Determinants of the Diastolic Calcium-Voltage Coupling Gain for Delayed Afterdepolarization Mediated Triggered Activity

Abstract

Spontaneous calcium (Ca) release causes delayed afterdepolarizations (DADs) which can result in triggered activity (TA) if the DAD amplitude reaches a critical threshold. It is known that increasing Na-Ca exchange (NCX) or deceasing IK1, which both occur in heart failure remodeling, increases the diastolic Ca-voltage coupling gain potentiating TA. However, the relative influence of NCX, IK1, and the Ca release amplitude on the Ca-voltage coupling gain and threshold for TA are not well understood. Using computer simulation and stability analysis, we show that elevation of the membrane voltage to the TA threshold is governed by non-linear dynamics, consistent with experiments in rabbit ventricular myocytes. This results in the Ca-voltage coupling gain being a nonlinear function of NCX, IK1, and peak Ca. For example, in the UCLA rabbit action potential model, a clamped submembrane Ca peak of 0.4 μM corresponds to a 3.5 mV subthreshold DAD (below the threshold for TA). For this DAD, the NCX conductance had to be increased by a factor of 4 to elicit TA, but decreasing IK1 conductance even to zero failed to elicit TA. For a clamped Ca peak of 0.6 μM corresponding to a 7.5 mV subthreshold DAD, NCX conductance had to be increased by a factor of 2 to elicit TA, and now reducing IK1 by a factor of 4 was able to cause TA. When the peak Ca was increased to 1.1 μM, TA occurred with the unchanged control conductance values of NCX and IK1. Analysis of the underlying nonlinear dynamics provides the theoretical basis for the differential and nonlinear dependence of TA threshold and Ca-voltage coupling gain on peak Ca, NCX, and IK1.