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

• 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
• 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

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）：在美国有超过50万人患有终末期肾病（ESRD）。这些患者心血管死亡发生率极高，但在普通人群中有效降低心血管死亡率的治疗方法在透析依赖性ESRD中效果较差，因此需要新的治疗方法。标准疗法令人失望的结果似乎可归因于ESRD中CV疾病的机制差异。猝死占ESRD患者心血管死亡的绝大多数，其频率比动脉粥样硬化性死亡或心肌梗死高5倍，而动脉粥样硬化性死亡或心肌梗死在其他情况下占心血管死亡率的比例更高。因此，针对ESRD特异性的心血管猝死机制，而不是潜在的动脉粥样硬化和心肌梗死机制，可能是改善ESRD患者心血管结局的一种特别有效的方法，但目前尚无明确的靶点或治疗方法。包括申请人的研究在内的大量数据表明，ESRD患者心脏的心肌纤维化和微血管脱落显著增加，并且心肌纤维化和微血管疾病的非侵入性测量可高度预测CV死亡，这表明它们是CV猝死的重要决定因素。其他研究表明，一氧化氮（NO）的低生物利用度和循环血管生成抑制剂的继发性增加是心肌病理进展的关键和协同因素。一氧化氮供体硝酸异山梨酯（ISD）和肼嗪（HY）联合治疗可以提高一氧化氮的生物利用度，限制硝酸盐耐受性，降低黑人心力衰竭患者的死亡率，但尚未在ESRD中进行试验。我们假设NO缺乏和相关血管生成抑制剂的继发性变化有助于ESRD的心肌纤维化和毛细血管稀疏的进展，并且在血液透析患者中使用ISD/HY可以抑制心肌纤维化和微血管损失。该建议将在人类中产生试点数据，证实NO和相关血管生成抑制剂与心肌组织学不良变化的关联。我们将通过分析心房附件和先前从接受心脏手术的患者收集的血液来验证我们的目标，并进行一项比较慢性血液透析患者联合ISD/HY与氨氯地平的试点试验。该试验将产生初步的安全性和耐受性数据，并将评估ISD/HY联合治疗是否能改善心肌纤维化和微血管供应，分别使用组织多普勒超声心动图和心肌灌注成像（PET）扫描测量。慢性透析患者的CV死亡率很高，尽管他们的医疗费用占医疗保险资金的近10%。该项目将提高对ESRD中导致CV死亡的重要途径的理解，并将测试靶向治疗是否有利地影响潜在机制，并在不断增长的高危人群中具有降低CV死亡率的潜力。