Spatial nonuniformity of contraction causes arrhythmogenic Ca²⁺ waves in rat cardiac muscle

Landesberg and Sideman's four state model of the cardiac crossbridge (XB) hypothesizes a feedback of force development to Ca²⁺ binding by troponin C (TnC). We have further modeled this behavior and observed that the force (F)-Ca²⁺ relationship as well as the F-sarcomere length (SL) relationship and the time course of F and Ca²⁺ transients in cardiac muscle can be reproduced faithfully by a single effect of F on deformation of the TnC-Ca complex and, thereby, on the dissociation rate of Ca²⁺. Furthermore, this feedback predicts that rapid decline of F in the activated sarcomere causes release of Ca²⁺ from TnC-Ca²⁺, which is sufficient to initiate arrhythmogenic Ca²⁺ release from the sarcoplasmic reticulum (SR). This work investigated the initiation of Ca ²⁺ waves underlying triggered propagated contractions (TPCs) in rat cardiac trabeculae under conditions that simulate functional nonuniformity caused by mechanical or ischemic local damage of the myocardium. A mechanical discontinuity along the trabeculae was created by exposing the preparation to a small constant flow jet of solution that reduces excitation-contraction coupling in myocytes within that segment. Force was measured, and SL as well as [Ca ²⁺]_i were measured regionally. When the jet contained caffeine, 2,3-butanedione monoxime or low-[Ca²⁺], muscle-twitch F decreased and the sarcomeres in the exposed segment were stretched by shortening the normal regions outside the jet. During relaxation, the sarcomeres in the exposed segment shortened rapidly. Short trains of stimulation at 2.5 Hz reproducibly caused Ca²⁺ waves to rise from the borders exposed to the jet. Ca²⁺ waves started during F relaxation of the last stimulated twitch and propagated into segments both inside and outside of the jet. Arrhythmias, in the form of nondriven rhythmic activity, were triggered when the amplitude of the Ca²⁺ wave increased by raising [Ca ²⁺]_o. The arrhythmias disappeared when the muscle uniformity was restored by turning the jet off. These results show that nonuniform contraction can cause Ca²⁺ waves underlying TPCs, and suggest that Ca²⁺ dissociated from myofilaments plays an important role in the initiation of arrhythmogenic Ca²⁺ waves.