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.

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Planning Grant (R34)
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Clinical Trials Review Committee (CLTR)
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Shah, Monica R
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University of Texas Health Science Center Houston
Schools of Medicine
United States
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Marian, Ali J; Tan, Yanli; Li, Lili et al. (2018) Hypertrophy Regression With N-Acetylcysteine in Hypertrophic Cardiomyopathy (HALT-HCM): A Randomized, Placebo-Controlled, Double-Blind Pilot Study. Circ Res 122:1109-1118
Marian, Ali J (2017) Non-syndromic cardiac progeria in a patient with the rare pathogenic p.Asp300Asn variant in the LMNA gene. BMC Med Genet 18:116
Marian, Ali J (2017) Congenital Heart Disease: The Remarkable Journey From the ""Post-Mortem Room"" to Adult Clinics. Circ Res 120:895-897
Li, Lili; Bainbridge, Matthew Neil; Tan, Yanli et al. (2017) A Potential Oligogenic Etiology of Hypertrophic Cardiomyopathy: A Classic Single-Gene Disorder. Circ Res 120:1084-1090
Bainbridge, Matthew Neil; Li, Lili; Tan, Yanli et al. (2017) Identification of established arrhythmogenic right ventricular cardiomyopathy mutation in a patient with the contrasting phenotype of hypertrophic cardiomyopathy. BMC Med Genet 18:24
Lombardi, Raffaella; Chen, Suet Nee; Ruggiero, Alessandra et al. (2016) Cardiac Fibro-Adipocyte Progenitors Express Desmosome Proteins and Preferentially Differentiate to Adipocytes Upon Deletion of the Desmoplakin Gene. Circ Res 119:41-54
Marian, Ali J (2016) Challenges in the Diagnosis of Anderson-Fabry Disease: A Deceptively Simple and Yet Complicated Genetic Disease. J Am Coll Cardiol 68:1051-3
Gurha, Priyatansh; Chen, Xiaofan; Lombardi, Raffaella et al. (2016) Knockdown of Plakophilin 2 Downregulates miR-184 Through CpG Hypermethylation and Suppression of the E2F1 Pathway and Leads to Enhanced Adipogenesis In Vitro. Circ Res 119:731-50
Marian, Ali J (2016) Clinical applications of molecular genetic discoveries. Transl Res 168:6-14
Marian, Ali J; van Rooij, Eva; Roberts, Robert (2016) Genetics and Genomics of Single-Gene Cardiovascular Diseases: Common Hereditary Cardiomyopathies as Prototypes of Single-Gene Disorders. J Am Coll Cardiol 68:2831-2849

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