Year: 2025
Type: editorial
Abstract: Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a predominantly genetically determined heart muscle disease characterized by progressive loss of cardiomyocytes and fibrofatty replacement. 1 Disruption of normal myocardial tissue in ARVC can result in severe right ventricular (RV) dysfunction, life-threatening arrhythmias and sudden cardiac death. 2 Up to 60% of patients with ARVC have pathogenic or likely pathogenic variants in genes encoding the cardiac desmosome.3 While significant efforts have been made into understanding the desmosomal basis for this disease, ARVC linked with non-desmosomal genetic mutations remain mostly undercharacterized.ARVC Type 5 is caused by the p.S358L mutation in TMEM43, a transmembrane protein localized to the nuclear envelope with unknown function.4,5 This mutation is one of the most aggressive and penetrant forms of cardiomyopathy, and no currently available therapies exist to prevent the disease.The only options for patients carrying the mutation are to address the symptoms, which might require an ICD implantation or even a heart transplantation.6 While different models have been generated to characterize the ARVC5-associated mutation, 7-10 the patho-mechanism of the mutation remains unknown, highlighting the importance and need for additional models and methodologies to investigate this disease.In this issue of Circulation Research, Lalaguna et al. 11 demonstrate that overexpression of wild-type human TMEM43 through adeno-associated virus (AAV)-mediated delivery improves cardiac function and delays disease progression in mouse models of ARVC5, demonstrating its potential as a gene therapy.The authors previous publication characterized transgenic mouse models overexpressing either human WT TMEM43 or TMEM43 p.S358L, specifically in cardiomyocytes under the control of the α-myosin heavy chain promoter.12 Transgenic mice overexpressing human TMEM43 p.S358L alone showed a significantly reduced survival in male and female littermates, distinct from WT human TMEM43 overexpressing mice.
Source: Circulation Research
Institution: University of California San Diego
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4409317261