Sleep Apnea and ST-Elevation Myocardial Infarction: A Multidisciplinary Translational Study

 描述(申请人提供)：睡眠呼吸暂停和ST段抬高心肌梗死：一项多学科的转译研究这项提案挑战了传统观点，即睡眠呼吸暂停只会导致有害的促炎和促血栓形成事件。相反，睡眠呼吸暂停可能是缺血预适应的一种形式--这是保护心肌免受缺血性损伤的最有效机制之一。我们假设，睡眠呼吸暂停引起的间歇性低氧对心脏的保护作用会导致血管生成因子的上调，进而触发冠脉侧支的发育，从而在严重缺血期保护心肌。缩小心肌梗死面积是过去40年来缺血性心肌病研究的主要目标。这项研究，如果证实了心脏保护，将有助于范式的转变。如果假设得到证实，候选人将着手未来的研究，结合个体基因分析进一步探索间歇性低氧对睡眠呼吸暂停的保护能力，这可能为心血管疾病提供新的治疗策略。我们研究的目的是：1.确定睡眠呼吸暂停与心肌梗死后早期心肌损伤之间的独立相关性。目的2.探讨睡眠呼吸暂停在心肌梗死后早期发挥心脏保护作用的机制。这项研究解决了目前文献中关于睡眠呼吸暂停和心肌梗死后早期损伤之间关系的空白。它包括：1)心脏MRI，以测量心肌梗死后早期的心肌梗死范围、微血管阻塞和心肌存活；2)使用Rtrop评分来测量侧支循环形成的程度；3)低氧应激的生物标志物，包括炎症和适应性；4)对睡眠呼吸暂停的纵向评估，在两个时间点进行测试，一次是在心肌梗死后几天内，另一次是在事件发生后的第二周。到目前为止，没有研究团队将这些组成部分合并到一项全面的研究中。因此，我们没有充分了解上述联系所需的信息。因此，我们的研究将为睡眠呼吸暂停和心肌损伤的作用提供一个重要的、新颖的、全面的评估。这位候选人目前是纽约阿尔伯特·爱因斯坦医学院的医学和流行病学/人口健康助理教授。这位候选人在耶鲁大学医学院完成了她的临床和研究奖学金，在此期间她在耶鲁大学公共卫生学院获得了慢性病流行病学硕士学位。在她担任研究员期间，她获得了Ruth L.Kirschstein国家研究服务奖(机构研究培训补助金)。申请人目前是为期三年的校内职业发展奖(KL-2)的最后一年。在该奖项的第一年和第二年，她测量了急性心肌梗死患者的血浆血管内皮生长因子水平(Shah，睡眠呼吸2012)。这是KL-2奖的主要目的，候选人报告了一项新的发现，即睡眠呼吸暂停患者的血管内皮生长因子水平高于急性心肌梗死患者的非睡眠呼吸暂停患者(ATS 2013)。然而，睡眠呼吸暂停是一种多组分的疾病，具有组织特异性反应。在KL-2期间，候选人认识到需要一种跨学科的方法来捕捉睡眠呼吸暂停与冠状动脉粥样硬化和相关结果(梗塞面积)之间的联系的复杂性。因此，在KL-2获奖期间，候选人扩大了项目范围。她包括先进的心脏成像技术，以准确测量梗死特征、冠状动脉侧支循环评分和心脏生物标志物。候选人已经成功地开始让患者参加这项跨学科的试点研究。候选人的长期职业目标是成为一名成功的转化型睡眠研究人员，能够领导睡眠和心血管疾病方面的重点临床试验和转化性研究。具体地说，她计划调查睡眠呼吸暂停及其治疗如何影响心肌梗死的严重程度和康复。这位候选人拥有一支非常强大的多学科指导团队。在他们的指导下，她概述了一项职业发展计划，其中包括临床心脏病学、心血管流行病学、生物标记物/翻译研究方法学和心脏成像方面的培训。它还包括高级统计、手稿编写和出版、参加国家和地方会议以及编写和提交R01的正式课程。因此，很明显，在NIH的支持下，候选人不仅有充分的优势来填补潜在的变革性研究问题的空白，而且还可以成功地实现成为睡眠医学领域的独立研究员的职业目标。

 DESCRIPTION (provided by applicant): Sleep Apnea and ST-Elevation Myocardial Infarction: A Multidisciplinary Translational Study This proposal challenges conventional wisdom that sleep apnea only contributes to deleterious pro- inflammatory and pro-thrombotic events. Instead, sleep apnea may be a form of ischemic preconditioning- one of the most potent mechanisms to protect against myocardial ischemic injury. We hypothesize that a cardioprotective influence of intermittent hypoxia from sleep apnea leads to up-regulation of angiogenic factors, which in turn triggers the development of coronary collaterals and thereby protects the myocardium during a period of severe ischemia. Reduction of myocardial infarct size has been the key objective of research on ischemic myocardial disease over the past four decades. This study, if confirmatory of cardioprotection, will contribute to a paradigm shift. If the hypotheses are proven, the candidate will embark on future investigations to further explore the protective abilities of intermittent hypoxia in sleep apnea combined with individual gene analysis, which may provide new treatment strategies for cardiovascular diseases. The Aims of our study are: Aim 1. To determine an independent association between sleep apnea and myocardial injury in the early post-infarction period. Aim 2. To investigate mechanistic pathways of a cardioprotective role of sleep apnea in the early post- myocardial infarction period. This study addresses the gaps in the current literature on the association between sleep apnea and myocardial injury in the early post-infarction period. It includes: 1) Cardiac MRI to measure myocardial infarct size, microvascular obstruction, and myocardial viability during the early post-infarction period 