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

项目总结 在美国，缺血性心脏病(IHD)是主要的死亡原因。它源于收窄了 冠状动脉(CAD)和/或最终导致心肌缺血的微血管功能障碍的发展 -心肌的需氧量远远超过可用供给量的情况。IHD 在美国，每年有超过1/3的死亡和100万人住院。范围和 心肌缺血的严重程度已被证明提供了比标准临床更高的预后价值。 IHD患者临床表现的不同变量。历史悠久的(SPECT或PET)和 最近建立的(例如，第一次通过-灌注MRI)方法被常规用于收集该信息。 尽管这些方法有其能力，但它们有关键的局限性--它们使患者暴露在电离或 放射或外源性造影剂，这会给患者带来风险。这是一个特别严重的问题 在美国至少50万终末期肾病(ESRD)患者中。对于终末期肾病患者，每年 由于心血管死亡的风险是一般情况下的10倍，因此需要进行缺血检测 人口。因此，对心肌梗死的安全和可靠评估的需求没有得到满足，而且还在不断增长。 缺血在所有患者中都存在，在终末期肾病患者中最为紧迫，其在美国的患病率正在上升。 血氧水平依赖(BOLD)心脏MRI(CMR)是一种潜在的替代标准临床 方法无电离辐射，无外源性造影剂。它还有能力为用户提供 对疾病的生理学洞察是基于对氧气供应受损的测量，而不是来自 替代指标(室壁运动、心电变化或对比动力学)。在过去的二十年里，技术上 BOLD CMR的能力已经导致了临床测试。然而，可靠性方面的限制(敏感性、特异性 和准确性)仍然是BOLD CMR广泛临床应用的主要障碍。要克服这个问题 大胆CMR的可靠性限制，在之前的R01资助(2013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)进行的大脑激活研究，可以改善 大胆的CMR的可靠性。随后，我们开始演示(I)动脉的靶向改变 二氧化碳分压(PaCO2)可以是有效的非侵入性血管活性刺激；以及(Ii)高分辨率， 全心在3T时大胆的CMR，当与统计学结合时，重复PaCO2刺激心脏 框架，可以可靠地检测大型健康动物的大胆信号变化。要成功地将 这一大胆的CMR方法有望在临床领域产生影响，进一步的进展和验证将是 必填项。这项提议旨在继续成功地推进这一大胆的CMR方法，以 临床可行性，以使其能够实现真正的非侵入性和成本效益的缺血测试，而不是 电离辐射、外源性造影剂、静脉注射药剂甚至针头。因此，这一点 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.