Menopause-related Vasomotor Symptoms and Cardiovascular Health - PROJECT SUMMARY/ABSTRACT The menopause transition is marked by a sharp rise in cardiovascular disease (CVD) events in women, but the mechanisms through which menopause contributes to CVD risk in midlife women are not known. Hot flashes are a hallmark feature of the menopause transition and are experienced by nearly 80% of menopausal women. Although hot flashes have been widely regarded as bothersome yet benign symptoms, emerging data have linked hot flashes to CVD risk. Inflammation and vascular dysfunction are potential drivers that may explain the relationship between hot flashes and CVD. We hypothesize that among peri- and post-menopausal women with elevated cardiometabolic risk, vasomotor instability triggers systemic inflammation that in turn promotes downstream vascular dysfunction, which contribute to heightened CVD risk. Neurokinin-3 receptor (NK3R) antagonists are a novel therapy that were recently approved for the treatment of moderate to severe menopause-related hot flashes. Because NK3R antagonists centrally suppress hot flashes, they offer a unique opportunity to test whether treating hot flashes in isolation improves CVD risk. We propose to prospectively study 120 peri- and post-menopausal women with cardiometabolic risk factors across a range of hot flash burden (low, moderate, high). To gain further mechanistic insights into the hot flash-CVD link, we will pursue two related lines of investigation. In Aim 1, we will study the effect of hot flash burden on peripheral endothelial and coronary vascular function as measured by brachial artery ultrasound flow mediated dilation (endothelial function) and cardiac perfusion PET (coronary microvascular function) among 120 peri- and post-menopausal women. In Aim 2, we will conduct a randomized placebo-controlled trial to assess the effect of hot flash suppression via NK3R antagonist on endothelial function and molecular pathways of inflammation (select eicosanoid metabolites and inflammatory biomarkers) among 80 peri- and post-menopausal women with moderate to high burden of hot flashes. This proposal leverages a unique and highly experienced multidisciplinary team of investigators with expertise in women’s CVD, menopause physiology, vascular biology, advanced cardiovascular imaging, clinical trials, and bioinformatics. These studies have the potential to be paradigm shifting and may recast hot flashes as an important driver of CVD in menopausal women and not just a bothersome symptom. If suppressing hot flashes improves vascular health and/or attenuates select inflammatory pathways, our findings will advance mechanistic insights into how menopause accelerates CVD risk in women and support broader efforts to identify women with moderate or severe hot flashes and abrogate symptoms as a means of optimizing CV health through the menopause transition.
