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

女性缺血综合征评估 (WISE) - 冠状动脉微血管功能障碍导致射血分数保留 (HFpEF) 的先兆心力衰竭的机制

• 批准号: 9922714
• 负责人: Cathleen Noel Bairey Merz
• 金额: $ 67.06万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922714
• 关键词: Address; Adrenergic beta-Antagonists; Arginine deiminase; Aspirin; Cardiac; Catheters; Chronic; Cicatrix; Clinical Trials; Coronary; Coronary Arteriosclerosis; Coronary sinus structure; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Diffuse; Dyslipidemias; EFRAC; Electrocardiogram; Enrollment; Estrogens; Evaluation; Event; Experimental Designs; Failure; Fibroblast Growth Factor; Fibrosis; Functional disorder; Future; Galectin 3; Goals; Great cardiac vein structure; Heart failure; Hypertension; Impairment; Infarction; Inflammatory; Ischemia; Isometric Exercise; Knowledge; Lead; Left; Left Ventricular Function; Left Ventricular Remodeling; Magnetic Resonance Imaging; Measurable; Measurement; Measures; Mechanics; Medical; Metabolic; Microcirculation; Microvascular Dysfunction; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Obesity; Oxygen; Patients; Perfusion; Pharmacology; Phenotype; Phosphotransferases; Play; Populations at Risk; Positioning Attribute; Prevention; Proteomics; Protocols documentation; Relaxation; Resources; Risk; Risk Factors; Role; Signs and Symptoms; Stress; Stress Tests; Structure; Study Subject; Syndrome; Testing; Therapeutic; Troponin; Ventricular; Vision; Woman; Work; acute coronary syndrome; coronary fibrosis; effective therapy; inhibitor/antagonist; men; mortality; novel; preservation; pressure; prevent; prevention clinical trial; prospective; valsartan

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).

项目摘要 冠状动脉微血管功能障碍（CMD）是由于冠状动脉功能和结构的改变， 在没有阻塞性冠状动脉疾病（CAD）的情况下，微循环的了解甚少， 非梗阻性CAD的心肌梗死（INOCA）和非梗阻性CAD的心肌梗死（MINOCA）的发病率越来越高， 在女性和男性中观察到。二十多年的研究使我们得出结论，CMD可以导致心脏 射血分数保留（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、代谢紊乱、雌激素损失）促进促炎、促氧化状态， 冠状动脉微血管和心肌容易受到：1）缺血，2）微梗死相关心肌 瘢痕，3）弥漫性纤维化，4）不良LV重塑。我们认为CMD在“前HFpEF”中起着关键作用， 尽管HFpEF被描绘成特定的表型，但不存在有效的治疗。当前 该申请将通过研究CMD相关缺血作为 肌细胞损伤、瘢痕、弥漫性纤维化和LV舒张功能障碍（HFpEF的标志性特征）。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 升高预测未来HFpEF。一旦建立，我们将处于有利地位，积极确定目标， 在特定的明确特征的高危人群中的机制性靶点，主要目标是预防 进展为HFpEF。我们的应用程序直接针对NHBLI战略愿景4.CQ.05“如何 非梗阻性缺血性心脏病的病理生物学基础及其急性冠状动脉粥样硬化的相关风险 综合征和早期死亡率在亚群之间存在差异，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：目的1：测试CMD相关缺血的假设， 导致肌细胞损伤和心室舒张受损。CMD将直接测量，使用我们的 在有缺血体征/症状但 无阻塞性CAD进行激发负荷试验，而心肌缺血将直接评估 通过侵入性动脉和冠状窦/心大静脉同时进行氧分压和乳酸 测量和连续ECG的记录，而左心室功能将直接评估使用 Millar导管LV压力-容积环和应力诱导的肌细胞损伤将通过以下方法直接测量： 冠状窦/心大静脉hs-cTnI。目的2：验证CMD相关缺血性心肌细胞损伤的假设。 损伤导致LV舒张功能障碍进展。目标1的受试者还将接受 在入组时和1-2年后进行全面的心脏磁共振成像（CMRI）。我们将评估 CMRI LV灌注、心肌瘢痕、弥漫性纤维化、LV重构和舒张功能。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，以建立慢性肌细胞 使用前瞻性重复动态hs-cTnI测定的损伤。结合我们正在进行的 当前应用的WARRIOR试验（NCT#03417388）结果将确定潜在的机械治疗 靶点：1）缺血/瘢痕，2）应变/重塑，和3）纤维化/心室僵硬，用于机械 支持的HFpEF预防临床试验，如：1）抗缺血/瘢痕治疗（他汀类/ACE-ARB，α-β 阻断剂，NO-环GMP），2）应变/重塑疗法（沙库巴曲/缬沙坦），和/或3）抗纤维化疗法 （半乳糖凝集素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）。