Cardiomyocyte Hypertrophy in Arrhythmogenic Cardiomyopathy

Abstract

Arrhythmogenic cardiomyopathy (AC) is a hereditary disease leading to sudden cardiac death or heart failure. AC pathology is characterized by cardiomyocyte loss and replacement fibrosis. Our goal was to determine whether cardiomyocytes respond to AC progression by pathological hypertrophy. To this end, we examined tissue samples from AC patients with end-stage heart failure and tissue samples that were collected at different disease stages from desmoglein 2-mutant mice, a well characterized AC model. We find that cardiomyocyte diameters are significantly increased in right ventricles of AC patients. Increased mRNA expression of the cardiac stress marker natriuretic peptide B is also observed in the right ventricle of AC patients. Elevated myosin heavy chain 7 mRNA expression is detected in left ventricles. In desmoglein 2-mutant mice, cardiomyocyte diameters are normal during the concealed disease phase but increase significantly after acute disease onset on cardiomyocyte death and fibrotic myocardial remodeling. Hypertrophy progresses further during the chronic disease stage. In parallel, mRNA expression of myosin heavy chain 7 and natriuretic peptide B is up-regulated in both ventricles with right ventricular preference. Calcineurin/nuclear factor of activated T cells (Nfat) signaling, which is linked to pathological hypertrophy, is observed during AC progression, as evidenced by Nfatc2 and Nfatc3 mRNA in cardiomyocytes and increased mRNA of the Nfat target regulator of calcineurin 1. Taken together, we demonstrate that pathological hypertrophy occurs in AC and is secondary to cardiomyocyte loss and cardiac remodeling.

Inflammation shapes pathogenesis of murine arrhythmogenic cardiomyopathy

“…We find, in contrast, a persistent enrichment of macrophages and T cells and upregulation of mRNAs coding for the chemokines and chemokine receptors Ccl2, Ccl7/Ccr2 and Cxcl10/Cxcr3. In parallel, pathologic hypertrophy occurs in the chronic disease phase [31]. Together, these findings point to fundamental differences between lesions formed in myocardial infarct and AC.…”

“…The chronic nature of this response is reflected by the continued presence of macrophages, dendritic cells, and T cells in scar tissue. Furthermore, the previously reported connexin 43 redistribution in cardiomyocytes next to immune cell-enriched scars, alterations of actin distribution and actin isoform expression as well as pathological cardiomyocyte hypertrophy in murine Dsg2 mutants [31,38,39] are known to be induced by the macrophage-derived cytokines TNFα, IL1β, TGFβ and also CX3CL1 [24,27,28,36,47,66]. These cytokines are also likely involved in the formation of interstitial fibrosis that spreads from the established scars and may thereby contribute to the formation of arrhythmogenic substrates [27].…”

“…Total RNA isolation, cDNA synthesis, and qRT-PCR experiments were performed as described [31]. In brief, total RNA was isolated using the PeqGOLD Total RNA Kit.…”

“…It is followed by the acute disease phase during which lesions are transformed into mature fibrous scars by the age of 10-12 weeks. At this time, the chronic disease phase sets in with progressive cardiac wall alterations in aging mice [31,40].…”

Desmoglein 2 mutation provokes skeletal muscle actin expression and accumulation at intercalated discs in murine hearts

“…It will be interesting to find out whether the accumulation of actin at intercalated discs precedes myofibrillar growth, which has been shown to occur in the transitional junction (Bennett et al, 2006;Wilson et al, 2014) and is coupled to transiently increased Acta1 expression during embryogenesis (Clement et al, 2007). It may be part of the hypertrophic response, which has been described to occur during the chronic disease stage in murine AC models and the human disease (Gerçek et al, 2017).…”