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 由于冠状动脉功能和结构的变化，冠状动脉微血管功能障碍（CMD） 在没有阻塞性冠状动脉疾病（CAD）的情况下，微循环的理解很少，缺血 没有阻塞性CAD（INOCA）和心肌梗塞，没有阻塞性CAD（MinoCa） 在男女中观察到。超过二十年的工作使我们包括CMD会导致心脏 保留的射血分数（HFPEF）的故障。我们的发现表明风险因素条件（高血压， 肥胖，血脂血症，血糖症，雌激素丧失）促进促炎性，促氧化状态，呈现 冠状动脉微举行和心肌容易受到：1）缺血，2）与微界面相关的心肌 疤痕，3）弥漫性纤维化，4）不良LV重塑。我们建议CMD在“ hfpef”中起关键作用 状态”。尽管将HFPEF划定为特定表型，但没有有效的治疗 应用将通过调查与CMD相关的缺血作为前体的先驱，以解决此治疗知识差距 心肌损伤，疤痕，弥漫性纤维化和LV舒张功能障碍（HFPEF的标志特征）。的确， CMD与高灵敏度心脏肌钙蛋白（HS-CTNI）和HS-CTNI的可测量增加有关 高程预测未来的HFPEF。一旦建立，我们将有能力积极地针对确定的 特定特定特定的高危人群中的机械目标，其主要目标是防止 向HFPEF发展。我们的应用程序直接解决了NHBLI战略愿景4.CQ.05“如何如何 病理生物学是基于非焦点缺血性心脏病和急性冠状动脉的相关风险的基础 亚种群之间的综合征和早期死亡率差异，以及治疗的目标是什么 预防吗？ 导致心肌损伤和心室松弛受损。 CMD将直接使用我们的 已建立的冠状动脉内药物血管活性方案，在具有缺血的症状/症状的受试者中 没有阻塞性CAD进行挑衅的应力测试，而心肌缺血将直接评估 通过侵入性同时进行动脉和冠状动脉窦/大心脏静脉氧张力和乳酸 测量和连续的ECG记录，而左心室功能将直接使用 Millar-Cather LV压力量环和应力诱导的心肌损伤将直接测量 冠状动脉/大心脏静脉HS-CTNI。 AIM 2：检验CMD相关缺血性心肌细胞的假设 损害导致LV舒张功能障碍的进展。 AIM 1的受试者也将经历 入学率和1 - 2年后的综合心脏磁共振成像（CMRI）。我们将评估 CMRI LV灌注，心肌疤痕，弥漫性纤维化，LV重塑和舒张功能。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，以建立慢性心肌的证据 使用前瞻性重复的卧床HS-CTNI确定的损害。结合我们正在进行的结果 战士试验（NCT＃03417388）的结果与当前申请一起确定潜在的机械处理 目标：1）缺血/疤痕，2）应变/重塑，3）纤维化/心室刚度，用于机械上 支持的HFPEF预防临床试验，例如：1）抗缺血/疤痕疗法（汀类药物/ACE-ARB，alpha-beta 阻滞剂，无周期GMP），2）应变/重塑疗法（sacubitril/valsartan）和/或3）抗纤维化治疗 （半乳糖素3，肽基精氨酸脱氨酸酶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）。