2) Coronary collateral scoring using Rentrop score to measure the degree of collateral formation 3) Biomarkers of hypoxic stress including inflammatory and adaptive 4) Longitudinal assessment of sleep apnea with testing at two time points, one within days of myocardial infarction and second weeks after the event No research team to date has merged these components into one comprehensive study. Consequently, we do not have the information required to fully understand the aforementioned association. Therefore our study will provide an important novel, overarching assessment of the role of sleep apnea and myocardial injury. The candidate is currently an Assistant Professor of Medicine and Epidemiology/Population Health at Albert Einstein College of Medicine in New York. The candidate completed her clinical and research fellowship at Yale University School of Medicine and during that period she received a Master's in Chronic Disease Epidemiology at the Yale School of Public Health. During her fellowship, she received the Ruth L. Kirschstein National Research Service Award (Institutional Research Training Grant). The applicant is currently in the final year of a three-year intramural career development award (KL-2). In years one and two of this award, she measured plasma vascular endothelial growth factor levels in acute myocardial infarction patients (Shah, Sleep Breath 2012). This was the primary aim of the KL-2 award and the candidate reported the novel finding that vascular endothelial growth factor levels are higher in sleep apnea patients vs. non-sleep apnea patients with acute myocardial infarction (ATS 2013). Sleep apnea is a multicomponent disorder, however, with tissue-specific responses. During the KL-2 duration, the candidate recognized that a transdisciplinary approach is required to capture the complexity of sleep apnea's link with coronary atherosclerosis and related outcomes (infarct size). Therefore, during the KL-2 award period, the candidate broadened the scope of the project. She included sophisticated cardiac imaging techniques to accurately measure infarction characteristics, coronary collateral scoring and cardiac biomarkers. The candidate has successfully begun patient enrollment into this transdisciplinary pilot study. The candidate's long-term career goal i to succeed as a translational sleep investigator who can lead focused clinical trials and translational studies in sleep and cardiovascular diseases. Specifically, she plans to investigate how sleep apnea and its treatment impact myocardial infarction severity and recovery. The candidate has an exceptionally strong multidisciplinary mentoring team. With their guidance, she has outlined a career development plan that includes training in clinical cardiology, cardiovascular epidemiology, biomarker/translational research methodology, and cardiac imaging. It also includes formal coursework in advanced statistics, manuscript preparation and publication, participation in national and local meetings/conferences and preparing and submitting R01s. It is therefore clear that with NIH support, the candidate has every advantage to not only fill the gap in a potential transformative research question, but to also succeed in he career goal of becoming an independent investigator in the field of sleep medicine.