Shaping a new Ca²⁺ conductance to suppress early afterdepolarizations in cardiac myocytes.
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 Ca(2+) current (I(Ca,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) H(2)O(2) (oxidative stress) or lowering the external [K(+)] from 5.4 to 2.0-2.7 mmol l(-1) (hypokalaemia). The role of I(Ca,L) in EAD formation was directly assessed using the dynamic clamp technique: the paced myocyte's V(m) was input to a myocyte model with tunable biophysical parameters, which computed a virtual I(Ca,L), which was injected into the myocyte in real time. This virtual current replaced the endogenous I(Ca,L), which was suppressed with nifedipine. Injecting a current with the biophysical properties of the native I(Ca,L) restored EAD occurrence in myocytes challenged by H(2)O(2) 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 Ca(i) transient. We propose that modifying the biophysical properties of I(Ca,L) has potential as a powerful therapeutic strategy for suppressing EADs and EAD-mediated arrhythmias.
Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at University of California, Los Angeles, CA 90095-7115, USA.
Roshni V
RV
Madhvani
Yuanfang
Y
Xie
Antonios
A
Pantazis
Alan
A
Garfinkel
Zhilin
Z
Qu
James N
JN
Weiss
Riccardo
R
Olcese
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D002118:Calcium / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007008:Hypokalemia / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D018408:Patch-Clamp Techniques; D011817:Rabbits
D002121:Calcium Channel Blockers; D016877:Oxidants; D006861:Hydrogen Peroxide; D009543:Nifedipine; D002118:Calcium