Randomized Controlled Trial

. 2025 Jun;18(6):e012393.

doi: 10.1161/CIRCHEARTFAILURE.124.012393. Epub 2025 May 9.

Proteomic Analysis of Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) Clinical Trial

Constantin-Cristian Topriceanu^{1

2

3

4}, Christoffer Rasmus Vissing⁵, Anna Axelsson Raja⁵, Sharlene M Day⁶, Mark W Russell⁷, Kenneth Zahka⁸, Alexandre C Pereira^{1

9}, Steven D Colan¹⁰, Anne M Murphy¹¹, Charles Canter¹², Richard G Bach¹², Matthew T Wheeler¹³, Joseph W Rossano¹⁴, Anjali T Owens⁶, Luisa Mestroni¹⁵, Matthew R G Taylor¹⁵, James C Moon^{2

4}, Gabriella Captur^{2

3

16}, Amit R Patel¹⁷, Ivan Wilmot¹⁸, Jonathan H Soslow¹⁹, Jason R Becker²⁰, Christine E Seidman^{1

21}, Neal K Lakdawala¹, Henning Bundgaard⁵, Usman A Tahir^#²², Carolyn Y Ho^#¹

Affiliations

¹ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.-C.T., A.C.P., C.E.S., N.K.L., C.Y.H.).
² UCL Institute of Cardiovascular Science, University College London, United Kingdom (C.-C.T., J.C.M., G.C.).
³ Unit for Lifelong Health and Ageing at UCL, University College London, United Kingdom (C.-C.T., G.C.).
⁴ Cardiac MRI Unit, Barts Heart Centre, London, United Kingdom (C.-C.T., J.C.M.).
⁵ Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark (C.R.V., A.A.R., H.B.).
⁶ Division of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia (S.M.D., A.T.O.).
⁷ University of Michigan, Ann Arbor (M.W.R.).
⁸ Cleveland Clinic Foundation, OH (K.Z.).
⁹ Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of São Paulo Medical School, Brazil (A.C.P.).
¹⁰ Department of Cardiology, Boston Children's Hospital, MA (S.D.C.).
¹¹ Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD (A.M.M.).
¹² Washington University School of Medicine, St Louis, MO (C.C., R.G.B.).
¹³ Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, CA (M.T.W.).
¹⁴ Children's Hospital of Philadelphia, PA (J.W.R.).
¹⁵ University of Colorado Anschutz Medical Campus, Aurora, CO (L.M., M.R.G.T.).
¹⁶ The Royal Free London NHS Foundation Trust, Centre for Inherited Heart Muscle Conditions, Cardiology Department, United Kingdom (G.C.).
¹⁷ Cardiovascular Division, Department of Medicine, University of Virginia Health System, Charlottesville (A.R.P.).
¹⁸ Heart Institute, Cincinnati Children's Hospital Medical Center, OH (I.W.).
¹⁹ Vanderbilt University Medical Center, Nashville, TN (J.H.S.).
²⁰ Division of Cardiology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA (J.R.B.).
²¹ Howard Hughes Medical Institute, Chevy Chase, MD (C.E.S.).
²² Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (U.A.T.).

^# Contributed equally.

PMID: 40340372
PMCID: PMC12173761 (available on 2026-06-01)
DOI: 10.1161/CIRCHEARTFAILURE.124.012393

Randomized Controlled Trial

Proteomic Analysis of Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) Clinical Trial

Constantin-Cristian Topriceanu et al. Circ Heart Fail. 2025 Jun.

. 2025 Jun;18(6):e012393.

doi: 10.1161/CIRCHEARTFAILURE.124.012393. Epub 2025 May 9.

