Accurate, Needle-Free, MRI-based Detection of Ischemic Heart Disease without Contrast Agents

项目摘要 缺血性心脏病（IHD）是美国的主要死因。它源于缩小 冠状动脉（CAD）和/或微血管功能障碍的发展，最终导致心肌缺血 - 心肌的氧需求远远超过可用供应的情况。IHD 在美国，每年超过三分之一的死亡和超过一百万的住院治疗。的程度和 心肌缺血的严重程度已经显示出提供超过标准临床诊断的增量预后价值， IHD患者表现谱中的变量。长期建立的（SPECT或PET）和 最近建立的（例如，第一次通过灌注MRI）方法常规地用于收集该信息。 尽管它们的能力，这些方法有关键的限制-他们暴露于患者或电离 放射或外源性造影剂，这会给患者带来风险。这是一个特别关键的问题 在美国至少有50万终末期肾病（ESRD）患者。在ESRD患者中，每年 由于心血管死亡的风险比一般情况高10倍以上，因此需要进行缺血试验。 人口因此，对安全可靠地评估心肌梗死的需要未得到满足，并且不断增长。 缺血在所有患者中是最紧迫的，并且在ESRD患者中是最紧迫的，其在美国的患病率正在上升。 血氧水平依赖性（BOLD）心脏MRI（CMR）是标准临床MRI的潜在替代方案， 方法，因为它不含电离辐射和外源性造影剂。它也有能力提供 根据受损的氧气供应的测量，而不是从生理上了解疾病， 替代指标（室壁运动、ECG变化或对比动力学）。在过去的二十年里，技术 BOLD CMR的能力已经导致了临床测试。然而，可靠性（灵敏度、特异性）的局限性 和准确性）仍然是BOLD CMR广泛临床应用的主要障碍。克服 BOLD CMR的可靠性限制，在之前的R 01资助（2013年至2017年）中，我们假设重复 心脏的刺激，类似于使用BOLD MRI（脑功能磁共振成像）的大脑激活研究，可以改善 BOLD CMR的可靠性。随后，我们继续证明（i）动脉的靶向变化 CO2分压（PaCO 2）可以是有效的非侵入性血管活性刺激;和（ii）高分辨率， 3 T下的全心脏BOLD CMR，心脏重复PaCO 2刺激，结合统计学 该框架可以可靠地检测大型健康动物的BOLD信号变化。要成功翻译 这种BOLD CMR方法对临床竞技场的影响是有希望的，进一步的进展和验证将是 必需的.本提案旨在继续成功推进BOLD CMR方法， 临床可行性，使其能够实现真正的无创和成本效益的缺血测试， 电离辐射、外源性造影剂、静脉内药物制剂或甚至针头。因此， 该提案是推进美国大部分IHD患者护理的关键一步。

PROJECT SUMMARY Ischemic heart disease (IHD) is the leading cause of death in the United States. It emanates from narrowing of coronary arteries (CAD) and/or development of microvascular dysfunction culminating in myocardial ischemia – a condition where the oxygen demand of the myocardium is far in excess of the available supply. IHD accounts for more than 1 in 3 deaths and >1 million hospitalizations each year in the US. The extent and severity of myocardial ischemia has been shown to provide incremental prognostic value over standard clinical variables across the spectrum of presentation of patients with IHD. Long-established (SPECT or PET) and more recently established (e.g., first pass-perfusion MRI) methods are routinely used to gather this information. In spite of their capabilities, these methods have key limitations – they expose the patients to either ionizing radiation or exogenous contrast agents, which carry risks to the patients. This is particularly a critical problem in at least half a million patients with end-stage renal disease (ESRD) in the US. In ESRD patients, annual ischemia testing is needed since the risk of cardiovascular mortality is > 10-fold greater than in the general population. Hence there is an unmet and growing need for safe and reliable assessment of myocardial ischemia in all patients, and is most pressing in ESRD patients, whose prevalence in the US is on the rise. Blood-Oxygen-Level-Dependent (BOLD) Cardiac MRI (CMR) is a potential alternative to standard clinical methods since it is free of ionizing radiation and exogenous contrast media. It also has the capability to provide physiological insight into the disease based on measurements of impaired oxygen supply, and not from surrogate metrics (wall motion, ECG changes, or contrast kinetics). Over the past two decades, the technical capabilities of BOLD CMR have led to clinical testing. However, limitations in reliability (sensitivity, specificity and accuracy) remain a major impediment for widespread clinical use of BOLD CMR. To overcome the reliability limitations of BOLD CMR, in a previous R01 funding (2013 to 2017), we hypothesized that repeat stimulations of the heart, analogous to brain activation studies using BOLD MRI (brain fMRI), could improve the reliability of BOLD CMR. Subsequently, we went onto demonstrate that (i) a targeted change in arterial partial pressure of CO2 (PaCO2) can be a potent non-invasive vasoactive stimulus; and a (ii) high-resolution, whole heart BOLD CMR at 3T with repeat PaCO2 stimulation of the heart, when combined with a statistical framework, can reliably detect BOLD signal changes in large, healthy, animals. To successfully translate the promising impact of this BOLD CMR approach into the clinical arena, further advances and validation will be required. This proposal aims to continue the successful advancement of this BOLD CMR approach towards clinical feasibility so that it can enable a truly noninvasive and cost-effective ischemia testing that is free of ionizing radiation, exogenous contrast agents, intravenous pharmacological agents or even needles. Thus, this proposal is a critical step towards advancing the care of a large segment of IHD patients in the US.