Mental Stress and Myocardial Ischemia after MI: Sex Differences, Mechanisms and Prognosis

年轻女性心肌梗死（MI）已成为一个需要特别研究的群体，因为他们 尽管疾病不太严重，但与年龄相仿的男性相比死亡率更高。这些差距仍然存在 提示急性心肌梗死的病理生理学、危险因素和预后因素存在性别差异。 在预防妇女缺血性心脏病方面，心理社会领域是一个很大程度上被忽视的领域。在 在上一个资助期（R 01 HL 109413），我们收集了一个早发性（≤60岁）MI后队列 患者，50%的女性，以及性别和年龄匹配的社区对照组-心肌梗死和精神病 压力（MIMS）2研究。我们使用实验室方案来研究精神应激诱导的心肌缺血（MSI）， 是冠心病患者压力脆弱性的标志和重要的预后因素。我们发现 患有MI的年轻女性的MSI率是同龄男性的两倍。我们还发现 MSI的机制因性别而异。男性的MSI主要是由于供需不匹配，而女性的MSI则是由于 由微血管收缩驱动 尽管我们在上一个供资期间取得了重大进展，但仍然存在许多问题。第一，临床 MSI在女性中的意义尚不清楚，因为以前的研究主要是检查男性。二是 MSI导致不良事件的途径尚不清楚。基于我们的数据、流程 涉及血管和免疫功能可能对女性特别重要，但这从来没有 测试.第三，年轻女性MSI发生率较高的潜在机制尚不清楚。除了 在生理学上的差异，MSI可以反映在持久的日常生活压力和/或影响/情绪的差异。 在此之前的工作的基础上，这次竞争性更新的目标是澄清性别差异的途径， 在年轻心肌梗死后患者中，将情绪压力与MSI和临床结果联系起来的风险。MI后8个月内， 300名年龄小于61岁的新患者（50%为女性）将在实验室中使用我们建立的MSI检测方法进行MSI检测。 使用与MIMS 2相同的模式进行心肌灌注成像。受试者将在 回家1周，然后随访临床事件。建议的样本（MIMS 3）将增强我们的 现有队列（MIMS 2），将其规模扩大一倍至600名患者，以使其适合评估 临床结果。具体目的是：1）检查MSI是否与两种临床结局相关 女性和男性（复发性MI、不稳定型心绞痛、心力衰竭住院和 心血管死亡）。2)检查血管对精神压力的反应是否与临床 终点，包括内皮依赖性和微血管功能，以及外周血管收缩; 探索性的方式，我们还将检查自主神经失调，炎症，心肌损伤的标志物 并在精神压力下进行修复3)检查压力事件和自主神经功能的性别差异 在一周的家庭监测中，观察其与MSI的关系。

Young women with a myocardial infarction (MI) have emerged as a group in need of special study, as they have higher mortality compared with men of similar age despite less severe disease. These disparities remain unexplained and suggest sex differences in the pathophysiology, risk factors and prognostic factors of acute MI. The psychosocial sphere is a largely neglected area for the prevention of ischemic heart disease in women. In the previous funding period (R01 HL109413) we assembled a cohort of early-onset (≤60 years of age) post-MI patients, 50% women, and sex- and age-matched community controls—the Myocardial Infarction and Mental Stress (MIMS)2 study. We used a laboratory protocol to study mental stress-induced myocardial ischemia (MSI), a marker of stress vulnerability and significant prognostic factor in people with coronary artery disease. We found that young women with MI have twice the rate of MSI than men of similar age. We also found that the mechanisms of MSI differ by sex. While in men MSI is primarily due to supply-demand mismatch, in women it is driven by microvascular vasoconstriction. Despite significant progress in our previous funding period, many questions still remain. First, the clinical implications of MSI in women are unknown, since former studies have mostly examined men. Second, the pathways through which MSI contributes to adverse events are unclear. Based on our data, processes involving vascular and immune function could be especially important for women, but this has never been tested. Third, the underlying mechanisms for the higher rate of MSI in young women are unclear. In addition to differences in physiology, MSI could reflect differences in enduring daily life stressors and/or affect/emotions. Building on this previous work, the goal of this competitive renewal is to clarify sex differences in pathways of risk linking emotional stress to MSI and clinical outcomes in young post-MI patients. Within 8 months of MI, 300 new patients younger than 61 years, 50% women, will be tested in the lab for MSI using our established protocol with myocardial perfusion imaging with the same modalities as MIMS2. Subjects will be monitored at home for 1 week, and then followed for clinical events. The proposed sample (MIMS3) will augment our existing cohort (MIMS2), doubling its size to 600 patients so as to make it suitable for the assessment of clinical outcomes. The specific aims are: 1) Examine whether MSI is related to clinical outcomes in both women and men (a composite endpoint of recurrent MI, unstable angina, heart failure hospitalization and cardiovascular death). 2) Examine whether vascular responses to mental stress are related to the clinical endpoint, including endothelium-dependent and microvascular function, and peripheral vasoconstriction; in an exploratory fashion, we will also examine markers of autonomic dysregulation, inflammation, myocardial injury and repair in response to mental stress. 3) Examine sex differences in stressful events and autonomic function during daily life and their relation with MSI during one week of home monitoring.