Abstract
Loss of ventricular action potential (AP) early phase 1 repolarization may contribute to the impaired Ca 2+ 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 Ca 2+ transient in both normal (guinea pig and rabbit) and in failing rabbit cardiac myocytes. Opposing native I tof in non-failing rabbit myocytes increased Ca 2+ release heterogeneity, late Ca 2+ 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 Ca 2+ transient amplitude, Ca 2+ release synchrony, and shortened APD. Computer simulations also showed faster Ca 2+ transient decay (mainly due to fewer LCS), decreased inward Na + /Ca 2+ 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), Ca 2+ release synchrony improved and AP duration decreased slightly. Further increases in I tof can cause Ca 2+ 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 Ca 2+ release synchrony and improve electrical stability in heart failure with the caveat that uncontrolled I tof enhancement should be avoided.
Original language | English |
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Pages (from-to) | 52-62 |
Number of pages | 11 |
Journal | Journal of Molecular and Cellular Cardiology |
Volume | 172 |
Early online date | 4 Aug 2022 |
DOIs | |
Publication status | Published - 1 Nov 2022 |
Bibliographical note
Funding Information:The authors acknowledge funding from Medical Research Council UK Program Grant MR/N002903/1 and British Heart Foundation ( PG/15/106/31915 ).
Publisher Copyright:
© 2022 The Authors