Intracellular Ca dynamics in ventricular fibrillation

Division of Cardiology, Cedars-Sinai Medical Center and Center for Health Sciences, University of California-Los Angeles (UCLA) Cardiovascular Research Laboratory, Departments of Medicine, Physiology, Physiological Science, and Computer Science, David Geffen School of Medicine, UCLA, Los Angeles, California 90095 Submitted 13 February 2003 ; accepted in final form 16 December 2003 In the heart, membrane voltage ( V m ) and intracellular Ca (Ca i ) are bidirectionally coupled, so that ionic membrane currents regulate Ca i cycling and Ca i affects ionic currents regulating action potential duration (APD). Although Ca i reliably and consistently tracks V m at normal heart rates, it is possible that at very rapid rates, sarcoplasmic reticulum Ca i cycling may exhibit intrinsic dynamics. Non-voltage-gated Ca i release might cause local alternations in APD and refractoriness that influence wavebreak during ventricular fibrillation (VF). In this study, we tested this hypothesis by examining the extent to which Ca i is associated with V m during VF. Ca i transients were mapped optically in isolated arterially perfused swine right ventricles using the fluorescent dye rhod 2 AM while intracellular membrane potential was simultaneously recorded either locally with a microelectrode (5 preparations) or globally with the voltage-sensitive dye RH-237 (5 preparations). Mutual information (MI) is a quantitative statistical measure of the extent to which knowledge of one variable ( V m ) predicts the value of a second variable (Ca i ). MI was high during pacing and ventricular tachycardia (VT; 1.13 ± 0.21 and 1.69 ± 0.18, respectively) but fell dramatically during VF (0.28 ± 0.06, P < 0.001). Ca i at sites 4–6 mm apart also showed decreased MI during VF (0.63 ± 0.13) compared with pacing (1.59 ± 0.34, P < 0.001) or VT (2.05 ± 0.67, P < 0.001). Spatially, Ca i waves usually bore no relationship to membrane depolarization waves during nonreentrant fractionated waves typical of VF, whereas they tracked each other closely during pacing and VT. The dominant frequencies of V m and Ca i signals analyzed by fast Fourier transform were similar during VT but differed significantly during VF. Ca i is closely associated with V m closely during pacing and VT but not during VF. These findings suggest that during VF, non-voltage-gated Ca i release events occur and may influence wavebreak by altering V m and APD locally. calcium transient; action potential; cardiac restitution; optical map