Absence of arrhythmogenic effects in cAMP subcellular compartments supports PDE8 as a target in atrial fibrillation

Targeting Phosphodiesterase 8B (PDE8B) has been proposed as a strategy to restore L-type Ca²⁺ current (I_Ca,L) in patients with atrial fibrillation (AF). However, the effects of total PDE8 inhibition on other Ca²⁺ handling or 3',5'-cyclic adenosine monophosphate (cAMP) nanodomains have not been assessed and thus the potential proarrhythmic consequences are still undetermined.

The aim of this study was to assess whether PDE8 contributes to the regulation of cAMP signaling in other Ca²⁺ handling-related compartments and to sarcoplasmic reticulum Ca²⁺ release-mediated arrhythmogenic events.

Fluorescence resonance energy transfer (FRET) live-cell imaging, confocal Ca²⁺ imaging and co-immunoprecipitation (Co-IP) were performed in atrial myocytes and tissues allocated across experimental assays from a total cumulative cohort of 141 patients with or without AF (sinus rhythm, Ctl). cAMP levels were not significantly increased upon non-isoform-selective total PDE8 inhibition in the cytosol, in ryanodine receptor 2 (RyR2) or in the sarcomere nanodomains, troponin I (TpnI) and myosin binding protein C (MyBP-C). Consistently, no significant changes in the frequency of arrhythmogenic Ca²⁺ sparks or Ca²⁺ waves after total PDE8 inhibitor application were detected.

These results suggest that PDE8 inhibition promotes a compartment-specific regulation of cAMP signaling that exclusively affects the L-type Ca²⁺ channel in human atrial myocytes. Therefore, PDE8 inhibition can be used to restore I_Ca,L in patients with AF, without promoting spontaneous arrhythmogenic Ca²⁺ releases in isolated human atrial myocytes.