Fibrosis in Arrhythmogenic Cardiomyopathy: The Phantom Thread in the Fibro-Adipose Tissue

Abstract

Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disorder, predisposing to malignant ventricular arrhythmias leading to sudden cardiac death, particularly in young and athletic patients. Pathological features include a progressive loss of myocardium with fibrous or fibro-fatty substitution. During the last few decades, different clinical aspects of ACM have been well investigated but still little is known about the molecular mechanisms that underlie ACM pathogenesis, leading to these phenotypes. In about 50% of ACM patients, a genetic mutation, predominantly in genes that encode for desmosomal proteins, has been identified. However, the mutation-associated mechanisms, causing the observed cardiac phenotype are not always clear. Until now, the attention has been principally focused on the study of molecular mechanisms that lead to a prominent myocardium adipose substitution, an uncommon marker for a cardiac disease, thus often recognized as hallmark of ACM. Nonetheless, based on Task Force Criteria for the diagnosis of ACM, cardiomyocytes death associated with fibrous replacement of the ventricular free wall must be considered the main tissue feature in ACM patients. For this reason, it urges to investigate ACM cardiac fibrosis. In this review, we give an overview on the cellular effectors, possible triggers, and molecular mechanisms that could be responsible for the ventricular fibrotic remodeling in ACM patients.

Psychosocial Stress Hastens Disease Progression and Sudden Death in Mice with Arrhythmogenic Cardiomyopathy

“…Fibrotic replacement of myocardium is a pathological hallmark of ACM [30], and glucocorticoids can stimulate fibrotic deposition via the mineralocorticoid receptor [31], particularly in the presence of heightened oxidative stress [31]. Therefore, we tested whether PSS is penetrant enough to induce myocyte loss and fibrotic replacement.…”

Excess TGF-β1 Drives Cardiac Mesenchymal Stromal Cells to a Pro-Fibrotic Commitment in Arrhythmogenic Cardiomyopathy

“…The ACM tissue heterogeneity may, in turn, cause re-entrant electrical activity, contributing to ventricular arrhythmias and causing, in the worst-case scenario, sudden cardiac death. The molecular mechanisms of fibrosis are well known for different cardiac diseases but few studies are focused on ACM-specific pro-fibrotic processes [ 6 ].…”

Cardiac Biomarkers and Autoantibodies in Endurance Athletes: Potential Similarities with Arrhythmogenic Cardiomyopathy Pathogenic Mechanisms

“…Although their remodeling usually ensues to properly respond to a greater mechanical stress, when a threshold of intensity is exceeded, dysfunction may occur due to increased oxidative stress [ 48 , 49 ] and changes in cell permeability [ 107 ]. The extent of fibrotic substitution that can follow endurance activity exacerbates the reduction of cell-to-cell contact [ 154 ]. Accordingly, the disruption of epithelial tight junctions has been already described during exercise due to heat- and oxidative damage-mediated stress [ 155 ].…”