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

Abstract

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