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(Circulation Research. 2006;99:740.)
© 2006 American Heart Association, Inc.

Cellular Biology

Cardiac Alternans Do Not Rely on Diastolic Sarcoplasmic Reticulum Calcium Content Fluctuations

Eckard Picht, Jaime DeSantiago, Lothar A. Blatter, Donald M. Bers

From the Department of Physiology, Loyola University Chicago, Stritch School of Medicine, Maywood, Ill.

Correspondence to Donald M. Bers, PhD, Department of Physiology, Loyola University Chicago, Stritch School of Medicine, 2160 S First Ave, Maywood, IL 60153. E-mail dbers{at}lumc.edu

Cardiac alternans are thought to be a precursor to life-threatening arrhythmias. Previous studies suggested that alterations in sarcoplasmic reticulum (SR) Ca²⁺ content are either causative or not associated with myocyte Ca²⁺ alternans. However, those studies used indirect measures of SR Ca²⁺. Here we used direct continuous measurement of intra-SR free [Ca²⁺] ([Ca²⁺]_SR) (using Fluo5N) during frequency-dependent Ca²⁺ alternans in rabbit ventricular myocytes. We tested the hypothesis that alternating [Ca²⁺]_SR is required for Ca²⁺ alternans. Amplitudes of [Ca²⁺]_SR depletions alternated in phase with cytosolic Ca²⁺ transients and contractions. Some cells showed clear alternation in diastolic [Ca²⁺]_SR during alternans, with higher [Ca²⁺]_SR before the larger SR Ca²⁺ releases. However, the extent of SR Ca²⁺ release during the small beats was smaller than expected for the modest decrease in [Ca²⁺]_SR. In other cells, clear Ca²⁺ alternans was observed without alternations in diastolic [Ca²⁺]_SR. Additionally, alternating cells were observed, in which diastolic [Ca²⁺]_SR fluctuations occurred interspersed by depletions in which the amplitude was unrelated to the preceding diastolic [Ca²⁺]_SR. In all forms of alternans, the SR Ca²⁺ release rate was higher during large depletions than during small depletions. Although [Ca²⁺]_SR exerts major influence on SR Ca²⁺ release, alternations in [Ca²⁺]_SR are not required for Ca²⁺ alternans to occur. Rather, it seems likely that some other factor, such as ryanodine receptor availability after a prior beat (eg, recovery from inactivation), is of greater importance in initiating frequency-induced Ca²⁺ alternans. However, once such a weak SR Ca²⁺ release occurs, it can result in increased [Ca²⁺]_SR and further enhance SR Ca²⁺ release at the next beat. In this way, diastolic [Ca²⁺]_SR alternans can enhance frequency-induced Ca²⁺ alternans, even if they initiate by other means.

Key Words: calcium • sarcoplasmic reticulum • alternans • excitation/contraction coupling

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