Noninvasive Testing of Coronary Microvascular Reactivity Using High-resolution Free-breathing MRI

使用高分辨率自由呼吸 MRI 进行冠状动脉微血管反应性无创测试

• 批准号: 10661188
• 负责人: Behzad Sharif
• 金额: $ 66.91万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661188
• 关键词: Animals; Blood flow; Breathing; Cardiac; Clinical; Coronary; Coronary Arteriosclerosis; Coronary Vessels; Coronary artery; Data; Detection; Diagnosis; Diagnostic tests; Diet; Echocardiography; Endothelium; Evaluation; Event; Functional disorder; Funding; Health; Heart Diseases; Heart failure; Heterogeneity; Hypertrophy; Image; Impairment; Ischemia; Lead; Machine Learning; Magnetic Resonance Imaging; Measurement; Medical center; Methods; Microcirculation; Microspheres; Microvascular Dysfunction; Monitor; Morphologic artifacts; Myocardial; Myocardial Ischemia; Myocardial perfusion; Nature; Non-Invasive Cancer Detection; Outcome; Patient Care; Patient imaging; Patients; Performance; Physiologic pulse; Physiology; Population; Positron-Emission Tomography; Procedures; Prognosis; Quality of life; Reference Standards; Research Personnel; Research Proposals; Resistance; Resolution; Risk; Scanning; Severities; Staging; Stress; Systole; Techniques; Testing; Vasodilator Agents; adverse event risk; base; experience; heart imaging; high resolution imaging; high risk; image guided; image reconstruction; imaging approach; improved; indexing; innovation; novel; novel therapeutics; perfusion imaging; personalized medicine; porcine model; recruit; sequence learning

PROJECT SUMMARY It was long taken for granted that obstructive coronary artery disease (CAD) is the primary driver of angina and major adverse cardiac events. However, recent landmark studies have shown that up to 50% of the patients referred for diagnostic testing have ischemia with no obstructive CAD (INOCA). A large proportion of INOCA patients have coronary microvascular dysfunction (CMD), which even in the absence of flow-limiting stenoses can lead to myocardial ischemia and carries a high risk of adverse events. The reference standard for assessment of CMD is the functional coronary reactivity (CR) test, which is invasive. Despite key studies showing value of stratifying therapy based on CR testing, the practical utility of CR testing in the INOCA population is limited by its invasive nature, which carries serious risks even at experienced centers. Hence, a noninvasive approach that can detect and stage the severity of CMD would be invaluable for managing INOCA patients. Driven by this unmet need, prior studies have employed imaging approaches to index myocardial perfusion reserve (MPR) against CR; however, the association shown to date between MPR and CR impairment has been weak, likely due to the suboptimal sensitivity of MPR to subendocardial myocardial blood flow (MBF) deficits which is a hallmark of CMD. Studies using invasive microsphere-based methods have established a stress subendocardial-to-subepicardial (endo-epi) MBF gradient of larger than 1.0 in healthy animals, and shown that it decreases well below 1 under abnormally elevated microvascular resistance. However, noninvasive detection of endo-epi MBF gradients using existing imaging strategies is challenging because of the need to resolve MBF transmurally. We have developed new MRI strategies aimed at overcoming key barriers for accurate evaluation of endo-epi MBF gradients and applied them in preliminary animal and patient studies. Based on our preliminary data, we hypothesize that in the setting of CMD, impaired microvascular CR manifests as a stress-induced endo- epi MBF gradient, and the magnitude of this gradient significantly correlates with CMD severity. To test this hypothesis, we propose 3 specific aims. In Aim 1, we will develop a free-breathing artifact-free MRI technique optimized for high-resolution imaging of endo-epi MBF gradients, combined with a machine learning approach for fully-automated objective quantification of MBF gradients. In Aim 2, we will test the hypothesis that CMD severity can be staged on the basis of MRI-derived stress MBF gradient in a pig model of CMD. In Aim 3, we will test the hypothesis that CMD severity in INOCA patients is highly correlated with MRI-derived stress MBF gradient. This project brings together multiple interdisciplinary investigators with a strong collective track record in developing cardiac imaging strategies to advance a noninvasive approach for determining CMD severity based on the MRI-derived stress MBF gradient. Hence the proposal is a major step towards improving the management of INOCA patients and towards imaging-guided evaluation of novel therapies aimed at CMD.

项目摘要 长期以来，人们认为阻塞性冠状动脉疾病（CAD）是心绞痛的主要驱动因素， 主要心脏不良事件。然而，最近具有里程碑意义的研究表明，高达50%的患者 被转诊进行诊断测试的患者患有无阻塞性CAD的缺血（INOCA）。INOCA的大部分 患者有冠状动脉微血管功能障碍（CMD），即使没有血流限制性狭窄， 可导致心肌缺血并具有高的不良事件风险。的参考标准 CMD的评估是功能性冠状动脉反应性（CR）测试，其是侵入性的。尽管关键研究显示 基于CR检测的分层治疗的价值，CR检测在INOCA人群中的实际效用是 由于其侵入性，即使在有经验的中心也存在严重风险。因此，非侵入性 一种可以检测和分期CMD严重程度的方法对于管理INOCA患者将是非常宝贵的。 在这种未满足的需求的驱动下，先前的研究采用成像方法来指示心肌灌注 储备（MPR）对CR;然而，到目前为止，MPR和CR减值之间的关联已经被证明是 弱，可能是由于MPR对心内膜下心肌血流（MBF）缺陷的敏感性不佳 这是CMD的标志。使用侵入性微球为基础的方法的研究已经建立了一个压力 健康动物的心内膜下至心外膜下（内-外膜）MBF梯度大于1.0，并显示， 在微血管阻力异常升高的情况下，它降低到远低于1。然而，非侵入性检测 由于需要解析MBF，因此使用现有成像策略进行内表观MBF梯度具有挑战性 透壁的我们开发了新的MRI策略，旨在克服准确评估的关键障碍 的endo-epi MBF梯度，并将其应用于初步的动物和患者研究。根据我们初步的 数据，我们假设，在CMD的设置，受损的微血管CR表现为应激诱导的内， epi MBF梯度，并且该梯度的大小与CMD严重程度显著相关。为了验证这一 假设，我们提出3个具体目标。在目标1中，我们将开发一种自由呼吸无伪影的MRI技术 优化用于endo-epi MBF梯度的高分辨率成像，结合机器学习方法 用于MBF梯度的全自动客观定量。在目标2中，我们将检验CMD 严重程度可以基于CMD猪模型中MRI衍生的应激MBF梯度来分级。在目标3中，我们 检验INOCA患者的CMD严重程度与MRI衍生的应激MBF高度相关的假设 梯度离心该项目汇集了多个跨学科的研究人员，具有强大的集体记录 在开发心脏成像策略，以推进非侵入性方法来确定CMD的严重程度， MRI导出的应力MBF梯度。因此，这项建议是改善管理的重要一步 INOCA患者的研究，并致力于成像引导评估针对CMD的新疗法。