Journal of molecular and cellular cardiology plus · 2026
Absence of arrhythmogenic effects in cAMP subcellular compartments supports PDE8 as a target in atrial fibrillation.
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Revuelta David, Grammatika Pavlidou Nefeli, Aceituno Cristina, Taha Issam Abu, Brunetti Andrea, Ginel Antonino, Girdauskas Evaldas, Dobrev Dobromir, Hove-Madsen Leif, Molina Cristina E
Аннотация
BACKGROUND: Targeting Phosphodiesterase 8B (PDE8B) has been proposed as a strategy to restore L-type Ca2+ current (ICa,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.
OBJECTIVE: 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.
RESULTS: 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.
CONCLUSION: 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 ICa,L in patients with AF, without promoting spontaneous arrhythmogenic Ca2+ releases in isolated human atrial myocytes.
OBJECTIVE: 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.
RESULTS: 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.
CONCLUSION: 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 ICa,L in patients with AF, without promoting spontaneous arrhythmogenic Ca2+ releases in isolated human atrial myocytes.