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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

基本信息

批准号：
10576287
负责人：
Cathleen Noel Bairey Merz
金额：
$ 61.68万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2025-02-28
项目状态：
未结题

项目摘要

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而导致冠状动脉微血管功能障碍（CMD）人们对无阻塞性冠状动脉疾病 (CAD) 情况下的微循环知之甚少，并且缺血不伴有梗阻性 CAD (INOCA) 和不伴有梗阻性 CAD (MINOCA) 的心肌梗塞越来越多在女性和男性中观察到。经过二十多年的研究，我们得出结论：CMD 可以导致心脏病射血分数保留（HFpEF）失败。我们的研究结果表明，危险因素状况（高血压、肥胖、血脂异常、血糖异常、雌激素损失）促进促炎、促氧化状态，冠状动脉微血管和心肌易受：1）缺血，2）微梗塞相关心肌疤痕，3) 弥漫性纤维化，4) 不良左心室重塑。我们认为 CMD 在“pre-HFpEF”中发挥着关键作用尽管将 HFpEF 划分为特定的表型，但尚无有效的治疗方法。目前该应用程序将通过调查 CMD 相关缺血作为先兆来解决这一治疗知识差距肌细胞损伤、疤痕、弥漫性纤维化和左心室舒张功能障碍（HFpEF 的标志性特征）。的确， CMD 与高敏心肌肌钙蛋白 (hs-cTnI) 和 hs-cTnI 可测量的增加相关海拔预测未来的 HFpEF。一旦建立，我们将处于有利位置，积极瞄准已确定的目标针对特定的高危人群制定机械目标，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“如何非阻塞性缺血性心脏病的病理生物学以及急性冠状动脉的相关风险亚人群之间的综合征和早期死亡率存在差异，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 CMD 相关缺血的假设导致肌细胞损伤和心室舒张受损。 CMD 将使用我们的直接测量在有缺血体征/症状的受试者中建立了冠状动脉内药理学血管活性方案，但无阻塞性 CAD 进行激发应激测试，同时直接评估心肌缺血情况通过侵入性同步动脉和冠状窦/心大静脉氧分压和乳酸测量和连续心电图记录，而左心室功能将直接评估 Millar 导管左心室压力-容积环和压力引起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。目标 2：检验以下假设：CMD 相关的缺血性肌细胞损伤导致左心室舒张功能障碍进展。目标 1 的受试者也将经历入组时和 1-2 年后进行全面心脏磁共振成像 (CMRI)。我们将评估 CMRI 左室灌注、心肌疤痕、弥漫性纤维化、左室重塑和舒张功能。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可建立慢性肌细胞疾病的证据使用前瞻性重复动态 hs-cTnI 测定来确定损伤。结合我们正在进行的结果当前应用的 WARRIOR 试验 (NCT#03417388) 结果将确定潜在的机械治疗目标：1) 缺血/疤痕，2) 应变/重塑，3) 纤维化/心室僵硬度，从机械角度支持 HFpEF 预防临床试验，例如：1) 抗缺血/疤痕治疗（他汀类药物/ACE-ARB、α-β 阻滞剂、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、肽基精氨酸脱亚氨酶 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）。