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: 8590218
• 负责人: Ali J Marian
• 金额: $ 19.1万
• 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 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8590218
• 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.

主要目的是对肥厚性心肌病（HCM）患者进行试验研究。 以及编码肌节蛋白的基因突变，以评估安全性并收集先决条件数据 随后使用N-乙酰半胱氨酸（NAC）进行鲁棒的随机安慰剂对照疗效研究。我们将聚集 HCM患者随机进行治疗的招募，应计，保留和合规率的数据 用安慰剂或两次不断升级的NAC剂量。同样，我们将确定任何潜在的副作用， 估计NAC对心脏肥大指数的影响大小。 HCM是过去二十年来我们研究的主要重点，是最常见的原因 年轻人的心脏死亡（SCD）是老年人发病率的重要原因。尽管它的临床 影响，HCM没有有效的药理疗法。目前的药理疗法均无 逆转或减轻心脏肥大或降低成人SCD的风险。心脏肥大， 人HCM的典型临床特征是发病率和SCD风险的主要决定因素。 心脏肥大的回归有望提高发病率并降低HCM的SCD风险，因为 观察到负荷依赖性心脏肥大的消退。 我们已经产生了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理干预措施逆转。 NAC的结果 谷胱甘肽的前体；针对氧化应激的最大的细胞内硫醇池是最有前途的。在 在两个不同的HCM（兔子和小鼠）的转基因模型中进行的三项独立研究，NAC处理 完全逆转心脏肥大，纤维化以及改善舒张功能指标。最终 每个医师科学家的目标是在床边施加长凳发现。我们建议测试我们的 由肌节蛋白突变引起的人类动物模型中的动物模型中的发现。 NAC的使用是 还得到了显示人类HCM氧化应激增加的数据。而且，NAC已被使用 在人类中广泛，具有良好的安全性。包括肉眼患者在内的资源 蛋白质突变可成功完成随机的安慰剂对照（n = 25）试验研究 测试两次升级剂量的NAC（n = 50），进行了一年。我们将确定招聘，应计， 保留和合规率；耐受性，安全性和副作用；并估计NAC对 心脏肥大的指标，通过在序列心脏磁共振成像（MRI）确定的指标 基线和一年的治疗后。只有HCM患有肌动蛋白突变的HCM患者 包括以排除表情。核心中心将解释表型数据以确保同质性。 数据协调中心将有助于研究，计划和进行研究和分析 数据。这些发现将为大规模强大的随机安慰剂控制功效研究奠定了基础。