Investigation of the presence and mechanisms of action potential alternans in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a common cardiac genetic disorder. It is a leading cause of sudden cardiac death in young adults, yet most patients remain asymptomatic. T wave alternans (TWA) have been proposed as a potential tool for HCM risk stratification [1] [2] [3] but the mechanisms at stake remain unclear [4] [5]. HCM has been associated with a dysregulation of Ca
²⁺
cycling and an elevation in intracellular calcium concentration [6] that may affect the cardiac action potential (AP). Our goal is to investigate whether these electrophysiological abnormalities may be a mechanism responsible for the presence of TWA in HCM. We use a population of 9,118 control and HCM models defined in [7] and measure alternans in AP and Ca
²⁺
transient biomarkers for pacing cycle lengths from 250ms to 700ms. HCM cardiomyocytes show a distinct AP phenotype with longer AP and Ca
²⁺
duration (486±84ms vs 286±52ms, 691±82ms vs 522±65ms p<;0.001). However, there is no significant difference in alternans propensity in HCM compared to controls, except for AP amplitude at low pacing lengths (300ms: 13.4% HCM models, 2.6% control models, p<; 0.001). HCM amplitude and duration alternans also presented larger magnitude than Controls. These findings suggest that TWA in HCM may be related to whole-organ tissue heterogeneities rather than an alteration of the cellular substrate.