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Cardiac Remodeling in Subclinical Hypertrophic Cardiomyopathy: The VANISH Randomized Clinical Trial. JAMA cardiology Vissing, C. R., Axelsson Raja, A., Day, S. M., Russell, M. W., Zahka, K., Lever, H. M., Pereira, A. C., Colan, S. D., Margossian, R., Murphy, A. M., Canter, C., Bach, R. G., Wheeler, M. T., Rossano, J. W., Owens, A. T., Benson, L., Mestroni, L., Taylor, M. R., Patel, A. R., Wilmot, I., Thrush, P., Soslow, J. H., Becker, J. R., Seidman, C. E., Lakdawala, N. K., Cirino, A. L., McMurray, J. J., MacRae, C. A., Solomon, S. D., Bundgaard, H., Orav, E. J., Ho, C. Y., Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) Investigators, Krieger, J. E., Sacilotto, L., Arteaga, E., Antunes, M. O., Ashley, E., Lin, K. Y., Hall, E. K., Choudhury, L., Pahl, E., Vargas, J. D., Lewis, G. D., Desai, A. S. 2023

Abstract

Importance: Valsartan has shown promise in attenuating cardiac remodeling in patients with early-stage sarcomeric hypertrophic cardiomyopathy (HCM). Genetic testing can identify individuals at risk of HCM in a subclinical stage who could benefit from therapies that prevent disease progression.Objective: To explore the potential for valsartan to modify disease development, and to characterize short-term phenotypic progression in subclinical HCM.Design, Setting, and Participants: The multicenter, double-blind, placebo-controlled Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) randomized clinical trial was conducted from April 2014 to July 2019 at 17 sites in 4 countries (Brazil, Canada, Denmark, and the US), with 2 years of follow-up. The prespecified exploratory VANISH cohort studied here included sarcomere variant carriers with subclinical HCM and early phenotypic manifestations (reduced E' velocity, electrocardiographic abnormalities, or an increased left ventricular [LV] wall thickness [LVWT] to cavity diameter ratio) but no LV hypertrophy (LVH). Data were analyzed between March and December 2022.Interventions: Treatment with placebo or valsartan (80 mg/d for children weighing <35 kg, 160 mg/d for children weighing =35 kg, or 320 mg/d for adults aged =18 years).Main Outcomes and Measures: The primary outcome was a composite z score incorporating changes in 9 parameters of cardiac remodeling (LV cavity volume, LVWT, and LV mass; left atrial [LA] volume; E' velocity and S' velocity; and serum troponin and N-terminal prohormone of brain natriuretic peptide levels).Results: This study included 34 participants, with a mean (SD) age of 16(5) years (all were White). A total of 18 participants (8 female [44%] and 10 male [56%]) were randomized to valsartan and 16 (9 female [56%] and 7 male [44%]) were randomized to placebo. No statistically significant effects of valsartan on cardiac remodeling were detected (mean change in composite z score compared with placebo: -0.01 [95% CI, -0.29 to 0.26]; P=.92). Overall, 2-year phenotypic progression was modest, with only a mild increase in LA volume detected (increased by 3.5 mL/m2 [95% CI, 1.4-6.0 mL/m2]; P=.002). Nine participants (26%) had increased LVWT, including 6 (18%) who developed clinically overt HCM. Baseline LA volume index (LAVI; 35 vs 28 mL/m2; P=.01) and average interventricular septum thickness (8.5 vs 7.0 mm; P=.009) were higher in participants who developed HCM.Conclusions and Relevance: In this exploratory cohort, valsartan was not proven to slow progression of subclinical HCM. Minimal changes in markers of cardiac remodeling were observed, although nearly one-fifth of patients developed clinically overt HCM. Transition to disease was associated with greater baseline interventricular septum thickness and LAVI. These findings highlight the importance of following sarcomere variant carriers longitudinally and the critical need to improve understanding of factors that drive disease penetrance and progression.Trial Registration: ClinicalTrials.gov Identifier: NCT01912534.

View details for DOI 10.1001/jamacardio.2023.2808

View details for PubMedID 37672268