Human iPSCs as a tool to investigate inflammatory processes in Brugada syndrome and mechanisms of occurrence and recurrence of TTC

Brugada syndrome (BrS) is an inherited cardiac channelopathy, associated with malignant ventricular arrhythmias and sudden cardiac death. Fever can trigger BrS phenotype manifestation, indicating an important role of inflammation in the pathogenesis of BrS. However, the molecular mechanisms underlying inflammation-related pathophysiology of BrS are not known. Takotsubo cardiomyopathy (TTC) is an acute acquired cardiomyopathy characterized by transient regional systolic dysfunction. TTC is triggered by pathological responses to stress, mediating endothelial dysfunction (and other processes), but the molecular mechanisms remain unclear. Although both BrS and TTC can cause severe cardiac events in patients, there are no specific therapeutic options yet. Thus, based on our previous studies funded by the DZHK (MA-BO-5), the objectives of this project are 1) to analyze molecular signaling in inflammation-induced phenotypic changes of BrS and to identify the impact of gene variants on drug effects; 2) to investigate the how ion channel function influences endothelial dysfunction in the occurrence and recurrence of TTC. Project aims will be studied using hiPSC-cardiomyocytes of BrS patients bearing different gene variants and hiPSC-cardiomyocytes and –endothelial cells of TTC patients. Understanding the molecular mechanisms of fever/inflammation-related pathogenesis of BrS and endothelial dysfunction-related pathogenesis of TTC will help to find novel therapeutic targets.