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.
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