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

描述(申请人提供)：美国有超过500,000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。在一般人群中有效降低心血管死亡率的治疗方法在依赖透析的终末期肾病中不太成功，迫切需要新的治疗方法。传统的心血管危险因素在晚期肾功能衰竭的发生中不那么重要，标准治疗的令人失望的结果似乎可归因于终末期肾病患者心血管疾病潜在机制的重要差异。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，后者在其他情况下更常导致心血管死亡。这些考虑表明，针对心血管猝死的ESRD特异性机制，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预后的特别有效的方法。然而，目前还没有明确的目标或疗法来达到这一目的。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猝死有很高的预测作用，表明纤维化和微血管疾病是心血管猝死的重要决定因素。更多的研究表明，一氧化氮和醛固酮生物利用度的异常是心肌纤维化和微血管疾病进展的关键和协同因素，螺内酯或L精氨酸的应用提高了一氧化氮的生物利用度，抑制了醛固酮的作用，在终末期肾病中是安全的。因此，我们假设，对依赖透析的终末期肾病患者应用L-精氨酸或醛固酮拮抗剂螺内酯可以抑制心肌纤维化和微血管脱落。我们将使用在Partners Health Care和贝丝以色列女执事医学中心进行的为期9个月的随机、安慰剂对照、2x2因素临床试验来测试我们的两个特定目标：目的1)验证使用螺内酯阻断醛固酮可改善终末期肾病患者心肌纤维化和微血管供应的假设，该假说分别通过组织多普勒超声心动图和心肌灌注成像来测量；目的2)测试L精氨酸可以改善心肌纤维化和微血管供应的假设，该假说是一种提高非生物利用度的药物，可以改善心肌纤维化和微血管供应。

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.