Action potential morphology influences intracellular calcium handling stability and the occurrence of alternans

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.