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

Di Zhao, Eliseo Guallar, Dhananjay Vaidya, Chiadi E. Ndumele, Pamela Ouyang, Wendy S. Post, Joao A. Lima, Wendy Ying, David A. Kass, Ron C. Hoogeveen, Sanjiv J. Shah, Vinita Subramanya, Erin D. Michos

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


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.

Original languageEnglish (US)
Article numbere013966
JournalJournal of the American Heart Association
Issue number2
StatePublished - Jan 21 2020


  • cardiovascular disease
  • coronary heart disease
  • cyclic GMP
  • heart failure
  • heart failure with preserved ejection fraction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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