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

摘要 这项K01建议的目的是促进申请者向独立研究职业的过渡 重点关注应激和性激素生物学，以了解心血管疾病性别差异的机制 妇女之间的疾病和潜在的差异。拟议研究的培训部分将包括 压力测试和血管生理学方面的直接临床培训，性激素的新培训，以及 卵巢功能，教师职业发展，积极的指导，以及完成拟议的研究。这个 本研究项目的前提是基于申请者自己的研究的初步数据，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)有明显的 血管机制与应激和心肌缺血有关，具有较高的基础和应激相关 发炎。我们还报道，60岁的女性≤更有可能患上心肌梗死 缺血期的精神压力比同龄男性要大。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。 并跨越更年期过渡。应激可能通过卵巢萎缩损害女性生殖能力 使更年期年龄提前，这可能与心血管风险有关 通过与性激素相关的途径影响免疫反应、血管和心脏功能。这个 这个项目的总体目标是了解炎症和血管中性别差异的机制。 对精神压力的反应，以及卵巢功能和更年期状态在女性中的作用。这个 申请者将利用心肌梗死和精神应激研究2(MIMS2： R01HL109413)，最近续签了新一轮招生浪潮(MIMS3：2R01HL109413)。两个人 Waves将共有300名男性和300名女性最近发生心肌梗死(MI)，≤年龄为60岁。这个 申请者将添加抗苗勒氏激素(AMH)的数据收集，AMH是卵巢储备和 妇女的绝经状态，并检查AMH水平与应激反应的关系。申请者还将 招募年龄与心肌梗死后女性年龄匹配的健康女性样本(n=100)，用于AMH的比较 绝经时的水平和年龄。这个项目的科学目标是：1)检查性别差异 炎症和血管功能在基线和对精神应激的反应以及性腺老化的作用 通过比较青年和中年女性和男性；2)检查和比较炎性和血管 与年龄匹配的对照组妇女的资料和性腺老化和绝经年龄；以及3)检查 心理社会应激源，如抑郁、早年逆境、歧视和邻里劣势 在最近有心肌梗塞和年龄匹配的对照组中，与性腺老化(较低的AMH水平)有关。 新的患者和控制组登记将为培训和数据收集提供关键机会 性腺老化和血管功能，以告知未来NIH-R01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.