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Cadherins are calcium dependent adhesion proteins that establish and maintain the intercellular mechanical contact by bridging the gap between adjacent cells. Desmoglein-2 (Dsg2) and desmocollin-2 (Dsc2) are tissue specific cadherin isoforms of the cell-cell contact in cardiac desmosomes. Mutations in the DSG2 -gene and in the DSC2 -gene are related to arrhythmogenic right ventricular cardiomyopathy (ARVC) a rare but severe heart muscle disease. Here, several possible homophilic and heterophilic binding interactions of wild-type Dsg2, wild-type Dsc2, as well as one Dsg2- and two Dsc2-variants, each associated with ARVC, are investigated. Using single molecule force spectroscopy (SMFS) with atomic force microscopy (AFM) and applying Jarzynski's equality the kinetics and thermodynamics of Dsg2/Dsc2 interaction can be determined. The free energy landscape of Dsg2/Dsc2 dimerization exposes a high activation energy barrier, which is in line with the proposed strand-swapping binding motif. Although the binding motif is not affected by any of the mutations, the binding kinetics of the interactions differ significantly from the wild-type. While wild-type cadherins exhibit an average complex lifetime of approx. 0.3 s interactions involving a variant consistently show - lifetimes that are substantially larger. The lifetimes of the wild-type interactions give rise to the picture of a dynamic adhesion interface consisting of continuously dissociating and (re)associating molecular bonds, while the delayed binding kinetics of interactions involving an ARVC-associated variant might be part of the pathogenesis. Our data provide a comprehensive and consistent thermodynamic and kinetic description of cardiac cadherin binding, allowing detailed insight into the molecular mechanisms of cell adhesion. [Display omitted] • Integrity of heart muscle tissue relies on weak molecular bonds between cadherins. • Single molecule force spectroscopy reveals cadherin binding kinetics. • Wild-type cadherin bonds exhibit characteristic fast (re-) binding kinetics. • Specific cardiomyopathy associated cadherin variants slow binding kinetics. • Impaired molecular dynamics could be a cardiomyopathy-specific pathomechanism. [ABSTRACT FROM AUTHOR]

Hereditary cardiomyopathies (CMPs), including arrhythmogenic cardiomyopathy (ACM), dilated cardiomyopathy (DCM), and hypertrophic cardiomyopathy (HCM), represent a group of heart disorders that significantly contribute to cardiovascular morbidity and mortality and are often driven by genetic factors. Recent advances in next-generation sequencing (NGS) technology have enabled the identification of rare variants in both well-established and minor genes associated with CMPs. Nowadays, a set of core genes is included in diagnostic panels for ACM, DCM, and HCM. On the other hand, despite their lesser-known status, variants in the minor genes may contribute to disease mechanisms and influence prognosis. This review evaluates the current evidence supporting the involvement of the minor genes in CMPs, considering their potential pathogenicity and clinical significance. A comprehensive analysis of databases, such as ClinGen, ClinVar, and GeneReviews, along with recent literature and diagnostic guidelines provides a thorough overview of the genetic landscape of minor genes in CMPs and offers guidance in clinical practice, evaluating each case individually based on the clinical referral, and insights for future research. Given the increasing knowledge on these less understood genetic factors, future studies are essential to clearly assess their roles, ultimately leading to improved diagnostic precision and therapeutic strategies in hereditary CMPs. [ABSTRACT FROM AUTHOR]

Background: Mutations in genes encoding desmosomal proteins are the leading cause of arrhythmogenic cardiomyopathy (ACM). The majority of the inherited ACM cases demonstrate autosomal dominant genotype. Several cases with the homozygous DSG2 c.1592T>G (p.F531C) variant genotype demonstrate adverse clinical outcomes, but the roles of associated genetic mutations are not clear. In this report, we describe three ACM cases with the homozygous DSG2 c.1592T>G (p.F531C) variant genotype combined with additional heterozygous cardiomyopathy-related genetic mutations that cause aggravated clinical manifestations and worse clinical outcomes. Case presentation: The three reported probands demonstrated similar clinical presentations such as heart failure, cardiac enlargement, and lethal arrhythmias. All of them experienced sudden cardiac death (SCD) before undergoing implantable cardioverter defibrillator (ICD) or heart transplantations. Wholeexome sequencing analysis demonstrated that the three patients inherited the homozygous DSG2 c.1592T>G (p.F531C) variant. Furthermore, probands I, II, and III also inherited additional heterozygous cardiomyopathy-associated mutations, including DSP c.7883T>C, SCN5a c.3577C>T, or MYH7 c.427C>T, respectively. These variants were confirmed as pathogenetic variants. A systematic review of all the reported ACM cases with the homozygous DSG2 variants suggested that the additional genetic mutations contributed to the early age onset of ACM and lethal cardiac events. Conclusion: In conclusion, we report three rare cases of ACM with the same homozygous DSG2 variant in combination with additional heterozygous mutations in cardiomyopathy-associated genes. A systematic review of all the ACM cases with homozygous DSG2 variants demonstrated that the additional genetic variants contributed to the aggravated clinical manifestations and worse clinical symptoms of the ACM patients because of homozygous DSG2 mutations, including early disease onset and lethal cardiac events. Our data suggested that comprehensive genetic evaluation should be performed to identify any potential additional pathogenic variants that may significantly influence the clinical prognosis and outcomes of patients with ACM. The knowledge of underlying molecular mutations would be useful in designing better therapeutic strategies for ACM patients with multiple genetic mutations. [ABSTRACT FROM AUTHOR]

Introduction: The 2023 European Society of Cardiology Guidelines for the management of Cardiomyopathies recommends a phenotype-based, multimodal, multidisciplinary, and multiparametric approach to the diagnosis of cardiomyopathies. Case report: We present the case of a 70-year-old man, who underwent a routine preoperative examination before dermatological surgery. Initially, on the electrocardiogram (ECG), non-sustained ventricular tachycardia (nsVT) was seen, whereas a dilated right ventricle was observed on transthoracic echocardiography (TTE). After further cardiological examination, ECG criteria for right ventricular arrhythmogenic cardiomyopathy (ARVC) were fulfilled (negative T waves in V1-V3, presence of an epsilon wave), in addition to significant bradycardia with sinus node dysfunction, and recurrent nsVTs were detected during monitoring. Cardiac magnetic resonance (CMR) scan was performed to assess right ventricular function and morphology, which confirmed a dilated right ventricle (end-diastolic volume normalized to body surface area 155 mL/m2), however, no wall motion abnormality was detected. Transesophageal echocardiography ruled out atrial septal defects as a potential cause for right ventricular dilatation. Overall, a diagnosis of ARVC was established based on the 3 major criteria fulfilled by the 2010 ARVC Task Force Criteria. Subsequently, in view of the sinus node dysfunction and ARVC diagnosis with high risk features, we opted for primary preventive DDD-ICD implantation, followed by long-term drug therapy with beta-blocker therapy. Conclusion: ARVC is a rare structural myocardial disease, which is often challenging to diagnose, and the search for clinical clues and "red flags" (functional and morphological abnormalities, electrophysiological features) is of strategic importance.

