Michael G Klein1, Matie Shou2, Jayna Stohlman3, Soroosh Solhjoo4, Myles Haigney2, Richard R Tidwell5, Robert E Goldstein2, Thomas P Flagg6, Mark C Haigney2. 1. Division of Cardiology, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland. Electronic address: michael.klein@usuhs.edu. 2. Division of Cardiology, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland. 3. Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, Maryland. 4. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland. 5. Department of Pathology and Laboratory Medicine, School of Medicine, The University of North Carolina, Chapel Hill, North Carolina. 6. Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
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. Published by Elsevier Inc.
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. Published by Elsevier Inc.
Authors: Michael G Klein; Mori J Krantz; Naheed Fatima; Ashlie Watters; Dayan Colon-Sanchez; Robert M Geiger; Robert E Goldstein; Soroosh Solhjoo; Philip S Mehler; Thomas P Flagg; Mark C Haigney Journal: J Am Heart Assoc Date: 2022-06-06 Impact factor: 6.106