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Arrhythmogenic right ventricular cardiomyopathy is a heritable heart-muscle disorder that causes progressive replacement of right ventricular myocardium by fibrofatty tissue. Mutations in genes encoding desmosomal proteins play a key role in the pathogenesis of the disease. Arrhythmogenic right ventricular cardiomyopathy (ARVC), also known as arrhythmogenic right ventricular dysplasia, is a heritable heart-muscle disorder that predominantly affects the right ventricle. Progressive loss of right ventricular myocardium and its replacement by fibrofatty tissue is the pathological hallmark of the disease. 1 ARVC is one of the leading causes of arrhythmic cardiac arrest in young people and athletes. Since the original report by Marcus and colleagues was published in 1982, describing 24 affected patients, 2 there have been substantial advances in our understanding of the pathogenesis, clinical manifestations, and long-term outcome of the disorder. The disease was initially designated as a . . .

This study demonstrates that an inheritable adult onset heart disease can be modelled in vitro within months with the help of metabolic maturation induction. Adult-onset disease modelled by iPSCs Recent advances in cellular reprogramming of fibroblasts as patient-specific induced pluripotent stem cells (iPSCs) have made it possible to model genetic disorders in vitro . But for adult-onset conditions, tissues derived from iPSCs or stem cells, such as cardiomyocytes or neurons, tend to 'reset' to an embryo-like state, losing the disease characteristic that emerged after a period of latency. This study demonstrates that an inheritable adult-onset disease can be modelled within months. The authors used patient-specific iPSCs with a plakophilin-2 mutation to model arrhythmogenic right ventricular dysplasia/cardiomyopathy. Typical pathology was not evident at first, but emerged within 2 months when adult-like energy metabolism was induced using a 5-factor protocol. Cellular reprogramming of somatic cells to patient-specific induced pluripotent stem cells (iPSCs) enables in vitro modelling of human genetic disorders for pathogenic investigations and therapeutic screens 1 , 2 , 3 , 4 , 5 , 6 , 7 . However, using iPSC-derived cardiomyocytes (iPSC-CMs) to model an adult-onset heart disease remains challenging owing to the uncertainty regarding the ability of relatively immature iPSC-CMs to fully recapitulate adult disease phenotypes. Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited heart disease characterized by pathological fatty infiltration and cardiomyocyte loss predominantly in the right ventricle 8 , which is associated with life-threatening ventricular arrhythmias. Over 50% of affected individuals have desmosome gene mutations, most commonly in PKP2 , encoding plakophilin-2 (ref. 9 ). The median age at presentation of ARVD/C is 26 years 8 . We used previously published methods 1 , 10 to generate iPSC lines from fibroblasts of two patients with ARVD/C and PKP2 mutations 11 , 12 . Mutant PKP2 iPSC-CMs demonstrate abnormal plakoglobin nuclear translocation and decreased β-catenin activity 13 in cardiogenic conditions; yet, these abnormal features are insufficient to reproduce the pathological phenotypes of ARVD/C in standard cardiogenic conditions. Here we show that induction of adult-like metabolic energetics from an embryonic/glycolytic state and abnormal peroxisome proliferator-activated receptor gamma (PPAR-γ) activation underlie the pathogenesis of ARVD/C. By co-activating normal PPAR-alpha-dependent metabolism and abnormal PPAR-γ pathway in beating embryoid bodies (EBs) with defined media, we established an efficient ARVD/C in vitro model within 2 months. This model manifests exaggerated lipogenesis and apoptosis in mutant PKP2 iPSC-CMs. iPSC-CMs with a homozygous PKP2 mutation also had calcium-handling deficits. Our study is the first to demonstrate that induction of adult-like metabolism has a critical role in establishing an adult-onset disease model using patient-specific iPSCs. Using this model, we revealed crucial pathogenic insights that metabolic derangement in adult-like metabolic milieu underlies ARVD/C pathologies, enabling us to propose novel disease-modifying therapeutic strategies.