Authors

Affiliations

¹ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.-C.T., A.C.P., C.E.S., N.K.L., C.Y.H.).
² UCL Institute of Cardiovascular Science, University College London, United Kingdom (C.-C.T., J.C.M., G.C.).
³ Unit for Lifelong Health and Ageing at UCL, University College London, United Kingdom (C.-C.T., G.C.).
⁴ Cardiac MRI Unit, Barts Heart Centre, London, United Kingdom (C.-C.T., J.C.M.).
⁵ Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark (C.R.V., A.A.R., H.B.).
⁶ Division of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia (S.M.D., A.T.O.).
⁷ University of Michigan, Ann Arbor (M.W.R.).
⁸ Cleveland Clinic Foundation, OH (K.Z.).
⁹ Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of São Paulo Medical School, Brazil (A.C.P.).
¹⁰ Department of Cardiology, Boston Children's Hospital, MA (S.D.C.).
¹¹ Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD (A.M.M.).
¹² Washington University School of Medicine, St Louis, MO (C.C., R.G.B.).
¹³ Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, CA (M.T.W.).
¹⁴ Children's Hospital of Philadelphia, PA (J.W.R.).
¹⁵ University of Colorado Anschutz Medical Campus, Aurora, CO (L.M., M.R.G.T.).
¹⁶ The Royal Free London NHS Foundation Trust, Centre for Inherited Heart Muscle Conditions, Cardiology Department, United Kingdom (G.C.).
¹⁷ Cardiovascular Division, Department of Medicine, University of Virginia Health System, Charlottesville (A.R.P.).
¹⁸ Heart Institute, Cincinnati Children's Hospital Medical Center, OH (I.W.).
¹⁹ Vanderbilt University Medical Center, Nashville, TN (J.H.S.).
²⁰ Division of Cardiology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA (J.R.B.).
²¹ Howard Hughes Medical Institute, Chevy Chase, MD (C.E.S.).
²² Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (U.A.T.).

^# Contributed equally.

PMID: 40340372
PMCID: PMC12173761 (available on 2026-06-01)
DOI: 10.1161/CIRCHEARTFAILURE.124.012393

Abstract

Background: In hypertrophic cardiomyopathy (HCM), the mechanisms through which pathogenic sarcomere variants (G+) lead to left ventricular hypertrophy (LVH) are not understood.

Methods: VANISH (Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy) was a multicenter, double-blind, placebo-controlled, randomized trial testing valsartan's ability to attenuate phenotypic progression in early sarcomeric (G+LVH+) and subclinical HCM (G+LVH‒). The outcome was a composite z-score reflecting change in cardiac remodeling from baseline to year 2 (end of study). Baseline and year 2 blood samples were used to quantify 276 proteins using a proximity extension assay (Olink, Sweden). We explored relative differences in protein abundance between early and subclinical HCM at baseline. In addition, we compared proteomic changes between baseline and year 2 in subclinical HCM participants who experienced phenotypic conversion to early HCM (convertors) versus nonconvertors; early HCM participants receiving valsartan versus placebo; and in association with changes in the phenotypic progression z-score. Comparisons were made using the t-test, Mann-Whitney U test, linear mixed models, and generalized linear models, correcting for multiple testing using a 5% false discovery rate.

Results: Circulating proteins were analyzed in 192 participants (32 subclinical and 160 early HCM [81 allocated to valsartan]). NT-proBNP (N-terminal pro-B-type natriuretic peptide) differentiated early from subclinical HCM and tracked with phenotypic progression in early HCM (1-unit worsening in z-score associated with a 27% increase in NT-proBNP [95% CI, 17-37%]). Some extracellular matrix remodeling proteins showed a higher abundance (eg, tissue-type plasminogen activator) in early compared with subclinical HCM or tracked with disease progression (decorin) in early HCM. Some growth factors had a higher relative abundance in early HCM (eg, fibroblast growth factor-21). While no individual protein was able to distinguish phenotypic convertors from nonconvertors, multiprotein panels including lipocalin 2, lectin-like oxidized low-density lipoprotein receptor 1, and either NT-proBNP or interleukin-17 receptor A, could distinguish these groups.

Conclusions: NT-proBNP was the most informative protein, showing a higher abundance in early compared with subclinical HCM and tracking with the phenotypic progression z-score in early-stage HCM. Studying pathways involving growth factors and extracellular matrix remodeling may yield additional insights into the mechanisms behind disease progression in sarcomevere variant carriers and early HCM.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01912534.

Keywords: cardiomyopathy, hypertrophic; proteomics; valsartan.

