Abstract
Cardiac arrhythmias are electrical phenomena; thus, sarcolemmal ion channels have long been considered as targets of antiarrhythmic therapy. The contribution of abnormal intracellular Ca2+ handling to digitalis-induced arrhythmogenesis is an old concept; however, the role of abnormal Ca2+ handling as a common cause of arrhythmia, i.e. relevant to all arrhythmogenic mechanisms, has been fully recognized in more recent times. Stability of the intracellular Ca2+ store (sarcoplasmic reticulum, SR) is crucial to physiological Ca2+ handling; when it is compromised, Ca2+ may be released independently from excitation and lead to secondary perturbation of membrane potential. Ca2+ store stability depends on the interplay between sarcolemmal and SR “effectors” (ion channels and transports), which are mutually linked by Ca2+-mediated feed-back control. While instrumental to cell homeostasis, such control makes any attempt to modulate SR stability dauntingly complex. This review discusses current knowledge on the factors leading to SR instability, the mechanisms by which SR instability translates into arrhythmias and which interventions may be best suited to prevent SR instability. Although still at an initial stage of development, such interventions might represent the future of antiarrhythmic drug therapy.
Keywords: Alternans, antiarrhythmic therapy, DADs, EADs, intracellular Ca2+, RyRs, SERCA.
Current Pharmaceutical Design
Title:Calcium Store Stability as an Antiarrhythmic Endpoint
Volume: 21 Issue: 8
Author(s): Antonio Zaza and Marcella Rocchetti
Affiliation:
Keywords: Alternans, antiarrhythmic therapy, DADs, EADs, intracellular Ca2+, RyRs, SERCA.
Abstract: Cardiac arrhythmias are electrical phenomena; thus, sarcolemmal ion channels have long been considered as targets of antiarrhythmic therapy. The contribution of abnormal intracellular Ca2+ handling to digitalis-induced arrhythmogenesis is an old concept; however, the role of abnormal Ca2+ handling as a common cause of arrhythmia, i.e. relevant to all arrhythmogenic mechanisms, has been fully recognized in more recent times. Stability of the intracellular Ca2+ store (sarcoplasmic reticulum, SR) is crucial to physiological Ca2+ handling; when it is compromised, Ca2+ may be released independently from excitation and lead to secondary perturbation of membrane potential. Ca2+ store stability depends on the interplay between sarcolemmal and SR “effectors” (ion channels and transports), which are mutually linked by Ca2+-mediated feed-back control. While instrumental to cell homeostasis, such control makes any attempt to modulate SR stability dauntingly complex. This review discusses current knowledge on the factors leading to SR instability, the mechanisms by which SR instability translates into arrhythmias and which interventions may be best suited to prevent SR instability. Although still at an initial stage of development, such interventions might represent the future of antiarrhythmic drug therapy.
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Cite this article as:
Zaza Antonio and Rocchetti Marcella, Calcium Store Stability as an Antiarrhythmic Endpoint, Current Pharmaceutical Design 2015; 21 (8) . https://dx.doi.org/10.2174/1381612820666141029100650
DOI https://dx.doi.org/10.2174/1381612820666141029100650 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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