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.

项目总结：！ 每年有数百万患者接受稳定型心绞痛的心血管评估，其通常由以下原因引起： 心外膜冠状动脉的限流性狭窄。然而，高达40%的男性和60%的女性 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）。 即使在负荷试验显示中度至重度缺血的患者中，21%的患者患有非梗阻性CAD， 冠状动脉正常或血管造影时所有心外膜冠状动脉直径狭窄<50%。在 在没有阻塞性心外膜CAD的情况下，缺血通常由冠状动脉微血管疾病介导。 25-40%的缺血性和非梗阻性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、心肌梗死和心绞痛的风险增加相关。 梗塞和心力衰竭。冠状动脉微血管病变的非侵入性替代指标 冠状血管床尚未确定。 尽管冠状动脉微血管疾病的患病率和不良临床影响， 未知冠状动脉微血管疾病可能反映了全身性微血管异常。中的减损 由于内皮功能障碍、对应激的异常血管舒张反应和 微血管阻塞是假设的。这些过程中的每一个都可能部分由血小板介导。 与血管内皮的相互作用。已知激活的血小板会诱导内皮功能障碍 直接或通过与炎症细胞的相互作用。据报道， 缺血和非梗阻性CAD稳定患者与梗阻性CAD患者相比 健康的对照。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 活动可以是治疗性的。 我们建议评估血小板活性作为冠状动脉微血管病变的潜在机制的措施 一组接受侵入性治疗的稳定性缺血和非梗阻性CAD男性和女性患者的疾病 微血管功能的测量（目的1）。我们还计划识别冠状动脉粥样硬化的非侵入性相关性， 非冠状动脉微血管床中的微血管疾病，可以在体内表征（目标2）。这可能 有助于在未来的临床试验中诊断微血管疾病。这项建议将促进培训 PI作为缺血性心脏病的临床和翻译研究者，通过结构化的课程， 指导，教学课程，参加与研究相关的会议，并保护时间 research.该提案解决了NHLBI战略愿景中的关键问题4.CQ.05，将产生新的 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 用于微血管疾病诊断、发病机制和治疗的未来研究。