Background and Aims Pathogenic desmoplakin (DSP) gene variants are associated with the development of a distinct form of arrhythmogenic cardiomyopathy known as DSP cardiomyopathy. Patients harbouring these variants are at high risk for sustained ventricular arrhythmia (VA), but existing tools for individualized arrhythmic risk assessment have proven unreliable in this population. Methods Patients from the multi-national DSP-ERADOS (Desmoplakin SPecific Effort for a RAre Disease Outcome Study) Network patient registry who had pathogenic or likely pathogenic DSP variants and no sustained VA prior to enrolment were followed longitudinally for the development of first sustained VA event. Clinically guided, step-wise Cox regression analysis was used to develop a novel clinical tool predicting the development of incident VA. Model performance was assessed by c -statistic in both the model development cohort (n = 385) and in an external validation cohort (n = 86). Results In total, 471 DSP patients [mean age 37.8 years, 65.6% women, 38.6% probands, 26% with left ventricular ejection fraction (LVEF) < 50%] were followed for a median of 4.0 (interquartile range: 1.6–7.3) years; 71 experienced first sustained VA events {2.6% [95% confidence interval (CI): 2.0, 3.5] events/year}. Within the development cohort, five readily available clinical parameters were identified as independent predictors of VA and included in a novel DSP risk score: female sex [hazard ratio (HR) 1.9 (95% CI: 1.1–3.4)], history of non-sustained ventricular tachycardia [HR 1.7 (95% CI: 1.1–2.8)], natural logarithm of 24-h premature ventricular contraction burden [HR 1.3 (95% CI: 1.1–1.4)], LVEF < 50% [HR 1.5 (95% CI:.95–2.5)], and presence of moderate to severe right ventricular systolic dysfunction [HR 6.0 (95% CI: 2.9–12.5)]. The model demonstrated good risk discrimination within both the development [ c -statistic.782 (95% CI:.77–.80)] and external validation [ c -statistic.791 (95% CI:.75–.83)] cohorts. The negative predictive value for DSP patients in the external validation cohort deemed to be at low risk for VA (<5% at 5 years; n = 26) was 100%. Conclusions The DSP risk score is a novel model that leverages readily available clinical parameters to provide individualized VA risk assessment for DSP patients. This tool may help guide decision-making for primary prevention implantable cardioverter-defibrillator placement in this high-risk population and supports a gene-first risk stratification approach. [ABSTRACT FROM AUTHOR]

Aims Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by progressive myocardial dysfunction and associated with an increased risk of major cardiovascular (CV) events. To determine right heart strain (ventricular and atrial global longitudinal strain (RVGLS and RAGLS) in patients with definite ARVC and its association with adverse events during follow-up. Methods and results RVGLS and RAGLS were analysed in focused right heart apical views from 70 patients using TomTec ImageArena and association with a composite endpoint was determined (sustained ventricular arrhythmia and cardiovascular death). Over a median follow-up duration of 4.9 years, 26 (37%) patients met the endpoint. RVGLS was significantly impaired in the event group (−11.5 [−13.3 to −10.2] %) vs. the no-event group (−15.8 [−17.1 to −14.5] %, P < 0.001), and so was RAGLS (22.8 [21.4–27.4] % vs. 31.5 [25.1–39.6] %, respectively, P < 0.001). In Cox regression, RVGLS (HR 1.36, P < 0.001) and RAGLS (HR 0.92, P = 0.002) were associated with a higher risk of adverse events. In multivariable Cox regression models, RVGLS and RAGLS remained independent of and were incremental to age, gender, and conventional RV parameters, and model fitness was improved when RVGLS and RAGLS were applied together rather than alone. Conclusion RVGLS and RAGLS are more impaired in patients with adverse events and associated with adverse events independent of age, gender, and conventional RV parameters. When RVGLS and RAGLS are applied together, prediction models are improved suggesting that right heart strain may form part of the echocardiographic routine protocol in patients with ARVC. [ABSTRACT FROM AUTHOR]

Cardiomyopathies (CMs), one of the main causes of sudden death among the young population, are a heterogeneous group of myocardial diseases, usually with a genetic cause. Next-Generation Sequencing (NGS) has expanded the genes studied for CMs; however, the yield is still around 50%. The systematic study of Copy Number Variants (CNVs) could contribute to improving our diagnostic capacity. These alterations have already been described as responsible for cardiomyopathies in some cases; however, their impact has been rarely assessed. We analyzed the clinical significance of CNVs in cardiomyopathies by studying 11,647 affected patients, many more than those considered in previously published studies. We evaluated the yield of the systematic study of CNVs in a production context using NGS and a novel CNV detection software tool v2.0 that has demonstrated great efficacy, maximizing sensitivity and avoiding false positives. We obtained a CNV analysis yield of 0.8% that fluctuated depending on the type of cardiomyopathy studied (0.29% HCM, 1.41% DCM, 1.88% ARVC, 1.8% LVNC, 1.45% RCM), and we present the frequency of occurrence for 18 genes that agglutinate the 95 pathogenic/likely pathogenic CNVs detected. We conclude the importance of including in diagnostic tests a systematic study of these genetic alterations for the different cardiomyopathies. [ABSTRACT FROM AUTHOR]

We report a case of ST segment elevation in left precordial leads with a convex shape caused by a rare etiology. By carefully analyzing the electrocardiogram (leads I, II, V3 to V9) of a patient with convex ST segment elevation in the left-sided chest leads, relevant etiological clues were derived. The findings were further supported by cardiac ultrasound and cardiac magnetic resonance imaging, ruling out other common causes. Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) was postulated as the underlying cause, and potential mechanisms were discussed. The diagnosis was further confirmed through a follow-up period of over three years. [ABSTRACT FROM AUTHOR]

Outcome comparisons among subcutaneous implantable cardioverter-defibrillator (S-ICD) recipients with nonischemic cardiomyopathies are scarce. The aim of this study was to evaluate differences in device-related outcomes among S-ICD recipients with different structural substrates. Patients enrolled in the i-SUSI (International SUbcutaneouS Implantable cardioverter defibrillator registry) project were grouped according to the underlying substrate (ischemic vs nonischemic) and subgrouped into dilated cardiomyopathy, hypertrophic cardiomyopathy, Brugada syndrome (BrS), arrhythmogenic right ventricular cardiomyopathy (ARVC). The main outcome of our study was to compare the rates of appropriate and inappropriate shocks and device-related complications. Among 1698 patients, the most common underlying substrate was ischemic (31.7%), followed by dilated cardiomyopathy (20.5%), BrS (10.8%), hypertrophic cardiomyopathy (8.5%), and ARVC (4.4%). S-ICD for primary prevention was more common in the nonischemic cohort (70.9% vs 65.4%; P =.037). Over a median (interquartile range) follow-up of 26.5 (12.6–42.8) months, no differences were observed in appropriate shocks between ischemic and nonischemic patients (4.8%/y vs 3.9%/y; log-rank, P =.282). ARVC (9.0%/y; hazard ratio [HR] 2.492; P =.001) and BrS (1.8%/y; HR 0.396; P =.008) constituted the groups with the highest and lowest rates of appropriate shocks, respectively. Device-related complications did not differ between groups (ischemic: 6.4%/y vs nonischemic: 6.1%/y; log-rank, P =.666), nor among underlying substrates (log-rank, P =.089). Nonischemic patients experienced higher rates of inappropriate shocks than did ischemic S-ICD recipients (4.4%/y vs 3.0%/y; log-rank, P =.043), with patients with ARVC (9.9%/y; P =.001) having the highest risk, even after controlling for confounders (adjusted HR 2.243; confidence interval 1.338–4.267; P =.002). Most S-ICD recipients were primary prevention nonischemic cardiomyopathy patients. Among those, patients with ARVC tend to receive the most frequent appropriate and inappropriate shocks and patients with BrS the least frequent appropriate shocks. [ABSTRACT FROM AUTHOR]

Hereditary cardiomyopathies (CMPs), including arrhythmogenic cardiomyopathy (ACM), dilated cardiomyopathy (DCM), and hypertrophic cardiomyopathy (HCM), represent a group of heart disorders that significantly contribute to cardiovascular morbidity and mortality and are often driven by genetic factors. Recent advances in next-generation sequencing (NGS) technology have enabled the identification of rare variants in both well-established and minor genes associated with CMPs. Nowadays, a set of core genes is included in diagnostic panels for ACM, DCM, and HCM. On the other hand, despite their lesser-known status, variants in the minor genes may contribute to disease mechanisms and influence prognosis. This review evaluates the current evidence supporting the involvement of the minor genes in CMPs, considering their potential pathogenicity and clinical significance. A comprehensive analysis of databases, such as ClinGen, ClinVar, and GeneReviews, along with recent literature and diagnostic guidelines provides a thorough overview of the genetic landscape of minor genes in CMPs and offers guidance in clinical practice, evaluating each case individually based on the clinical referral, and insights for future research. Given the increasing knowledge on these less understood genetic factors, future studies are essential to clearly assess their roles, ultimately leading to improved diagnostic precision and therapeutic strategies in hereditary CMPs.

