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 Ca(2+) 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 [Ca(2+)](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) Ca(2+) in control beats (102.1 +/- 12.9 nM, n = 639), although larger, is not statistically significantly different as compared to beats corresponding to small [Ca(2+)](i) (99.3 +/- 35.4 nM, n = 310, p = NS), but is significantly smaller as compared to beats corresponding to large [Ca(2+)](i) (122.6 +/- 31.0 nM, n = 311, p < 0.000001) during alternans. The model indicates that the increased SR Ca(2+) in these beats triggers multiple ryanodine receptor (RyR) channel openings and delayed Ca(2+) 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 [Ca(2+)](i) alternans-type oscillations, which, in turn, give rise to AP alternans.
Armoundas
Antonis A
AA
Harvard Medical School, Massachusetts General Hospital, Charlestown, MA 02129 USA. aarmoundas@partners.org
D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003627:Data Interpretation, Statistical; D016757:Death, Sudden, Cardiac / Q000517:prevention & control; D004285:Dogs; D004562:Electrocardiography; D006321:Heart / Q000503:physiopathology; D006339:Heart Rate / Q000502:physiology; D006352:Heart Ventricles / Q000166:cytology / Q000503:physiopathology*; D008297:Male; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D012815:Signal Processing, Computer-Assisted
D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium