The cGMP-induced PDE2 stimulation as a novel antiarrhythmic strategy

Patients with myocardial infarction (MI) and heart failure (HF) often develop life-threatening arrhythmia. In the diseased heart, arrhythmia are forced by the imbalance between cyclic nucleotide pathways displaying a detrimental overactive cAMP- and a suppressed beneficial cGMP-signaling. Phosphodiesterase 2 (PDE2) is a keynode enzyme that connects both pathways via its unique property of cGMP-mediated activation to increase cAMP hydrolysis in cardiomyocytes (CM). PDE2 expression is upregulated in HF. Thus, the cGMP-induced PDE2 activation by either natriuretic peptides (NP) or vericiguat (VE) stimulating particulate or soluble guanylate cyclases might represent a new antiarrhythmic therapy.

First, we demonstrated that the pharmacological inhibition or the CM-specific genetic deletion of PDE2 increased arrhythmia development after ischemia reperfusion injury in ex-vivo perfused mouse hearts. Importantly, the cGMP-mediated PDE2 stimulation with CNP or its approved drug analogue vosoritide (VO) reduced arrhythmia in WT hearts, while the PDE2 inhibitor BAY60-7550 prevent the observed antiarrhythmic effect.

Second, we studied the underlying mechanisms on cellular level. In isolated CM, the β-adrenergic stimulation with isoprenaline (ISO) enhanced pro-arrhythmic triggers, like the I _CaL, Ca ²⁺-sparks (CaSp) and -waves (SCW). Interestingly, the simultaneous incubation with CNP or VO significantly reduced the number of CaSp, SCW and I _CaL amplitude. Of note, VE also decreased ISO-induced arrhythmogenic triggers in CM. Selective PDE2 inhibition or knockout clearly prevented the beneficial effects of cGMP-generating stimulators. Finally, we verified the antiarrhythmic effects of cGMP-induced PDE2 activation in CM and ex-vivo perfused hearts from diseased mice with HF, showing evidence for a novel therapeutic strategy.