Transforming Growth Factor-β Analysis of the VANISH Trial Cohort

HomeCirculation: Heart FailureVol. 16, No. 4Transforming Growth Factor-β Analysis of the VANISH Trial Cohort Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBTransforming Growth Factor-β Analysis of the VANISH Trial Cohort Yuri Kim, Mitra Mastali, Jennifer E. Van Eyk, E. John Orav, Christoffer R. Vissing, Sharlene M. Day, Anna Axelsson Raja, Mark W. Russell, Kenneth Zahka, Harry M. Lever, Alexandre C. Pereira, Anne M. Murphy, Charles Canter, Richard G. Bach, Matthew T. Wheeler, Joseph W. Rossano, Anjali T. Owens, Henning Bundgaard, Lee Benson, Luisa Mestroni, Matthew R.G. Taylor, Amit R. Patel, Ivan Wilmot, Philip Thrush, Jonathan H. Soslow, Jason R. Becker, Christine E. Seidman and Carolyn Y. Ho Yuri KimYuri Kim Correspondence to: Yuri Kim, MD, PhD, Division of Cardiovascular Medicine, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. Email E-mail Address: [email protected] https://orcid.org/0000-0001-5978-5779 Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (Y.K., C.R.V., C.E.S., C.Y.H.). , Mitra MastaliMitra Mastali Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (M.M., J.E.V.E.). , Jennifer E. Van EykJennifer E. Van Eyk https://orcid.org/0000-0001-9050-148X Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (M.M., J.E.V.E.). , E. John OravE. John Orav Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA (E.J.O.). , Christoffer R. VissingChristoffer R. Vissing https://orcid.org/0000-0002-0834-206X Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (Y.K., C.R.V., C.E.S., C.Y.H.). Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Denmark (C.R.V., A.A.R., H.B.). , Sharlene M. DaySharlene M. Day https://orcid.org/0000-0001-9802-7188 Division of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia (S.M.D., A.T.O.). , Anna Axelsson RajaAnna Axelsson Raja https://orcid.org/0000-0001-8665-3309 Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Denmark (C.R.V., A.A.R., H.B.). , Mark W. RussellMark W. Russell https://orcid.org/0000-0003-4855-9260 Division of Pediatric Cardiology, Department of Pediatrics, University of Michigan Medical Center, Ann Arbor (M.W.R.). , Kenneth ZahkaKenneth Zahka Department of Pediatric Cardiology, Cleveland Clinic Children's, Pediatric Institute, Cleveland Clinic Foundation, OH (K.Z., H.M.L.). , Harry M. LeverHarry M. Lever Department of Pediatric Cardiology, Cleveland Clinic Children's, Pediatric Institute, Cleveland Clinic Foundation, OH (K.Z., H.M.L.). , Alexandre C. PereiraAlexandre C. Pereira https://orcid.org/0000-0002-7782-5540 Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of Sao Paulo Medical School, Brazil (A.C.P.). , Anne M. MurphyAnne M. Murphy https://orcid.org/0000-0001-9254-3202 Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD (A.M.M.). , Charles CanterCharles Canter https://orcid.org/0000-0002-0007-7337 Department of Pediatrics (C.C.), Washington University School of Medicine, St. Louis, MO. , Richard G. BachRichard G. Bach Department of Medicine (R.G.B.), Washington University School of Medicine, St. Louis, MO. , Matthew T. WheelerMatthew T. Wheeler https://orcid.org/0000-0001-8721-3022 Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, CA (M.T.W.). , Joseph W. RossanoJoseph W. Rossano https://orcid.org/0000-0002-8284-0673 Division of Cardiology, Children's Hospital of Philadelphia, PA (J.W.R.). , Anjali T. OwensAnjali T. Owens https://orcid.org/0000-0002-9669-8495 Division of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia (S.M.D., A.T.O.). , Henning BundgaardHenning Bundgaard https://orcid.org/0000-0002-0563-7049 Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Denmark (C.R.V., A.A.R., H.B.). Department of Clinical Medicine, University of Copenhagen, Denmark (H.B.). , Lee BensonLee Benson https://orcid.org/0000-0002-1407-1825 The Labatt Family Heart Centre, The Hospital for Sick Children, University of Toronto, ON, Canada (L.B.). , Luisa MestroniLuisa Mestroni https://orcid.org/0000-0003-1116-2286 Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora (L.M., M.R.G.T.). , Matthew R.G. TaylorMatthew R.G. Taylor https://orcid.org/0000-0001-9043-0810 Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora (L.M., M.R.G.T.). , Amit R. PatelAmit R. Patel https://orcid.org/0000-0001-7621-6463 Division of Cardiology, University of Virginia, Charlottesville (A.R.P.). , Ivan WilmotIvan Wilmot Heart Institute, Cincinnati Children's Hospital Medical Center, OH (I.W.). , Philip ThrushPhilip Thrush Division of Pediatric Cardiology, Ann & Robert H. Lurie Children's Hospital of Chicago, IL (P.T.). , Jonathan H. SoslowJonathan H. Soslow https://orcid.org/0000-0001-9194-5330 Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN (J.H.S.). , Jason R. BeckerJason R. Becker https://orcid.org/0000-0002-2107-8179 Division of Cardiology, University of Pittsburgh School of Medicine, PA (J.R.B.). , Christine E. SeidmanChristine E. Seidman https://orcid.org/0000-0001-6380-1209 Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (Y.K., C.R.V., C.E.S., C.Y.H.). Howard Hughes Medical Institute, Chevy Chase, MD (C.E.S.). and Carolyn Y. HoCarolyn Y. Ho https://orcid.org/0000-0002-7334-7924 Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (Y.K., C.R.V., C.E.S., C.Y.H.). and on behalf of the VANISH Investigators Originally published31 Mar 2023https://doi.org/10.1161/CIRCHEARTFAILURE.122.010314Circulation: Heart Failure. 