Improved Ca2+ release synchrony following selective modification of Itof and phase 1 repolarization in normal and failing ventricular myocytes

Abstract

Loss of ventricular action potential (AP) early phase 1 repolarization may contribute to the impaired Ca²⁺ release and increased risk of sudden cardiac death in heart failure. Therefore, restoring AP phase 1 by augmenting the fast transient outward K⁺ current (I_tof) might be beneficial, but direct experimental evidence to support this proposition in failing cardiomyocytes is limited. Dynamic clamp was used to selectively modulate the contribution of I_tof to the AP and Ca²⁺ transient in both normal (guinea pig and rabbit) and in failing rabbit cardiac myocytes. Opposing native I_tof in non-failing rabbit myocytes increased Ca²⁺ release heterogeneity, late Ca²⁺ sparks (LCS) frequency and AP duration. (APD). In contrast, increasing I_tof in failing myocytes and guinea pig myocytes (the latter normally lacking I_tof) increased Ca²⁺ transient amplitude, Ca²⁺ release synchrony, and shortened APD. Computer simulations also showed faster Ca²⁺ transient decay (mainly due to fewer LCS), decreased inward Na⁺/Ca²⁺ exchange current and APD. When the I_tof conductance was increased to ~0.2 nS/pF in failing cells (a value slightly greater than seen in typical human epicardial myocytes), Ca²⁺ release synchrony improved and AP duration decreased slightly. Further increases in I_tof can cause Ca²⁺ release to decrease as the peak of the bell-shaped I_Ca-voltage relationship is passed and premature AP repolarization develops. These results suggest that there is an optimal range for I_tof enhancement that may support Ca²⁺ release synchrony and improve electrical stability in heart failure with the caveat that uncontrolled I_tof enhancement should be avoided.

Keywords: Arrhythmias; Calcium cycling/excitation-contraction coupling; Electrophysiology; Heart failure; Sudden cardiac death.