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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

基本信息

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
项目类别：
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

项目摘要

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.

主要目的是在肥厚性心肌病（HCM）患者中进行一项初步研究。