Pharmacological suppression of the WNT signaling pathway attenuates age-dependent expression of the phenotype in a mouse model of arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM) is a genetic disease of the myocardium, characterized by cardiac arrhythmias, dysfunction, and sudden cardiac death. The pathological hallmark of ACM is fibro-adipocytes replacing cardiac myocytes. The canonical WNT pathway is implicated in the pathogenesis of ACM.The study aimed to determine the effects of the suppression of the WNT pathway on cardiac phenotype in a mouse model of ACM.One copy of the Dsp gene, a known cause of ACM in humans, was deleted specifically in cardiac myocytes (Myh6-Cre-DspW/F). Three-month-old wild type and Myh6-Cre-DspW/F mice, without a discernible phenotype, were randomized to either untreated or daily administration of a vehicle (placebo), or WNT974, the latter an established inhibitor of the WNT pathway, for three months. The Myh6-Cre-DspW/F mice in the untreated or placebo-treated groups exhibited cardiac dilatation and dysfunction, increased myocardial fibrosis, and apoptosis upon completion of the study, which was verified by complementary methods. Daily administration of WNT974 prevented and/or attenuated evolving cardiac dilatation and dysfunction, normalized myocardial fibrosis, and reduced apoptosis, compared to the untreated or placebo-treated groups. However, administration of WNT974 increased the number of adipocytes only in the Myh6-Cre-DspW/F hearts. There were no differences in the incidence of cardiac arrhythmias and survival rates.Suppression of the WNT pathway imparts salutary phenotypic effects by preventing or attenuating age-dependent expression of cardiac dilatation and dysfunction, myocardial fibrosis, and apoptosis in a mouse model of ACM. The findings set the stage for large-scale studies and studies in larger animal models to test the beneficial effects of the suppression of the WNT pathway in ACM.Suppression of the WNT signaling pathway has beneficial effects on cardiac dysfunction, myocardial apoptosis, and fibrosis in a mouse model of arrhythmogenic cardiomyopathy.