Arrhythmogenic right ventricular cardiomyopathy is a rare inherited heart-muscle disease that is a cause of sudden death in young people and athletes. Causative mutations in genes encoding desmosomal proteins have been identified and the disease is nowadays regarded as a genetically determined myocardial dystrophy. The left ventricle is so frequently involved as to support the adoption of the broad term arrhythmogenic cardiomyopathy. Clinical diagnosis can be achieved by demonstrating function and structure changes of the right ventricle, electrocardiogram depolarisation and repolarisation abnormalities, ventricular arrhythmias, and fibrofatty replacement through endomyocardial biopsy. Although specific, the standardised diagnostic criteria lack sensitivity for early disease and their primary application remains in establishing the diagnosis in probands. However, the main clinical targets are early detection of concealed forms and risk stratification for preventive strategies, which include physical exercise restriction, antiarrhythmic drugs, and implantable cardioverter-defibrillator therapy. Cascade genetic screening of family members of gene-positive probands allows the identification of asymptomatic carriers who would require lifelong follow-up due to the age-related penetrance.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disease characterised by fibrofatty replacement of the ventricular myocardium due to specific mutations, leading to ventricular arrhythmias and sudden cardiac death. Treating this condition can be challenging due to progressive fibrosis, phenotypic variations and small patient cohorts limiting the feasibility of conducting meaningful clinical trials. Although widely used, the evidence base for anti-arrhythmic drugs is limited. Beta-blockers are theoretically sound, yet their efficacy in reducing arrhythmic risk is not robust. Additionally, the impact of sotalol and amiodarone is inconsistent with studies reporting contradictory results. Emerging evidence suggests that combining flecainide and bisoprolol may be efficacious.Radiofrequency ablation has shown some potential in disrupting ventricular tachycardia circuits, with combined endo and epicardial ablation yielding better results which could be considered at the index procedure. In addition, stereotactic radiotherapy may be a future option that can decrease arrhythmias beyond simple scar formation by altering levels of Nav1.5 channels, Connexin 43 and Wnt signalling, potentially modifying myocardial fibrosis.Future therapies, such as adenoviruses and GSk3b modulation, are still in early-stage research. While implantable cardioverter-defibrillator implantation is a key intervention for reducing arrhythmic death, the risks of inappropriate shocks and device complications must be carefully considered.

•Impaired strain can identify both right and left ventricular involvement in ARVC.•Biventricular strain assessment is crucial as patients can present LV involvement only.•Patients can be grouped into normal, discordant (LV or RV) or impaired (both) strain.•Involvement of one or both ventricles is associated with mortality and arrhythmias.•Biventricular strain impairment has prognostic value across ARVC diagnosis spectrum. The upper panel shows the RV and LV strain measurements (RV free wall strain and LV global longitudinal strain) performed to define the strain groups based on the relative ventricular function and with the cut-off value of 18%: impaired strain, discordant and normal strain. Lower panel depicts the difference in outcome between the strain groups based on Kaplan-Meier analysis (left) and the incremental value of using strain groups in assessing prognosis in addition to age, sex and ARVC diagnosis, as compared to solely using LV or RV strain (right). ARVC, Arrhythmogenic Right Ventricular Cardiomyopathy; FWLS, right ventricular free wall longitudinal strain; LV, left ventricle; LV GLS, left ventricular global longitudinal strain; RV, Right ventricle. [Display omitted] Despite arrhythmogenic right ventricular cardiomyopathy (ARVC) being predominantly a right ventricular (RV) disease, concomitant left ventricular (LV) involvement has been recognized. ARVC is diagnosed by the RV-centric 2010 Task Force Criteria(TFC) using routine echocardiography, but previous studies have suggested that strain imaging may be more sensitive to detect RV and LV dysfunction. No data however are available regarding the additional value of combining biventricular strain for risk stratification. This study aims to assess the prognostic value of both LV global longitudinal strain (GLS) and RV free wall strain (FWLS) in patients with ARVC. To accomplish this, 204 patients who met the TFC for the ARVC spectrum were included. Patients (age 41 ± 17 years,55% men) were divided into impaired(n = 33), discordant (RV or LV impaired, n = 70), and normal (n = 101) strain groups based on a value of ≥18% for both ventricles. During a follow-up of 87 [24–136] months, 57 (28%) experienced the composite outcome of all-cause mortality, arrhythmic events, implantable cardioverter defibrillator therapy and heart failure events, and a significant difference in event-free survival was observed (p <0.001) between the 3 groups. In the multivariable analysis, the strain groups remained associated with outcomes (p = 0.014) after adjusting for age, sex, history of syncope and definite ARVC diagnosis. A subanalysis including only definite and borderline diagnosed ARVC confirmed that the strain groups were independently predictive of the endpoint (p = 0.023). In conclusion, biventricular involvement by strain analysis may help risk stratification in ARVC patients, with the worst outcomes of patients with both RV and LV impaired strain.

