| 1. |
- Madhvani, Roshni V., et al.
(author)
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Shaping a New Ca2+ Conductance to Suppress Early Afterdepolarizations in Cardiac Myocytes
- 2011
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In: Journal of Physiology. - : John Wiley & Sons. - 0022-3751 .- 1469-7793. ; 589:24, s. 6081-6092
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Journal article (peer-reviewed)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.
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| 2. |
- Madhvani, Roshni V., et al.
(author)
-
Targeting the Late Component of the Cardiac L-type Ca2+ Current to Suppress Early Afterdepolarizations
- 2015
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In: The Journal of General Physiology. - : Rockefeller University Press. - 0022-1295 .- 1540-7748. ; 145:5, s. 395-404
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Journal article (peer-reviewed)abstract
- Early afterdepolarizations (EADs) associated with prolongation of the cardiac action potential (AP) can create heterogeneity of repolarization and premature extrasystoles, triggering focal and reentrant arrhythmias. Because the L-type Ca2+ current (ICa,L) plays a key role in both AP prolongation and EAD formation, L-type Ca2+ channels (LTCCs) represent a promising therapeutic target to normalize AP duration (APD) and suppress EADs and their arrhythmogenic consequences. We used the dynamic-clamp technique to systematically explore how the biophysical properties of LTCCs could be modified to normalize APD and suppress EADs without impairing excitation–contraction coupling. Isolated rabbit ventricular myocytes were first exposed to H2O2 or moderate hypokalemia to induce EADs, after which their endogenous ICa,L was replaced by a virtual ICa,L with tunable parameters, in dynamic-clamp mode. We probed the sensitivity of EADs to changes in the (a) amplitude of the noninactivating pedestal current; (b) slope of voltage-dependent activation; (c) slope of voltage-dependent inactivation; (d) time constant of voltage-dependent activation; and (e) time constant of voltage-dependent inactivation. We found that reducing the amplitude of the noninactivating pedestal component of ICa,L effectively suppressed both H2O2- and hypokalemia-induced EADs and restored APD. These results, together with our previous work, demonstrate the potential of this hybrid experimental–computational approach to guide drug discovery or gene therapy strategies by identifying and targeting selective properties of LTCC.
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