ABSTRACT The purpose of this K01 proposal is to facilitate the applicant's transition to an independent research career focused on stress and sex hormone biology to understand mechanisms of sex differences in cardiovascular disease and potential disparities among women. Training components for the proposed research will include direct clinical training in stress testing and vascular physiology, new training in sex hormones and measures of ovarian function, faculty career development, active mentoring, and completion of the proposed research. The premise of this research project is based on preliminary data from the applicant's own research which suggest that compared to men, women (and particularly, younger women) with coronary heart disease have distinct vascular mechanisms in relation to stress and myocardial ischemia, and have higher basal and stress-related inflammation. We have also reported that women ≤ 60 years of age are more likely to develop myocardial ischemia during mental stress than men of similar age. The underlying explanation for these sex differences is unknown; however, one potential mechanism involves sex hormone biology among premenopausal women and across the menopausal transition. Stress may impair female reproduction through diminished ovarian reserve and induce earlier age at menopause, which have been associated with cardiovascular risk, possibly through sex hormone-related pathways influencing immune response, vascular, and cardiac function. The overall goal of this project is to understand mechanisms for sex differences in inflammatory and vascular responses to mental stress, and the role of ovarian function and menopausal status among women. The applicant will leverage the infrastructure of the Myocardial Infarction and Mental Stress Study 2 (MIMS2: R01HL109413), which was recently renewed for a new enrollment wave (MIMS3: 2R01HL109413). The two waves will total 300 men and 300 women with a recent myocardial infarction (MI), ≤ 60 years of age. The applicant will add the collection of data on anti-Müllerian Hormone (AMH), a biomarker of ovarian reserve and menopausal status in women and examine AMH levels in relation to stress responses. The applicant will also recruit a sample of healthy women (n = 100) matched for age to the post-MI women, for comparison of AMH levels and age at menopause. The scientific aims of this project are to: 1) Examine sex differences in inflammation and vascular function at baseline and in response to mental stress and the role of gonadal aging by comparing young and middle-aged women and men; 2) Examine and compare inflammatory and vascular profiles and gonadal aging and age at menopause with age-matched control women; and 3) Examine whether psychosocial stressors such as depression, early life adversity, discrimination, and neighborhood disadvantage are associated with gonadal aging (lower AMH levels) in women with a recent MI and age matched controls. The new enrollment of patients and controls will provide key opportunities for training and data collection on gonadal aging and vascular function to inform the development of a future NIH-R01 proposal.

NARRATIVE The current K01 application seeks to understand the role of gonadal aging on stress physiology, particularly inflammatory and vascular responses, in order to clarify stress-related pathways that may increase vulnerability towards cardiovascular disease in women. Understanding whether sex hormones mediate these stress- related pathways may inform prevention efforts and treatments for women with heart disease to reduce cardiovascular mortality among women.