Arrhythmogenic right ventricular cardiomyopathy is an inherited cardiomyopathy, characterized by abnormal cell adhesions, disrupted intercellular signaling, and fibrofatty replacement of the myocardium. These changes serve as a substrate for ventricular arrhythmias, placing patients at risk of sudden cardiac death, even in the early stages of the disease. Current echocardiographic criteria for diagnosing arrhythmogenic right ventricular cardiomyopathy lack sensitivity, but novel markers of cardiac deformation are not subject to the same technical limitations as current guideline-recommended measures. Measuring cardiac deformation using speckle tracking allows for meticulous quantification of global systolic function, regional function, and dyssynchronous contraction. Consequently, speckle tracking to quantify myocardial strain could potentially be useful in the diagnostic process for the determination of disease progression and to assist risk stratification for ventricular arrhythmias and sudden cardiac death. This narrative review provides an overview of the potential use of different myocardial right ventricular strain measures for characterizing right ventricular dysfunction in arrhythmogenic right ventricular cardiomyopathy and its utility in assessing the risk of ventricular arrhythmias. [ABSTRACT FROM AUTHOR]

The presence of multiple pathogenic variants in desmosomal genes (DSC2, DSG2, DSP, JUP, and PKP2) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) has been linked to a severe phenotype. However, the pathogenicity of variants is reclassified frequently, which may result in a changed clinical risk prediction. Here, we present the collection, reclassification, and clinical outcome correlation for the largest series of ARVC patients carrying multiple desmosomal pathogenic variants to date (n = 331). After reclassification, only 29% of patients remained carriers of two (likely) pathogenic variants. They reached the composite endpoint (ventricular arrhythmias, heart failure, and death) significantly earlier than patients with one or no remaining reclassified variant (hazard ratios of 1.9 and 1.8, respectively). Periodic reclassification of variants contributes to more accurate risk stratification and subsequent clinical management strategy. [ABSTRACT FROM AUTHOR]

ABSTRACT: Background: While late gadolinium enhancement (LGE) is proposed as a diagnostic criterion for arrhythmogenic right ventricular cardiomyopathy (ARVC), the potential of LGE to distinguish ARVC from differentials remains unknown. We aimed to assess the diagnostic value of LGE for ARVC diagnosis. Methods: We included 132 subjects (60% male, 47 ± 11 years) who had undergone cardiac magnetic resonance imaging with LGE assessment for ARVC or ARVC differentials. ARVC was diagnosed as per 2010 Task Force Criteria (n = 55). ARVC differentials consisted of familial/genetic dilated cardiomyopathy (n = 25), myocarditis (n = 13), sarcoidosis (n = 20), and amyloidosis (n = 19). The diagnosis of all differentials was based on the most current standard of reference. The presence of LGE was evaluated using a 7-segment right ventricle (RV) and 17-segment left ventricle (LV) model. Subsequently, we assessed LGE patterns for every patient individually for fulfilling LV- and/or RV-LGE per Padua criteria, independent of their clinical diagnosis (i.e. phenotype). Diagnostic values were analyzed using sensitivity and specificity for any RV-LGE, any LV-LGE, RV-LGE per Padua criteria, and prevalence graphs for LV-LGE per Padua criteria. The optimal integration of LGE for ARVC diagnosis was determined using classification and regression tree analysis. Results: One-third (38%) of ARVC patients had RV-LGE, while half (51%) had LV-LGE. RV-LGE was less frequently observed in ARVC vs non-ARVC patients (38% vs 58%, p = 0.034) leading to a poor discriminatory potential (any RV-LGE: sensitivity 38%, specificity 42%; RV-LGE per Padua criteria: sensitivity 36%, specificity 44%). Compared to ARVC patients, non-ARVC patients more often had LV-LGE (91% vs 51%, p

COVID-19 infection can cause cardiac arrhythmias through both direct and indirect mechanisms. We report a case of a patient who presented with sustained ventricular tachycardia in the context of a COVID-19 infection, leading to a diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC). Management of this patient was further influenced by post-acute sequelae of SARS-COV-2 infection. [ABSTRACT FROM AUTHOR]

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by fibrofatty replacement of primarily the right ventricular myocardium, a substrate for life-threatening ventricular arrhythmias (VAs). Repeated cardiac imaging of at-risk relatives is important for early disease detection. However, it is not known whether screening should be age-tailored. The goal of this study was to assess the need for age-tailoring of follow-up protocols in early ARVC by evaluating myocardial disease progression in different age groups. We divided patients with early-stage ARVC and genotype-positive relatives without overt structural disease and VA at first evaluation into 3 groups: age <30 years, 30 to 50 years, and ≥50 years. Longitudinal biventricular deformation characteristics were used to monitor disease progression. To link deformation abnormalities to underlying myocardial disease substrates, Digital Twins were created using an imaging-based computational modeling framework. We included 313 echocardiographic assessments from 82 subjects (57% female, age 39 ± 17 years, 10% probands) during 6.7 ± 3.3 years of follow-up. Left ventricular global longitudinal strain slightly deteriorated similarly in all age groups (0.1%-point per year [95% CI: 0.05-0.15]). Disease progression in all age groups was more pronounced in the right ventricular lateral wall, expressed by worsening in longitudinal strain (0.6%-point per year [95% CI: 0.46-0.70]) and local differences in myocardial contractility, compliance, and activation delay in the Digital Twin. Six patients experienced VA during follow-up. Disease progression was similar in all age groups, and sustained VA also occurred in patients aged >50 years without overt ARVC phenotype at first evaluation. Unlike recommended by current guidelines, our study suggests that follow-up of ARVC patients and relatives should not stop at older age. [Display omitted] [ABSTRACT FROM AUTHOR]

