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This Article Full Text Full Text (PDF) Supplemental Videos All Versions of this Article: 297/3/H997    most recent 00390.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Xie, L.-H. Articles by Weiss, J. N. PubMed PubMed Citation Articles by Xie, L.-H. Articles by Weiss, J. N.

Arrhythmogenic consequences of intracellular calcium waves

¹Cardiovascular Research Laboratory, Departments of Medicine (Cardiology) and Physiology, David Geffen School of Medicine, University of California, Los Angeles, California; and ²Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey

Submitted 27 April 2009 ; accepted in final form 24 June 2009

Intracellular Ca²⁺ (Ca_i²⁺) waves are known to cause delayed afterdepolarizations (DADs), which have been associated with arrhythmias in cardiac disease states such as heart failure, catecholaminergic polymorphic ventricular tachycardia, and digitalis toxicity. Here we show that, in addition to DADs, Ca_i²⁺ waves also have other consequences relevant to arrhythmogenesis, including subcellular spatially discordant alternans (SDA, in which the amplitude of the local Ca_i²⁺ transient alternates out of phase in different regions of the same cell), sudden repolarization changes promoting the dispersion of refractoriness, and early afterdepolarizations (EADs). Ca_i²⁺ was imaged using a charge-coupled device-based system in fluo-4 AM-loaded isolated rabbit ventricular myocytes paced at constant or incrementally increasing rates, using either field stimulation, current clamp, or action potential (AP) clamp. Ca_i²⁺ waves were induced by Bay K 8644 (50 nM) + isoproterenol (100 nM), or low temperature. When pacing was initiated during a spontaneous Ca_i²⁺ wave, SDA occurred abruptly and persisted during pacing. Similarly, during rapid pacing, SDA typically arose suddenly from spatially concordant alternans, due to an abrupt phase reversal of the subcellular Ca_i²⁺ transient in a region of the myocyte. Ca_i²⁺ waves could be visualized interspersed with AP-triggered Ca_i²⁺ transients, producing a rich variety of subcellular Ca_i²⁺ transient patterns. With free-running APs, complex Ca_i²⁺ release patterns were associated with DADs, EADs, and sudden changes in AP duration. These findings link Ca_i²⁺ waves directly to a variety of arrhythmogenic phenomena relevant to the intact heart.

calcium transient; cardiac myocytes; discordant alternans; sarcoplasmic reticulum; ryanodine receptor