Hypertrophy Regression with N-Acetylcysteine in Hypertrophic Cardiomyopathy

描述（由申请人提供）： 主要目的是在肥厚型心肌病（HCM）和编码肌节蛋白的基因突变患者中进行初步研究，以评估安全性并为后续N-乙酰半胱氨酸（NAC）的稳健随机安慰剂对照疗效研究收集必要数据。我们将收集随机接受安慰剂或两种递增剂量NAC治疗的HCM患者的招募、累积、保留和依从率的数据。同样，我们将确定任何潜在的副作用，并估计NAC对心脏肥大指数的影响大小。 在过去的二十年中，HCM是我们研究的主要焦点，是年轻人心脏性猝死（SCD）的最常见原因，也是老年人发病的重要原因。尽管其临床影响，有没有有效的药物治疗HCM。目前的药物治疗均不能逆转或减轻成人心脏肥大或降低SCD的风险。心脏肥大是人类HCM的典型临床特征，是SCD发病率和风险的主要决定因素。正如负荷依赖性心肌肥大消退后所观察到的，预计心肌肥大消退可改善HCM患者的发病率并降低SCD风险。 我们已经建立了转基因HCM兔和小鼠模型，并表明心脏肥大和纤维化可以通过遗传或药物干预逆转。结果与NAC，前体谷胱甘肽，最大的细胞内巯基池对氧化应激，是最有前途的。在两种不同的HCM转基因模型（兔和小鼠）的三项独立研究中，NAC治疗完全逆转了心脏肥大和纤维化，并改善了舒张功能指数。每一位医生兼科学家的最终目标都是将实验室的发现应用于临床。我们建议在人类肌节蛋白突变引起的HCM动物模型中测试我们的发现。NAC的使用也得到了显示人HCM中氧化应激增加的数据的支持。此外，NAC已广泛用于人类，并具有良好的安全性。包括肌节蛋白突变患者在内的资源可用于成功完成随机安慰剂对照（N=25）试点研究，以测试两种递增剂量的NAC（N=50），给药一年。我们将确定招募率、招募率、保留率和依从率;耐受性、安全性和副作用;并估计NAC对心脏肥大指数的影响大小，如在基线和治疗一年后通过连续心脏磁共振成像（MRI）确定的。只有肌节蛋白突变的HCM患者将被纳入，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、计划和开展研究以及数据分析。这些发现将为大规模的随机安慰剂对照有效性研究奠定基础。 公共卫生相关性： 总体目标是在肥厚型心肌病（HCM）患者中进行安慰剂对照可行性研究，以确定随机接受安慰剂或两种递增剂量N-乙酰半胱氨酸（NAC）治疗的HCM患者的安全性，并确定招募、累积、保留和依从率。我们将检测和分析任何潜在的副作用，并估计NAC对心脏肥大指数的影响大小。这些数据是后续稳健随机化疗效研究的先决条件。

DESCRIPTION (provided by applicant): 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, wer 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. PUBLIC HEALTH RELEVANCE: The overall objective is to perform a placebo control feasibility study in patients with hypertrophic cardiomyopathy (HCM) to establish safety and determine recruitment, accrual, retention, and compliance rates of HCM patients randomized to treatment with a placebo or two escalating doses of N-acetylcysteine (NAC). We will detect and analyze any potential side effects and estimate the effect size of NAC on indices of cardiac hypertrophy. The data are pre-requisite for subsequent robust randomized efficacy studies.