People diagnosed with genetic heart diseases (GHDs) associated with sudden cardiac death (SCD) have historically been restricted from competitive sports. Recent data documenting return-to-play (RTP) experiences following shared decision making (SDM) suggest that cardiac event rates for athletes with a GHD are lower than previously described, thereby suggesting an opportunity to reconsider this paradigm. The purpose of this study was to evaluate clinical outcomes among National Collegiate Athletic Association Division I university and professional athletes diagnosed with a GHD. A multicenter retrospective analysis was performed to examine demographics, clinical characteristics, RTP outcomes, and cardiac events among elite athletes with a GHD. A total of 76 elite (66%, Division I, 34% professional) athletes (age 19.9 ± 5 years, 28% women) diagnosed with a GHD (hypertrophic cardiomyopathy [53%], long QT syndrome, long QT syndrome [26%]) comprise this cohort. Most athletes were asymptomatic (48 of 76, 63%) before diagnosis and had their GHD detected during routine preparticipation cardiovascular screening. Most athletes (55 of 76, 72%) were initially disqualified from their sport but subsequently opted for unrestricted RTP after comprehensive clinical evaluation and SDM. To date, (mean follow-up 7 ± 6 years), only 1 exercise-related (1.3%) and 2 nonexercise-related GHD-associated adverse cardiac events occurred. There have been no fatalities during follow-up. This is the first study describing the experience of athletes with a known SCD-predisposing GHD who are competing at the elite level. After careful evaluation, risk stratification, and tailoring of their GHD therapy, RTP following SDM appears associated with low, nonfatal events rates at elite levels of sport. [Display omitted] [ABSTRACT FROM AUTHOR]

Clinical guidelines recommend regular screening for arrhythmogenic right ventricular cardiomyopathy (ARVC) to monitor at-risk relatives, resulting in a significant burden on clinical resources. Prioritizing relatives on their probability of developing definite ARVC may provide more efficient patient care. The aim of this study was to determine the predictors and probability of ARVC development over time among at-risk relatives. A total of 136 relatives (46% men, median age 25.5 years [IQR: 15.8-44.4 years]) from the Netherlands Arrhythmogenic Cardiomyopathy Registry without definite ARVC by 2010 task force criteria were included. Phenotype was ascertained using electrocardiography, Holter monitoring, and cardiac imaging. Subjects were divided into groups with "possible ARVC" (only genetic or familial predisposition) and "borderline ARVC" (1 minor task force criterion plus genetic or familial predisposition). Cox regression was performed to determine predictors and multistate modeling to assess the probability of ARVC development. Results were replicated in an unrelated Italian cohort (57% men, median age 37.0 years [IQR: 25.4-50.4 years]). At baseline, 93 subjects (68%) had possible ARVC, and 43 (32%) had borderline ARVC. Follow-up was available for 123 relatives (90%). After 8.1 years (IQR: 4.2-11.4 years), 41 (33%) had developed definite ARVC. Independent of baseline phenotype, symptomatic subjects (P = 0.014) and those 20 to 30 years of age (P = 0.002) had a higher hazard of developing definite ARVC. Furthermore, patients with borderline ARVC had a higher probability of developing definite ARVC compared with those with possible ARVC (1-year probability 13% vs 0.6%, 3-year probability 35% vs 5%; P < 0.01). External replication showed comparable results (P > 0.05). Symptomatic relatives, those 20 to 30 years of age, and those with borderline ARVC have a higher probability of developing definite ARVC. These patients may benefit from more frequent follow-up, while others may be monitored less often. [Display omitted] [ABSTRACT FROM AUTHOR]

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable progressive myocardial disorder that predisposes patients to ventricular arrhythmias and sudden cardiac death. Antiarrhythmic medications have an important role in reducing the frequency of ventricular arrhythmias and the morbidity associated with recurrent implantable cardioverter-defibrillator (ICD) shocks. Although several studies have examined the use of antiarrhythmic drugs in ARVC, these have been mostly retrospective in nature and inconsistent in their methodology, patient population and endpoints. Thus, current prescribing practices are largely based on expert opinion and extrapolation from other diseases. Herein, we discuss the major studies of the use of antiarrhythmics in ARVC, present the current approach employed at the Johns Hopkins Hospital and identify areas where further research is needed. Most notably, there is a great need for high-quality studies with consistent methodology and randomized controlled trial data into the use of antiarrhythmic drugs in ARVC. This would improve management of the condition and ensure antiarrhythmic prescribing is based on robust evidence. [ABSTRACT FROM AUTHOR]

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disorder of the myocardium that can lead to ventricular arrhythmia and sudden cardiac death. The condition has been identified as a significant cause of arrhythmic death among young people and athletes, therefore, early recognition of the disease by emergency clinicians is critical to prevent subsequent death. The diagnosis of ARVC can be very challenging and requires a systematic approach. This publication reviews the pathophysiology, classification, clinical presentations, and appropriate approach to diagnosis and management of ARVC. [ABSTRACT FROM AUTHOR]

Background: Hereditary cardiac arrhythmias result from mutations in various genes encoding ion channels. One major channelopathy is long QT syndrome, which has excel-lent genetic and clinical heterogeneity. Arrhythmogenic right ventricular cardiomyopathy, another hereditary arrhythmia type, also shows high genetic heterogeneity and variable expressivity. Next-generation sequencing is an effective tool to reveal the dis-ease's underlying genetic etiology. Methods: In this study, we performed clinical exome sequencing or gene panel including cardiac arrhythmia and cardiomyopathy-associated genes by next-generation sequencing in 13 unrelated patients. Results: Five pathogenic or likely pathogenic mutations, including three novel mutations, were found in the total cases. Conclusion: This research shows a strong genetic heterogeneity in the disease. In addition, the study revealed that patients with QT interval prolongation on electrocardiogram might also have mutations in genes that are not associated with long QT syndrome, such as MYLK2 and DSG2. Therefore, our data helped expand the molecular scope of long QT syndrome. It is necessary to study with a broad perspective to elucidate the underly-ing molecular etiology in patients with hereditary cardiac arrhythmias.

• Extended disease at diagnosis is frequent in patients with ARVC who need HT. • Patients have LV dysfunction, diffuse repolarization abnormalities & DSG2 mutations. • The main indication for HT is end-stage biventricular dysfunction. • Usually, it takes a long time to progress to end-stage heart failure needing HT. • The median time between ARVC diagnosis and HT was 9 years. • Primary graft dysfunction needing ECMO was frequent after HT. • Primary graft dysfunction occurred despite the absence of PH and low PVR. • Survival after HT improved over the years, with better outcomes from the 2010s. Few data exist on the characteristics and outcomes of patients with arrhythmogenic right ventricular cardiomyopathy and advanced heart failure who undergo heart transplantation. To explore the pretransplant course and outcomes of patients with arrhythmogenic right ventricular cardiomyopathy after heart transplantation. This observational retrospective monocentric study included all consecutive patients with arrhythmogenic right ventricular cardiomyopathy who underwent heart transplantation during a 13-year period (2006–2019) at Pitié-Salpêtrière University Hospital (Paris). A total of 23 patients with arrhythmogenic right ventricular cardiomyopathy underwent heart transplantation between 2006 and 2019. The median time from diagnosis to heart transplantation was 9 years, and the median age at transplantation was 50 years. At diagnosis, half of the patients had left ventricular dysfunction, 59% had extensive T-wave inversion and 43% had a history of sustained ventricular tachycardia. Only five patients were involved in intensive sport activity. Indications for heart transplantation were end-stage biventricular dysfunction in 13 patients, end-stage right ventricular heart failure in seven and electrical storm in three. Only three patients had pulmonary hypertension, and half of the patients had atrial arrhythmias. The survival rate 1 year after heart transplantation was 74% (95% confidence interval 53–88%). Eight patients experienced primary graft dysfunction needing extracorporeal membrane oxygenation. Patients with arrhythmogenic right ventricular cardiomyopathy who eventually needed heart transplantation mostly exhibited extended disease with biventricular dysfunction at diagnosis. Intensive sport activity did not seem to be a major determinant. Advanced heart failure usually occurred late in the course of the disease. Primary graft dysfunction after heart transplantation was frequent, and should be anticipated. Additional data are needed to identify the optimal timing for heart transplantation and predictors of end-stage heart failure in patients with arrhythmogenic right ventricular cardiomyopathy. [ABSTRACT FROM AUTHOR]

