PROJECT ABSTRACT/SUMMARY There are clear sex differences between women and men in the presentation, etiology, and outcomes of cardiovascular disease (CVD). Among the most prominent sex-specific risk factors for women are those related to pregnancy, including hypertensive disorders of pregnancy such as gestational hypertension and preeclampsia. In fact, preeclampsia increases risk of coronary artery disease by 2-fold, heart failure (HF) by 4- fold, and CV mortality by up to 8-fold in affected compared to unaffected women. Despite this substantial risk burden, surprisingly little is known regarding the mechanisms that drive the development of pregnancy-related hypertensive disorders or the subsequent CVD outcomes in these vulnerable women. Emerging but limited data suggest that some, but not all, women with the presence of pre-conception clinical metabolic traits are predisposed to hypertensive disorders of pregnancy. There is also heterogeneity in the extent to which some, but not all, women with a history of preeclampsia have abnormalities in cardiovascular structure or function. We hypothesize that: (i) the stress of pregnancy augments pre-existing metabolic and inflammatory derangements in certain women, making them more susceptible to hypertensive disorders of pregnancy; (ii) in this setting, the hypertensive disorder of pregnancy triggers a cascade of inflammation and oxidative stress that persists and results in additional endothelial damage and coronary microvascular dysfunction (CMD), a previously unrecognized driver of CVD risk; and, (iii) women affected by a hypertensive disorder of pregnancy, especially in the setting of pre-existing metabolic and inflammatory risk and CMD, are more likely to experience accelerated subclinical cardiac disease and progression to clinical CVD. To test our hypotheses and clarify the mechanisms by which certain women are made vulnerable to hypertensive disorders of pregnancy and subsequent CVD, we will comprehensively interrogate clinical, biochemical, and physiological determinants across the spectrum of pregnancy-related CVD risk in both a community cohort enriched with metabolic traits and a clinical cohort that is deeply phenotyped using advanced non-invasive CV diagnostics. This K-23 award will support my goal of becoming a translational clinical investigator in women’s cardiovascular health with expertise in epidemiology, population science, advanced cardiac imaging and hypertensive disorders of pregnancy. The proposed project aligns with the National Institute of Health’s (NIH) mission and highlights the need for “investigations of the many factors underlying the health of women (https://orwh.od.nih.gov).”

PROJECT NARRATIVE Despite the substantial cardiovascular risk burden associated with the development pregnancy related- hypertensive disorders, surprisingly little is known regarding the mechanisms that drive the development of these hypertensive disorders of pregnancy in some women or the subsequent cardiovascular disease (CVD) outcomes in these vulnerable women. We hypothesize that: (i) the stress of pregnancy augments pre-existing metabolic and inflammatory derangements in certain women, making them more susceptible to hypertensive disorders of pregnancy; (ii) in this setting, affected women are prone to developing coronary microvascular dysfunction (CMD), a previously unrecognized driver of CVD risk; and, (iii) women affected by a hypertensive disorder of pregnancy, especially in the setting of pre-existing metabolic and inflammatory risk and CMD, are more likely to experience accelerated subclinical cardiac disease and progression to clinical CVD. To test our hypotheses and determine mechanisms by which certain women are made vulnerable to hypertensive disorders of pregnancy and subsequent CVD, we will comprehensively interrogate the clinical, biochemical, and physiological determinants of pregnancy-associated CVD risk in both a community cohort enriched with cardiometabolic traits and a clinical cohort that is deeply phenotyped using advanced non-invasive cardiovascular imaging.