C-type natriuretic peptide and vericiguat reduce proarrhythmic Ca2+ signals via PDE2 in heart failure

Background: Chronic heart failure (HF) is among the most common causes of death. The prevalence of HF in people over 70 years of age is more than 15 %. Patients with HF develop lethal arrhythmias due to structural and electrophysiological remodeling. The reduced cardiac function is attempted to be compensated by the chronically activated beta-adrenergic cAMP system. However, this leads to a dysregulated proarrhythmic Ca²⁺ homeostasis in cardiomyocytes (CM). While other phosphodiesterases are downregulated in HF, the PDE2 is increasingly expressed in failing cardiac tissue and might contribute to reduce pro-arrhythmic cAMP levels.  As a cGMP-activated enzyme, PDE2 activity could be induced by both membrane-bound (pGC) and soluble guanylate cyclases (sGC).

Purpose: Here, we aim to evaluate the antiarrhythmic effects of cGMP-mediated PDE2 activation by C-type natriuretic peptide (CNP) and vericiguat (VE) via its pGC and sGC stimulation in CM of mice with HF.

Methods: Mice with CM-specific PDE2 knockout (KO) and control mice were subjected to a high-fat diet (HFD) as well as oral treatment with the NO synthase inhibitor L-NAME via drinking water for 5 weeks. In isolated ventricular CM the number of proarrhythmogenic Ca²⁺ waves (SCW) and Ca²⁺ sparks (CaSp) were quantified. The cellular contractility was measured video-based on relative sarcomere shortening.

Results: After treatment with HFD and L-NAME, mice exhibited an increase in body weight and blood pressure as well as a reduction in systolic and diastolic cardiac performance. In isolated CM from failing mice, the β-adrenergic stimulation with isoprenaline (ISO) increased the number of spontaneous intracellular SCW and CaSp. Interestingly, CNP significantly decreased the occurrence of ISO-induced Ca²⁺ releases, whereas the specific PDE2 inhibitor BAY 60-7550 (BAY) counteracted the antiarrhythmic effect of CNP. The Ca²⁺ transient amplitude and kinetics as well as the cellular contraction properties were not affected by CNP and BAY. In cells from diseased PDE2 KO mice, CNP did not reduce the number of proarrhythmic Ca²⁺ releases. Similar results were observed upon cGMP-mediated PDE2 activation with VE.  In CM from mice with HF, VE clearly reduced the number of ISO-induced arrhythmic Ca²⁺ releases, which was not detected in PDE2 KO cells. In addition, VE did not influence ISO-mediated Ca²⁺ transients and cellular contraction of diseased CM.

Conclusion: cGMP-mediated stimulation of PDE2 by CNP and vericiguat decreases cAMP-dependent proarrhythmic signals in mice with HF and represents a potential target for a novel antiarrhythmic strategy.