Improved Ca release synchrony following selective modification of I and phase 1 repolarization in normal and failing ventricular myocytes.

Loss of ventricular action potential (AP) early phase 1 repolarization may contribute to the impaired Ca 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) 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 to the AP and Ca transient in both normal (guinea pig and rabbit) and in failing rabbit cardiac myocytes. Opposing native I in non-failing rabbit myocytes increased Ca release heterogeneity, late Ca sparks (LCS) frequency and AP duration. (APD). In contrast, increasing I in failing myocytes and guinea pig myocytes (the latter normally lacking I) increased Ca transient amplitude, Ca release synchrony, and shortened APD. Computer simulations also showed faster Ca transient decay (mainly due to fewer LCS), decreased inward Na/Ca exchange current and APD. When the I conductance was increased to ~0.2 nS/pF in failing cells (a value slightly greater than seen in typical human epicardial myocytes), Ca release synchrony improved and AP duration decreased slightly. Further increases in I can cause Ca release to decrease as the peak of the bell-shaped I-voltage relationship is passed and premature AP repolarization develops. These results suggest that there is an optimal range for I enhancement that may support Ca release synchrony and improve electrical stability in heart failure with the caveat that uncontrolled I enhancement should be avoided.