Systemic metabolomic dysregulation linking endometriosis to subsequent cardiovascular disease

ABSTRACT Cardiovascular disease (CVD) is the number one cause of death for women in the U.S.. Endometriosis is a common, female-specific condition defined by endometrial-like tissue thriving outside the uterus that affects ~200 million women globally. Several studies show that endometriosis is associated with higher CVD risk and other cardiometabolic conditions, however, endometriosis patients do not present with traditional CVD risk profiles. Indeed, our prospective study confirmed that endometriosis is associated with CVD risk independent of traditional CVD risk factors. Therefore, there is an urgent need to elucidate the underlying pathophysiology and biological pathways linking endometriosis with subsequent CVD risk, which will discover unique, potentially preventable and treatable, CVD mechanisms specific to women. Our long-term goal is to accelerate novel strategies to reduce CVD incidence in women through a life-course approach. We will identify systemic metabolic alterations in endometriosis patients and their associations with future CVD risk. Our central hypothesis is that systemic metabolic dysregulation occurs in women with endometriosis starting in adolescence, leading to increased CVD risk in mid-life. Our preliminary evidence shows that adolescents with endometriosis have higher blood levels of ceramides and phosphatidylcholines compared to those without, which are known to contribute to CVD pathophysiology. Our data also suggest that these metabolites are persistently elevated despite surgical removal of endometriotic lesions. The rationale for this project is that understanding systemic metabolic alteration in adolescents and young adults with endometriosis will elucidate the biologic underpinning of endometriosis as a female-specific risk factor for CVD as well as discover novel markers that will allow detection of early metabolic dysregulation leading to future CVD risk. We will apply state-of-the-art metabolomics technology and leverage the deeply phenotyped data and biospecimens from six existing prospective cohort studies: The Women’s Health Study: From Adolescence to Adulthood (A2A; n=1,002), the Nurses’ Health Studies [NHS (n=7,735), NHSII (n=3,410)], the Women’s Health Initiative (WHI; n=2,306), UK BioBank (UKBB; n=~145,000), MGB Biobank (MGBB; n=~30,000). In Aim 1, we will determine the endometriosis-related metabolic dysregulation profile in adolescents (A2A). In Aim 2, we will Identify the endometriosis-related metabolic dysregulation profile in adults (NHSII). In Aim 3, we will develop and validate the metabolite-based endometriosis score and examine its association with subsequent CVD risk using data from six cohorts. Results from this study will 1) identify systemic metabolic alterations linking endometriosis and CVD and 2) identify novel CVD risk biomarkers that can be assessed as early as adolescence to young adulthood. Determining the systemic metabolic alterations in women with endometriosis that emerge and persist from adolescence to adulthood and their association with future CVD risk will lead to novel targeted strategies to detect early indications of a change toward declined cardiometabolic health and formulate preventive interventions in women.