Phosphodiesterase 2 Protects against Catecholamine-induced Arrhythmias and Preserves Contractile Function after Myocardial Infarction

Christiane Vettel , Marta Lindner (1) , Matthias Dewenter , Kristina Lorenz , Constanze Schanbacher , Merle Riedel , Simon Lämmle , Simone Meinecke , Fleur Mason , Samuel Sossalla , Andreas Geerts , Michael Hoffmann , Frank Wunder , Fabian Brunner , Thomas Wieland , Hind Mehel (2) , Sarah Karam (3) , Patrick Lechêne (2) , Jérôme Leroy (1) , Grégoire Vandecasteele (2) , Michael Wagner , Rodolphe Fischmeister (2) , Ali El-Armouche

1 CARPAT (UMRS1180) - Signalisation et physiopathologie cardiovasculaire
2 Signalisation et physiopathologie cardiaque
3 PhyMedExp - Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046]

Rationale: Phosphodiesterase 2 is a dual substrate esterase, which has the unique property to be stimulated by cGMP, but primarily hydrolyzes cAMP. Myocardial phosphodiesterase 2 is upregulated in human heart failure, but its role in the heart is unknown. Objective: To explore the role of phosphodiesterase 2 in cardiac function, propensity to arrhythmia, and myocardial infarction. Methods and Results: Pharmacological inhibition of phosphodiesterase 2 (BAY 60–7550, BAY) led to a significant positive chronotropic effect on top of maximal β-adrenoceptor activation in healthy mice. Under pathological conditions induced by chronic catecholamine infusions, BAY reversed both the attenuated β-adrenoceptor–mediated inotropy and chronotropy. Conversely, ECG telemetry in heart-specific phosphodiesterase 2-transgenic (TG) mice showed a marked reduction in resting and in maximal heart rate, whereas cardiac output was completely preserved because of greater cardiac contraction. This well-tolerated phenotype persisted in elderly TG with no indications of cardiac pathology or premature death. During arrhythmia provocation induced by catecholamine injections, TG animals were resistant to triggered ventricular arrhythmias. Accordingly, Ca2+-spark analysis in isolated TG cardiomyocytes revealed remarkably reduced Ca2+ leakage and lower basal phosphorylation levels of Ca2+-cycling proteins including ryanodine receptor type 2. Moreover, TG demonstrated improved cardiac function after myocardial infarction. Conclusions: Endogenous phosphodiesterase 2 contributes to heart rate regulation. Greater phosphodiesterase 2 abundance protects against arrhythmias and improves contraction force after severe ischemic insult. Activating myocardial phosphodiesterase 2 may, thus, represent a novel intracellular antiadrenergic therapeutic strategy protecting the heart from arrhythmia and contractile dysfunction.

Mots clés: phosphodiesterase; β-adrenoceptors; heart rate; arrhythmia

Domaines: Cardiologie et système cardiovasculaire

Christiane Vettel, Marta Lindner, Matthias Dewenter, Kristina Lorenz, Constanze Schanbacher, et al.. Phosphodiesterase 2 Protects against Catecholamine-induced Arrhythmias and Preserves Contractile Function after Myocardial Infarction. Circulation Research, 2017, 120 (1), pp.120-132. ⟨10.1161/CIRCRESAHA.116.310069⟩. ⟨hal-02471411⟩