Contribution of lipids and their oxidized metabolites on Arrhythmogenic Cardiomyopathy pathogenesis

Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder characterized by severe heart rhythm disturbances and fat accumulation in the heart, leading to sudden death and heart dysfunction in young people and athletes. No therapies are available to prevent the progression of the disease. The proposed research project is aimed to characterize the mechanism of ACM development, in order to introduce new therapeutics. The genetic defect alone is often not sufficient for the clinical manifestation of ACM, suggesting the involvement of other determinants. In patients with ACM, we observed higher plasma LDL-cholesterol and oxidized LDL compared to healthy individuals; therefore we hypothesized that LDL and oxidative stress (increased in athletes) may contribute to ACM. We took advantage of human cultured cells, mimicking either the contractile or the support (stromal) cells of the heart, observing that oxidized cholesterol administration activate differentiation to fat cells. Moreover, we observed fat accumulation in ACM-mutated mouse hearts, naturally protected by low LDL cholesterol levels, just by feeding them with a high cholesterol diet. In the context of this project we will: 1) thoroughly investigate the mechanisms of adipose differentiation of cardiac stromal cells in ACM and the relative contribution of the genetic predisposition and of external co-factors and test approaches of pharmacological rescue; 2) study the effects of precipitating co-factors on the contractile cardiac cells compartment by means of ACM cardiomyocytes, obtained from adult induced stem cells (iPSC); 3) determine the effect of high cholesterol diet and exercise on the ACM mouse heart function and fat accumulation. The data obtained from the three proposed approaches will likely open new perspectives for future pharmacological prevention/treatment of ACM, a relevant aspect, given the fact that today pharmacologic therapies are available to contrast both high cholesterol levels and oxidative stress.