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Hypertrophy Regression With N-Acetylcysteine in Hypertrophic Cardiomyopathy (HALT-HCM): A Randomized,
Ali J Marian1, Yanli Tan2, Lili Li2
1From the Center for Cardiovascular Genetics, Brown Foundation Institute of Molecular Medicine, Texas Heart Institute (A.J.M., Y.T., L.L., J.C., J.T.W., B.Y.C.), Biostatistics/Epidemiology/Research Design Component, Center for Clinical and Translational Sciences (M.H., M.H.R.), Department of Epidemiology, Human Genetics, and Environmental Sciences (M.H.R.), Division of Clinical and Translational Sciences (M.H.R.), and Department of Internal Medicine, University of Texas Health Science Center, Houston (M.H.R.); Institute of Cardiovascular Science, University College London, United Kingdom (P.S.); Department of Radiology, Johns Hopkins Hospital, Baltimore, MD (C.-Y.L.); Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison (D.A.B.); and Department of Medicine, Methodist DeBakey Heart and Vascular Center, Houston, TX (N.S.K., S.F.N.). ali.j.marian@uth.tmc.edu.
Insights
N-acetylcysteine (NAC) showed small effects on cardiac hypertrophy and fibrosis in hypertrophic cardiomyopathy (HCM) patients. The HALT-HCM study suggests larger trials are needed to confirm NAC
Area of Science:
- Cardiology
- Genetics
- Pharmacology
Background:
- Hypertrophic cardiomyopathy (HCM) is a genetic heart condition characterized by cardiac hypertrophy and fibrosis, increasing sudden death risk.
- Oxidative stress plays a role in HCM pathogenesis, and N-acetylcysteine (NAC) has shown promise in animal models.
Purpose of the Study:
- To evaluate the effect size of NAC on cardiac hypertrophy and fibrosis markers in patients with established HCM.
- To assess the safety and efficacy of NAC in a clinical trial setting for HCM.
Main Methods:
- The HALT-HCM study was a double-blind, randomized, placebo-controlled pilot trial involving 42 HCM patients.
- Patients received either NAC (up to 2.4 g/day) or placebo for 12 months, with regular clinical, echocardiographic, and cardiac MRI assessments.
- Genetic testing identified pathogenic variants in HCM-related genes in a subset of participants.
Main Results:
- NAC treatment demonstrated small effect sizes on indices of cardiac hypertrophy, function, and fibrosis (late gadolinium enhancement) after 12 months.
- No significant adverse events were attributed to NAC, though six severe events occurred in the NAC group.
- The study identified a spectrum of genetic variants associated with HCM in participants.
Conclusions:
- Twelve months of NAC treatment had minimal impact on cardiac hypertrophy and fibrosis in HCM patients.
- The small sample size of the HALT-HCM study limits definitive conclusions on NAC's efficacy.
- Further research with larger cohorts is warranted to ascertain the therapeutic potential of NAC in HCM.
Rationale:
Hypertrophic cardiomyopathy (HCM) is a genetic paradigm of cardiac hypertrophy. Cardiac hypertrophy and interstitial fibrosis are important risk factors for sudden death and morbidity in HCM. Oxidative stress is implicated in the pathogenesis of cardiac hypertrophy and fibrosis. Treatment with antioxidant N-acetylcysteine (NAC) reverses cardiac hypertrophy and fibrosis in animal models of HCM.
Objective:
To determine effect sizes of NAC on indices of cardiac hypertrophy and fibrosis in patients with established HCM.
Methods And Results:
HALT-HCM (Hypertrophy Regression With N-Acetylcysteine in Hypertrophic Cardiomyopathy) is a double-blind, randomized, sex-matched, placebo-controlled single-center pilot study in patients with HCM. Patients with HCM, who had a left ventricular wall thickness of ≥15 mm, were randomized either to a placebo or to NAC (1:2 ratio, respectively). NAC was titrated ≤2.4 g per day. Clinical evaluation, blood chemistry, and 6-minute walk test were performed every 3 months, and electrocardiography, echocardiography, and cardiac magnetic resonance imaging, the latter whenever not contraindicated, before and after 12 months of treatment. Eighty-five of 232 screened patients met the eligibility criteria, 42 agreed to participate; 29 were randomized to NAC and 13 to placebo groups. Demographic, echocardiographic, and cardiac magnetic resonance imaging phenotypes at the baseline between the 2 groups were similar. WSE in 38 patients identified a spectrum of 42 pathogenic variants in genes implicated in HCM in 26 participants. Twenty-four patients in the NAC group and 11 in the placebo group completed the study. Six severe adverse events occurred in the NAC group but were considered unrelated to NAC. The effect sizes of NAC on the clinical phenotype, echocardiographic, and cardiac magnetic resonance imaging indices of cardiac hypertrophy, function, and extent of late gadolinium enhancement-a surrogate for fibrosis-were small.
Conclusions:
Treatment with NAC for 12 months had small effect sizes on indices of cardiac hypertrophy or fibrosis. The small sample size of the HALT-HCM study hinders from making firm conclusions about efficacy of NAC in HCM.
Clinical Trial Registration:
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01537926.
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