Longitudinal Evaluation of Ovarian Aging and Cardiovascular Risk

摘要 尽管在预防和治疗心血管疾病（CVD）方面取得了显着进展， 人口老龄化表明心血管疾病将继续构成重大的公共卫生负担。女人是一种特殊的 微血管疾病更常见，传统的风险因素可能无法完全识别风险。 女性的生殖史（如初潮年龄、月经周期、不孕、怀孕、绝经）可能 构成独特的风险，并为新方法提供了机会。我们提出以女性为中心的方法 早期识别处于危险中的妇女，调查在一个年龄段生殖功能的独特丧失， 在其他重要系统失效之前尽管这个过程很重要，但人们对它知之甚少。 卵巢老化的决定因素或相关因素，或健康影响，特别是在不同的人群中。与 可靠的生物标志物的剩余卵母细胞池可用，我们有一个独特的机会来表征 “卵巢年龄”与卵母细胞加速损失的健康影响之间的关系。我们假设 风险独立的众所周知的影响，绝经期提前和雌激素缺乏。而是 提出共同的潜在细胞衰老机制，首先在卵巢中明显，由于其敏感性， 以及更早的死亡，使卵巢成为潜在的身体健康的窗口。建立一个协会 卵巢年龄标志物下降与CVD风险之间的关系将使潜在的高危人群 在传统风险因素发展之前几十年就被发现。卵巢衰老（OVA）队列是最大的 最具种族多样性，以社区为基础的队列，可用于确定 卵巢老化的种族/民族和行为决定因素及其与年轻骑自行车者CVD风险的关系 人口评估卵巢年龄标志物（反映既往暴露和遗传因素）之间的关系， 风险），卵巢老化率（代表当前暴露）和CVD风险，我们建议：1。确定 卵巢年龄/衰老的标志物是否与CVD风险增加相关，通过检测卵巢是否 年龄/衰老与CVD风险增加独立相关，通过外周内皮细胞测量 功能测试; 2.确定卵巢老化是否可能缓和或介导已建立的关联 种族/民族和/或社会/情绪健康与CVD风险之间的关系， 差异，或社会/情绪健康的影响，对心血管疾病的风险，可能会有所不同（适度模型）或部分 归因于（中介模型）卵巢老化;和3.确定卵巢老化、心血管疾病风险以及 与细胞衰老标志物相关的外观时间模式： 外周血白细胞、氧化应激（血浆F2α-异前列腺素）和炎症指数（C-反应性 蛋白、白细胞介素-6和可溶性细胞间粘附分子-1）。整体影响：我们的小说纵向 评估卵巢和细胞衰老标记物作为CVD预测因子的方法可能会导致一种新的方法， 识别早期和/或增加CVD风险的女性，并用于制定新的降低风险策略。

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.