Aptamer Proteomics for Biomarker Discovery in Heart Failure With Reduced Ejection Fraction

HomeCirculationVol. 146, No. 18Aptamer Proteomics for Biomarker Discovery in Heart Failure With Reduced Ejection Fraction Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBAptamer Proteomics for Biomarker Discovery in Heart Failure With Reduced Ejection Fraction Luqing Zhang, Jonathan W. Cunningham, Brian L. Claggett, Jaison Jacob, Michael M. Mendelson, Pablo Serrano-Fernandez, Sergio Kaiser, Denise P. Yates, Margaret Healey, Chien-Wei Chen, Gordon M. Turner, Natasha L. Patel-Murray, Faye Zhao, Michael T. Beste, Jason M. Laramie, William T. Abraham, Pardeep S. Jhund, Lars Kober, Milton Packer, Jean Rouleau, Michael R. Zile, Margaret F. Prescott, Martin Lefkowitz, John J.V. McMurray, Scott D. Solomon and William Chutkow Luqing ZhangLuqing Zhang https://orcid.org/0000-0001-7252-643X Novartis Institutes for Biomedical Research, Cambridge, MA (L.Z., J.J., M.M.M., D.P.Y., M.H., C.-W.C., G.M.T., N.L.P.-M., F.Z., M.T.B., J.M.L., W.C.). *L. Zhang and J.W. Cunningham contributed equally. Search for more papers by this author , Jonathan W. CunninghamJonathan W. Cunningham https://orcid.org/0000-0003-4481-7867 Brigham and Women’s Hospital, Boston, MA (J.W.C., B.L.C., S.D.S.). *L. Zhang and J.W. Cunningham contributed equally. Search for more papers by this author , Brian L. ClaggettBrian L. Claggett https://orcid.org/0000-0002-4215-9218 Brigham and Women’s Hospital, Boston, MA (J.W.C., B.L.C., S.D.S.). Search for more papers by this author , Jaison JacobJaison Jacob Novartis Institutes for Biomedical Research, Cambridge, MA (L.Z., J.J., M.M.M., D.P.Y., M.H., C.-W.C., G.M.T., N.L.P.-M., F.Z., M.T.B., J.M.L., W.C.). Search for more papers by this author , Michael M. MendelsonMichael M. Mendelson https://orcid.org/0000-0001-7590-3958 Novartis Institutes for Biomedical Research, Cambridge, MA (L.Z., J.J., M.M.M., D.P.Y., M.H., C.-W.C., G.M.T., N.L.P.-M., F.Z., M.T.B., J.M.L., W.C.). Search for more papers by this author , Pablo Serrano-FernandezPablo Serrano-Fernandez Novartis Institutes for Biomedical Research, Basel, Switzerland (P.S.-F., S.K.). Search for more papers by this author , Sergio KaiserSergio Kaiser Novartis Institutes for Biomedical Research, Basel, Switzerland (P.S.-F., S.K.). Search for more papers by this author , Denise P. YatesDenise P. Yates https://orcid.org/0000-0003-1039-515X Novartis Institutes for Biomedical Research, Cambridge, MA (L.Z., J.J., M.M.M., D.P.Y., M.H., C.-W.C., G.M.T., N.L.P.-M., F.Z., M.T.B., J.M.L., W.C.). Search for more papers by this author , Margaret HealeyMargaret Healey https://orcid.org/0000-0001-8525-6571 Novartis Institutes for Biomedical Research, Cambridge, MA (L.Z., J.J., M.M.M., D.P.Y., M.H., C.-W.C., G.M.T., N.L.P.-M., F.Z., M.T.B., J.M.L., W.C.). