Aims: Arrhythmogenic cardiomyopathy (AC) is one of the most common inherited cardiomyopathies, characterized by progressive fibro-fatty replacement in the myocardium. Clinically, AC manifests itself with ventricular arrhythmias, syncope, and sudden death and shows wide inter- and intra-familial variability. Among the causative genes identified so far, those encoding for the desmosomal proteins plakophilin-2 (PKP2), desmoplakin (DSP), and desmoglein-2 (DSG2) are the most commonly mutated. So far, little is known about the molecular mechanism(s) behind such a varied spectrum of phenotypes, although it has been shown that the causative mutations not only lead to structural abnormalities but also affect the miRNA profiling of cardiac tissue. Here, we aimed at studying the pathogenic effects of a nonsense mutation of the desmoglein-2 gene, both at the structural level and in terms of miRNA expression pattern.
Methods And Results: We generated transgenic mice with cardiomyocyte-specific overexpression of a FLAG-tagged human desmoglein-2 harbouring the Q558* nonsense mutation found in an AC patient. The hearts of these mice showed signs of fibrosis, decrease in desmosomal size and number, and reduction of the Wnt/β-catenin signalling. Genome-wide RNA-Seq performed in Tg-hQ hearts and non-transgenic hearts revealed that 24 miRNAs were dysregulated in transgenic animals. Further bioinformatic analyses for selected miRNAs suggested that miR-217-5p, miR-499-5p, and miR-708-5p might be involved in the pathogenesis of the disease.
Conclusion: Down-regulation of the canonical Wnt/β-catenin signalling might be considered a common key event in the AC pathogenesis. We identified the miRNA signature in AC hearts, with miR-708-5p and miR-217-5p being the most up-regulated and miR-499-5p the most down-regulated miRNAs. All of them were predicted to be involved in the regulation of the Wnt/β-catenin pathway and might reveal the potential pathophysiology mechanisms of AC, as well as be useful as therapeutic targets for the disease.
Download full-text PDF |
Source |
---|---|
http://dx.doi.org/10.1093/cvr/cvy253 | DOI Listing |
JACC Case Rep
January 2025
Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Structural abnormalities within the right ventricular outflow tract (RVOT) can present similarly to Brugada syndrome. A 34-year-old woman with no medical history presented with polymorphic ventricular tachycardia/ventricular fibrillation cardiac arrest and initial electrocardiogram showed type I Brugada pattern. Cardiac magnetic resonance imaging revealed prominent tissue thickening at the RVOT with late gadolinium enhancement.
View Article and Find Full Text PDFJACC Adv
December 2024
Department of Medicine, The Cardiac Clinic, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa.
Background: Cardiomyopathies are an important cause of heart failure in Africa yet there are limited data on etiology and clinical phenotypes.
Objectives: The IMHOTEP (African Cardiomyopathy and Myocarditis Registry Program) was designed to systematically collect data on individuals diagnosed with cardiomyopathy living in Africa.
Methods: In this multicenter pilot study, patients (age ≥13 years) were eligible for inclusion if they had a diagnosis of cardiomyopathy or myocarditis.
J Arrhythm
February 2025
Department of Cardiology ULSSM Lisbon Portugal.
Background: Integration of preprocedural imaging techniques in ventricular tachycardia (VT) ablation may improve the identification of arrhythmogenic substrates, particularly relevant for patients with nonischemic cardiomyopathy (NICM) with sub-optimal outcomes. We assessed the impact of advanced preprocedural imaging on the safety and long-term efficacy of radiofrequency catheter ablation (RCA) for VT, comparing patients with NICM and ischemic cardiomyopathy (ICM).
Methods: In this prospective, single-center study, consecutive patients referred for scar-related VT ablation underwent multidetector computed tomography (MDCT) and late gadolinium enhancement cardiac magnetic resonance (LGE-CMR).
Am J Cardiol
January 2025
Department of Cardiology, Heart Lung Center, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, The Netherlands. Electronic address:
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.
View Article and Find Full Text PDFJ Cardiovasc Electrophysiol
January 2025
Department of Cardiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China.
Ryanodine receptor 2 (RyR2) protein, a calcium ion release channel in the sarcoplasmic reticulum (SR) of myocardial cells, plays a crucial role in regulating cardiac systolic and diastolic functions. Mutations in RyR2 and its dysfunction are implicated in various congenital heart diseases (CHDs). Studies have shown that mutations in the RYR2 gene, which encodes the RyR2 protein, are linked to several cardiac arrhythmias, including catecholaminergic polymorphic ventricular tachycardia (CPVT), long QT syndrome (LQTS), calcium release deficiency syndrome (CRDS), and atrial fibrillation (AF).
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!