NO, myocardial fibrosis, and microvascular rarefaction in ESRD: Pilot Studies

ESRD 中的 NO、心肌纤维化和微血管稀疏：试点研究

基本信息

批准号：
8623052
负责人：
David M Charytan
金额：
$ 22.07万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-21 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8623052
关键词：
Accounting Adverse event Amlodipine Angiogenesis Inhibitors Architecture Arginine Arrhythmia Atherosclerosis Bees Biological Availability Biology Blinded Blood Blood capillaries Blood flow Cardiac Cardiac Surgery procedures Cardiovascular Diseases Cardiovascular system Caring Cessation of life Chronic Collection Combined Modality Therapy Coronary Data Dialysis patients Dialysis procedure Doppler Echocardiography Dropout Echocardiography End stage renal failure Endostatins Endothelial Cells Expenditure Failure Fibrosis Frequencies Functional disorder Funding General Population Growth Harvest Heart Heart Diseases Heart failure Hemodialysis Histology Homeostasis Human Hydralazine Image Image Analysis Incidence Individual Isosorbide Dinitrate Lead Left Ventricular Hypertrophy Link Malignant - descriptor Measures Medicare Microvascular Dysfunction Myocardial Myocardial Infarction Myocardial perfusion Nature Nitrates Nitric Oxide Nitric Oxide Donors Outcome Outcome Measure Oxygen Pathogenesis Pathology Pathway interactions Patients Physiology Pilot Projects Population Positron-Emission Tomography Randomized Renal function Research Research Design Research Personnel Rest Risk Factors Role Safety Serum Staging Stress Structure Sudden Death Testing Therapeutic Time Tissues United States angiogenesis auricular appendage capillary cardiovascular risk factor clinically relevant density digital imaging effective therapy experience follow-up heart function high risk improved indexing inhibitor/antagonist insight interstitial mortality novel pilot trial public health relevance thrombospondin 2 trial comparing

项目摘要

DESCRIPTION (provided by applicant): More than 500,000 people in United States have end stage renal disease (ESRD). These individuals suffer from an extremely high incidence of cardiovascular (CV) death, but treatments effective in reducing CV mortality in the general population are less efficacious in dialysis-dependent ESRD, and new therapies are needed. The disappointing results with standard therapies appear to be attributable to differences in the mechanisms underlying CV disease in ESRD. Sudden death accounts for the vast majority of CV deaths in individuals with ESRD, with a 5-folder higher frequency than atherosclerotic death or myocardial infarction which account for a higher proportion of CV mortality in other settings. Targeting ESRD-specific mechanisms for sudden CV death rather than the mechanisms underlying atherosclerosis and myocardial infarction may thus be a particularly potent way to improve CV outcomes in ESRD, but there are currently no well-established targets or therapies for this purpose. A wealth of data including studies by the applicants demonstrate that myocardial fibrosis and microvascular dropout are dramatically increased in the hearts of individuals with ESRD, and that non-invasive measures of myocardial fibrosis and microvascular disease are highly predictive of CV death, suggesting that they are important determinants of sudden CV death. Additional studies suggest that low bioavailability of nitric oxide (NO) and secondary increases in circulating inhibitors of angiogenesis are critical and synergistic contributors to progression of myocardial pathology. Combination therapy with the NO donor isosorbide dinitrate (ISD) and hydralazine (HY) increases NO bioavailability, limits nitrate tolerance, and decreases mortality in black patients with heart failure, but it has not bee tested in ESRD. We hypothesize that NO deficiency and secondary changes in related angiogenesis inhibitors contribute to the progression of myocardial fibrosis and capillary rarefaction in ESRD and that use of ISD/HY in hemodialysis patients will inhibit myocardial fibrosis and microvascular loss. This proposal will generate pilot data in humans confirming the associations of NO and related angiogenesis inhibitors with adverse changes in myocardial histology. We will test our aims by analyzing atrial appendages and blood previously collected from patients undergoing cardiac surgery and with a pilot trial comparing combination ISD/HY with amlodipine in chronic hemodialysis patients. This trial will generate preliminary safety and tolerability data for the combination and will assess whether combined ISD/HY improves myocardial fibrosis and microvascular supplying measured using tissue Doppler Echocardiography and myocardial perfusion imaging (PET) scans, respectively. Chronic dialysis patients have a high incidence of CV death despite the expenditure of nearly 10% of Medicare funding on their care. This project will improve understanding of important pathways contributing to CV death in ESRD and will test whether a targeted therapy favorably impacts the underlying mechanisms and has the potential to reduce CV mortality in a growing, high-risk population.

描述（由申请人提供）：美国有500,000多人患有末期肾脏疾病（ESRD）。这些人患心血管（CV）死亡的发病率极高，但是在降低普通人群中CV死亡率的有效治疗中，依赖透析依赖性ESRD的治疗效率较小，需要新的疗法。标准疗法的令人失望的结果似乎归因于ESRD中CV疾病的机制差异。 ESRD患者的绝大多数CV死亡是突然的死亡，其频率高于动脉粥样硬化死亡或心肌梗塞的频率高5倍，在其他情况下，CV死亡率更高。因此，针对ESRD特异性的CV死亡机制，而不是靶向动脉粥样硬化和心肌梗死的机制可能是改善ESRD中CV结果的一种特别有效的方法，但目前尚无公认的目标或疗法。包括申请人的研究在内的大量数据表明，心肌纤维化和微血管辍学在ESRD患者的心脏中大大增加，并且对心肌纤维化和微血管疾病的非侵入性测量高度预测了CV死亡，这表明它们是CV突然CV死亡的重要决定性。其他研究表明，一氧化氮（NO）的生物利用度低（NO）和血管生成抑制剂的次要增加至关重要，并且是心肌病理发展的协同作用。与NO供体异糖二硝酸盐（ISD）和氢化嗪（HY）的联合疗法不会增加生物利用度，限制了硝酸盐耐受性，并降低了心力衰竭的黑人患者的死亡率，但尚未在ESRD中测试过蜜蜂。我们假设没有缺乏和二次变化相关的血管生成抑制剂有助于ESRD中心肌纤维化和毛细血管稀有性的进展，并且在血液透析患者中使用ISD/HY将抑制心肌纤维纤维纤维化和微血管丧失。该建议将在人类中产生试点数据，从而确认NO和相关的血管生成抑制剂与心肌组织学的不良变化的关联。我们将通过分析先前从接受心脏手术的患者中收集的心房附属物和血液来测试我们的目标，并进行试验试验，将ISD/HY组合与慢性血液透析患者的合并ISD/HY与氨氯地平进行比较。该试验将为组合生成初步的安全性和耐受性数据，并将评估使用组织多普勒超声心电图和心肌灌注成像（PET）扫描测量的ISD/HY联合改善心肌纤维化和微血管供应。慢性透析患者的CV死亡发病率很高，尽管他们的医疗保险基金的支出近10％。该项目将提高对导致ESRD CV死亡的重要途径的理解，并将测试目标治疗是否有利地影响基本机制，并有可能在不断增长的高风险人群中降低CV死亡率。