Phosphodiesterase 2 Protects Against Catecholamine-Induced Arrhythmia and Preserves Contractile Function After Myocardial Infarction

Rationale: Phosphodiesterase 2 (PDE2) is a dual substrate esterase, which has the unique property to be stimulated by cGMP, but primarily hydrolyses cAMP. Myocardial PDE2 is upregulated in human heart failure (HF), but its role in the heart is unknown. Objective: To explore the role of PDE2 in cardiac function, propensity to arrhythmia and in myocardial infarction. Methods and Results: Pharmacological inhibition of PDE2 (BAY 60-7550, BAY) led to a significant positive chronotropic effect on top of maximal β-adrenoceptor (β-AR) activation in healthy mice. Under pathological conditions induced by chronic catecholamine infusions, BAY reversed both the attenuated β- AR mediated inotropy and chronotropy. Conversely, ECG telemetry in heart specific PDE2 transgenic mice (TG) showed a marked reduction in resting as well as in maximal heart rate, while cardiac output was completely preserved due to 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. Conclusion: Endogenous PDE2 contributes to heart rate regulation. Greater PDE2 abundance protects against arrhythmias and improves contraction force after severe ischemic insult. Activating myocardial PDE2 may thus represent a novel intracellular anti-adrenergic therapeutic strategy protecting the heart from arrhythmia and contractile dysfunction.