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Impact of PDE2 modulation in Heart Failure and Arrhythmia

Subject Area Pharmacology
Cardiology, Angiology
Term from 2015 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 289281296
 
Final Report Year 2024

Final Report Abstract

Arrhythmias are frequent complications in patients with heart failure (HF) and contribute significantly to mortality because they can lead to sudden cardiac death. The pharmacotherapy of arrhythmias is challenging and new concepts are desirable. Among the pathophysiological changes in HF, the chronic stimulation of β-adrenoceptors (β-AR) and the associated permanent activation of the cAMP signalling pathway play a prominent role for HF progression. While betablockers inhibit the detrimental cAMP-pathway, new therapeutic strategies support the cardioprotective actions of cGMP-generating natriuretic peptides (NP). Phosphodiesterases (PDEs) are cAMP degrading enzymes. In contrast to others, PDE2 is upregulated in HF and stimulated by cGMP to increase its cAMP hydrolysis. The role of PDE2 in the heart is controversially discussed. In this project, we studied the impact of PDE2 on cardiac function and arrhythmia development. First, we demonstrated that PDE2 overexpression protects against catecholamine-induced arrhythmias. Higher PDE2 abundance significantly reduced the incidence of β-AR-induced cardiac arrhythmias like afterdepolarizations and spontaneous action potentials in mice. Thus, activating myocardial PDE2 could represent a novel intracellular antiarrhythmic therapeutic strategy for HF. In the project, we identified the cGMP-dependent PDE2 stimulation via CNP as a new antiarrhythmic therapy option. Indeed, CNP significantly reduced arrhythmias following ischemia/reperfusion injury and blunted catecholamine-mediated pro-arrhythmic excitations and intracellular Ca2+ releases. The antiarrhythmic effects of CNP were reversed by pharmacological PDE2 inhibition or cardiomyocyte-specific PDE2 deletion. In cooperation, we were able to show a significant improvement of HF after increasing PDE2 expression in murine hearts of mice using gene therapeutic approaches. Detrimental arrhythmia occur also frequently in patients with diabetic cardiomyopathy. To evaluate antiarrhythmic effects of cGMP-dependent PDE2 activation under pathophysiological conditions, we quantified arrhythmia in diabetic mice using the CNP analogue vosoritide, which provide longer plasma half-life and is already approved for treatment of achondroplasia. We could show that vosoritide attenuated abnormal cardiac Ca2+ cycling and thereby reducing arrhythmia in STZ-induced diabetic mice. Thus, vosoritide may be repurposed as a novel anti-arrhythmic drug. In summary, our studies emphasize the vital role of PDE2 in regulating cardiac function and its potential as a therapeutic target for treating arrhythmias and heart failure.

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