Abstract
Introduction: Cyclic guanosine monophosphate (cGMP) is an intracellular second messenger, synthesized through nitric oxide (NO) and natriuretic peptide (NP) pathways, with two different downstream effects on the cardiovascular system. Stimulators of cGMP are potential candidates in treating heart failure with preserved ejection fraction (HFpEF). However, the associations between plasma cGMP, HFpEF, and atherosclerotic cardiovascular disease (ASCVD) in the general population are unknown. We hypothesized that cGMP mediates HFpEF and ASCVD events, and that associations differ by sex. Methods: We included 1,034 ARIC participants selected by case-cohort design with over-sampling of participants with incident HFpEF. cGMP was measured using visit 4 plasma samples. Cox proportional hazard regression models were used to assess the relationship of cGMP with incident HFpEF, coronary heart disease (CHD), and ASCVD (CHD + stroke). Models were adjusted for sampling weights to provide estimates applicable to the overall ARIC population. Covariates included demographics and CVD risk factors. Models also adjusted for NT-proBNP, which is upstream of cGMP production in the NP regulated pathway. Results: Mean (SD) age was 63.2 (5.6) years and median (IQR) cGMP was 3.4 pmol/mL (2.4, 4.6). During 16.7 years of follow-up, there were 272 HFpEF, 179 ASCVD, and 129 CHD incident events. In models adjusted for CVD risk factors, the HRs (95% CI) comparing 3 rd tertile with 1 st tertile of cGMP for ASCVD, CHD and HF were 1.8 (1.1, 2.9), 1.9 (1.2, 3.0) and 2.0 (1.2, 3.3), respectively. In models further adjusted for NT-proBNP, associations were attenuated and not significant [HRs 1.2 (0.7, 2.0), 1.5 (0.96, 2.5) and 1.7 (0.98, 2.9), respectively]. There were no significant interactions by sex. Conclusions: cGMP levels are associated incident HFpEF, ASCVD, and CHD; however, after NT-proBNP adjustment, associations were attenuated, suggesting that plasma cGMP levels reflect a greater effect as a downstream messenger in NP than NO signaling pathways.
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