Shaping a new Ca2+ conductance to suppress early afterdepolarizations in cardiac myocytes

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Abstract

Non–technical summary

Diseases, genetic defects, or ionic imbalances can alter the normal electrical activity of cardiac myocytes causing an anomalous heart rhythm, which can degenerate to ventricular fibrillation (VF) and sudden cardiac death. Well–recognized triggers for VF are aberrations of the cardiac action potential, known as early afterdepolarizations (EADs). In this study, combining mathematical modelling and experimental electrophysiology in real–time (dynamic clamp), we investigated the dependence of EADs on the biophysical properties of the L–type Ca2+ current (ICa,L) and identified modifications of ICa,L properties which effectively suppress EAD. We found that minimal changes in the voltage dependence of activation or inactivation of ICa,L can dramatically reduce the occurrence of EADs in cardiac myocytes exposed to different EAD–inducing conditions. This work assigns a critical role to the L–type Ca2+ channel biophysical properties for EADs formation and identifies the L–type Ca2+ channel as a promising therapeutic target to suppress EADs and their arrhythmogenic effects.

Sudden cardiac death (SCD) due to ventricular fibrillation (VF) is a major world–wide health problem. A common trigger of VF involves abnormal repolarization of the cardiac action potential causing early afterdepolarizations (EADs). Here we used a hybrid biological–computational approach to investigate the dependence of EADs on the biophysical properties of the L–type Ca2+ current (ICa,L) and to explore how modifications of these properties could be designed to suppress EADs. EADs were induced in isolated rabbit ventricular myocytes by exposure to 600 μmol l−1 H2O2 (oxidative stress) or lowering the external [K+] from 5.4 to 2.0–2.7 mmol l−1 (hypokalaemia). The role of ICa,L in EAD formation was directly assessed using the dynamic clamp technique: the paced myocyte's Vm was input to a myocyte model with tunable biophysical parameters, which computed a virtual ICa,L, which was injected into the myocyte in real time. This virtual current replaced the endogenous ICa,L, which was suppressed with nifedipine. Injecting a current with the biophysical properties of the native ICa,L restored EAD occurrence in myocytes challenged by H2O2 or hypokalaemia. A mere 5 mV depolarizing shift in the voltage dependence of activation or a hyperpolarizing shift in the steady–state inactivation curve completely abolished EADs in myocytes while maintaining a normal Cai transient. We propose that modifying the biophysical properties of ICa,L has potential as a powerful therapeutic strategy for suppressing EADs and EAD–mediated arrhythmias.

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