Cyclic Guanosine Monophosphate and Risk of Incident Heart Failure and Other Cardiovascular Events: the ARIC Study

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 ( HF p EF ) and atherosclerotic cardiovascular disease ( ASCVD ). We hypothesized that plasma cGMP levels would be associated with lower risk for incident HF p EF , 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 HF p EF cases. We used Cox proportional hazard models to assess associations of cGMP with incident HF p EF , 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 HF p EF , 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 HF p EF , 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 HF p EF 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 HF p EF may be explained by N‐terminal‐proB‐type natriuretic peptide, but not for ASCVD and CHD.