Prognostic Role of Myocarditis-Like Episodes and Their Treatment in Patients With Pathogenic Desmoplakin Variants.

Background: Inflammatory, myocarditis-like episodes precede and are associated with higher risk of sustained ventricular arrhythmias and heart failure in patients with pathogenic or likely pathogenic desmoplakin (DSP) variants. Whether the recurrence and treatment of myocarditis-like episodes influence the outcomes in this population is unknown. This study aimed to assess the prognostic impact of the recurrence and treatment of myocarditis-like episodes in patients with pathogenic or likely pathogenic DSP variants.

Titin-related familial dilated cardiomyopathy: factors associated with disease onset.

Background And Aims: Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv.

Methods: An international multicentre retrospective observational study was performed in families with TTNtv-related DCM.

Diagnostic Criteria and Disease Staging for Desmoplakin Cardiomyopathy.

Background: Desmoplakin (DSP) cardiomyopathy, caused by variants in the gene , is a unique subtype of cardiomyopathy distinct from typical dilated or arrhythmogenic right ventricular cardiomyopathies. Specific diagnostic and disease staging criteria have yet to be developed for DSP cardiomyopathy.

Objective: Utilizing a large cohort of DSP cardiomyopathy patients and their genotype-positive family members, this study aims to develop diagnostic and disease staging criteria for DSP cardiomyopathy.

Machine Learning Models Enhance Prediction of Arrhythmogenic Right Ventricular Cardiomyopathy.

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a leading contributor to sudden cardiac death worldwide, yet its diagnosis remains complex, expensive and time-consuming. Machine-learning (ML) classifiers offer a practical solution by delivering rapid, scalable predictions that can lessen dependence on expert interpretation and speed clinical decision-making. Here, we benchmarked eight ML algorithms for ARVC detection using area-under-the-curve (AUC) and accuracy as primary metrics.

Family Screening in Relatives at Risk for Plakophilin-2-Associated Arrhythmogenic Right Ventricular Cardiomyopathy.

Background: Penetrance and risk of ventricular arrhythmias (VAs) in arrhythmogenic right ventricular cardiomyopathy (ARVC) are increasingly recognized as being genotype specific. Therefore, genotype-informed family screening protocols may lead to safer and more personalized recommendations than the current one-size-fits-all screening recommendations. We aimed to develop a safe, evidence-based plakophilin-2 ()-specific longitudinal screening algorithm.

Reproductive decision-making for Barth syndrome carriers: Unexplored complexities.

Reproductive decision-making is a complex process, especially for carriers of a pathogenic X-linked genetic variant. Studies of X-linked carriers have identified various personal values and concerns that influence reproductive decisions, but these studies provide limited insight into decisional conflict during the reproductive decision-making process. This study aims to explore how carriers of variants known to cause Barth syndrome, a rare X-linked disorder, navigate and experience decisional conflict during reproductive decision-making.

Natural History and Clinical Outcomes of Patients With Variant-Related Arrhythmogenic Right Ventricular Cardiomyopathy.

Background: Genetic variants in desmosomal cadherins, desmoglein 2 () and desmocollin 2 (), cause a distinct form of arrhythmogenic right ventricular cardiomyopathy (ARVC), which remains poorly reported. In this study, we aimed to provide a comprehensive description of the phenotypic expression, natural history, and clinical outcomes of patients with this ARVC subset.

Methods: Genetic and clinical data of and variant carriers were collected from 5 countries in Europe and Asia.

Predicted Risk of Ventricular Arrhythmias in a Genome-First Population With Genetic Risk for Arrhythmogenic Right Ventricular Cardiomyopathy.

Background: Population genomic screening for desmosome variants associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) may facilitate early disease detection and protective intervention. The validated ARVC risk calculator offers a novel means to risk stratify individuals with diagnosed ARVC, but predicted risk in the context of genomic screening identification has not been explored.

Methods: Individuals harboring a pathogenic/likely pathogenic variant in a desmosome gene (, , , or ) were identified through the Geisinger MyCode Genomic Screening and Counseling program.

Genes Associated With Hypertrophic Cardiomyopathy: A Reappraisal by the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel.

Background: Hypertrophic cardiomyopathy (HCM) is an inherited cardiac condition affecting ∼1 in 500 and exhibits marked genetic heterogeneity. Previously published in 2019, 57 HCM-associated genes were curated providing the first systematic evaluation of gene-disease validity.

Objectives: The authors report work by the Clinical Genome Resource Hereditary Cardiovascular Disease (HCVD) Gene Curation Expert Panel (GCEP) to reappraise the clinical validity of previously curated and new putative HCM genes.

Natural History, Phenotype Spectrum, and Clinical Outcomes of Desmin ()-Associated Cardiomyopathy.