This study aimed at investigating whether tissue Doppler imaging (TDI) is associated with adverse events in arrhythmogenic right ventricular cardiomyopathy (ARVC). Transthoracic echocardiography was performed in 72 patients with definite (n = 63) or borderline (n = 9) ARVC diagnosed according to the 2010 Task Force Criteria and included in the prospective Zurich ARVC registry. Myocardial peak systolic tissue velocity (S′) was measured by TDI at lateral tricuspid (tricuspid S′), medial mitral (septal S′), and lateral mitral annulus (lateral S′). Association of echocardiographic parameters with outcome was assessed by univariable Cox regression. During a median follow-up of 4.9 ± 2.6 years, 6 (8.3%) patients died of cardiovascular cause or received heart transplantation and 21 (29.2%) patients developed sustained ventricular arrhythmia. Tricuspid, septal, and lateral S′ were lower in patients who died (p = 0.001; p < 0.001; p = 0.008; respectively), while tricuspid and septal S′ were lower in those with ventricular arrhythmia (p = 0.001; p = 0.008; respectively). There was a significant association of tricuspid, septal, and lateral S′ with mortality (HR = 1.61, p = 0.011; HR = 2.15, p = 0.007; HR = 1.67, p = 0.017; respectively), while tricuspid and septal S′ were associated with ventricular arrhythmia (HR = 1.20, p = 0.022; HR = 1.37, p = 0.004; respectively). Kaplan-Meier analyses demonstrated a higher freedom from mortality with tricuspid S′ >8 cm/s (p = 0.001) and from ventricular arrhythmia with S′ >10.5 cm/s (p = 0.021). This study demonstrates that TDI provides information on the ARVC phenotype, is associated with adverse events in ARVC patients, and differentiates between patients with and without adverse events. [Display omitted] • Tissue Doppler tricuspid and mitral annulus velocity useful for assessing ARVC phenotype. • Tissue Doppler tricuspid and mitral annulus velocity associated with adverse events in ARVC. • Tissue Doppler annulus velocity differentiates patients with and without adverse events in ARVC. [ABSTRACT FROM AUTHOR]

[Display omitted] [ABSTRACT FROM AUTHOR]

Homozygous frameshift variant in desmoglein 2 gene causes biventricular arrhythmogenic right ventricular cardiomyopathy Keywords: DSG2; ARVC; exome sequencing; frameshift mutation; incomplete penetrance EN DSG2 ARVC exome sequencing frameshift mutation incomplete penetrance 266 268 3 07/06/23 20230801 NES 230801 Arrhythmogenic right ventricular cardiomyopathy caused by a homozygous frameshift variant (c.2358delA) in DSG2. Whole genome sequence identified a rare homozygous pathogenic mutation of the DSG2 gene in a familial arrhythmogenic cardiomyopathy involving both ventricles. [Extracted from the article]

Background: Diverse genetic backgrounds often lead to phenotypic heterogeneity in cardiomyopathies (CMPs). Previous genotype-phenotype studies have primarily focused on the analysis of a single phenotype, and the diagnostic and prognostic features of the CMP genotype across different phenotypic expressions remain poorly understood.Objectives: We sought to define differences in outcome prediction when stratifying patients based on phenotype at presentation compared with genotype in a large cohort of patients with CMPs and positive genetic testing.Methods: Dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy, left-dominant arrhythmogenic cardiomyopathy, and biventricular arrhythmogenic cardiomyopathy were examined in this study. A total of 281 patients (80% DCM) with pathogenic or likely pathogenic variants were included. The primary and secondary outcomes were: 1) all-cause mortality (D)/heart transplant (HT); 2) sudden cardiac death/major ventricular arrhythmias (SCD/MVA); and 3) heart failure-related death (DHF)/HT/left ventricular assist device implantation (LVAD).Results: Survival analysis revealed that SCD/MVA events occurred more frequently in patients without a DCM phenotype and in carriers of DSP, PKP2, LMNA, and FLNC variants. However, after adjustment for age and sex, genotype-based classification, but not phenotype-based classification, was predictive of SCD/MVA. LMNA showed the worst trends in terms of D/HT and DHF/HT/LVAD.Conclusions: Genotypes were associated with significant phenotypic heterogeneity in genetic cardiomyopathies. Nevertheless, in our study, genotypic-based classification showed higher precision in predicting the outcome of patients with CMP than phenotype-based classification. These findings add to our current understanding of inherited CMPs and contribute to the risk stratification of patients with positive genetic testing. [ABSTRACT FROM AUTHOR]

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by risk of malignant ventricular arrhythmia (VA). ARVC is diagnosed using an array of clinical tests in the consensus-based Task Force Criteria (TFC), one of which is genetic testing.Objective: The purpose of this study was to investigate the value of genetic testing in diagnosing ARVC and its relation to the occurrence of first malignant VA.Methods: A multicenter cohort of patients with ARVC was scored using the revised 2010 TFC with and without genetic criterion, analyzing any resulting loss or delay of diagnosis. Malignant VA was defined as sustained VA (≥30-second duration at ≥100 beats/min or requiring intervention).Results: We included 402 subjects (221 [55%] male; 216 [54%] proband; 40 [27-51] years old at presentation) who were diagnosed with definite ARVC. A total of 232 subjects (58%) fulfilled genetic testing criteria. Removing the genetic criterion caused loss of diagnosis in 18 patients (4%) (11 of 216 probands [5%] and 7 of 186 relatives [4%]) and delay of diagnosis by ≥30 days in 22 patients (5%) (21 of 216 probands [10%] and 1 of 186 relative [0.5%]). A first malignant VA occurred in no patients who lost diagnosis and in 3 patients (3 of 216 probands [1%] and no relatives) during their diagnosis delay, none fatal. Time-to-event analysis showed no significant difference in time from diagnosis to malignant VA between pathogenic variant carriers and noncarriers.Conclusion: Disregarding the genetic criterion of the TFC caused loss or delay of diagnosis in 10% of patients with ARVC (40 of 402). Malignant VA occurred in 1% of cases with lost or delayed diagnosis (3 of 402), none fatal. [ABSTRACT FROM AUTHOR]

Human stems cells have sparked many novel strategies for treating heart disease and for elucidating their underlying mechanisms. For example, arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disorder that is associated with fatal arrhythmias often occurring in healthy young adults. Fibro‐fatty infiltrate, a clinical hallmark, progresses with the disease and can develop across both ventricles. Pathogenic variants in genes have been identified, with most being responsible for encoding cardiac desmosome proteins that reside at myocyte boundaries that are critical for cell‐to‐cell coupling. Despite some understanding of the molecular signaling mechanisms associated with ARVC mutations, their relationship with arrhythmogenesis is complex and not well understood for a monogenetic disorder. This review article focuses on arrhythmia mechanisms in ARVC based on clinical and animal studies and their relationship with disease causing variants. We also discuss the ways in which stem cells can be leveraged to improve our understanding of the role cardiac myocytes, nonmyocytes, metabolic signals, and inflammatory mediators play in an early onset disease such as ARVC. [ABSTRACT FROM AUTHOR]

