Hypertrophy Regression with N-Acetylcysteine in Hypertrophic Cardiomyopathy

N-乙酰半胱氨酸治疗肥厚型心肌病的肥厚消退

• 批准号: 8403983
• 负责人: Ali J Marian
• 金额: $ 18.48万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403983
• 关键词: 4 hydroxynonenal; Acetylcysteine; Adult; Adverse effects; Animal Model; Attenuated; Biological; Cardiac; Clinical; Data; Data Analyses; Data Coordinating Center; Dinoprost; Disease; Dose; Elderly; Family; Feasibility Studies; Fibrosis; Functional disorder; Future; Genes; Genetic; Glutathione; Glycogen Storage Disease; Goals; Heart Hypertrophy; Human; Hypertrophic Cardiomyopathy; Hypertrophy; Intervention; Literature; Magnetic Resonance Imaging; Malondialdehyde; Metabolic Diseases; Modification; Molecular; Morbidity - disease rate; Mortality Determinants; Mus; Mutation; Myocardial; Oryctolagus cuniculus; Outcome; Oxidative Stress; Pathogenesis; Patients; Phenocopy; Phenotype; Physicians; Pilot Projects; Placebo Control; Placebos; Prevention; Proteins; Randomized; Research; Research Design; Resources; Risk; Safety; Sarcomeres; Scientist; Secondary to; Serum Proteins; Staging; Sulfhydryl Compounds; Target Populations; Testing; Therapeutic Agents; Transgenic Model; Transgenic Organisms; base; biobank; clinical phenotype; design; enzyme replacement therapy; human data; improved; indexing; mouse model; placebo controlled study; prevent; sudden cardiac death

The primary objective is to perform a pilot study in patients with hypertrophic cardiomyopathy (HCM) and mutations in genes encoding sarcomere proteins to assess safety and gather the pre-requisite data for subsequent robust randomized placebo-controlled efficacy studies with N-acetylcysteine (NAC). We will gather data on the recruitment, accrual, retention, and compliance rates of HCM patients randomized to treatment with a placebo or two escalating doses of NAC. Likewise, we will determine any potential side effects and estimate the effect size of NAC on indices of cardiac hypertrophy. HCM, the main focus of our research during the past two decades, is the most common cause of sudden cardiac death (SCD) in the young and an important cause of morbidity in the elderly. Despite its clinical impact, there is no effective pharmacological therapy for HCM. None of the current pharmacological therapies reverses or attenuates cardiac hypertrophy or reduces the risk of SCD in adults. Cardiac hypertrophy, the quintessential clinical feature of human HCM, is a major determinant of morbidity and the risk of SCD. Regression of cardiac hypertrophy is expected to improve morbidity and decrease the risk of SCD in HCM, as observed upon regression of load-dependent cardiac hypertrophy. We have generated transgenic rabbit and mouse models of HCM and shown that cardiac hypertrophy and fibrosis could be reversed through genetic or pharmacological interventions. Results with NAC, a precursor to glutathione; the largest intracellular thiol pool against oxidative stress, were most promising. In three independent studies in two different transgenic models of HCM (rabbits and mouse), treatment with NAC completely reversed cardiac hypertrophy and fibrosis and improved indices of diastolic function. The ultimate goal of every physician-scientist is to apply the bench discoveries at the bedside. We propose to test our findings in the animal models in humans with HCM caused by sarcomere protein mutations. The use of NAC is also supported by data showing increased oxidative stress in human HCM. Moreover, NAC has been used extensively in humans and has a well-established safety profile. Resources including patients with sarcomere protein mutations are available to successfully complete a randomized placebo-controlled (N=25) pilot study to test two escalating doses of NAC (N=50), administered for one year. We will determine recruitment, accrual, retention and compliance rates; tolerability, safety and side effects; and estimate the effect size of NAC on the indices of cardiac hypertrophy, as determined by serial cardiac magnetic resonance imaging (MRI) at the baseline and after one year of treatment. Only HCM patients with sarcomere proteins mutations will be included to exclude phenocopy. The Core centers will interpret the phenotypic data to assure homogeneity. Data Coordinating Center will assist in the research design, planning and conduct of the study and analysis of the data. The findings will set the stage for large-scale robust randomized placebo-control efficacy studies.

主要目标是对肥厚型心肌病 (HCM) 患者进行初步研究 和编码肌节蛋白的基因突变，以评估安全性并收集必要的数据 随后对 N-乙酰半胱氨酸 (NAC) 进行了稳健的随机安慰剂对照疗效研究。我们将聚集 有关随机接受治疗的 HCM 患者的招募、应计、保留和依从率的数据 服用安慰剂或两次递增剂量的 NAC。同样，我们将确定任何潜在的副作用和 估计 NAC 对心脏肥大指数的影响大小。 HCM 是我们过去 20 年来研究的主要焦点，它是导致 HCM 的最常见原因。 年轻人心源性猝死（SCD）和老年人发病的重要原因。尽管其临床 目前，HCM 尚无有效的药物治疗方法。目前尚无任何药物疗法 逆转或减轻成人心脏肥大或降低心源性猝死的风险。心脏肥大， 人类 HCM 的典型临床特征是发病率和 SCD 风险的主要决定因素。 心脏肥大的消退有望改善 HCM 的发病率并降低 SCD 的风险，因为 在负荷依赖性心脏肥大消退后观察到。 我们已经建立了 HCM 的转基因兔和小鼠模型，并表明心脏肥大 纤维化可以通过遗传或药物干预来逆转。 NAC 的结果，a 谷胱甘肽的前体；抗氧化应激的最大细胞内硫醇库是最有前途的。在 在两种不同的 HCM 转基因模型（兔子和小鼠）中进行的三项独立研究，用 NAC 治疗 完全逆转心脏肥大和纤维化，改善舒张功能指数。终极 每个医师科学家的目标都是将实验室发现应用到床边。我们建议测试我们的 在患有由肌节蛋白突变引起的 HCM 的动物模型中发现。 NAC的用途是 显示人类 HCM 氧化应激增加的数据也支持了这一点。此外，还使用了NAC 广泛应用于人类并具有完善的安全性。资源包括肌节患者 蛋白质突变可成功完成一项随机安慰剂对照（N = 25）试点研究 测试两次递增剂量的 NAC (N=50)，持续一年。我们将确定招聘、应计、 保留率和合规率；耐受性、安全性和副作用；并估计 NAC 对 心脏肥大指数，通过连续心脏磁共振成像 (MRI) 确定 基线和治疗一年后。只有具有肌节蛋白突变的 HCM 患者才会接受 包括在内以排除表型。核心中心将解释表型数据以确保同质性。 数据协调中心将协助研究设计、规划和进行研究和分析 数据。这些发现将为大规模稳健的随机安慰剂对照功效研究奠定基础。