Abstract 19048: Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Reveals Hypokalemia Induced Exacerbation of Ventricular Arrhythmogenicity of Antiarrhythmic Drugs
Hypokalemia is an independent risk factor associated with an increased risk of arrhythmia and all-cause mortality in patients with cardiovascular disease and exacerbates the cardiac arrhythmia (i.e., torsades de pointes; TdP) induced by QT-prolonging drugs. Thus understanding the hypokalemia-induce cardiac arrhythmia is of great importance both clinically and in new drug screening. Here we generated a library of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from patients with hereditary long QT syndrome (LQT), familial hypertrophic cardiomyopathy (HCM), and familial dilated cardiomyopathy (DCM) to elucidate the mechanism(s) of hypokalemia-induced ventricular arrhythmogenicity and responsiveness to QT-prolonging drugs. Specific disease phenotypes were verified in iPSC-CMs by immunostaining, calcium (Ca2+) imaging and single cell patch clamp. Disease-specific iPSC-CMs demonstrated increased susceptibility to hypokalemia (2.5-3.5 mM/l) induced arrhythmogenicity, and a severe exacerbation of dofetilide-induced arrhythmogenicity under moderate hypokalemic (3.5 mM/l) conditions as assessed by APD prolongation and quantification of drug-induced arrhythmias such as early afterdepolarizations (EADs), delayed afterdepolarizations (DADs) and triggered arrhythmias. Ca2+ imaging indicated the hypokalemia-induced increase in diastolic Ca2+ levels and reduction of Ca2+ transient amplitude. Moreover, the rate of cytosolic Ca2+ removal was prolonged both under basal conditions and after caffeine application, indicating weaker sodium-calcium exchanger (NCX) and/or sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) activities. We have recapitulated hypokalemia-induced ventricular arrhythmogenicity for healthy subjects, LQT, HCM, and DCM patients at the single cell level for the first time. Our data indicate that healthy and diseased individuals exhibit different susceptibilities to hypokalemia and/or QT prolonging cardiotoxic drugs. The results of these studies may have important physiological and pathophysiological implications inasmuch as the results obtained could suggest a mechanistic link between cardiac diseases (substrate), hypokalemia (trigger), and TdP tachyarrhythmias.
Author Disclosures: P. Shukla: None. C. Lam: None. J. Churko: None. E. Matsa: None. N. Shao: None. O.J. Abilez: None. J.C. Wu: None.
- © 2016 by American Heart Association, Inc.