Background: The heart-to-mediastinum ratio (H/M-Ratio) of 123 iodo-metaiodobenzylguanidine ( 123 I-MIBG) represents state-of-the-art assessment for sympathetic dysfunction in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aims to evaluate quantitative reconstruction of 123 I-MIBG uptake and to demonstrate its correlation with echocardiographic parameters., Methods: Cardiac innervation was assessed in 23 patients diagnosed with definite ARVC or borderline ARVC and 12 patients with other cardiac disease presenting arrhythmia, using quantitative 123 I-MIBG Single Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) imaging. Tracer uptake was evaluated in the left (LV) and right ventricle (RV) based on a CT scan after quantitative image reconstruction. The relationship between tracer uptake and echocardiographic parameter data was examined., Results: Absolute quantification of 123 I-MIBG uptake in the LV and RV is feasible and correlates accurately with the gold standard H/M Ratio. When comparing sensitivity and specificity, the area under the curve (AUC) favors standardized uptake value (SUV) of the RV over the right-ventricle-to-mediastinum-ratio (RV/M-Ratio) for diagnosing ARVC. A reduced RV-SUV in patients with definite ARVC is associated with reduced RV function. RV polar maps revealed globally reduced 123 I-MIBG uptake without segment-specific reduction in the RV., Conclusions: Quantitative 123 I-MIBG SPECT in ARCV patients offers robust potential for clinical reporting and demonstrates a significant correlation with RV function. Segmental RV analysis needs to be evaluated in larger samples. In summary, cardiac 123 I-MIBG imaging using SUV could facilitate image-guided therapy in patients diagnosed with ARVC., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Dilated cardiomyopathy (DCM) is an umbrella term entailing a wide variety of genetic and non-genetic etiologies, leading to left ventricular systolic dysfunction and dilatation, not explained by abnormal loading conditions or coronary artery disease. The clinical presentation can vary from asymptomatic to heart failure symptoms or sudden cardiac death (SCD) even in previously asymptomatic individuals. In the last 2 decades, there has been striking progress in the understanding of the complex genetic basis of DCM, with the discovery of additional genes and genotype–phenotype correlation studies. Rigorous clinical work-up of DCM patients, meticulous family screening, and the implementation of advanced imaging techniques pave the way for a more efficient and earlier diagnosis as well as more precise indications for implantable cardioverter defibrillator implantation and prevention of SCD. In the era of precision medicine, genotype-directed therapies have started to emerge. In this review, we focus on updates of the genetic background of DCM, characteristic phenotypes caused by recently described pathogenic variants, specific indications for prevention of SCD in those individuals and genotype-directed treatments under development. Finally, the latest developments in distinguishing athletic heart syndrome from subclinical DCM are described. [ABSTRACT FROM AUTHOR]

Background: Hereditary cardiac arrhythmias result from mutations in various genes encoding ion channels. One major channelopathy is long QT syndrome, which has excellent genetic and clinical heterogeneity. Arrhythmogenic right ventricular cardiomyopathy, another hereditary arrhythmia type, also shows high genetic heterogeneity and variable expressivity. Next-generation sequencing is an effective tool to reveal the disease's underlying genetic etiology. Methods: In this study, we performed clinical exome sequencing or gene panel including cardiac arrhythmia and cardiomyopathy-associated genes by next-generation sequencing in 13 unrelated patients. Results: Five pathogenic or likely pathogenic mutations, including three novel mutations, were found in the total cases. Conclusion: This research shows a strong genetic heterogeneity in the disease. In addition, the study revealed that patients with QT interval prolongation on electrocardiogram might also have mutations in genes that are not associated with long QT syndrome, such as MYLK2 and DSG2. Therefore, our data helped expand the molecular scope of long QT syndrome. It is necessary to study with a broad perspective to elucidate the underlying molecular etiology in patients with hereditary cardiac arrhythmias. [ABSTRACT FROM AUTHOR]

BackgroundArrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable heart muscle disorder that predominantly affects the right ventricle. Mutations in genes that encode components of desmosomes, the adhesive junctions that connect cardiomyocytes, are the predominant cause of ARVC. A case with novel heterozygous mutation in the LAMA2 gene is reported here. The protein encoded by LAMA2 gene is the α2 chain of laminin-211 protein, which establishes a stable relationship between the muscle fiber membrane and the extracellular matrix. We explored the potential mechanism and the relationship between the mutation and ARVC.Case PresentationAt the age of 8, the patient developed syncope and palpitation after exercise. Dynamic electrocardiogram recorded continuous premature ventricular beats, and MRI showed the right ventricle was significantly enlarged and there were many localized distensions at the edge of the right ventricular wall. The patient was diagnosed with ARVC and received heart transplantation at the age of 14 due to severe heart dysfunction. The myocardial histological pathological staining revealed a large amount of fibrosis and adipose migration. Whole exome sequencing (WES) identified the heterozygous mutation in the LAMA2 gene [NM_000426.3: c.8842G > A (p.G2948S)]. This is the first report of these variants. Analysis was performed on genetic disorders to reveal splice site changes and damage to protein structure. LAMA2 p.G2948S predicted unstable protein structure and impaired function. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were established. RNA-seq and the western blot were performed on IPSC-CMs to explore the ARVC-related signaling pathway.ConclusionThis is the first case report to describe an ARVC phenotype in patients possessing a novel LAMA2 c.8842G > A (p.G2948S) mutation. Our results aid in understanding of the pathogenesis of ARVC. The molecular mechanism of LAMA2 leading to ARVC disease still needs further study.

Rui Huang,1,* YinHua Luo,2,* Jingbo Zhao,1 Ke Su,1 YuHua Lei,1 Yuanhong Li1 1Cardiovascular Disease Center, Central Hospital of Tujia and Miao Autonomous Prefecture, Enshi Clinical College of Wuhan University, Enshi Prefecture, 445000, Hubei Province, People’s Republic of China; 2Department of Central Hospital of Tujia and Miao Autonomous Prefecture, Hubei University of Medicine, Shiyan, 442000, Hubei Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuanhong LiCardiovascular Disease Center, Central Hospital of Tujia and Miao Autonomous Prefecture, Enshi Clinical College of Wuhan University, Enshi Prefecture, No. 158 Wuyang Avenue, Enshi City, Hubei Province, People’s Republic of ChinaEmail lyh0101@vip.163.comBackground: ARVC is a rare genetic-related disease characterized by fibrous fat replacement in the ventricular myocardium, caused by mutations in genes encoding for the desmosomal proteins, such as the desmoglein-2 gene (DSG2). It is reported in the literature that other genetic factors may play a role in disease penetrance. Herein, we report a Chinese proband with ARVC, which was probably caused by DSG2 p.Val149Ile mutation as genetic background when carrying heterozygous PRRT2 p.Arg217ProfsTer8 mutation.Case Presentation: A 17-year-old male with a history of paroxysmal kinesigenic dyskinesia (PKD) presented to the hospital for syncope induced by ventricular tachycardia. According to relevant clinical data and the diagnostic criteria of ARVC, a precise positive diagnosis of ARVC was finally made. Gene testing revealed that the patient carried a DSG2 heterozygous missense mutation (NM_001943: exon5: c.445G>A, p.Val149Ile) as well as frameshift mutation of PRRT2 (NM_001256442: exon2: p. Arg217Profs Ter8).Conclusion: This is the first time to report a Chinese proband with ARVC and a history of PKD carrying both DSG2 p. val149ile mutation and PRRT2 p. Arg217ProfsTer8 mutation, which can provide a new direction for gene screening of patients with ARVC and further supplements for its diagnostic criteria.Keywords: arrhythmogenic right ventricular cardiomyopathy, ARVC, desmosomal proteins, desmoglein-2 gene, DSG2

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable progressive myocardial disorder that predisposes patients to ventricular arrhythmias and sudden cardiac death. Antiarrhythmic medications have an important role in reducing the frequency of ventricular arrhythmias and the morbidity associated with recurrent implantable cardioverter-defibrillator (ICD) shocks. Although several studies have examined the use of antiarrhythmic drugs in ARVC, these have been mostly retrospective in nature and inconsistent in their methodology, patient population and endpoints. Thus, current prescribing practices are largely based on expert opinion and extrapolation from other diseases. Herein, we discuss the major studies of the use of antiarrhythmics in ARVC, present the current approach employed at the Johns Hopkins Hospital and identify areas where further research is needed. Most notably, there is a great need for high-quality studies with consistent methodology and randomized controlled trial data into the use of antiarrhythmic drugs in ARVC. This would improve management of the condition and ensure antiarrhythmic prescribing is based on robust evidence.

