Stress, Vascular Function, and Inflammation as Mechanisms of Sex Differences in Cardiovascular Risk

摘要 本K 01提案的目的是促进申请人向独立研究职业的过渡 专注于压力和性激素生物学，以了解心血管疾病的性别差异机制 疾病和妇女之间的潜在差距。拟议研究的培训内容将包括 压力测试和血管生理学的直接临床培训，性激素和 卵巢功能，教师职业发展，积极指导，并完成拟议的研究。的 本研究项目的前提是基于申请人自己研究的初步数据，这些数据表明 与男性相比，患有冠心病的女性（尤其是年轻女性） 血管机制与应激和心肌缺血有关，并具有较高的基础和应激相关性 炎症我们还报道，≤ 60岁的女性更容易发生心肌梗死， 在精神压力下的心肌缺血比同龄男性更严重。对这些性别差异的潜在解释是 未知;然而，一个潜在的机制涉及绝经前妇女的性激素生物学 以及更年期的过渡期。压力可能会通过减少卵巢功能损害女性生殖能力 保留和诱导绝经年龄提前，这与心血管风险有关，可能 通过影响免疫反应、血管和心脏功能的性行为相关途径。的 该项目的总体目标是了解炎症和血管性疾病中性别差异的机制， 对精神压力的反应，以及卵巢功能和妇女绝经状态的作用。的 申请人将利用心肌梗死和精神压力研究2（MIMS 2： R 01 HL 109413），最近更新了新的入组浪潮（MIMS 3：2 R 01 HL 109413）。两 波将总计300名男性和300名女性，近期心肌梗死（MI），≤ 60岁。的 申请人将增加收集抗苗勒管激素（AMH）数据，AMH是卵巢储备的生物标志物， 妇女的绝经状态，并检查AMH水平与应激反应的关系。申请人还将 招募年龄与MI后女性相匹配的健康女性样本（n = 100），以比较AMH 水平和绝经年龄。该项目的科学目标是：1）检查性别差异， 炎症和血管功能在基线和精神压力的反应和性腺衰老的作用 通过比较青年和中年妇女和男子; 2）检查和比较炎症和血管 与年龄匹配的对照妇女的概况和性腺衰老和绝经年龄;和3）检查是否 心理社会压力源，如抑郁症，早期生活逆境，歧视和邻里劣势 与近期MI女性和年龄匹配对照组的性腺衰老（较低AMH水平）相关。 新入组的患者和对照组将为培训和数据收集提供关键机会， 性腺衰老和血管功能，以告知未来NIH-R 01提案的发展。

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.