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

项目总结 长期以来，人们一直认为阻塞性冠状动脉疾病(CAD)是心绞痛的主要驱动因素 主要不良心脏事件。然而，最近具有里程碑意义的研究表明，多达50%的患者 建议进行诊断测试的对象为无梗阻性冠心病(INOCA)的患者。INOCA的很大比例 患者有冠状动脉微血管功能障碍(CMD)，即使在没有限流狭窄的情况下也是如此 会导致心肌缺血，并有很高的不良事件风险。的参考标准 CMD的评估是有创的功能性冠状动脉反应性(CR)试验。尽管关键研究表明 分层治疗的价值基于CR检测，CR检测在INOCA人群中的实际效用是 受其侵袭性的限制，即使在经验丰富的中心也存在严重风险。因此，一种非侵入性 能够检测和分期CMD严重程度的方法对于INOCA患者的治疗将是非常有价值的。 在这种未得到满足的需求的推动下，以前的研究已经使用了成像方法来指示心肌灌注 针对CR的储备(MPR)；然而，迄今为止显示的MPR和CR损害之间的关联 较弱，可能是由于MPR对心内膜下心肌血流量(MBF)不足的敏感性不佳 这是CMD的一个标志。使用侵入性微球方法的研究已经确定了一种压力 健康动物心内膜下-心外膜下(Endo-epi)MBF梯度大于1.0，并显示 在微血管阻力异常升高的情况下，它会降低到1以下。然而，非侵入性检测 由于需要解析MBF，使用现有成像策略的Endo-epi MBF梯度是具有挑战性的 超凡脱俗。我们开发了新的磁共振成像策略，旨在克服关键障碍，进行准确的评估 并将其应用于动物和患者的初步研究。根据我们的初步调查 数据，我们假设在CMD的环境中，受损的微血管CR表现为应激诱导的内吞- EPI MBF梯度，且该梯度的大小与CMD严重程度显著相关。为了测试这一点 假设，我们提出了三个具体目标。在目标1中，我们将开发一种自由呼吸的无伪影mri技术。 针对Endo-EPI MBF梯度的高分辨率成像进行了优化，并结合了机器学习方法 用于MBF梯度的全自动客观量化。在目标2中，我们将检验CMD的假设 在CMD的猪模型中，严重程度可以根据MRI得出的应激性MBF梯度进行分期。在《目标3》中，我们将 检验INOCA患者CMD严重程度与MRI应激MBF高度相关的假设 渐变。这个项目汇集了多个跨学科的调查人员，他们有着良好的集体记录 在开发心脏成像策略以推进非侵入性方法确定CMD严重程度方面 在MRI得出的应力MBF梯度上。因此，这项建议是朝着改善管理迈出的重要一步 对INOCA患者进行评估，并对针对CMD的新疗法进行影像引导评估。

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.