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Conflict of interest statement

Dr Day reported receiving grants from Lexicon Pharmaceuticals, personal fees from Lexicon Pharmaceuticals and Cytokinetics, and consulting fees from Bristol Myers Squibb (BMS) outside the submitted work. Dr Colan reported receiving consulting fees from Autus Valve Technologies Inc, Clementia Pharmaceuticals, and Rocket Pharmaceuticals, Inc outside the submitted work. Dr Bach reported receiving grants from BMS/MyoKardia and Cytokinetics (paid to Washington University School of Medicine) outside the submitted work. Dr Wheeler reported receiving research funding from BMS, Pfizer, Cytokinetics, and SalubrisBio during the conduct of the study and consulting fees from Leal Therapeutics outside the submitted work. Dr Rossano reported receiving consulting fees from BMS, Merck, Bayer, American Regent Inc, CRI Biotech, and BioMarin outside the submitted work. Dr Owens reported receiving grants from BMS and consulting fees from BMS, Cytokinetics, Tenaya, Pfizer, Renovacor, Lexicon, Edgewise, Stealth, and BioMarin outside the submitted work. Dr Mestroni reported receiving grants from the US National Institutes of Health (NIH) outside the submitted work. Dr Captur is supported by the British Heart Foundation (BHF; SP/20/2/34841), the BHF Accelerator Award (AA/18/6/34223), the National Institutes of Health Research (NIHR) Invention for Innovation (i4i) Funding At the Speed of Translation (FAST) grant scheme (NIHR205960), Barts Charity HeartOME Grant, and the NIHR University College London (UCL) Hospitals Biomedical Research center (BRC). Dr Moon is directly and indirectly supported by the UCL Hospitals NIHR BRC and Biomedical Research Unit at Barts Hospital, respectively. Dr Patel reported receiving payment from the NIH for VANISH subject recruitment during the conduct of the study. Dr Soslow reported receiving consulting fees from Sarepta and PepGen outside the submitted work. Dr Seidman reported receiving a salary from Howard Hughes Medical Institute and grants from the NIH during the conduct of the study, as well as consulting fees from Maze, Merck, and Tenaya. Dr Lakdawala reported receiving research funding from Pfizer and consulting fees from Alexion, BMS, Tenaya, Cytokinetics, Akros, Neuvocor, and Pfizer outside the submitted work. Dr Bundgaard reported receiving lecture fees from MSD, Pfizer, BMS, and Sanofi. Dr Ho reported receiving research funding and consulting fees from BMS, Pfizer, Cytokinetics, Tenaya, and BioMarin outside the submitted work. The other authors report no conflicts.

References

1. Topriceanu C-C, Pereira AC, Moon JC, Captur G, Ho CY. Meta-analysis of Penetrance and Systematic Review on Transition to Disease in Genetic Hypertrophic Cardiomyopathy. Circulation. 2023;149:107–123. - PMC - PubMed
1. Topriceanu C-C, Moon JC, Raja AA, Captur G, Ho CY. Phenotypic Spectrum of Subclinical Sarcomere-Related Hypertrophic Cardiomyopathy and Transition to Overt Disease. Circ: Genom Precis Med. 2024;17:e004580. - PMC - PubMed
1. Coats CJ, Heywood WE, Virasami A, Ashrafi N, Syrris P, Remedios CD, Treibel TA, Moon JC, Lopes LR, Mcgregor CGA, Ashworth M, Sebire NJ, Mckenna WJ, Mills K, Elliott PM. Proteomic Analysis of the Myocardium in Hypertrophic Obstructive Cardiomyopathy. Circ: Genom Precis Med. 2018;11:e001974. - PubMed
1. Shimada YJ, Raita Y, Liang LW, Maurer MS, Hasegawa K, Fifer MA, Reilly MP. Comprehensive Proteomics Profiling Reveals Circulating Biomarkers of Hypertrophic Cardiomyopathy. Circ: Hear Fail. 2021;14:e007849. - PMC - PubMed
1. Captur G, Heywood WE, Coats C, Rosmini S, Patel V, Lopes LR, Collis R, Patel N, Syrris P, Bassett P, O’Brien B, Moon JC, Elliott PM, Mills K. Identification of a Multiplex Biomarker Panel for Hypertrophic Cardiomyopathy Using Quantitative Proteomics and Machine Learning. Molecular & cellular proteomics. 2020;19:114. - PMC - PubMed

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Proteomic Analysis of Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) Clinical Trial

Affiliations

Proteomic Analysis of Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) Clinical Trial

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials