Scientific Publications by FDA Staff

Heart Rhythm 2017 Aug;14(8):1217-23

Role of suppression of the inward rectifier current (IK1) on terminal action potential repolarization in the failing heart.

Klein MG, Shou M, Stohlman J, Sohljoo S, Haigney M, Tidwell RR, Goldstein RE, Flagg TP, Haigney MC

BACKGROUND: The failing heart exhibits an increased arrhythmia susceptibility that is often attributed to action potential (AP) prolongation due to significant ion channel remodeling. 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: To define the effect of IK1 suppression on the cardiac AP and excitability in the normal and failing heart. METHODS: We used electrophysiological and pharmacological approaches to investigate IK1 function in a swine tachy-pacing model of heart failure. 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 HF animals. TRAP was increased by 54.1 % in HF myocytes (p<0.001) and 26.2% in HF wedges (p=0.014). The increase in TRAP was recapitulated by the potent and specific IK1 inhibitor, PA-6, indicating that IK1 is the primary determinant of the final phase of repolarization. Moreover, we find that IK1 suppression reduced the ratio of ERP to APD90, permitting re-excitation prior to full repolarization, depressed 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 post-repolarization refractoriness, without marked effects on the overall APD. Collectively, these findings demonstrate how IK1 suppression may contribute to arrhythmogenesis in the failing heart.