Aims Exercise increases arrhythmia risk and cardiomyopathy progression in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients, but the mechanisms remain unknown. We investigated transcriptomic changes caused by endurance training in mice deficient in plakophilin-2 (PKP2cKO), a desmosomal protein important for intercalated disc formation, commonly mutated in ARVC and controls. Methods and results Exercise alone caused transcriptional downregulation of genes coding intercalated disk proteins. The changes converged with those in sedentary and in exercised PKP2cKO mice. PKP2 loss caused cardiac contractile deficit, decreased muscle mass and increased functional/transcriptomic signatures of apoptosis, despite increased fractional shortening and calcium transient amplitude in single myocytes. Exercise accelerated cardiac dysfunction, an effect dampened by pre-training animals prior to PKP2-KO. Consistent with PKP2-dependent muscle mass deficit, cardiac dimensions in human athletes carrying PKP2 mutations were reduced, compared to matched controls. Conclusions We speculate that exercise challenges a cardiomyocyte "desmosomal reserve" which, if impaired genetically (e.g. PKP2 loss), accelerates progression of cardiomyopathy. [ABSTRACT FROM AUTHOR]

The Wnt-activated $\beta $ -catenin and $Ca^{2+}$ ions play a critical role in the regulation of physiology of cardiomyocytes. The dysregulation of both the components causes the replacement of myocardial mass right ventricle with fibrous and adipose tissue which results in the condition of Arrhythmogenic Right ventricular Cardiomyopathy (ARVC). The major hurdle in ARVC treatment is lack of effective therapies targeting the underlying root molecular biomarkers of pathogenesis. Despite major advancements in interpreting the mechanism of ARVC etiology, the dynamics of molecular links in underlying biological machinery are still being delineated. Previously, formal methods based computational modeling techniques including kinetic logic, Petri Nets, hybrid automata and static analysis have greatly contributed in increasing our comprehension to decipher the molecular systems dynamics. It has allowed the identification of biomarkers which can be utilized for target-based therapies owing to meticulous biological abstractions along with implementing reference map that confines together the discrete biological insights. In this study, we have performed the static analysis of the Biological Regulatory Networks (BRNs) of the Wnt/ $\beta $ -catenin and Wnt/Ca 2+ signaling pathways to identify the significant biomarkers for ARVC. The abstracted qualitative models of afore mentioned BRNs are first constructed in GINsim software tool and then these models are converted into Automata Network (ANs) Models using Pint software tool. The fix point analysis is performed which contributed in pinpointing the possible therapeutic strategies for ARVC treatment by identification of drug targets such as Gsk3, Ck1 and Axin in Wnt/ $\beta $ -catenin AN and Bak & Bax, Parp, mCalpain, JNk and CIn in Wnt/Ca 2+ AN. Moreover, the Bcl2 gene is identified as novel therapeutic remedy in both the ANs of ARVC. The Bcl2 gene prevents the cardiac apoptosis via positive regulation of Wnt in Wnt/ $\beta $ -catenin AN and through inhibition of Bak & Bax (apoptotic component) in Wnt/Ca 2+ AN. The current study tends to fulfill the scientific gap between wet lab studies and provides cost effective and time saving computational strategies for an effectual treatment for deadly diseases like ARVC.

Exercise has a deleterious effect on the phenotypic expression of arrhythmogenic right ventricular cardiomyopathy (ARVC) and increases the risk of sudden death. The aim of the study was to determine the prevalence and correlates of exercise-induced arrhythmias during exercise tolerance test (ETT) in patients with ARVC. Between 2010 and 2019, 30 (47% males, mean age 42 ± 12 years) consecutive patients with a definite diagnosis of ARVC underwent a full genotypic and phenotypic characterization at our center. Exercise-induced arrhythmic response (EIAR) was defined by the development of complex or repetitive ventricular arrhythmias after stage 2 of exercise. A heart rate ≥ 85% of predicted was achieved by 23 (77%) patients. In 16 (53%) cases, a desmosomal pathogenic variant was found [most commonly PKP2 (n = 7) and DSP (n = 3)]. In 12 (40%) cases, an EIAR was observed. In 2 (6%) patients, ETT was interrupted due to the onset of ventricular tachycardia (sustained with a LBBB/inferior axis pattern in one case, and non-sustained LBBB/superior axis pattern in the other). Mean body surface area (BSA)-indexed left ventricular (LV) end-diastolic volumes (EDV) were higher in the EIAR group (92 ± 12 ml/m2 vs 80 ± 7 ml/m2, p = 0.002), as well as right ventricular EDV/BSA (110 ± 18 ml/m2 vs 91 ± 27 ml/m2, p = 0.04). Subepicardial/mid-wall LV late gadolinium enhancement (LGE) was more common in the EIAR group (67% vs 22%, p = 0.01). ARVC patients commonly exhibit exercise-induced ventricular arrhythmias. Patients with more significant RV remodeling and LV involvement (based on the presence of LV dilatation and LGE) appear more susceptible to exercise-induced arrhythmias. [ABSTRACT FROM AUTHOR]

Background: Mutations in genes encoding desmosomal proteins are the leading cause of arrhythmogenic cardiomyopathy (ACM). The majority of the inherited ACM cases demonstrate autosomal dominant genotype. Several cases with the homozygous DSG2 c.1592T>G (p.F531C) variant genotype demonstrate adverse clinical outcomes, but the roles of associated genetic mutations are not clear. In this report, we describe three ACM cases with the homozygous DSG2 c.1592T>G (p.F531C) variant genotype combined with additional heterozygous cardiomyopathy-related genetic mutations that cause aggravated clinical manifestations and worse clinical outcomes., Case Presentation: The three reported probands demonstrated similar clinical presentations such as heart failure, cardiac enlargement, and lethal arrhythmias. All of them experienced sudden cardiac death (SCD) before undergoing implantable cardioverter defibrillator (ICD) or heart transplantations. Whole-exome sequencing analysis demonstrated that the three patients inherited the homozygous DSG2 c.1592T>G (p.F531C) variant. Furthermore, probands I, II, and III also inherited additional heterozygous cardiomyopathy-associated mutations, including DSP c.7883T>C, SCN5a c.3577C>T, or MYH7 c.427C>T, respectively. These variants were confirmed as pathogenetic variants. A systematic review of all the reported ACM cases with the homozygous DSG2 variants suggested that the additional genetic mutations contributed to the early age onset of ACM and lethal cardiac events., Conclusion: In conclusion, we report three rare cases of ACM with the same homozygous DSG2 variant in combination with additional heterozygous mutations in cardiomyopathy-associated genes. A systematic review of all the ACM cases with homozygous DSG2 variants demonstrated that the additional genetic variants contributed to the aggravated clinical manifestations and worse clinical symptoms of the ACM patients because of homozygous DSG2 mutations, including early disease onset and lethal cardiac events. Our data suggested that comprehensive genetic evaluation should be performed to identify any potential additional pathogenic variants that may significantly influence the clinical prognosis and outcomes of patients with ACM. The knowledge of underlying molecular mutations would be useful in designing better therapeutic strategies for ACM patients with multiple genetic mutations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wei, Li, Liu, Zhou, Qiu, Liu, Huang and Liu.)

