Discordant Calcium Transient and Action Potential Alternans in a Canine Left-Ventricular Myocyte

Electrocardiographic alternans is known to predispose to increased susceptibility to life threatening arrhythmias and sudden cardiac death. While this decreased level of cardiac electrical stability is often due to the presence of discordant action potential (AP) alternans in the heart, the mechanism of discordant cardiac alternans remains unknown. This study presents a case report of cellular discordant cardiac alternans between AP and [Ca[superscript 2+]]i and employs a novel reverse engineering approach that applies a simultaneous AP and [Ca2[superscript 2+]]i clamp of experimentally obtained data to a left-ventricular canine myocyte model, to probe its underlying mechanism. The model results indicate that during alternans, the increased sarcoplasmic reticulum Ca[superscript 2+], triggers multiple ryanodine receptor (RyR) channel openings and delayed Ca[superscript 2+] release, which subsequently triggers an inward depolarizing current, a subthreshold early after-depolarization, and AP prolongation. The amplitude of [Ca[superscript 2+]]i plays a critical role in defining the concordant or discordant relationship between the [Ca[superscript 2+]]i and AP at the myocyte level. In conclusion, the results presented in this study support the idea that aberrant RyR openings on alternate beats are responsible for the [Ca[superscript 2+]]i alternan-type oscillations, which, in turn, give rise to an in- or out-of-phase relationship between [Ca[superscript 2+]]i and AP alternans.Scientist Development (Grant 0635127N)American Heart Association awards (Beginning Grant-in-Aid 0365304U