Intracellular Calcium and the Mechanism of the Dip in the Anodal Strength-Interval Curve in Cardiac Tissue

Abstract

The strength-interval (SI) curve is an important measure of refractoriness in cardiac tissue. The anodal SI curve contains a "dip" in which the S2 threshold increases with interval. Two explanations exist for this dip: (1) electrotonic interaction between regions of depolarization and hyperpolarization; and (2) the sodium-calcium exchange (NCX) current. The goal of this study is to use mathematical modeling to determine which explanation is correct. The bidomain model represents cardiac tissue and the Luo-Rudy model describes the active membrane. The SI curve is determined by applying a threshold stimulus at different time intervals after a previous action potential. During space-clamped and equal-anisotropy-ratios simulations, anodal excitation does not occur. During unequal-anisotropy-ratios simulations, electrotonic currents, not membrane currents, are present during the few milliseconds before excitation. The dip disappears with no NCX current, but is present with 50% or 75% reduction of it. The calcium-induced-calcium-release (CICR) current has little effect on the dip. These results indicate that neither the NCX nor the CICR current is responsible for the dip in the anodal SI curve. It is caused by the electrotonic interaction between regions of depolarization and hyperpolarization following the S2 stimulus.