Mechanisms of Coronary Microvascular Disease

冠状动脉微血管疾病的机制

• 批准号: 10444980
• 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/10444980
• 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; 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; Strategic vision; Stress; Stress Tests; Structure; Symptoms; Testing; Therapeutic; Thermodilution; Time; Training; United States; Vascular Diseases; Vascular Endothelium; Woman; cardiac magnetic resonance imaging; 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.

项目概要：！ 每年有数以百万计的患者接受稳定性心绞痛的心血管评估，这通常是由以下原因引起的： 心外膜冠状动脉的血流限制性狭窄。然而，高达约 40% 的男性和约 60% 的女性 转诊进行冠状动脉造影的稳定型心绞痛患者没有阻塞性冠状动脉疾病 (CAD)。 即使在压力测试显示为中度至重度缺血的患者中，21% 的患者患有非阻塞性 CAD，定义为 冠状动脉正常或血管造影时所有心外膜冠状血管直径狭窄<50%。在 如果没有阻塞性心外膜 CAD，缺血通常是由冠状动脉微血管疾病介导的。 25-40% 的缺血性和非阻塞性 CAD 患者存在冠状动脉微血管疾病， 通过侵入性检测诊断微血管疾病与死亡、心肌梗塞等风险增加相关 梗塞和心力衰竭。非侵入性冠状动脉微血管疾病的替代测量 冠状血管床尚未确定。 尽管冠状动脉微血管疾病普遍存在并具有不良的临床影响，但其发病机制仍是 未知。冠状动脉微血管疾病可能反映全身微血管异常。减值 由于内皮功能障碍、对应激的血管舒张反应异常以及 推测微血管阻塞。这些过程中的每一个都可能部分由血小板介导 与血管内皮细胞的相互作用。已知活化的血小板会诱发内皮功能障碍 直接或通过与炎症细胞的相互作用。据报道，血小板聚集增加 与患有阻塞性 CAD 的患者相比，患有缺血和非阻塞性 CAD 的稳定患者 和健康的控制。如果血小板确实介导冠状动脉微血管疾病，那么血小板的调节 活动可能具有治疗作用。 我们建议评估血小板活性的测量作为冠状动脉微血管的潜在机制 一组患有稳定缺血和非阻塞性 CAD 并接受侵入性治疗的男性和女性患者的疾病 微血管功能的测量（目标 1）。我们还计划确定冠状动脉的非侵入性相关性 可在体内表征的非冠状动脉微血管床中的微血管疾病（目标 2）。这可能 促进未来临床试验中微血管疾病的诊断。该提案将促进培训 PI 作为缺血性心脏病的临床和转化研究者，通过结构化课程 指导、教学课程、参加研究相关会议以及受保护的时间 研究。该提案解决了 NHLBI 战略愿景中的关键问题 4.CQ.05，将产生新颖的成果 深入了解冠状动脉微血管疾病的生理学和机制，并将提供基础 用于未来微血管疾病诊断、发病机制和治疗的研究。