Vericiguat significantly reduced pulmonary vein spontaneous activity and diastolic tension in heart failure models, attenuating arrhythmogenesis through PKG- and PKA-dependent mechanisms.
Does vericiguat reduce pulmonary vein arrhythmogenesis in heart failure models?
Vericiguat attenuates pulmonary vein arrhythmogenesis in heart failure models through PKG- and PKA-dependent mechanisms, providing a potential mechanistic basis for antiarrhythmic benefits in HF.
Background Heart failure (HF) and atrial fibrillation (AF) often coexist and exacerbate each other. HF enhances pulmonary vein (PV; a key AF trigger) arrhythmogenesis and calcium dysregulation, thereby promoting AF initiation. Purpose Vericiguat, a soluble guanylate cyclase stimulator, improves outcomes in HF; however, its electrophysiological effects on PV arrhythmogenesis remain unclear. Methods Using conventional microelectrodes, we examined the effects of vericiguat (0.1, 1, and 10 μM) on PV action potential and electrical activity; the effects of vericiguat (10 μM) on PVs pretreated with the protein kinase K (PKG) inhibitor KT5823 (1 μM) or the protein kinase A (PKA) inhibitor H89 (10 μM); and the effects of vericiguat (0.2 mg/kg, intravenous, 5 days/week for 4 weeks) on the electrical activity of HF PVs. Whole-cell patch-clamp recordings measured L -type calcium current, sodium/calcium exchanger current, and late sodium current in isolated PV myocytes with or without vericiguat (10 μM). Fluorescence imaging assessed calcium transients and cytosolic calcium content in PV myocytes with or without vericiguat (10 μM). Results Vericiguat significantly reduced PV spontaneous activity and diastolic tension without altering resting membrane potential or action potential amplitude. These antiarrhythmic effects were abolished by KT5823 or H89, indicating involvement of PKG- and PKA-dependent signaling. Vericiguat suppressed L -type calcium current, sodium/calcium exchanger current, and late sodium current and improved intracellular calcium transients and sarcoplasmic reticulum calcium content. Moreover, vericiguat significantly reduced PV spontaneous activity in HF rabbits. Conclusions Vericiguat attenuates PV arrhythmogenesis in HF through PKG- and PKA-dependent mechanisms.
Chan et al. (Wed,) conducted a other in Heart failure and atrial fibrillation. Vericiguat vs. Without vericiguat was evaluated on Pulmonary vein spontaneous activity, diastolic tension, and electrical activity. Vericiguat significantly reduced pulmonary vein spontaneous activity and diastolic tension in heart failure models, attenuating arrhythmogenesis through PKG- and PKA-dependent mechanisms.