy, so-called "arrhythmogenic cardiomyopathy" (ACM), that carries an inherent propensity for arrhythmia in all stages of the disease, even preceding ventricular dysfunction. The aim of this review is to identify cardiomyopathies, other than ischemic and dilated cardiomyopathies, that are associated with ventricular arrhythmias (VAs) and SCD. We discuss prevalence, diagnosis, natural history and management of arrhythmogenic right ventricular dysplasia/cardiomyopathy, ACM, and exercise-induced cardiomyopathy, with emphasis on the morbidity and mortality of VAs associated with these cardiomyopathies and how they can be mitigated through lifestyle modification, medical management, and implantation of cardioverter defibrillators.

Cardiomyopathies are a heterogeneous group of heart muscle diseases and an important cause of heart failure (HF). Current knowledge on incidence, pathophysiology and natural history of HF in cardiomyopathies is limited, and distinct features of their therapeutic responses have not been systematically addressed. Therefore, this position paper focuses on epidemiology, pathophysiology, natural history and latest developments in treatment of HF in patients with dilated (DCM), hypertrophic (HCM) and restrictive (RCM) cardiomyopathies. In DCM, HF with reduced ejection fraction (HFrEF) has high incidence and prevalence and represents the most frequent cause of death, despite improvements in treatment. In addition, advanced HF in DCM is one of the leading indications for heart transplantation. In HCM, HF with preserved ejection (HFpEF) affects most patients with obstructive, and ∼10% of patients with non-obstructive HCM. A timely treatment is important, since development of advanced HF, although rare in HCM, portends a poor prognosis. In RCM, HFpEF is common, while HFrEF occurs later and more frequently in amyloidosis or iron overload/haemochromatosis. Irrespective of RCM aetiology, HF is a harbinger of a poor outcome. Recent advances in our understanding of the mechanisms underlying the development of HF in cardiomyopathies have significant implications for therapeutic decision-making. In addition, new aetiology-specific treatment options (e.g. enzyme replacement therapy, transthyretin stabilizers, immunoadsorption, immunotherapy, etc.) have shown a potential to improve outcomes. Still, causative therapies of many cardiomyopathies are lacking, highlighting the need for the development of effective strategies to prevent and treat HF in cardiomyopathies.

Arrhythmogenic cardiomyopathy is an inherited heart muscle disorder, predisposing to sudden cardiac death, particularly in young patients and athletes. Pathological features include loss of myocytes and fibrofatty replacement of right ventricular myocardium; biventricular involvement is often observed. It is a cell-to-cell junction cardiomyopathy, typically caused by genetically determined abnormalities of cardiac desmosomes, which leads to detachment of myocytes and alteration of intracellular signal transduction. The diagnosis of arrhythmogenic cardiomyopathy does not rely on a single gold standard test but is achieved using a scoring system, which encompasses familial and genetic factors, ECG abnormalities, arrhythmias, and structural/functional ventricular alterations. The main goal of treatment is the prevention of sudden cardiac death. Implantable cardioverter defibrillator is the only proven lifesaving therapy; however, it is associated with significant morbidity because of device-related complications and inappropriate implantable cardioverter defibrillator interventions. Selection of patients who are the best candidates for implantable cardioverter defibrillator implantation is one of the most challenging issues in the clinical management.