Methadone Blockade of Cardiac Inward Rectifier K + Current Augments Membrane Instability and Amplifies U Waves on Surface ECGs: A Translational Study.

Autor: Klein MG; Cardiology Division Department of Medicine Uniformed Services University Bethesda MD., Krantz MJ; Denver Health Medical Center Cardiology Division Denver CO.; Department of Medicine University of Colorado School of Medicine Aurora CO., Fatima N; Department of Anatomy, Physiology & Genetics Uniformed Services University Bethesda MD., Watters A; ACUTE at Denver Health Denver CO.; Department of Medicine University of Colorado School of Medicine Aurora CO., Colon-Sanchez D; Psychiatry Division Outpatient Behavioral Health Services, Denver Health, & University of Colorado School of Medicine Denver CO., Geiger RM; Department of Anatomy, Physiology & Genetics Uniformed Services University Bethesda MD., Goldstein RE; Cardiology Division Department of Medicine Uniformed Services University Bethesda MD., Solhjoo S; Cardiology Division Department of Medicine Uniformed Services University Bethesda MD.; Military Cardiovascular Outcomes Research (MiCOR) Bethesda MD., Mehler PS; ACUTE at Denver Health Denver CO.; Department of Medicine University of Colorado School of Medicine Aurora CO., Flagg TP; Department of Anatomy, Physiology & Genetics Uniformed Services University Bethesda MD., Haigney MC; Cardiology Division Department of Medicine Uniformed Services University Bethesda MD.; Military Cardiovascular Outcomes Research (MiCOR) Bethesda MD.
Jazyk: angličtina
Zdroj: Journal of the American Heart Association [J Am Heart Assoc] 2022 Jun 07; Vol. 11 (11), pp. e023482. Date of Electronic Publication: 2022 Jun 06.
DOI: 10.1161/JAHA.121.023482
Abstrakt: Background Methadone is associated with a disproportionate risk of sudden death and ventricular tachyarrhythmia despite only modest inhibition of delayed rectifier K + current ( I Kr ) , the principal mechanism of drug-associated arrhythmia. Congenital defects of inward rectifier K + current ( I K1 ) have been linked to increased U-wave amplitude on ECG and fatal arrhythmia. We hypothesized that methadone may also be a potent inhibitor of I K1 , contributing to delayed repolarization and manifesting on surface ECGs as augmented U-wave integrals. Methods and Results Using a whole-cell voltage clamp, methadone inhibited both recombinant and native I K1 with a half-maximal inhibitory concentration IC50) of 1.5 μmol/L, similar to that observed for I Kr block (half-maximal inhibitory concentration of 2.9 μmol/L). Methadone modestly increased the action potential duration at 90% repolarization and slowed terminal repolarization at low concentrations. At higher concentrations, action potential duration at 90% repolarization lengthening was abolished, but its effect on terminal repolarization rose steadily and correlated with increased fluctuations of diastolic membrane potential. In parallel, patient ECGs were analyzed before and after methadone initiation, with 68% of patients having a markedly increased U-wave integral compared with premethadone (lead V3; mean +38%±15%, P =0.016), along with increased QT and T Peak to T End intervals, likely reflective of I Kr block. Conclusions Methadone is a potent I K1 inhibitor that causes augmentation of U waves on surface ECG. We propose that increased membrane instability resulting from I K1 block may better explain methadone's arrhythmia risk beyond I Kr inhibition alone. Drug-induced augmentation of U waves may represent evidence of blockade of multiple repolarizing ion channels, and evaluation of the effect of that agent on I K1 may be warranted.
Databáze: MEDLINE