Mechanisms of Coronary Microvascular Disease

冠状动脉微血管疾病的机制

• 批准号: 10055467
• 负责人: Nathaniel Rosso Smilowitz
• 金额: $ 19.31万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-04 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10055467
• 关键词: Address; Affect; Angiography; Binding; Biological Assay; Blood Platelets; Blood Vessels; Blood flow; Caliber; Cardiac; Cardiac Catheterization Procedures; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cells; Chest Pain; Clinical; Clinical Investigator; Clinical Trials; Coronary; Coronary Angiography; Coronary Arteriosclerosis; Coronary Vessels; Coronary artery; Data; Diagnosis; Distal; Educational Curriculum; Endothelium; Enrollment; Evaluation; Event; Foundations; Future; Glycocalyx; Heart; Heart failure; Image; Impairment; Inflammatory; Investigation; Ischemia; Leukocytes; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Mentorship; Microcirculatory Bed; Microscopic; Microvascular Dysfunction; Modality; Myocardial Infarction; Myocardial Ischemia; National Heart, Lung, and Blood Institute; Obstruction; Outcome; Pain; Pathogenesis; Patients; Physiology; Platelet aggregation; Play; Positive Test Result; Positron-Emission Tomography; Prevalence; Process; Reporting; Research; Resistance; Role; Specialized Center; Stenosis; Stress; Stress Tests; Structure; Symptoms; Testing; Therapeutic; Thermodilution; Time; Training; United States; Vascular Diseases; Vascular Endothelium; Vision; Woman; cohort; density; disability; disease diagnosis; endothelial dysfunction; in vivo; indexing; insight; light transmission; men; monocyte; mortality risk; novel; pressure; response; symposium; translational scientist; vascular bed; vascular inflammation

PROJECT SUMMARY:! Each year millions of patients undergo cardiovascular evaluation for stable angina, which is typically caused by flow-limiting stenosis of the epicardial coronary arteries. However, up to ~40% of men and ~60% of women with stable angina referred for coronary angiography do not have obstructive coronary artery disease (CAD). Even in patients with moderate to severe ischemia by stress testing, 21% have non-obstructive CAD, defined as normal coronary arteries or <50% diameter stenosis in all epicardial coronary vessels at angiography. In the absence of obstructive epicardial CAD, ischemia is often mediated by coronary microvascular disease. Coronary microvascular disease is present in 25-40% of patients with ischemia and non-obstructive CAD and a diagnosis of microvascular disease by invasive testing is associated with increased risks of death, myocardial infarction, and heart failure. Non-invasive surrogate measures of coronary microvascular disease in non- coronary vascular beds have not been identified. Despite its prevalence and adverse clinical implications, the pathogenesis of coronary microvascular disease is unknown. Coronary microvascular disease may reflect a systemic microvascular abnormality. Impairments in microvascular function due to endothelial dysfunction, abnormal vasodilatory responses to stress, and microvascular obstruction are hypothesized. Each of these processes may be in part mediated by platelet interactions with the vascular endothelium. Activated platelets are known to induce endothelial dysfunction directly and through interactions with inflammatory cells. Increased platelet aggregation has been reported in stable patients with ischemia and non-obstructive CAD in comparison to both patients with obstructive CAD and healthy controls. If platelets do mediate coronary microvascular disease, then modulation of platelet activity could be therapeutic. We propose to evaluate measures of platelet activity as a potential mechanism of coronary microvascular disease in a cohort of men and women with stable ischemia and non-obstructive CAD undergoing invasive measurements of microvascular function (Aim 1). We also plan to identify non-invasive correlates of coronary microvascular disease in non-coronary microvascular beds that can be characterized in vivo (Aim 2). This may facilitate diagnosis of microvascular disease in future clinical trials. This proposal will advance the training of the PI as a clinical and translational investigator in ischemic heart disease through a curriculum of structured mentorship, didactic coursework, participation in research-related conferences, and protected time for research. The proposal addresses critical question 4.CQ.05 in NHLBI strategic visioning, will yield novel insights into the physiology and mechanisms of coronary microvascular disease, and will provide a foundation for future investigations into microvascular disease diagnosis, pathogenesis, and treatment.

项目摘要：！ 每年，数百万患者接受稳定心绞痛的心血管评估，这通常是由 心外膜冠状动脉的流动狭窄。但是，多达约40％的男性和约60％的女性 引用冠状动脉造影的稳定心绞痛没有阻塞性冠状动脉疾病（CAD）。 即使在通过压力测试中中度至重度缺血的患者中，有21％的患者具有非刺激性CAD的定义 作为正常的冠状动脉或血管造影上所有心外膜冠状动脉血管中的直径狭窄<50％。在 缺乏阻塞性心外膜CAD，缺血通常是由冠状动脉微血管疾病介导的。 25-40％的缺血患者和非目标CAD和A 通过侵入性测试诊断微血管疾病与死亡风险增加有关 梗塞和心力衰竭。非侵入性替代冠状动脉微血管疾病的措施 尚未确定冠状动脉血管床。 尽管冠状动脉微血管疾病的发病机理流行和不良临床意义是 未知。冠状动脉微血管疾病可能反映了全身微血管异常。障碍 由于内皮功能障碍引起的微血管功能，对压力异常的血管舒张反应和 假设微血管阻塞。这些过程中的每一个都可以部分由血小板介导 与血管内皮相互作用。已知活化的血小板会诱导内皮功能障碍 直接通过与炎症细胞相互作用。据报道，血小板聚集增加 与两名阻塞性CAD患者相比 和健康对照。如果血小板确实介导冠状动脉微血管疾病，则调节血小板 活动可能是治疗性的。 我们建议评估血小板活性的度量，作为冠状动脉微血管的潜在机制 在稳定缺血和非刺激性CAD的男女队列中的疾病 微血管功能的测量（AIM 1）。我们还计划确定冠状动脉的非侵入性相关性 可以在体内表征的非冠状微血管床中的微血管疾病（AIM 2）。这可能 在未来的临床试验中促进诊断微血管疾病。该提议将推进培训 PI通过结构化的课程作为缺血性心脏病的临床和转化研究者 指导，教学课程，与研究相关会议的参与以及保护时间 研究。该提案解决了关键问题4.CQ.05在NHLBI战略愿景中，将产生新颖 洞悉冠状动脉微血管疾病的生理和机制，并将提供基础 为了将来研究微血管疾病诊断，发病机理和治疗。