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(Circulation Research. 2005;96:1266.)
© 2005 American Heart Association, Inc.

Cellular Biology

Spatial Nonuniformity of Excitation–Contraction Coupling Causes Arrhythmogenic Ca²⁺ Waves in Rat Cardiac Muscle

Yuji Wakayama, Masahito Miura, Bruno D. Stuyvers, Penelope A. Boyden, Henk E.D.J. ter Keurs

From the First Department of Internal Medicine (Y.W., M.M.), Tohoku University School of Medicine, Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; the Departments of Medicine, Physiology, and Biophysics (B.D.S., H.E.D.J.t.K.), Health Sciences Centre, University of Calgary, Canada; and the Department of Pharmacology (P.A.B.), Columbia University, New York.

Correspondence to Henk E.D.J. ter Keurs, Department of Medicine, University of Calgary, 3330 Hospital Dr NW, Calgary, Alberta T2N4N1 Canada. E-mail terkeurs{at}ucalgary.ca

Ca²⁺ waves underlying triggered propagated contractions (TPCs) are initiated in damaged regions in cardiac muscle and cause arrhythmias. We studied Ca²⁺ waves underlying TPCs in rat cardiac trabeculae under experimental conditions that simulate the functional nonuniformity caused by local mechanical or ischemic local damage of myocardium. A mechanical discontinuity along the trabeculae was created by exposing the preparation to a small jet of solution with a composition that reduces excitation–contraction coupling (ECC) in myocytes within that segment. The jet solution contained either caffeine (5 mmol/L), 2,3-butanedione monoxime (BDM; 20 mmol/L), or low Ca²⁺ concentration ([Ca²⁺]; 0.2 mmol/L). Force was measured with a silicon strain gauge and sarcomere length with laser diffraction techniques in 15 trabeculae. Simultaneously, [Ca²⁺]_i was measured locally using epifluorescence of Fura-2. The jet of solution was applied perpendicularly to a small muscle region (200 to 300 µm) at constant flow. When the jet contained caffeine, BDM, or low [Ca²⁺], during the stimulated twitch, muscle-twitch force decreased and the sarcomeres in the exposed segment were stretched by shortening normal regions outside the jet. Typical protocols for TPC induction (7.5 s-2.5 Hz stimulus trains at 23°C; [Ca²⁺]_o=2.0 mmol/L) reproducibly generated Ca²⁺ waves that arose from the border between shortening and stretched regions. Such Ca²⁺ waves started during force-relaxation of the last stimulated twitch of the train and propagated (0.2 to 2.8 mm/sec) into segments both inside and outside of the jet. Arrhythmias, in the form of nondriven rhythmic activity, were induced when the amplitude of the Ca²⁺-wave was increased by raising [Ca²⁺]_o. Arrhythmias disappeared rapidly when uniformity of ECC throughout the muscle was restored by turning the jet off. These results show, for the first time, that nonuniform ECC can cause Ca²⁺ waves underlying TPCs and suggest that Ca²⁺ dissociated from myofilaments plays an important role in the initiation of Ca²⁺ waves.

Key Words: rat trabeculae • nonuniformity • troponin C • Ca²⁺ waves • arrhythmias

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