2023;16Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: March 31, 2023: Ahead of Print Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder characterized by unexplained left ventricular hypertrophy. Rare damaging genetic variants in sarcomere genes, including myosin binding protein C3 (MYBPC3) and myosin heavy chain 7 (MYH7) are responsible for ≈70% of familial disease.1 Patients with HCM are at increased risk of developing heart failure, arrhythmias, and sudden cardiac death.1Previous basic investigation demonstrated that TGF-β (transforming growth factor β) plays an essential role in activating profibrotic pathways involved in the early pathogenesis of HCM.2,3 Furthermore, in a mouse model of sarcomeric HCM, treatment with either a TGF-β neutralizing antibody or with the angiotensin II receptor blocker (ARB) losartan attenuated the development of left ventricular hypertrophy and fibrosis. However, treatment was only effective if administered early in life, prior to the emergence of clinically overt features of HCM.3 These studies were the foundation for the VANISH trial (Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy).4 One hundred seventy-eight participants with early stage sarcomeric HCM were randomized to receive placebo (n=90) or valsartan (n=88) for 2 years. The primary outcome assessed a composite z score reflecting changes in cardiac structure and function from baseline to end of study. The score included left ventricular (LV) wall thickness, LV mass, LV 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. VANISH demonstrated that ARB valsartan attenuated disease progression in this cohort. Participants receiving valsartan had an increase in composite z score, indicating relative improvement, whereas those receiving placebo had a decrease, indicating relative worsening (P=0.001; Figure [A]). However, the mechanism underlying this treatment benefit is unknown. While data in HCM are currently limited, a previous study in Marfan syndrome patients suggested that beneficial effects of ARB may be associated with a reduction in circulating TGF-β levels.5 Therefore, here, we investigated if circulating TGF-β levels changed in response to valsartan therapy in the VANISH trial cohort.Download figureDownload PowerPointFigure. Description of the study cohort and changes in TGF-β levels with placebo and valsartan treatment. A, Baseline characteristics of the study cohort and results of the primary outcome of the VANISH trial (Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy).4 Nine clinical components, including serum troponin T and NT-proBNP (N-terminal pro-B-type natriuretic protein) levels, left ventricular (LV) mass index, LV end diastolic volume index, LV end systolic volume index, maximal LV wall thickness, left atrial volume index, E′ velocity, and S′ velocity, were integrated to create the composite z score (primary efficacy outcome). The positive z-score value indicates relative improvement. *n=77 and 80 for placebo and valsartan groups, respectively. ^n=73 and 77 for placebo and valsartan groups, respectively. B, Differences in log values of circulating TGF-β (transforming growth factor β) measurements (pg/mL) from baseline to year 2. No significant difference was identified between the 2 treatment groups in the primary cohort with early hypertrophic cardiomyopathy in the VANISH trial. P values were calculated using unpaired t test. IQR indicates interquartile range.The study population included 178 participants with early stage HCM in the VANISH trial. All participants provided informed consent, and the study was approved by institutional review committees. Peripheral blood was collected prior to randomization (placebo n=90 or valsartan n=88) and at end of study at year 2. We measured circulating TGF-β levels (pg/mL) in free and total (free plus TGF-β bound to latent TGF-β binding proteins) forms using an enzyme-linked immunosorbent assay (Quanterix, Billerica, MA) and compared the change in levels from baseline to year 2. TGF-β values were not normally distributed, therefore, log transformed for analysis. P values were calculated using paired t test when comparing changes within each subject and unpaired t test when comparing differences between 2 groups. Participants, who did not have interpretable TGF-β measurements available from both time points were excluded (21 for total TGF-β and 28 for free TGF-β). The data and analytic methods will be made available to other researchers upon request.We compared the change in TGF-β levels in placebo- and valsartan-treated participants. Overall, total TGF-β levels increased significantly during follow-up in both placebo (mean from 8.27 to 8.52; P=0.003) and valsartan-treated groups (mean from 8.26 to 