Methadone blockade of I K1 promotes both long QT and Brugada-like arrhythmias: Mechanistic insights from computational modeling

Background Methadone is widely used for chronic pain relief and in the maintenance therapy of opioid use disorder, however, it also increases the risk of ventricular arrhythmias and sudden cardiac death. Methadone blocks several ionic currents with different half-maximal inhibitory concentrations (IC 50 ), including the rapid component of the delayed rectifier potassium current (I Kr ), the inward rectifier potassium current (I K1 ), the L-type calcium current (I Ca,L ), and the late component of the sodium current (I NaL ). Despite the well-known proarrhythmic effect of I Kr blockade, the effects of blocking other ionic currents on arrhythmogenesis remain less well understood. Methods Computer simulations were used to explore the proarrhythmic effects of methadone by investigating how its blocking effects on ionic currents act alone or together in arrhythmogenesis. Results The major findings are: 1) blocking I K1 potentiates QT prolongation-related arrhythmogenesis by enhancing a tissue-scale dynamical instability for the spontaneous genesis of ectopic excitations. Blocking I K1 and I Kr together results in a synergistic effect, greatly increasing the arrhythmia propensity, much larger than that of blocking either one alone; 2) blocking I K1 in combination with lowering I Ca,L potentiates phase-2 reentry caused by spike-and-dome action potential morphology, an arrhythmia mechanism of Brugada syndrome. Blocking I Kr exhibits little effect for this mechanism of arrhythmias; and 3) hypoxia, often comorbid in methadone populations, can potentiate QT prolongation-related arrhythmias at high sympathetic activity and phase-2 reentry at low or basal sympathetic activity, mainly via its effect on I Ca,L. Conclusions These simulation results provide mechanistic insights into the genesis of QT prolongation-related Torsades de Pointes and Brugada-like ECG related arrhythmias caused by methadone use.