Background cGMP mediates numerous cardioprotective functions and is a potential therapeutic target for cardiovascular disease. Preclinical studies suggest that plasma cGMP is reflective of natriuretic peptide stimulation. Epidemiologic associations between cGMP and natriuretic peptide, as well as cardiovascular disease risk factors, are unknown. Methods and Results We measured plasma cGMP in 542 men and 496 women free of cardiovascular disease and heart failure in MESA (Multi-Ethnic Study of Atherosclerosis). Cross-sectional associations of N-terminal pro-B type natriuretic peptide, sex hormones, and cardiovascular disease/heart failure risk factors with log(cGMP) were analyzed using multivariable linear regression models. Mean (SD) cGMP was 4.7 (2.6) pmol/mL, with no difference between the sexes. After adjusting for cardiovascular risk factors, N-terminal pro-B type natriuretic peptide was significantly positively associated with cGMP (P<0.05). Higher blood pressure and lower estimated glomerular filtration rate were associated with higher cGMP (P<0.05). Triglyceride levels, total/high-density lipoprotein cholesterol ratio, presence of diabetes mellitus, and the homeostatic model assessment of insulin resistance were inversely associated with cGMP (P<0.05). Among women, free testosterone and dehydroepiandrosterone were inversely associated with cGMP, while sex hormone binding globulin was positively associated (P<0.05). Conclusions In a community-cohort, plasma cGMP was associated with natriuretic peptide signaling. Higher blood pressure and greater renal dysfunction were positively associated with cGMP, while adverse metabolic risk factors were inversely associated. Increased androgenicity in postmenopausal women was inversely associated with cGMP. These novel associations further our understanding of the role of cGMP in a general population.

Background Cyclic guanosine monophosphate (cGMP) is a second messenger regulated through natriuretic peptide and nitric oxide pathways. Stimulation of cGMP signaling is a potential therapeutic strategy for heart failure with preserved ejection fraction (HFpEF) and atherosclerotic cardiovascular disease (ASCVD). We hypothesized that plasma cGMP levels would be associated with lower risk for incident HFpEF, any HF, ASCVD, and coronary heart disease (CHD). Methods and Results We conducted a case-cohort analysis nested in the ARIC (Atherosclerosis Risk in Communities) study. Plasma cGMP was measured in 875 participants at visit 4 (1996-1998), with oversampling of incident HFpEF cases. We used Cox proportional hazard models to assess associations of cGMP with incident HFpEF, HF, ASCVD (CHD+stroke), and CHD. The mean (SD) age was 62.4 (5.6) years and median (interquartile interval) cGMP was 3.4 pmol/mL (2.4-4.6). During a median follow-up of 9.9 years, there were 283 incident cases of HFpEF, 329 any HF, 151 ASCVD, and 125 CHD. In models adjusted for CVD risk factors, the hazard ratios (95% CI) associated with the highest cGMP tertile compared with lowest for HFpEF, HF, ASCVD, and CHD were 1.88 (1.17-3.02), 2.18 (1.18-4.06), 2.84 (1.44-5.60), and 2.43 (1.19-5.00), respectively. In models further adjusted for N-terminal-proB-type natriuretic peptide, associations were attenuated for HFpEF and HF but remained statistically significant for ASCVD (2.56 [1.26-5.20]) and CHD (2.25 [1.07-4.71]). Conclusions Contrary to our hypothesis, higher cGMP levels were associated with incident CVD in a community-based cohort. The associations of cGMP with HF or HFpEF may be explained by N-terminal-proB-type natriuretic peptide, but not for ASCVD and CHD.

Cyclic guanosine monophosphate (cGMP) is a second messenger molecule that transduces nitric-oxide- and natriuretic-peptide-coupled signalling, stimulating phosphorylation changes by protein kinase G. Enhancing cGMP synthesis or blocking its degradation by phosphodiesterase type 5A (PDE5A) protects against cardiovascular disease. However, cGMP stimulation alone is limited by counter-adaptions including PDE upregulation. Furthermore, although PDE5A regulates nitric-oxide-generated cGMP, nitric oxide signalling is often depressed by heart disease. PDEs controlling natriuretic-peptide-coupled cGMP remain uncertain. Here we show that cGMP-selective PDE9A (refs 7, 8) is expressed in the mammalian heart, including humans, and is upregulated by hypertrophy and cardiac failure. PDE9A regulates natriuretic-peptide- rather than nitric-oxide-stimulated cGMP in heart myocytes and muscle, and its genetic or selective pharmacological inhibition protects against pathological responses to neurohormones, and sustained pressure-overload stress. PDE9A inhibition reverses pre-established heart disease independent of nitric oxide synthase (NOS) activity, whereas PDE5A inhibition requires active NOS. Transcription factor activation and phosphoproteome analyses of myocytes with each PDE selectively inhibited reveals substantial differential targeting, with phosphorylation changes from PDE5A inhibition being more sensitive to NOS activation. Thus, unlike PDE5A, PDE9A can regulate cGMP signalling independent of the nitric oxide pathway, and its role in stress-induced heart disease suggests potential as a therapeutic target.

Inhibition of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterases (PDEs) is a cornerstone of pulmonary arterial hypertension (PAH)-specific therapy. PDE9A, expressed in the heart and lung tissue, has the highest affinity for cGMP of all known PDEs. PDE9A deficiency protects mice against chronic left ventricular (LV) pressure overload via increased natriuretic peptide (NP)-dependent cGMP signaling. Chronic-hypoxic pulmonary hypertension (CH-PH) is a model of chronic right ventricular (RV) pressure overload, and previous studies have demonstrated a protective role for NPs in the murine model. Therefore, we hypothesized that PDE9A deficiency would promote NP-dependent cGMP signaling and prevent RV remodeling in the CH-PH model, analogous to findings in the LV. We exposed wild-type and PDE9A-deficient (Pde9a-/- ) C57BL/6 mice to CH-PH for 3 weeks. We measured RV pressure, hypertrophy, and levels of lung and RV cGMP, PDE9A, PDE5A, and phosphorylation of the protein kinase G substrate VASP (vasodilatory-stimulated phosphoprotein) after CH-PH. In wild-type mice, CH-PH was associated with increased circulating ANP and lung PDE5A, but no increase in cGMP, PDE9A, or VASP phosphorylation. Downstream effectors of cGMP were not increased in Pde9a-/- mice exposed to CH-PH compared with Pde9a+/+ littermates, and CH-PH induced increases in RV pressure and hypertrophy were not attenuated in knockout mice. Taken together, these findings argue against a prominent role for PDE9A in the murine CH-PH model.