Title: Sleep Apnea and ST-Elevation Myocardial Infarction: A Multidisciplinary Translational Study The candidate is currently an Assistant Professor of Medicine and Epidemiology/Population Health at Einstein. The candidate's post-doctoral research at Yale identified sleep apnea (SA) as a risk factor for coronary artery disease related events. Her cohort study of acute MI patients at Einstein, who underwent SA testing during hospitalization, yielded the novel finding that SA may chronically influence cardiac angiogenesis, potentially exerting myocardial protective actions. Given a possible protective effect of SA on myocardial infarct size, the candidate is investigating several candidate pathways that may be responsive to intermittent hypoxemia (from SA) and influence vascular growth factor levels and release of angiogenic proteins. Also, in order to refine the measurement of myocardial infarct size (beyond Troponin T), the candidate has become involved in cardiac imaging. As a result, the candidate has a multidisciplinary mentoring team including seasoned investigators with expertise in (1) cardiovascular disease (CVD) epidemiology (Dr. Kaplan, Einstein, NY), (2) clinical cardiology (Dr. Kizer, Einstein, NY), and (3) sleep medicine (Dr. Redline, Harvard, Boston). Her consulting team includes investigators with specific expertise in (4) cardiothoracic imaging (Dr. Arai - NHLBI and Dr. Haramati, Einstein, NY), (5) translational/biomarker research (Dr. Karumanchi, BI, Boston) and (6) advanced statistical methods (Dr. Xue, Einstein, NY). The candidate will spend the next few years examining the relationship between chronic exposure to SA and myocardial recovery post-MI at a clinical, radiographic and molecular level (K-award). Her proposed study builds on her years of experience recruiting MI patients for in-hospital SA testing at Einstein, and will leverage an ongoing ST-elevation MI (STEMI) registry at Einstein's two main hospitals. The study is IRB approved and the candidate has successfully recruited participants into the study who have completed all aspects of this multidisciplinary project, including: SA testing, biochemical analysis, coronary collateral scoring, and CMR imaging. This illustrates the feasibility of the proposed project and the candidate's ability to make the planned measurements. Owing to a lack of definitive evidence on the relationship between SA and myocardial infarct related characteristics, there is a compelling need to complete the research proposed in this application, gaining additional insights into biological pathways, before designing a definitive clinical trial conducted within the complex setting of an acute MI.
The Specific Aims are: 1. To evaluate the relationship between SA and myocardial injury using contrast-enhanced cardiac magnetic resonance (CMR) imaging in early post-STEMI patients undergoing primary PCI. 2. To examine the association of SA with biochemical markers of hypoxic stress and with collateral coronary circulation in patients with STEMI undergoing primary PCI. This proposal will address an unresolved question surrounding the implications of SA and its subtypes (central and obstructive) for patients with STEMI: whether the ischemic preconditioning that could result from chronic hypoxia has a predominantly favorable effect in terms of myocardial protection, offsetting associated pro- inflammatory and pro-thrombotic influences. The study, whether supportive or not of cardioprotection, will provide information crucial to the proper design of a focused biologically based clinical trial bridging several areas including sleep, cardiology, cardiovascular epidemiology, with translational methods (future R01). The applicant's career development plan consists of 1) Formal coursework, 2) Broadening understanding of MI epidemiology, pathophysiology, treatment and prognosis, 3) Advancing knowledge and skills pertaining to cardiac imaging in STEMI patients, and 4) Broadening knowledge of biomarker use and application. The candidate's primary long-term career goal is to succeed as a translational sleep investigator who can lead focused biologically based clinical trials and translational studies in sleep and CVD. She will begin accomplishing this goal during her K-23 award, which includes joint mentorship from experienced researchers who have a deep understanding of CVD, sleep medicine, and rigorous methodology and logistics. The candidate will enhance her understanding of translational methods through new training in cutting edge imaging and biomarker studies via her collaborators and consultants. The proposed research and complementary training will prepare the candidate to lead future intervention studies that integrate imaging, biomarker, and genetic data for risk stratification. She is committed to developing a career as both a leader within her institution in sleep and cardiovascular medicine as well as an independently funded investigator.
This will be the first multidisciplinary translational study to systematically examine the association between sleep apnea, coronary artery collateral flow, biochemical markers of hypoxic stress, and myocardial infarct characteristics in patients with acute myocardial infarction. Specifically, the proposed study will examine whether the favorable influence of sleep apnea as a stimulus to myocardial ischemic preconditioning could, in the acute myocardial infarction setting, outweigh deleterious pro-inflammatory and pro-thrombotic consequences prevailing in the chronic setting to provide early post-MI cardioprotection. This study, whether supportive or not of cardioprotection, will provide information crucial to the proper design of clinical trials governing the optimal timing of evaluation and treatment of sleep apnea in this population.
