Autonomic neuroscience : basic & clinical · 2026
Role of beta-adrenergic modulation of action potential duration in arrhythmogenesis in Long QT Syndrome Type 1 & 2.
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Lim Zhia, Chauhan Reshma A, Roper-Jones Bethan, Allen Emily, Mitcheson John, Clayton Richard H, Brack Kieran E, Ng G Andre
Аннотация
INTRODUCTION: Congenital Long QT Syndromes type 1 and 2 (LQT1 and LQT2) are life-threatening conditions that arise from functional impairment of delayed rectifier potassium channels and predispose individuals to ventricular arrhythmias (VAs) such as polymorphic ventricular tachycardia and ventricular fibrillation (VF). Sympathetic surges have been associated with VA onset in LQTS, but mechanisms of initiation are not fully understood. It is therefore necessary to investigate the effects of β-adrenergic receptor (β-AR) stimulation on ventricular electrophysiology in LQT1 and LQT2.
METHODS: HMR-1556 (0.1 μM, 0.5 μM, 1.0 μM) and E4031 (0.02 μM, 0.05 μM, 0.10 μM) were applied to selectively inhibit the slowly and rapidly activating delayed rectifier potassium currents (IKs and IKr), thereby pharmacologically modelling LQT1 and LQT2, respectively. The effects of β-AR stimulation using isoproterenol (ISO) were investigated on monophasic action potential duration (MAPD90), effective refractory period (ERP), MAPD90 restitution (RT Slopemax) and VF threshold (VFT).
RESULTS: Both HMR and E4031 displayed concentration dependent bradycardic effects and increased MAPD90, ERP and VFT. β-AR stimulation on both LQTS models induced tachycardia, and reduced MAPD90, ERP and VFT. In LQT1, the presence of ISO caused a greater decrease in VFT and flattening of RT Slopemax, but in LQT2 RT Slopemax was steeper.
CONCLUSION: The preliminary data suggest that both LQT1 and LQT2 are associated with an increase in VF susceptibility when sympathetic activity is enhanced. However, the dichotomy in the effect on RT slopemax suggest that each LQT subtype may have different arrhythmogenic mechanisms.
METHODS: HMR-1556 (0.1 μM, 0.5 μM, 1.0 μM) and E4031 (0.02 μM, 0.05 μM, 0.10 μM) were applied to selectively inhibit the slowly and rapidly activating delayed rectifier potassium currents (IKs and IKr), thereby pharmacologically modelling LQT1 and LQT2, respectively. The effects of β-AR stimulation using isoproterenol (ISO) were investigated on monophasic action potential duration (MAPD90), effective refractory period (ERP), MAPD90 restitution (RT Slopemax) and VF threshold (VFT).
RESULTS: Both HMR and E4031 displayed concentration dependent bradycardic effects and increased MAPD90, ERP and VFT. β-AR stimulation on both LQTS models induced tachycardia, and reduced MAPD90, ERP and VFT. In LQT1, the presence of ISO caused a greater decrease in VFT and flattening of RT Slopemax, but in LQT2 RT Slopemax was steeper.
CONCLUSION: The preliminary data suggest that both LQT1 and LQT2 are associated with an increase in VF susceptibility when sympathetic activity is enhanced. However, the dichotomy in the effect on RT slopemax suggest that each LQT subtype may have different arrhythmogenic mechanisms.