Dataset Information

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 (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.

SUBMITTER: Zhao D

PROVIDER: S-EPMC7033823 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Zhao Di D Guallar Eliseo E Vaidya Dhananjay D Ndumele Chiadi E CE Ouyang Pamela P Post Wendy S WS Lima Joao A JA Ying Wendy W Kass David A DA Hoogeveen Ron C RC Shah Sanjiv J SJ Subramanya Vinita V Michos Erin D ED

Journal of the American Heart Association 20200113 2

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-co ...[more]

PMID: 31928156

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Project description:AimsIdentifying early right ventricular (RV) dysfunction and impaired vasodilator reserve is challenging in heart failure with preserved ejection fraction (HFpEF). We hypothesized that cardiac magnetic resonance (CMR)-based exercise imaging and serial cyclic guanosine monophosphate (cGMP) measurements can identify dynamic RV-arterial uncoupling and responsiveness to pulmonary vasodilators at early stages of the HFpEF syndrome.Methods and resultsPatients with HFpEF (n = 16), impaired left ventricular relaxation due to concentric remodelling (LVCR, n = 7), and healthy controls (n = 8) underwent CMR at rest and during supine bicycle exercise with simultaneous measurements of central haemodynamics and circulating cGMP levels, before and after oral administration of 50 mg sildenafil. At rest, mean pulmonary artery pressures (mPAP) were higher in HFpEF, compared with LVCR and controls (27 ± 2, 18 ± 1, and 11 ± 1, respectively; P = 0.01), whereas biventricular volumes, heart rate, and stroke volume were similar. During exercise, LVCR and HFpEF had a greater increase in the ratio of mPAP over cardiac output than controls (5.50 ± 0.77 and 6.34 ± 0.86 vs. 2.24 ± 0.55 in controls, P = 0.005). The ratio of peak exercise to rest RV end-systolic pressure-volume, a surrogate of RV contractility, was significantly reduced in LVCR and HFpEF (2.32 ± 0.17 and 1.56 ± 0.08 vs. 3.49 ± 0.35 in controls, P < 0.001) and correlated with peak exercise VO2 (R2 = 0.648, P < 0.001). cGMP levels increased with exercise across the HFpEF spectrum (P < 0.05 vs. baseline), except when postcapillary pulmonary hypertension was present at rest (P = 0.73 vs. baseline). A single sildenafil administration failed to increase circulating cGMP levels and did not improve RV performance.ConclusionExercise CMR identifies impaired RV-arterial coupling at an early stage of HFpEF. Circulating cGMP levels phenocopy the haemodynamic spectrum in HFpEF but fail to increase after phosphodiesterase type 5 inhibition, endorsing the need for alternative interventions to increase cGMP signalling in HFpEF.

Dataset Information

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

Publications

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

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