Longitudinal Evaluation of Ovarian Aging and Cardiovascular Risk

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ABSTRACT Despite significant improvements in prevention and treatment of cardiovascular disease (CVD), the growing aging population suggests CVD will continue to pose a significant public health burden. Women are a special group where microvascular disease is more common and traditional risk factors may not fully identify risk. Women's reproductive history (e.g. menarcheal age, menstrual cycles, infertility, pregnancy, menopause) may pose unique risk and suggests an opportunity for new approaches. We propose a women-centered approach for early identification of women at risk that investigates the unique loss of reproductive function at an age long before other vital systems fail. Despite the importance of this process, little is known about the determinants or correlates of ovarian aging, or the health implications, especially in diverse populations. With reliable bio-markers of the remaining oocyte pool available, we have a unique opportunity to characterize the association between “ovarian age” and the health implications of accelerated oocyte loss. We hypothesize a risk independent of the well-known impact of early menopause and estrogen deficiency. Rather, we propose that common underlying cellular aging mechanisms, first evident in the ovary due to its sensitivity and earlier demise, make the ovary a window on underlying somatic health. Confirming an association between a decline in markers of ovarian age and CVD risk would allow a potentially high-risk population to be identified decades before traditional risk factors develop. The Ovarian Aging (OVA) cohort is the largest and most ethnically diverse, community-based cohort available that can be used to determine the race/ethnic and behavioral determinants of ovarian aging and its association with CVD risk in a young cycling population. To assess the relationship between markers of ovarian age (reflecting past exposures and genetic risk), the rate of ovarian aging (representing current exposures) and CVD risk, we propose to: 1. Determine whether markers of ovarian age/aging are associated with increased CVD risk by testing if ovarian age/aging is independently associated with increased CVD risk, as measured by peripheral endothelial function testing; 2. Determine whether ovarian aging may moderate or mediate established associations between race/ethnicity and/or socio/emotional health and CVD risk by examining whether observed race/ethnic disparities, or effects of socio/emotional health, on CVD risk, may vary by (moderation model) or be partially attributable to (mediation model) ovarian aging; and 3. Determine whether ovarian aging, CVD risk, and the temporal pattern of appearance correlate with markers of cellular aging: telomere length and mtDNA in peripheral leukocytes, oxidative stress (plasma F2α-isoprostanes), and indices of inflammation (C-reactive protein, interleukin- 6, and soluble intercellular adhesion molecule-1). Overall Impact: Our novel longitudinal approach to evaluating markers of ovarian and cellular aging as predictors of CVD could lead to a new way to identify women at earlier and/or increased CVD risk and be used to develop new risk-reduction strategies.