Stress, inflammation and coronary endothelial injury in preeclampsia

Hypertensive disorders of pregnancy, such as preeclampsia (PEC) cause significant maternal morbidity and mortality, and have emerged as an important early life, and potentially modifiable, risk factor of heart disease in younger women. PEC is diagnosed as new onset hypertension after 20 weeks gestation with evidence of end organ damage, thought to occur because of placental ischemia and an imbalance of angiogenesis. Importantly, PEC is associated with significantly increased CVD risk that persists into later life, far beyond the pregnancy period. Understanding how PEC affects cardiovascular (CV) health both from a biological and socio-behavioral perspective (ie. socially constructed gender roles and stress) is critical to inform risk communication, stratification and to identify and target new treatments to reduce CV disease (CVD), especially among young, high risk women. Although patients with PEC often have traditional pre-pregnancy CV risk factors such as type 2 diabetes and obesity, these risk factors do not fully explain the elevated CV risk conferred after a pregnancy complicated by PEC. Two factors thought to contribute to the pathogenesis of PEC and injure endothelial cells are an imbalance of angiogenesis and alterations in renin-angiotensin-system (RAS), driven by placental ischemia and resulting in oxidative stress with systemic inflammation. From a socio-behavioral perspective, there is evidence that social determinants of health and psychological stress influence PEC severity and future CVD outcomes. Women’s lived experience, including how they experience socially constructed gender roles, stress and neighborhood factors affect health outcomes significantly in PEC. We recently developed noninvasive, reproducible MRI-based methods to measure coronary endothelial function (CEF), offering a means to probe mechanisms contributing to coronary artery disease (CAD) pathophysiology in postpartum women with recent PEC. Abnormal CEF plays a critical role in the development, progression and clinical manifestations of CAD, independently predicts CV events, and is a target for medical interventions. We propose in this application to determine in postpartum women with PEC: 1) whether CEF, and markers of inflammation/imbalanced angiogenesis are inversely related and 2) whether measures of stress (both psychosocial stress and physiologic measures) are associated with endothelial abnormalities and postpartum hypertension. We will determine, in women with a history of PEC, whether reduced CEF can be explained, at least in part, by increased inflammation/abnormal angiogenesis/stress. Together these studies will offer new pathophysiologic insights into increased CVD risk in women with PEC, and which factors contribute most to vascular dysfunction. This study, if funded, will address significant knowledge gaps regarding sex and gender specific variables that affect postpartum vascular health in young women and provide data to design future interventional studies to improve health outcomes in PEC.