Background: Pathogenic/likely pathogenic (LP) desmin () variants cause heterogeneous cardiomyopathy and skeletal myopathy phenotypes. Limited data suggest a high incidence of major adverse cardiac events (MACEs), including cardiac conduction disease, sustained ventricular arrhythmias (VA), and heart failure (HF) events (HF hospitalization, left ventricular assist device/cardiac transplant, HF-related death) in patients with pathogenic/LP variants. However, pleiotropic presentation and small cohort sizes have limited clinical phenotype and outcome characterization.

Causes TRPV4-Mediated Autosomal Recessive Arrhythmogenic Cardiomyopathy.

Background: Arrhythmogenic cardiomyopathy (ACM) is one of the leading causes of sudden cardiac death in children, young adults, and athletes and is characterized by the fibro-fatty replacement of the myocardium, predominantly of the right ventricle. Sixty percent of patients with ACM have a known genetic cause, but for the remainder, the pathogenesis is unknown. This lack of mechanistic understanding has slowed the development of disease-modifying therapies, and children with ACM have a high degree of morbidity and mortality.

Arrhythmic Risk Stratification of Carriers of Filamin C Truncating Variants.

Importance: Filamin C truncating variants (FLNCtv) are a rare cause of cardiomyopathy with heterogeneous phenotypic presentations. Despite a high incidence of life-threatening ventricular arrhythmias and sudden cardiac death (SCD), reliable risk predictors to stratify carriers of FLNCtv are lacking.

Objective: To determine factors predictive of SCD/major ventricular arrhythmias (MVA) in carriers of FLNCtv.

Endurance exercise promotes episodes of myocardial injury in individuals with a pathogenic desmoplakin (DSP) variant.

Background: Desmoplakin (DSP) variants are associated with left predominant or biventricular arrhythmogenic cardiomyopathy. Exercise promotes penetrance and sustained ventricular arrhythmias (VAs) in right-sided arrhythmogenic right ventricular cardiomyopathy, but its effect is unknown in DSP variant carriers.

Objective: The purpose of this study was to assess whether exercise is associated with clinical outcomes in individuals with a pathogenic or likely pathogenic DSP variant.

Arrhythmogenic Cardiomyopathy: Towards Genotype Based Diagnoses and Management.

Arrhythmogenic cardiomyopathy (ACM) is a genetically heterogeneous inherited cardiomyopathy with an estimated prevalence of 1:5000-10 000 that predisposes patients to life-threatening ventricular arrhythmias (VA) and sudden cardiac death (SCD). ACM diagnostic criteria and risk prediction models, particularly for arrhythmogenic right ventricular cardiomyopathy (ARVC), the most common form of ACM, are typically genotype-agnostic, but numerous studies have established clinically meaningful genotype-phenotype associations. Early signs of ACM onset differ by genotype indicating the need for genotype-specific diagnostic criteria and family screening paradigms.

Impaired Atrial and Ventricular Strain Predicts Heart Failure in Arrhythmogenic Right Ventricular Cardiomyopathy.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) increases the risk of heart failure (HF) and arrhythmias. Speckle-tracking echocardiography (STE) detects myocardial dysfunction, but its predictive role for HF in this population remains unclear.

Methods: Seventy-one patients with ARVC (age 43.

Patient Perceptions of Emerging Gene Therapies for Arrhythmogenic Right Ventricular Cardiomyopathy.

Background: No disease-specific therapy currently exists for arrhythmogenic right ventricular cardiomyopathy (ARVC), a progressive cardiogenetic condition conferring elevated risk for ventricular arrhythmias, heart failure, and sudden cardiac death. Emerging gene therapies have the potential to fill this gap. However, little is known about how adults with ARVC, or any other inherited cardiomyopathy or arrhythmia syndrome, appraise the risks and benefits of gene therapy research and which considerations may influence their decisions about clinical trial participation.

Promise and Peril of a Genotype-First Approach to Mendelian Cardiovascular Disease.

Precision medicine, which among other aspects includes an individual's genomic data in diagnosis and management, has become the standard-of-care for Mendelian cardiovascular disease (CVD). However, early identification and management of asymptomatic patients with potentially lethal and manageable Mendelian CVD through screening, which is the promise of precision health, remains an unsolved challenge. The reduced costs of genomic sequencing have enabled the creation of biobanks containing in-depth genetic and health information, which have facilitated the understanding of genetic variation, penetrance, and expressivity, moving us closer to the genotype-first screening of asymptomatic individuals for Mendelian CVD.

Desmoplakin mutations in cardiac fibroblasts cause TGFβ1-mediated pathological fibrogenesis in desmoplakin cardiomyopathy via beclin-1 regulation.

Background: Pathological fibrosis is a major finding in cardiovascular diseases and can result in arrhythmia and heart failure. Desmosome gene mutations can lead to arrhythmogenic cardiomyopathy (ACM). Among ACM, pathogenic desmoplakin ( ) variants cause a distinctive cardiomyopathy with excessive cardiac fibrosis that could precede ventricular dysfunction.