Hypertrophic cardiomyopathy (HCM) is often caused by pathogenic variants in sarcomeric genes and characterized by left ventricular (LV) hypertrophy, myocardial fibrosis and increased risk of heart failure and arrhythmias. There are no existing therapies to modify disease progression. In this study, we conducted a multi-center, double-blind, placebo-controlled phase 2 clinical trial to assess the safety and efficacy of the angiotensin II receptor blocker valsartan in attenuating disease evolution in early HCM. In total, 178 participants with early-stage sarcomeric HCM were randomized (1:1) to receive valsartan (320 mg daily in adults; 80–160 mg daily in children) or placebo for 2 years (NCT01912534). Standardized changes from baseline to year 2 in LV wall thickness, mass and volumes; left atrial volume; tissue Doppler diastolic and systolic velocities; and serum levels of high-sensitivity troponin T and N-terminal pro-B-type natriuretic protein were integrated into a single composite z-score as the primary outcome. Valsartan (n = 88) improved cardiac structure and function compared to placebo (n = 90), as reflected by an increase in the composite z-score (between-group difference +0.231, 95% confidence interval (+0.098, +0.364); P = 0.001), which met the primary endpoint of the study. Treatment was well-tolerated. These results indicate a key opportunity to attenuate disease progression in early-stage sarcomeric HCM with an accessible and safe medication.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Drugs Open Access 13 June 2022
Subscribe to Nature+
Get immediate online access to the entire Nature family of 50+ journals
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
The final study protocol and statistical analysis plan are provided as Supplementary Note. The corresponding author will consider requests for collaborative study and analysis of de-identified individual participant data to further understanding of the trial results or genetic cardiomyopathies. Interested researchers should submit proposals and analytic plans to the corresponding author, and approval will be granted by consensus of the executive committee. A data use agreement will be issued and will be compliant with relevant patient confidentiality and privacy regulations.
Writing Committee M. et al. 2020 AHA/ACC guideline for the diagnosis and treatment of patients with hypertrophic cardiomyopathy: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 142, e558–e631 (2020).
Seidman, C. E. & Seidman, J. G. Identifying sarcomere gene mutations in hypertrophic cardiomyopathy: a personal history. Circ. Res. 108, 743–750 (2011).
Ho, C. Y. et al. Genotype and lifetime burden of disease in hypertrophic cardiomyopathy: insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Circulation 138, 1387–1398 (2018).
Kim, J. B. et al. Polony multiplex analysis of gene expression (PMAGE) in mouse hypertrophic cardiomyopathy. Science 316, 1481–1484 (2007).
Lopez, B., Gonzalez, A. & Diez, J. Circulating biomarkers of collagen metabolism in cardiac diseases. Circulation 121, 1645–1654 (2010).
Teekakirikul, P. et al. Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β. J. Clin. Invest. 120, 3520–3529 (2010).
Habashi, J. P. et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 312, 117–121 (2006).
Kawano, H. et al. Valsartan decreases type I collagen synthesis in patients with hypertrophic cardiomyopathy. Circ. J. 69, 1244–1248 (2005).
Araujo, A. Q. et al. Effect of losartan on left ventricular diastolic function in patients with nonobstructive hypertrophic cardiomyopathy. Am. J. Cardiol. 96, 1563–1567 (2005).
Yamazaki, T. et al. A new therapeutic strategy for hypertrophic nonobstructive cardiomyopathy in humans. A randomized and prospective study with an angiotensin II receptor blocker. Int. Heart J. 48, 715–724 (2007).
Penicka, M. et al. The effects of candesartan on left ventricular hypertrophy and function in nonobstructive hypertrophic cardiomyopathy: a pilot, randomized study. J. Mol. Diagn. 11, 35–41 (2009).
Shimada, Y. J. et al. Effects of losartan on left ventricular hypertrophy and fibrosis in patients with nonobstructive hypertrophic cardiomyopathy. JACC Heart Fail. 1, 480–487 (2013).
Axelsson, A. et al. Efficacy and safety of the angiotensin II receptor blocker losartan for hypertrophic cardiomyopathy: the INHERIT randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 3, 123–131 (2015).
Ho, C. Y. et al. The design of the Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) trial. Am. Heart J. 187, 145–155 (2017).
Axelsson Raja, A. et al. Baseline characteristics of the VANISH cohort. Circ. Heart Fail. 12, e006231 (2019).
Sun, H., Davison, B. A., Cotter, G., Pencina, M. J. & Koch, G. G. Evaluating treatment efficacy by multiple end points in phase II acute heart failure clinical trials: analyzing data using a global method. Circ. Heart Fail. 5, 742–749 (2012).
Semsarian, C. et al. The L-type calcium channel inhibitor diltiazem prevents cardiomyopathy in a mouse model. J. Clin. Invest. 109, 1013–1020 (2002).
Richards, S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 17, 405–424 (2015).
Landrum, M. J. et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 44, D862–D868 (2016).
Ho, C. Y. et al. Echocardiographic strain imaging to assess early and late consequences of sarcomere mutations in hypertrophic cardiomyopathy. Circ. Cardiovasc. Genet. 2, 314–321 (2009).
Ho, C. Y. et al. Evolution of hypertrophic cardiomyopathy in sarcomere mutation carriers. Heart 102, 1805–1812 (2016).
Ho, C. Y. et al. The burden of early phenotypes and the influence of wall thickness in hypertrophic cardiomyopathy mutation carriers: findings from the HCMNet study. JAMA Cardiol. 2, 419–428 (2017).
Ho, C. Y. et al. Diltiazem treatment for pre-clinical hypertrophic cardiomyopathy sarcomere mutation carriers: a pilot randomized trial to modify disease expression. JACC Heart Fail. 3, 180–188 (2015).
We are indebted to the families and individuals who partnered with us in conducing this trial. This study was funded by the National Heart, Lung, and Blood Institute (P50HL112349 to C.Y.H.). The views expressed in this manuscript are those of the authors and do not reflect official positions of the National Heart, Lung, and Blood Institute or the National Institutes of Health. Study medication (blinded valsartan and matching placebo) was provided by Novartis. Novartis was not involved in the design or conduct of the study; data collection, data management, data analysis or data interpretation; preparation, review or approval of the manuscript; or decision to submit the manuscript for publication.
The authors declare no competing interests.
Peer review information Nature Medicine thanks John Atherton and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Michael Basson was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Measures at baseline, Year 1, and Year 2 (end of study) for systolic (a) and diastolic (b) blood pressure are shown for participants treated with valsartan (n = 88; red) and placebo (n = 90; blue). Values are presented as mean and standard deviation.
Mean values and standard deviation are shown for serum creatinine (a) and potassium (b) levels for participants treated with valsartan (n = 88; red) and placebo (n = 90; blue).
About this article
Cite this article
Ho, C.Y., Day, S.M., Axelsson, A. et al. Valsartan in early-stage hypertrophic cardiomyopathy: a randomized phase 2 trial. Nat Med 27, 1818–1824 (2021). https://doi.org/10.1038/s41591-021-01505-4
Current Cardiology Reports (2022)
Nature Reviews Cardiology (2021)