Aldosterone, nitric oxide, myocardial fibrosis, and capillary loss in ESRD

描述（由申请人提供）：美国有超过50万人患有终末期肾病（ESRD），这些人的心血管（CV）死亡发生率极高。在一般人群中有效降低CV死亡率的治疗在透析依赖性ESRD中不太成功，迫切需要新的治疗方法。传统的CV风险因素在晚期肾衰竭背景下不太重要，标准治疗的令人失望的结果似乎可归因于ESRD个体中CV疾病基础机制的重要差异。猝死占ESRD个体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，后者在其他环境中更常见于CV死亡。这些考虑表明，靶向ESRD特异性CV猝死机制而非动脉粥样硬化和心肌梗死潜在机制可能是改善ESRD结局的特别有效的方法。然而，目前还没有明确的目标或治疗方法。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非侵入性测量高度预测CV死亡，表明纤维化和微血管疾病是CV猝死的重要决定因素。其他研究表明，一氧化氮和醛固酮的生物利用度异常是心肌纤维化和微血管疾病进展的关键和协同因素，并且螺内酯或L-精氨酸的给药改善NO生物利用度，抑制醛固酮的作用，并且在ESRD中是安全的。因此，我们假设，L-精氨酸或醛固酮拮抗剂螺内酯的透析依赖性终末期肾病患者的管理将抑制心肌纤维化和微血管脱落。我们将使用在Partners Health Care和Beth Israel Deaconess Medical Center进行的9个月、随机、安慰剂对照、2x2析因临床试验来测试我们的2个具体目标：目的1）通过组织多普勒超声心动图（TDI）和心肌灌注显像（PET）检测，验证使用螺内酯阻断醛固酮可改善ESRD患者心肌纤维化和微血管供应的假设扫描，分别;目的2）通过TDI和PET检测，验证L-精氨酸改善心肌纤维化和微血管供应的假设，L-精氨酸是一种提高NO生物利用度的药物。

DESCRIPTION (provided by applicant): More than 500,000 people in United States have end stage renal disease (ESRD), and these individuals suffer from an extremely high incidence of cardiovascular (CV) death. Treatments that are effective in reducing CV mortality in the general population have been less successful in dialysis-dependent ESRD, and new therapies are sorely needed. Traditional CV risk factors are less important in the setting of advanced kidney failure, and the disappointing results with standard therapies appear to be attributable to important differences in the mechanisms underlying CV disease in individuals with 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 more commonly account for CV mortality in other settings. These considerations suggest that targeting ESRD-specific mechanisms for sudden CV death rather than mechanisms underlying atherosclerosis and myocardial infarction may be a particularly potent way to improve outcomes in ESRD. However, 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 fibrosis and microvascular disease are important determinants of sudden CV death. Additional studies show that abnormalities in the bioavailability of nitric oxide and aldosterone are critical and synergistic contributors to the progression of myocardial fibrosis and microvascular disease and that administration of spironolactone or L-arginine improve NO bioavailability, inhibit the effects of aldosterone, and are safe in ESRD. We therefore hypothesize that administration of L-arginine or the aldosterone antagonist spironolactone to patients with dialysis-dependent ESRD will inhibit myocardial fibrosis and microvascular dropout. We will test our 2 specific aims using a 9-month, randomized, placebo- controlled, 2x2 factorial clinical trial conducted at Partners Health Care and Beth Israel Deaconess Medical Center: Aim 1) To test the hypothesis that blockade of aldosterone using spironolactone improves myocardial fibrosis and microvascular supply in individuals with ESRD as measured using tissue Doppler Echocardiography (TDI) and myocardial perfusion imaging (PET) scans, respectively; Aim 2) To test the hypothesis that L-arginine, an agent which improves NO bioavailability, improves myocardial fibrosis and microvascular supply as measured by TDI and PET.