Abstract
Background The failing heart exhibits an increased arrhythmia susceptibility that is often attributed to action potential (AP) prolongation due to significant ion channel remodeling. The inwardly rectifying K+ current (IK1) has been reported to be reduced, but its contribution to shaping the AP waveform and cell excitability in the failing heart remains unclear. Objective The purpose of this study was to define the effect of IK1 suppression on the cardiac AP and excitability in the normal and failing hearts. Methods We used electrophysiological and pharmacological approaches to investigate IK1 function in a swine tachy-pacing model of heart failure (HF). Results Terminal repolarization of the AP (TRAP; the time constant of the exponential fit to terminal repolarization) was markedly prolonged in both myocytes and arterially perfused wedges from animals with HF. TRAP was increased by 54.1% in HF myocytes (P <.001) and 26.2% in HF wedges (P =.014). The increase in TRAP was recapitulated by the potent and specific IK1 inhibitor, PA-6 (pentamidine analog 6), indicating that IK1 is the primary determinant of the final phase of repolarization. Moreover, we find that IK1 suppression reduced the ratio of effective refractory period to AP duration at 90% of repolarization, permitting re-excitation before full repolarization, reduction of AP upstroke velocity, and likely promotion of slow conduction. Conclusion Using an objective measure of terminal repolarization, we conclude that IK1 is the major determinant of the terminal repolarization time course. Moreover, suppression of IK1 prolongs repolarization and reduces postrepolarization refractoriness without marked effects on the overall AP duration. Collectively, these findings demonstrate how IK1 suppression may contribute to arrhythmogenesis in the failing heart.
Original language | English |
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Pages (from-to) | 1217-1223 |
Number of pages | 7 |
Journal | Heart Rhythm |
Volume | 14 |
Issue number | 8 |
DOIs | |
State | Published - Aug 2017 |
Externally published | Yes |
Keywords
- Andersen syndrome
- Arrhythmia
- Diastolic variance
- Effective refractory period
- Inward rectifier
- PA-6
- Pentamidine