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is one of the most arrhythmogenic forms of inherited cardiomyopathy and a frequent cause of sudden death in the young. Affected individuals typically present between the second and fourth decade of life with arrhythmias coming from the right ventricle. Pathogenic mutations in genes encoding the cardiac desmosome can be found in approximately 60% of index patients, leading to our current perception of ARVC as a desmosomal disease. Although ARVC is known to preferentially affect the right ventricle, early and/or predominant left ventricular involvement is increasingly recognized. Diagnosis is made by combining multiple sources of diagnostic information as prescribed by the “Task Force” criteria. Recent research suggests that electrical abnormalities precede structural changes in ARVC. Cardiovascular Magnetic Resonance (CMR) is an ideal technique in ARVC workup, as it provides comprehensive information on cardiac morphology, function, and tissue characterization in a single investigation. Prevention of sudden cardiac death using implantable cardioverter-defibrillators is the most important management consideration. This purpose of this paper is to provide an updated review of our understanding of the genetics, diagnosis, current state-of-the-art CMR acquisition and analysis, and management of patients with ARVC.

Arrhythmogenic cardiomyopathy (AC) is a clinically heterogeneous cardiac disease that is associated with ventricular arrhythmias and sudden cardiac death. The authors discuss the diagnosis and genetic basis of AC, and how disruption of desmosomal crosstalk with the nucleus, gap junctions, and ion channels might underlie the pathophysiology of this condition. Arrhythmogenic cardiomyopathy (AC) is a clinically and genetically heterogeneous disorder of heart muscle that is associated with ventricular arrhythmias and risk of sudden cardiac death, particularly in the young and athletes. Mutations in five genes that encode major components of the desmosomes, namely junction plakoglobin, desmoplakin, plakophilin-2, desmoglein-2, and desmocollin-2, have been identified in approximately half of affected probands. AC is, therefore, commonly considered a 'desmosomal' disease. No single test is sufficiently specific to establish a diagnosis of AC. The diagnostic criteria for AC were revised in 2010 to improve sensitivity, but maintain specificity. Quantitative parameters were introduced and identification of a pathogenic mutation in a first-degree relative has become a major diagnostic criterion. Caution in the interpretation of screening results is highly recommended because a 'pathogenic' mutation is difficult to define. Experimental data confirm that this genetically determined cardiomyopathy develops after birth because of progressive myocardial dystrophy, and is initiated by cardiomyocyte necrosis; cellular and animal models are necessary to gain insight into the cascade of underlying molecular events. Crosstalk from the desmosome to the nucleus, gap junctions, and ion channels is under investigation, to move from symptomatic to targeted therapy, with the ultimate aim to stop disease onset and progression. Key Points Arrhythmogenic cardiomyopathy (AC) is a familial heart-muscle disease that is usually inherited with an autosomal-dominant pattern; mutations in desmosomal-protein genes are found in approximately 50% of probands The 1994 diagnostic criteria were updated in 2010 to increase their sensitivity, but maintain their specificity; differential diagnosis with AC 'phenocopies' is mandatory when dealing with sporadic forms of AC Emerging tools offer the possibility to visualize the fibrofatty scar, as either low-voltage myocardial areas using electroanatomical mapping, or areas of delayed contrast-enhancement with cardiac MRI Genotype–phenotype studies show that the clinicomorphological spectrum of AC is wider than originally thought, and includes variants with predominant or even isolated left ventricular involvement within a single family Animal and cellular models indicate that both abnormal biomechanical properties and crosstalk from the desmosome to the nucleus, gap junctions, and ion channels are implicated in the pathobiology of AC Electrical instability is the main clinical manifestation of AC; in addition to re-entry arrhythmias caused by fibrofatty replacement, current hypotheses implicate acute cell death, gap-junction remodeling, and ion-channel crosstalk

BackgroundCardiac sarcoidosis (CS) is a chronic inflammatory disease characterised by non-caseating granulomas, while arrhythmogenic cardiomyopathy (ACM) is a genetic condition mainly affecting desmosomal proteins. The coexistence of CS and genetic variants associated with ACM is not well understood, creating challenges in diagnosis and management. This study aimed to describe the clinical, imaging and genetic features of patients with both conditions.MethodsThis was a multicentre retrospective case-control study involving three groups of patients: those with biopsy-proven CS and pathogenic or likely pathogenic genetic variants linked to ACM (n=5); patients with genetic variants but no CS (n=5); and patients with CS without genetic variants (n=5). Clinical data, including symptoms, electrocardiographic findings and imaging results from echocardiography, cardiac magnetic resonance and positron-emission tomography, were analysed.ResultsPatients with CS and genetic variants were more likely to exhibit atrioventricular block (100%), PR prolongation (204 ms vs 160 ms) and paroxysmal atrial fibrillation (80%) compared with those with genetic variants alone (0% for both). Imaging findings showed a higher prevalence of septal involvement in patients with both conditions (80%) than in those with genetic variants alone (20%). No significant differences were observed between patients with CS and genetic variants and those with CS without genetic variants. The genetic variants identified included variants in PKP2 (40%), DSG2 (20%), DSP (20%) and TTN (20%).ConclusionsThe coexistence of CS and ACM-associated genetic variants is associated with distinct clinical features, including PR prolongation, AVB1°, septal involvement and paroxysmal atrial fibrillation. These findings emphasise the need to evaluate for CS in individuals with ACM and associated genetic variants who present with conduction abnormalities or septal involvement, guiding tailored diagnostic and therapeutic strategies.