8.49; P=0.02). However, the degree of increase of total TGF-β levels was not significantly different between the treatment groups (P=0.85; Figure [B]). Changes in free TGF-β levels were also similar between the 2 treatment groups (P=0.63; Figure [B]).In this study, we analyzed changes in circulating TGF-β levels in the VANISH trial to determine if valsartan treatment was associated with a decrease in TGF-β levels as a potential mechanism underlying the improvement in cardiac remodeling seen in patients with early HCM. No significant difference was seen in the change in circulating TGF-β levels between placebo- and valsartan-treated participants.Limitations of the current study include the small number of participants, uncertain relationship between the circulating levels of TGF-β measured and myocardial levels of TGF-β, which may be more biologically relevant, and inability to differentiate between the TGF-β isoforms (TGF-β1, TGF-β2, and TGF-β3). Although a previous study using animal models suggested potential effects of ARBs in downregulating TGF-β signaling,3 findings from animal studies may not directly translate to human studies. In addition, the current study focused on only 1 aspect of a very complex TGF-β signaling pathway, which includes a wide array of upstream and downstream regulators and interacts with multiple other signaling pathways. For example, ARBs may affect clinical progression of HCM via signaling pathways other than the TGF-β pathway such as the renin-angiotensin system or the PI3K/AKT pathway.Recognizing these limitations, our results suggest that disease-modifying effects of ARBs identified in early stage HCM are not dependent on decreasing circulating TGF-β levels. Further studies are needed to better characterize how ARBs improve cardiac remodeling in early HCM, to elucidate the pathogenesis of HCM, and to refine development of additional disease-modifying therapies.Article InformationAcknowledgmentsThe authors thank the families and patients, who participated in this study and the Cedars-Sinai Medical Center Proteomics and Metabolomics Core, who performed the ELISA.Sources of FundingThe VANISH trial (Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy) was funded by the National Institutes of Health/National Heart, Lung, and Blood Institute (P50HL112349; Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01912534).AppendixVANISH Investigators: E. Kevin Hall, MD (Department of Pediatrics, Yale University School of Medicine, New Haven, CT); Lubna Choudhury, MD (Division of Cardiology, Feinberg School of Medicine, Bluhm Cardiovascular Institute, Northwestern University, Chicago, IL); Elfriede Pahl, MD (Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN); Kimberly Y. Lin, MD (Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA).Disclosures 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 article for publication.Footnotes*A list of VANISH Investigators is provided in the Appendix.This manuscript was sent to John C. Burnett, Jr, MD, Guest Editor, for review by expert referees, editorial decision, and final disposition.For Sources of Funding and Disclosures, see page 376.Correspondence to: Yuri Kim, MD, PhD, Division of Cardiovascular Medicine, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. Email ykim@genetics.med.harvard.eduReferences1. Ho CY, Day SM, Ashley EA, Michels M, Pereira AC, Jacoby D, Cirino AL, Fox JC, Lakdawala NK, Ware JS, et al. Genotype and lifetime burden of disease in hypertrophic cardiomyopathy.Circulation. 2018; 138:1387–1398. doi: 10.1161/CIRCULATIONAHA.117.033200LinkGoogle Scholar2. Kim JB, Porreca GJ, Song L, Greenway SC, Gorham JM, Church GM, Seidman CE, Seidman JG. Polony multiplex analysis of gene expression (PMAGE) in mouse hypertrophic cardiomyopathy.Science. 2007; 316:1481–1484. doi: 10.1126/science.1137325CrossrefMedlineGoogle Scholar3. Teekakirikul P, Eminaga S, Toka O, Alcalai R, Wang L, Wakimoto H, Nayor M, Konno T, Gorham JM, Wolf CM, et al. Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β.J Clin Invest. 2010; 120:3520–3529. doi: 10.1172/JCI42028CrossrefMedlineGoogle Scholar4. Ho CY, Day SM, Axelsson A, Russell MW, Zahka K, Lever HM, Pereira AC, Colan SD, Margossian R, Murphy AM, et al. Valsartan in early-stage hypertrophic cardiomyopathy: a randomized phase 2 trial.Nat Med. 2021; 27:1818–1824. doi: 10.1038/s41591-021-01505-4CrossrefMedlineGoogle Scholar5. Matt P, Schoenhoff F, Habashi J, Holm T, Van Erp C, Loch D, Carlson OD, Griswold BF, Fu Q, De Backer J, et al. Circulating TGFβ in Marfan's syndrome.Circulation. 2009; 120:526–532. doi: 10.1161/CIRCULATIONAHA.108.841981LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails April 2023Vol 16, Issue 4 Advertisement Article Information Metrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/CIRCHEARTFAILURE.122.010314PMID: 36999957 Originally publishedMarch 31, 2023 Keywordsangiotensin receptor blockershypertrophic cardiomyopathyTGF-βPDF download Advertisement Subjects Cardiomyopathy Hypertrophy Remodeling Translational Studies

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