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bioRxiv · 10.1101/2024.09.09.612118

Acute sildenafil administration reduces susceptibility to induced atrial fibrillation in sheep

denham, N.·Madders, G. W.·Hutchings, D.·Smith, C. E.·Whitley, A.·Obeidat, M.·Trafford, A.·Pearman, C.·Dibb, K.
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Abstract

BackgroundSildenafil is a PDE5 inhibitor with a very good safety profile and animal models suggest it may be beneficial in the treatment of heart failure and ventricular fibrillation. Sildenafil has also been associated with a reduced incidence of atrial fibrillation (AF) in a retrospective observational study. We have therefore sought to determine whether sildenafil has a direct effect on atrial electrophysiology and resultant AF burden. MethodsInvasive electrophysiological studies were performed in 12 anaesthetised healthy adult female Welsh mountain sheep. Pacing protocols were performed in the right atrium before and after administration of an acute 10 mg intravenous bolus of sildenafil and the burden of AF assessed. ResultsSildenafil profoundly reduced the vulnerability to AF, decreasing AF duration (112.2 {+/-} 73.5 s vs. 3.3 {+/-} 1.4 s), the number of burst pacing inductions causing AF (90 % vs 70 %) and the complexity of AF. The antiarrhythmic effects of sildenafil were determined to be resultant of prolongation of both the atrial effective refractory period (146.9 {+/-} 7.2 ms vs 166.2 {+/-} 32.5 ms) and the atrial excitation wavelength (12.9 {+/-} 0.07 cm vs 15.0 {+/-} 0.07 cm) and resulted in a shallower restitution curve, reflected in a decreased magnitude of monophasic action potential alternans (0.09 {+/-} 0.001 mV vs 0.05 {+/-} 0.10 mV). ConclusionsIn the subjectively healthy atria of a highly translational model a strong antiarrhythmic effect upon acute sildenafil application was observed suggestive of a potential clinical benefit in AF.

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denham, N., Madders, G. W., Hutchings, D., Smith, C. E., Whitley, A., Obeidat, M., Trafford, A., Pearman, C., Dibb, K.. 2024-09-14. Acute sildenafil administration reduces susceptibility to induced atrial fibrillation in sheep. https://doi.org/10.1101/2024.09.09.612118

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