Hypertrophy Regression with N-AcetyLcysTeine in Hypertrophic CardioMyopathy (HALT-HCM): A Randomized Placebo Controlled Double Blind Pilot Study

• Published in: Circulation research 2018-04, Vol.122 (8), p.1109-1118
• Main Authors: Marian, Ali J, Tan, Yanli, Li, Lili, Chang, Jeffrey, Syrris, Petros, Hessabi, Manouchehr, Rahbar, Mohammad H, Willerson, James T, Cheong, Benjamin Y, Liu, Chia-Ying, Kleiman, Neal S, Bluemke, David A, Nagueh, Sherif F
• Format: Article
• Language: English
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.117.312647

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 anti-oxidant 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:Hypertrophy Regression with N-AcetyLcysTeine in Hypertrophic CardioMyopathy (HALT-HCM) is a double blind randomized, sex-matched, placebo-control single center pilot study in patients with HCM. HCM patients, 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 up to 2.4 g per day. Clinical evaluation, blood chemistry, and six-minute walk test were performed every 3 months, and electrocardiography, echocardiography, and cardiac magnetic resonance imaging (CMR), the latter whenever not contraindicated, before and after 12 months of treatment. 85 out of 232 screened patients met the eligibility criteria, 42 agreed to participate; 29 were randomized to NAC and 13 to placebo groups. Demographics, echocardiographic, and CMR phenotypes at the baseline between the two groups were similar. Whole exome sequencing in 38 patients identified a spectrum of 42 pathogenic variants in genes implicated in HCM in 26 participants. Twenty-four patients in the NAC and eleven in the placebo groups 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 CMR 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:NCT01537926.