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

ESRD 中的醛固酮、一氧化氮、心肌纤维化和毛细血管损失

基本信息

批准号：
8506326
负责人：
David M Charytan
金额：
$ 38.79万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-22 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8506326
关键词：
Accounting Address Aldosterone Aldosterone Antagonists Architecture Arginine Arrhythmia Atherosclerosis Biological Availability Biological Markers Biology Blood capillaries Blood flow Cardiac Cardiovascular Diseases Cardiovascular system Cessation of life Chronic Clinical Clinical Data Conduct Clinical Trials Coronary Data Diabetic Angiopathies Dialysis procedure Disease Doppler Echocardiography Double-Blind Method Dropout Echocardiography End stage renal failure Event Expenditure Failure Fibrosis Frequencies Functional disorder General Population Healthcare Heart Heart Diseases Homeostasis Human Image Incidence Individual Israel Kidney Failure Lead Left Ventricular Hypertrophy Malignant - descriptor Measures Medical center Medicare Mineralocorticoid Receptor Myocardial Myocardial Infarction Myocardial perfusion Nature Nitric Oxide Outcome Oxygen Pathway interactions Patients Pharmaceutical Preparations Physiology Placebo Control Placebos Play Population Positron-Emission Tomography Randomized Renal function Research Rest Risk Factors Role Spironolactone Stress Sudden Death Testing Tissues United States Ventricular Function angiogenesis capillary cardiovascular risk factor design effective therapy heart function high risk improved indexing insight mortality novel preclinical study prospective public health relevance

项目摘要

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.

描述（由申请人提供）：美国有500,000多人患有末期肾脏疾病（ESRD），这些人患心血管（CV）死亡的发病率极高。有效降低普通人群中CV死亡率的治疗方法在透析依赖性ESRD中的成功率较低，并且非常需要新的疗法。传统的简历危险因素在晚期肾衰竭的情况下不太重要，而标准疗法的令人失望的结果似乎归因于ESRD患者CV疾病的重要差异。 ESRD个体中绝大多数CV死亡的突然死亡频率高于动脉粥样硬化死亡或心肌梗死的频率高5倍，这更常见于其他情况下的CV死亡率。这些考虑因素表明，针对ESRD特异性的CV死亡机制，而不是针对动脉粥样硬化和心肌梗塞的机制，这可能是改善ESRD结果的一种特别有效的方法。但是，目前尚无针对此目的的目标或疗法。包括申请人的研究在内的大量数据表明，心肌纤维化和微血管辍学在ESRD患者的心脏中大大增加，并且对心肌纤维化和微血管疾病的非侵入性测量值高度预测了CV死亡，这表明纤维化和微血管疾病是重要的CV型CV死亡。其他研究表明，一氧化氮和醛固酮的生物利用度异常至关重要，并且对心肌纤维化和微血管疾病进展的进展以及螺内乳痛或L-精氨酸的给药不可改善生物利用度的施用，这是至关重要的，并且有效的促进者，抑制了醛固酮的影响，并且在Esrd and Esrd and Sauce in eSrd。因此，我们假设给予L-精氨酸或醛固酮拮抗剂螺内酯对透析依赖性ESRD的患者将抑制心肌纤维化和微血管辍学。我们将使用9个月，随机，安慰剂控制的2x2阶乘临床试验测试我们的两个特定目标，该试验在合作伙伴医疗保健和贝丝以色列执事医疗中心进行：目标1）测试使用螺旋酮改善甲状腺纤维的纤维化和小血管造影的假设，该假说是使用卵巢纤维供应和微血管供应量的人脉络供应，并衡量了Esried assred and essred and tet aS the and tet aS the and tet aS the and tet aS tred。心肌灌注成像（PET）扫描；目的2）检验以下假设：L-精氨酸（一种没有生物利用度的药物）改善了TDI和PET测量的心肌纤维化和微血管供应。