Improved Ca2+ release synchrony following selective modification of I-tof and phase 1 repolarization in normal and failing ventricular myocytes
Social Science Research Network(2022)
摘要
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 Itof 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 Itof conductance was increased to similar 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 Itof 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 Itof enhancement should be avoided.
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关键词
Electrophysiology, Heart failure, Arrhythmias, Sudden cardiac death, Calcium cycling/excitation-contraction, coupling
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