Vericiguat, a soluble guanylate cyclase stimulator, regulates heart failure-enhanced atrial and pulmonary vein arrhythmogenesis.

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.