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Action Potential Morphology Influences Intracellular Calcium Handling Stability and the Occurrence of Alternans

Peter N. Jordan ^* and David J. Christini ^* 

^* Department of Physiology and Biophysics, Weill Graduate School of Medical Sciences of Cornell University, New York, New York, 10021; and Division of Cardiology, Department of Medicine, Weill Medical College of Cornell University, New York, New York, 10021

Correspondence: Address reprint requests to David J. Christini, PhD, Div. of Cardiology, Weill Medical College of Cornell University, 520 East 70th St., Starr 463, New York, NY 10021. Tel.: 212-746-6280; Fax: 212-746-8451; E-mail: dchristi{at}med.cornell.edu.

Instability in the intracellular Ca²⁺ handling system leading to Ca²⁺ alternans is hypothesized to be an underlying cause of electrical alternans. The highly coupled nature of membrane voltage and Ca²⁺ regulation suggests that there should be reciprocal effects of membrane voltage on the stability of the Ca²⁺ handling system. We investigated such effects using a mathematical model of the cardiac intracellular Ca²⁺ handling system. We found that the morphology of the action potential has a significant effect on the stability of the Ca²⁺ handling system at any given pacing rate, with small changes in action potential morphology resulting in a transition from stable nonalternating Ca²⁺ transients to stable alternating Ca²⁺ transients. This bifurcation occurs as the alternans eigenvalue of the system changes from absolute value <1 to absolute value >1. These results suggest that the stability of the intracellular Ca²⁺ handling system and the occurrence of Ca²⁺ alternans are not dictated solely by the Ca²⁺ handling system itself, but are also modulated to a significant degree by membrane voltage (through its influence on sarcolemmal Ca²⁺ currents) and, therefore, by all ionic currents that affect membrane voltage.