TY - JOUR
T1 - Validation of quantitative measure of repolarization reserve as a novel marker of drug induced proarrhythmia
AU - Gaur, Namit
AU - Ortega, Francis
AU - Verkerk, Arie O.
AU - Mengarelli, Isabella
AU - Krogh-Madsen, Trine
AU - Christini, David J.
AU - Coronel, Ruben
AU - Vigmond, Edward J.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - Repolarization reserve, the robustness of a cell to repolarize even when one of the repolarization mechanisms is failing, has been described qualitatively in terms of ionic currents, but has not been quantified by a generic metric that is applicable to drug screening. Prolonged repolarization leading to repolarization failure is highly arrhythmogenic. It may lead to ventricular tachycardia caused by triggered activity from early afterdepolarizations (EADs), or it may promote the occurrence of unidirectional conduction block and reentry. Both types of arrhythmia may deteriorate into ventricular fibrillation (VF) and death. We define the Repolarization Reserve Current (RRC) as the minimum constant current necessary to prevent normal repolarization of a cell. After developing and testing RRC for nine computational ionic models of various species, we applied it experimentally to atrial and ventricular human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM), and isolated guinea-pig ventricular cardiomyocytes. In simulations, repolarization was all-or-none with a precise, model-dependent critical RRC, resulting in a discrete shift in the Action Potential Duration (APD) - RRC relation, in the occurrence of EADs and repolarization failure. These data were faithfully reproduced in cellular experiments. RRC allows simple, fast, unambiguous quantification of the arrhythmogenic propensity in cardiac cells of various origins and species without the need of prior knowledge of underlying currents and is suitable for high throughput applications, and personalized medicine applications.
AB - Repolarization reserve, the robustness of a cell to repolarize even when one of the repolarization mechanisms is failing, has been described qualitatively in terms of ionic currents, but has not been quantified by a generic metric that is applicable to drug screening. Prolonged repolarization leading to repolarization failure is highly arrhythmogenic. It may lead to ventricular tachycardia caused by triggered activity from early afterdepolarizations (EADs), or it may promote the occurrence of unidirectional conduction block and reentry. Both types of arrhythmia may deteriorate into ventricular fibrillation (VF) and death. We define the Repolarization Reserve Current (RRC) as the minimum constant current necessary to prevent normal repolarization of a cell. After developing and testing RRC for nine computational ionic models of various species, we applied it experimentally to atrial and ventricular human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM), and isolated guinea-pig ventricular cardiomyocytes. In simulations, repolarization was all-or-none with a precise, model-dependent critical RRC, resulting in a discrete shift in the Action Potential Duration (APD) - RRC relation, in the occurrence of EADs and repolarization failure. These data were faithfully reproduced in cellular experiments. RRC allows simple, fast, unambiguous quantification of the arrhythmogenic propensity in cardiac cells of various origins and species without the need of prior knowledge of underlying currents and is suitable for high throughput applications, and personalized medicine applications.
KW - All-or-none repolarization
KW - Arrhythmias
KW - Early afterdepolarization
KW - Human induced pluripotent stem cell cardiomyocytes (hiPSC-CM)
KW - Repolarization failure
KW - Repolarization reserve
KW - Torsade de pointes
UR - http://www.scopus.com/inward/record.url?scp=85087526786&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.yjmcc.2020.04.019
DO - https://doi.org/10.1016/j.yjmcc.2020.04.019
M3 - Article
C2 - 32325153
SN - 0022-2828
VL - 145
SP - 122
EP - 132
JO - Journal of molecular and cellular cardiology
JF - Journal of molecular and cellular cardiology
ER -