Aims: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by progressive myocardial dysfunction and associated with an increased risk of major cardiovascular (CV) events. To determine right heart strain (ventricular and atrial global longitudinal strain (RVGLS and RAGLS) in patients with definite ARVC and its association with adverse events during follow-up., Methods and Results: RVGLS and RAGLS were analysed in focused right heart apical views from 70 patients using TomTec ImageArena and association with a composite endpoint was determined (sustained ventricular arrhythmia and cardiovascular death). Over a median follow-up duration of 4.9 years, 26 (37%) patients met the endpoint. RVGLS was significantly impaired in the event group (-11.5 [-13.3 to -10.2] %) vs. the no-event group (-15.8 [-17.1 to -14.5] %, P < 0.001), and so was RAGLS (22.8 [21.4-27.4] % vs. 31.5 [25.1-39.6] %, respectively, P < 0.001). In Cox regression, RVGLS (HR 1.36, P < 0.001) and RAGLS (HR 0.92, P = 0.002) were associated with a higher risk of adverse events. In multivariable Cox regression models, RVGLS and RAGLS remained independent of and were incremental to age, gender, and conventional RV parameters, and model fitness was improved when RVGLS and RAGLS were applied together rather than alone., Conclusion: RVGLS and RAGLS are more impaired in patients with adverse events and associated with adverse events independent of age, gender, and conventional RV parameters. When RVGLS and RAGLS are applied together, prediction models are improved suggesting that right heart strain may form part of the echocardiographic routine protocol in patients with ARVC., Competing Interests: Conflict of interest: A.M.S. received educational grants from Abbott, Bayer Healthcare, Biosense Webster, Biotronik, Boston Scientific, BMS/Pfizer, and Medtronic; and speaker fees from Boston Scientific and BMS/Pfizer. The other authors report no potential conflicts of interest related to this work., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: While late gadolinium enhancement (LGE) is proposed as a diagnostic criterion for arrhythmogenic right ventricular cardiomyopathy (ARVC), the potential of LGE to distinguish ARVC from differentials remains unknown. We aimed to assess the diagnostic value of LGE for ARVC diagnosis., Methods: We included 132 subjects (60% male, 47 ± 11 years) who had undergone cardiac magnetic resonance imaging with LGE assessment for ARVC or ARVC differentials. ARVC was diagnosed as per 2010 Task Force Criteria (n = 55). ARVC differentials consisted of familial/genetic dilated cardiomyopathy (n = 25), myocarditis (n = 13), sarcoidosis (n = 20), and amyloidosis (n = 19). The diagnosis of all differentials was based on the most current standard of reference. The presence of LGE was evaluated using a 7-segment right ventricle (RV) and 17-segment left ventricle (LV) model. Subsequently, we assessed LGE patterns for every patient individually for fulfilling LV- and/or RV-LGE per Padua criteria, independent of their clinical diagnosis (i.e. phenotype). Diagnostic values were analyzed using sensitivity and specificity for any RV-LGE, any LV-LGE, RV-LGE per Padua criteria, and prevalence graphs for LV-LGE per Padua criteria. The optimal integration of LGE for ARVC diagnosis was determined using classification and regression tree analysis., Results: One-third (38%) of ARVC patients had RV-LGE, while half (51%) had LV-LGE. RV-LGE was less frequently observed in ARVC vs non-ARVC patients (38% vs 58%, p = 0.034) leading to a poor discriminatory potential (any RV-LGE: sensitivity 38%, specificity 42%; RV-LGE per Padua criteria: sensitivity 36%, specificity 44%). Compared to ARVC patients, non-ARVC patients more often had LV-LGE (91% vs 51%, p < 0.001) which was also more globally distributed (median 9 [interquartile range (IQR): 3-13] vs 0 [IQR: 0-3] segments, p < 0.001). The absence of anteroseptal and absence of extensive (≥5 segments) mid-myocardial LV-LGE, and absence of moderate (≥2 segments) mid-myocardial LV-LGE predicted ARVC with good diagnostic performance (sensitivity 93%, specificity 78%)., Conclusion: LGE is often present in ARVC differentials and may lead to false positive diagnoses when used without knowledge of LGE patterns. Moderate RV-LGE without anteroseptal and mid-myocardial LV-LGE is typically observed in ARVC., Competing Interests: Declaration of competing interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. A.G. has served as part of the advisory board of LEXEO Therapeutics for unrelated work. The remaining authors have no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Special Operations Servicemembers presenting with palpitations, pre-syncope, or exertional syncope during rigorous physical training are often experiencing a benign condition; however, life-threatening etiologies should be considered. We describe a 43-year-old Special Operator who presented to his medics during selection physical assessment testing with palpitations and lightheadedness, with a subsequent workup revealing arrhythmogenic right ventricular cardiomyopathy (ARVC). His initial electrocardiogram was unremarkable without characteristic ARVC changes. Outpatient evaluation with ambulatory cardiac monitoring recorded numerous episodes of non-sustained ventricular tachycardia. Transthoracic echocardiography demonstrated findings concerning for ARVC, with subsequent cardiac MRI confirming the diagnosis via the 2020 Padua criteria. Management includes activity modification, class III anti-arrhythmic medications, and possible placement of an implantable cardioverter defibrillator to prevent sudden cardiac death. This case demonstrates the importance of maintaining high clinical suspicion for rare diagnoses that present with exertional palpitations, such as arrhythmogenic right ventricular cardiomyopathy, in even our fittest Special Operators., (2024.)

Competing Interests: All the authors have no conflicts of interest to disclose.

[Display omitted] [ABSTRACT FROM AUTHOR]

There is growing recognition that COVID-19 does cause cardiac sequelae. The underlying mechanisms involved are still poorly understood to date. Viral infections, including COVID-19, have been hypothesized to contribute to autoimmunity, by exposing previously hidden cryptic epitopes on damaged cells to an activated immune system. Given the high incidence of cardiac involvement seen in COVID-19, our aim was to determine the frequency of anti-DSG2 antibodies in a population of post COVID-19 patients. 300 convalescent serum samples were obtained from a group of post COVID-19 infected patients from October 2020 to February 2021. 154 samples were drawn 6 months post-COVID-19 infection and 146 samples were drawn 9 months post COVID infection. 17 samples were obtained from the same patient at the 6- and 9- month mark. An electrochemiluminescent-based immunoassay utilizing the extracellular domain of DSG2 for antibody capture was used. The mean signal intensity of anti-DSG2 antibodies in the post COVID-19 samples was significantly higher than that of a healthy control population (19 ± 83.2 in the post-COVID-19 sample vs. 2.1 ± 7.2 (p < 0. 0001) in the negative control healthy population). Of note, 29.3% of the post COVID-19 infection samples demonstrated a signal higher than the 90th percentile of the control population and 8.7% were higher than the median found in ARVC patients. The signal intensity between the 6-month and 9-month samples did not differ significantly. We report for the first time that recovered COVID-19 patients demonstrate significantly higher and sustained levels of anti-DSG2 autoantibodies as compared to a healthy control population, comparable to that of a diagnosed ARVC group. [Display omitted] • High levels of anti-DSG2 antibodies were found in post COVID 19 serum. • The antibodies persisted long term- at least 9 months post COVID 19 infection. • First demonstration of a sustained rise of specific antibody implicated in cardiac pathology in COVID 19. [ABSTRACT FROM AUTHOR]