Arrhythmogenic cardiomyopathy (AC) is an inherited cardiac disease, clinically characterized by life-threatening ventricular arrhythmias and progressive cardiac dysfunction. Patient-specific computational models could help understand the disease progression and may help in clinical decision-making. We propose an inverse modelling approach using the CircAdapt model to estimate patient-specific regional abnormalities in tissue properties in AC subjects. However, the number of parameters ( n  = 110) and their complex interactions make personalized parameter estimation challenging. The goal of this study is to develop a framework for parameter reduction and estimation combining Morris screening, quasi-Monte Carlo (qMC) simulations and particle swarm optimization (PSO). This framework identifies the best subset of tissue properties based on clinical measurements allowing patient-specific identification of right ventricular tissue abnormalities. We applied this framework on 15 AC genotype-positive subjects with varying degrees of myocardial disease. Cohort studies have shown that atypical regional right ventricular (RV) deformation patterns reveal an early-stage AC disease. The CircAdapt model of cardiovascular mechanics and haemodynamics has already demonstrated its ability to capture typical deformation patterns of AC subjects. We, therefore, use clinically measured cardiac deformation patterns to estimate model parameters describing myocardial disease substrates underlying these AC-related RV deformation abnormalities. Morris screening reduced the subset to 48 parameters. qMC and PSO further reduced the subset to a final selection of 16 parameters, including regional tissue contractility, passive stiffness, activation delay and wall reference area. This article is part of the theme issue ‘Uncertainty quantification in cardiac and cardiovascular modelling and simulation’.

Objectives The present study aimed to investigate the incremental prognostic value of the right ventricular fractal dimension (FD), a novel marker of myocardial trabecular complexity by cardiac magnetic resonance (CMR) in patients with arrhythmogenic cardiomyopathy (ACM). Methods Consecutive patients with ACM undergoing CMR were followed up for major cardiac events, including sudden cardiac death, aborted cardiac arrest, and appropriate implantable cardioverter defibrillator intervention. Prognosis prediction was compared by Cox regression analysis. We established a multivariable model supplemented with RV FD and evaluated its discrimination by Harrell’s C -statistic. We compared the category-free, continuous net reclassification improvement (cNRI) and integrated discrimination index (IDI) before and after the addition of FD. Results A total of 105 patients were prospectively included from three centers and followed up for a median of 60 (48, 66) months; experienced 36 major cardiac events were recorded. Trabecular FD displayed a strong unadjusted association with major cardiac events ( p  < 0.05). In the multivariable Cox regression analysis, RV maximal apical FD maintained an independent association with major cardiac events (hazard ratio, 1.31 (1.11–1.55), p  < 0.002). The Hosmer–Lemeshow goodness of fit test displayed good fit ( X 2  = 0.68, p  = 0.99). Diagnostic performance was significantly improved after the addition of RV maximal apical FD to the multivariable baseline model, and the continuous net reclassification improvement increased 21% ( p  = 0.001), and the integrated discrimination index improved 16% ( p  = 0.045). Conclusions In patients with ACM, CMR-assessed myocardial trabecular complexity was independently correlated with adverse cardiovascular events and provided incremental prognostic value. Clinical relevance statement The application of FD values for assessing RV myocardial trabeculae may become an accessible and promising parameter in monitoring and early diagnosis of risk factors for adverse cardiovascular events in patients with ACM. Key Points • Ventricular trabecular morphology, a novel quantitative marker by CMR, has been explored for the first time to determine the severity of ACM. • Patients with higher maximal apical fractal dimension of RV displayed significantly higher cumulative incidence of major cardiac events. • RV maximal apical FD was independently associated with major cardiac events and provided incremental prognostic value in patients with ACM.