History of hypertensive pregnancy and cardiovascular risk during the menopause transition: a lifecourse approach - PROJECT SUMMARY Cardiovascular disease (CVD) is a leading cause of worldwide mortality. A history of a hypertensive disorder of pregnancy (HDP), such as gestational hypertension and preeclampsia, increases the risk of later-life CVD 2-8- fold, and these individuals develop CVD along an accelerated pathway. The period following the reproductive years but before evident CVD directly overlaps with the menopause transition (MT). The MT itself is associated with accelerating changes in cardiovascular (CV) risk, characterized by changes in body composition, lipids, and inflammatory markers. Furthermore, the molecular pathways contributing to increased CVD risk in those with HDP history are not well understood. Although the symptoms of HDP overwhelmingly resolve following the HDP pregnancy, persistent clinical and molecular aberrations related to vascular function and the immune system are demonstrated in several short and long-term studies. To reduce CVD incidence in those with HDP history, it is critical to establish a phenotype of midlife CV risk post-HDP in the context of the menopause transition. We hypothesize that a history of HDP is associated with adverse changes in key physical (Aim 1) and circulating (Aim 2) measures of CV risk during the midlife period, and that this is mediated by characteristics of the MT (menopausal stage and endogenous sex hormone levels). We also hypothesize that HDP history, compared to no HDP history, will be associated with differences in proteomic measures, regardless of menopausal stage at sampling (Aim 3). To test our hypotheses, we will leverage the rich data within the Study of Women’s Health Across the Nation (SWAN) cohort. SWAN enrolled 3302 premenopausal or early perimenopausal individuals aged 42 to 52 years at seven research sites in the United States. To date, SWAN has completed 17 study visits, spanning approximately 28 years of follow-up. Importantly, SWAN captured reproductive history, details of the MT at each visit, longitudinal measures of CV risk, and stored serum that we will use to perform proteomics. We leverage all of these strengths of SWAN in our proposal. To address the above-listed hypotheses we will take into consideration the stage of the MT while evaluating HDP history compared to no HDP history in relation to: (1) longitudinal trends in existing physical (blood pressure, body mass index, anthropometric) and circulating (lipids, lipoproteins, glucose, insulin, creatinine, N-terminal pro-B-type natriuretic peptide, hemostatic/inflammatory) measures of CV risk, and (2) >7000 serum proteins measured by a proteomic assay. Leveraging SWAN’s rich longitudinal CV risk and MT data, this study aims to establish a phenotype of midlife CV risk post-HDP. An improved understanding of midlife trajectories of CV risk factors and unique molecular profiles in individuals with HDP history has significant
