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

描述（由申请人提供）：美国有超过50万人患有终末期肾病（ESRD）。这些个体的心血管（CV）死亡发生率极高，但在一般人群中有效降低CV死亡率的治疗在透析依赖性ESRD中效果较差，因此需要新的治疗方法。标准治疗的令人失望的结果似乎可归因于ESRD中CV疾病基础机制的差异。猝死占ESRD患者CV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，后者在其他环境中占CV死亡的比例更高。因此，靶向ESRD特异性CV猝死机制，而不是动脉粥样硬化和心肌梗死的潜在机制，可能是改善ESRD CV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。大量数据（包括申请人的研究）表明，ESRD患者的心脏中心肌纤维化和微血管脱落显著增加，心肌纤维化和微血管疾病的无创性指标高度预测CV死亡，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）的低生物利用度和血管生成循环抑制剂的继发性增加是心肌病理学进展的关键和协同因素。NO供体硝酸异山梨酯（ISD）和肼苯哒嗪（HY）的联合治疗增加了NO的生物利用度，限制了硝酸盐耐受性，并降低了黑人心力衰竭患者的死亡率，但尚未在ESRD中进行测试。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患者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将抑制心肌纤维化和微血管损失。该提案将产生初步数据，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系。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件和血液以及在慢性血液透析患者中比较ISD/HY组合与ESTA的初步试验来测试我们的目标。该试验将产生联合用药的初步安全性和耐受性数据，并将评估联合使用ISD/HY是否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死亡发生率很高，尽管医疗保险基金的近10%用于他们的护理。该项目将提高对导致ESRD CV死亡的重要途径的理解，并将测试靶向治疗是否对潜在机制产生有利影响，并有可能降低不断增长的高风险人群的CV死亡率。

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.