• Dony Yugo, Yao-Chang Chen, Yung-Kuo Lin, Chih Min Liu, Jen Hung Huang, Shih-Ann Chen, and Yi-Jen Chen.
• Heart Rhythm Center and Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
• Eur. J. Clin. Invest. 2021 Sep 1; 51 (9): e13585.

IntroductionPhosphodiesterase (PDE) isoform inhibitors have mechanical and electrical effects on the heart. Inhibition of PDE-1 enzymes is a novel strategy for treating heart failure. However, the electrophysiological effects of PDE-1 inhibition on the heart remain unclear. This study explored the effects of PDE-1 inhibition using ITI-214 on electrical activity in the pulmonary vein (PV), the most common trigger of atrial fibrillation, and investigated the underlying ionic mechanisms.MethodsConventional microelectrodes or whole-cell patch clamps were employed to study the effects of ITI-214 (0.1-10 μM) on PV electrical activity, mechanical responses and ionic currents in isolated rabbit PV tissue specimens and isolated single PV cardiomyocytes.ResultsITI-214 at 1 μM and 10 μM (but not 0.1 μM) significantly reduced PV spontaneous beating rate (10 ± 2% and 10 ± 3%, respectively) and PV diastolic tension (11 ± 3% and 17 ± 3%, respectively). ITI-24 (1 μM) significantly reduced late sodium current (INa-Late ), L-type calcium current (ICa-L ) and the reverse mode of the sodium-calcium exchanger (NCX), but it did not affect peak sodium currents.ConclusionsITI-214 reduces PV spontaneous activity and PV diastolic tension by reducing INa-Late , ICa-L and NCX current. Considering its therapeutic potential in heart failure, targeting PDE-1 inhibition may provide a novel strategy for managing atrial arrhythmogenesis.© 2021 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.

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