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

描述(申请人提供)：美国有超过50万人患有终末期肾病(ESRD)。这些人患有极高的心血管(CV)死亡发生率，但在普通人群中有效降低心血管死亡率的治疗方法对依赖透析的终末期肾病(ESRD)的疗效较差，需要新的治疗方法。标准疗法的令人失望的结果似乎可归因于终末期肾病的心血管疾病基础机制的不同。猝死占ESRD患者心血管死亡的绝大多数，其发生率比动脉粥样硬化性死亡或心肌梗死高5倍，后者在其他环境下的心血管死亡中所占比例更高。因此，针对ESRD特定的心血管猝死机制，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心血管预后的特别有效的方法，但目前还没有针对这一目的的良好靶点或治疗方法。包括申请者的研究在内的大量数据表明，终末期肾病患者心脏的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非侵入性测量对心血管死亡有很高的预测作用，表明它们是心血管猝死的重要决定因素。更多的研究表明，一氧化氮(NO)的低生物利用度和循环中血管生成抑制物的继发性增加是心肌病理进展的关键和协同作用因素。NO供体硝酸异山梨酯(ISD)和肼丙嗪(HY)的联合治疗增加了黑人心力衰竭患者的NO生物利用度，限制了硝酸盐耐受性，并降低了死亡率，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物的继发性改变有助于ESRD心肌纤维化和毛细血管稀疏的进展，在血液透析患者中使用ISD/HY将抑制心肌纤维化和微血管丢失。这项提议将在人类身上产生试点数据，证实一氧化氮和相关的血管生成抑制剂与心肌组织学不良变化的关联。我们将通过分析之前从心脏手术患者身上收集的心耳和血液来测试我们的目标，并在慢性血液透析患者中比较ISD/HY和氨氯地平的联合应用。这项试验将为联合用药产生初步的安全性和耐受性数据，并将评估ISD/HY联合用组织多普勒超声心动图和心肌灌注成像(PET)扫描分别测量的心肌纤维化和微血管供应是否改善。慢性透析患者的心血管死亡发生率很高，尽管医疗保险资金的近10%花在了他们的护理上。该项目将提高对导致ESRD心血管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危人群的心血管死亡率。

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.