Mechanism of Abnormal Sarcoplasmic Reticulum Calcium Release in Canine Left-Ventricular Myocytes Results in Cellular Alternans

Electrocardiographic alternans are known to predispose to increased susceptibility to life threatening arrhythmias and sudden cardiac death. While deficiencies in Ca²⁺ transport processes have been implicated in the genesis of cellular alternans, the underlying mechanisms have been elusive, and are the goal of this study. A novel reverse engineering approach that applies a simultaneous action potential (AP) and [Ca²⁺ ]i clamp of experimentally obtained data, to a previously described left-ventricular canine myocyte model, is employed to isolate the molecular and cellular mechanisms underlying cardiac alternans. The model-derived sarcoplasmic reticulum (SR) Ca²⁺ in control beats (102.1 plusmn 12.9 nM, n = 639 ), although larger, is not statistically significantly different as compared to beats corresponding to small [Ca²⁺ ]_i (99.3 plusmn 35.4 nM, n = 310, p = NS), but is significantly smaller as compared to beats corresponding to large [Ca²⁺ ]_i (122.6 plusmn 31.0 nM, n = 311, p<0.000001) during alternans. The model indicates that the increased SR Ca²⁺ in these beats triggers multiple ryanodine receptor (RyR) channel openings and delayed Ca²⁺ release that subsequently triggers an inward depolarizing current, a subthreshold early after depolarization, and AP prolongation. In conclusion, the results presented in this study support the idea that aberrant RyR openings on alternate beats are responsible for the [Ca²⁺ ]_i alternans-type oscillations, which, in turn, give rise to AP alternans.