Differential Response of Hypertrophic Cardiomyopathy to Ischemia Caused by Remodelling of Late Sodium and Rapidly Delayed Rectifier Channels

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy and a leading cause of sudden cardiac death (SCD) in the young. Myocardial ischemia plays a central role in HCM, as characterised by multiple microvascular disease and perfusion studies. However, the electrophysiological mechanisms linking SCD and ischemia in HCM remain poorly understood. Using the ToR-ORd ventricular cardiomyocyte model, populations of experimentally calibrated action potential models for control and HCM cardiomyocytes were created. The populations were subjected to acidosis, hyperkalemia and hypoxia separately and in combined cases of ischemia. HCM cardiomyocytes exhibited increased sensitivity to ischemia, with effective refractory periods significantly decreasing by $(-153\pm 57)ms$ in HCM during hyperkalemia, yet increasing by $(+14\pm 45)$ , ms in control models. Selective removal of HCM ionic remodelling demonstrated that remodelling of the late sodium and rapidly delayed rectifier channels caused this abnormal response.