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

Abstract

Instability in the intracellular Ca 2+ handling system leading to Ca 2+ alternans is hypothesized to be an underlying cause of electrical alternans. The highly coupled nature of membrane voltage and Ca 2+ regulation suggests that there should be reciprocal effects of membrane voltage on the stability of the Ca 2+ handling system. We investigated such effects using a mathematical model of the cardiac intracellular Ca 2+ handling system. We found that the morphology of the action potential has a significant effect on the stability of the Ca 2+ handling system at any given pacing rate, with small changes in action potential morphology resulting in a transition from stable nonalternating Ca 2+ transients to stable alternating Ca 2+ 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 Ca 2+ handling system and the occurrence of Ca 2+ alternans are not dictated solely by the Ca 2+ handling system itself, but are also modulated to a significant degree by membrane voltage (through its influence on sarcolemmal Ca 2+ currents) and, therefore, by all ionic currents that affect membrane voltage.