Grant: Project Grant

Certain heritable arrhythmias, like catecholaminergic polymorphic ventricular tachycardia (CPVT) have a high risk of triggering sudden cardiac arrest (SCA) in some afflicted individuals. Most cases of CPVT are related to inherited mutations in a large protein in the cardiac cells (cardiomyocytes) called the ryanodine receptor (RyR). We propose to develop means of better understanding the risk of SCA in specific individuals by understanding how the mutation affects the structure of the RyR and developing highly sensitive and personalized means of assessing the risk of SCA using a sophisticated human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) approach to reduce mortality rates. This is important to patients' treatment because: 1) Different patients react differently to drug treatments. In some cases, beta-adrenergic receptor blockers do not work; in other cases, flecainide may be used, but not without risk. The hiPSC-CMs can be used directly to test the effect of various types of beta-blockers (including carvedilol, which has multiple effects) without having to pre-screen them in patients. In particular, this study will allow us to test whether there is a correlation between drug response in patients and drug response in the CMs which will help one derive more informed decisions on treatment regime in the future. 2) The hiPSC-CMs will be used to establish causality. It is crucial to know whether these inherited mutations cause this often lethal arrhythmia, as this informs family members with the same mutation and who are thus at risk.