Women's Ischemia Syndrome Evaluation (WISE) - Mechanisms of Coronary Microvascular Dysfunction Leading to Pre-Heart Failure with Preserved Ejection Fraction (HFpEF)

项目摘要 冠状动脉功能和结构改变所致的冠状动脉微血管功能障碍 在没有阻塞性冠状动脉疾病(CAD)的情况下，人们对微循环知之甚少，而缺血 无梗阻性冠状动脉病变(INOCA)和心肌梗死无梗阻性冠状动脉病变(MINOCA)越来越多 在女性和男性身上都能观察到。二十多年的研究使我们得出结论，CMD可以导致心脏 射血分数保存失败(HFpEF)。我们的研究结果表明，危险因素条件(高血压、 肥胖、血脂异常、血糖异常、雌激素丢失)促进促炎、促氧化状态 冠状动脉微血管和心肌易受以下因素影响：1)缺血，2)微小心肌梗死 瘢痕，3)弥漫性纤维化，4)不良的左室重构。我们认为CMD在“前HFpEF”中起着关键作用 尽管将HFpEF描述为特定的表型，但没有有效的治疗方法。海流 应用程序将通过研究CMD相关的缺血作为先兆来解决这一治疗知识差距 心肌细胞损伤、瘢痕、弥漫性纤维化和左室舒张功能障碍(HFpEF的显著特征)。的确， CMD与高敏心肌肌钙蛋白(hs-cTnI)和hs-cTnI的可测量增加相关 海拔高度预示着未来的HFpEF。一旦成立，我们将处于有利地位，积极瞄准已确定的目标 在特定的、特征良好的高危人群中的机械性目标，主要目标是预防 进展到HFpEF。我们的应用程序直接满足NHBLI战略愿景4.CQ.05的要求 非梗阻性缺血性心脏病的病理生物学基础及其与急性冠脉病变的相关风险 综合征和早期死亡率在不同亚群之间不同，治疗和治疗的目标是什么？ 预防？“我们提出以下建议来解决这个问题：目标1：检验与CMD相关的缺血的假设 导致心肌细胞损伤和心脏松弛功能受损。CMD将使用我们的 在有缺血体征/症状的受试者中建立冠脉内药物血管活性方案，但 在直接评估心肌缺血的同时，无梗阻性CAD进行激励性负荷试验 通过有创的同时动脉和冠状静脉窦/心大静脉氧分压和乳酸 测量和连续的心电记录，而左心功能将直接使用 毫米波导管LV压力-容量环和应激诱导的心肌细胞损伤将直接通过 冠状静脉窦/心大静脉hs-cTnI。目的2：验证CMD相关缺血性心肌细胞的假说 损伤导致左室舒张功能不全的进展。来自AIM 1的受试者也将接受 在入选时和1-2年后进行全面的心脏磁共振成像(CMRI)。我们将评估 CMRI左室血流灌注、心肌瘢痕、弥漫性纤维化、左室重构和舒张期功能。我们将利用 我们世界知名的蛋白质组学核心的优势和资源，以建立慢性心肌细胞的证据 使用前瞻性重复的动态hs-cTnI测定进行损伤。结合我们正在进行的 勇士试验(NCT#03417388)与当前应用的结果将确定潜在的机械性治疗 靶点：1)缺血/疤痕，2)劳损/重塑，3)纤维化/心室僵硬，机械上 支持的HFpEF预防临床试验，例如：1)抗缺血/疤痕疗法(他汀类/ACE-ARB、α-β 阻滞剂，非环状GMP)，2)应变/重塑治疗(萨舒比利/valsartan)，和/或3)抗纤维化治疗 (Galectin 3，肽基精氨酸脱亚胺酶IV型抑制剂，应激激活激酶-1抑制剂，蛋白激酶G， 成纤维细胞生长因子)。

Project Abstract Coronary microvascular dysfunction (CMD) due to changes in the function and structure of coronary microcirculation in the absence of obstructive coronary artery disease (CAD) is poorly understood, and ischemia with no obstructive CAD (INOCA) and myocardial infarction with no obstructive CAD (MINOCA) are increasingly observed in women and men. More than two decades of work has led us to conclude that CMD can lead to heart failure with preserved ejection fraction (HFpEF). Our findings indicate that risk factor conditions (hypertension, obesity, dyslipidemia, dysglycemia, estrogen loss) promote a pro-inflammatory, pro-oxidative state, rendering the coronary microvasculature and myocardium vulnerable to: 1) ischemia, 2) micro-infarction-related myocardial scar, 3) diffuse fibrosis, 4) adverse LV remodeling. We propose that CMD plays a critical role in a “pre-HFpEF state”.Despite delineation of HFpEF into specific phenotypes, no effective treatments exist. The current application will address this therapeutic knowledge gap by investigating CMD-related ischemia as a precursor of myocellular damage, scar, diffuse fibrosis, and LV diastolic dysfunction (hallmark features of HFpEF). Indeed, CMD is associated with measurable increases in high sensitivity cardiac troponin (hs-cTnI), and hs-cTnI elevations predict future HFpEF. Once established, we will be well positioned to aggressively target identified mechanistic targets in a specific well-characterized at-risk population, with the primary goal of preventing progression to HFpEF. Our application directly addresses the NHBLI Strategic Vision 4.CQ.05 “How does the pathobiology that underlies nonobstructive ischemic heart disease and the associated risks for acute coronary syndrome and early mortality differ between subpopulations, and what are the targets for treatment and prevention?” We propose the following to address this: Aim 1: Test the hypothesis that CMD-related ischemia contributes to myocellular damage and impaired ventricular relaxation. CMD will be measured directly, using our established intracoronary pharmacological vasoactive protocol, in subjects with signs/symptoms of ischemia but no obstructive CAD perform provocative stress testing while myocardial ischemia will be assessed directly through invasive simultaneous arterial and coronary sinus/great cardiac vein oxygen tension and lactate measurements, and continuous ECG’s recordings, while left ventricular function will be directly assessed using Millar-catheter LV pressure-volume loops and stress-induced myocellular damage will be directly measured by coronary sinus/great cardiac vein hs-cTnI. Aim 2: Test the hypothesis that CMD-related ischemic myocellular damage contributes to LV diastolic dysfunction progression. Subjects from Aim 1 will also undergo comprehensive cardiac magnetic resonance imaging (CMRI) at enrollment and 1-2 years later. We will evaluate CMRI LV perfusion, myocardial scar, diffuse fibrosis, LV remodeling, and diastolic function. We will leverage the strengths and resources of our world-renowned proteomics core to establish evidence of chronic myocellular damage using prospectively repeated ambulatory hs-cTnI determinations. Combining the results of our ongoing WARRIOR trial (NCT#03417388) results with the current application will identify potential mechanistic treatment targets of: 1) ischemia/scar, 2) strain/remodeling, and 3) fibrosis/ventricular stiffness, for mechanistically supported HFpEF prevention clinical trials such as: 1) anti-ischemic/scar therapies (statin/ACE-ARB, alpha-beta blockers, NO-cyclic GMP), 2) strain/remodeling therapies (sacubitril/valsartan), and/or 3) anti-fibrotic therapies (galectin 3, peptidyl arginine deiminase type IV inhibitor, stress-activated kinase-1 inhibitor, protein kinase G, fibroblast growth factor).