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

Introduction: 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. Aim: The study aimed to determine the effects of the suppression of the WNT pathway on cardiac phenotype in a mouse model of ACM. Methods and Results: 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. Conclusion: 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. One sentence summary: Suppression of the WNT signaling pathway has beneficial effects on cardiac dysfunction, myocardial apoptosis, and fibrosis in a mouse model of arrhythmogenic cardiomyopathy.