Validation of quantitative measure of repolarization reserve as a novel marker of drug induced proarrhythmia

Autor: Isabella Mengarelli, Arie O. Verkerk, Francis A. Ortega, Ruben Coronel, David J. Christini, Trine Krogh-Madsen, Edward J. Vigmond, Namit Gaur
Přispěvatelé: Institut de Mathématiques de Bordeaux (IMB), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS), Medical Biology, Amsterdam Cardiovascular Sciences, Cardiology, ACS - Heart failure & arrhythmias
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
medicine.medical_specialty
Heart Ventricles
[SDV]Life Sciences [q-bio]
Guinea Pigs
Induced Pluripotent Stem Cells
Action Potentials
030204 cardiovascular system & hematology
Arrhythmias
Ventricular tachycardia
Afterdepolarization
03 medical and health sciences
0302 clinical medicine
Risk Factors
Internal medicine
medicine
Animals
Humans
Repolarization
Computer Simulation
Myocytes
Cardiac
Repolarization reserve
Molecular Biology
Early afterdepolarization
Human induced pluripotent stem cell cardiomyocytes (hiPSC-CM)
Torsade de pointes
Ions
Proarrhythmia
business.industry
Arrhythmias
Cardiac
Reentry
medicine.disease
3. Good health
Quantitative measure
All-or-none repolarization
030104 developmental biology
Pharmaceutical Preparations
Ventricular fibrillation
Cardiology
Rabbits
Cardiology and Cardiovascular Medicine
business
Biomarkers
Repolarization failure
Zdroj: Journal of Molecular and Cellular Cardiology
Journal of Molecular and Cellular Cardiology, Elsevier, 2020, 145, pp.122-132. ⟨10.1016/j.yjmcc.2020.04.019⟩
Journal of molecular and cellular cardiology, 145, 122-132. Academic Press Inc.
ISSN: 0022-2828
1095-8584
Popis: 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.
Databáze: OpenAIRE
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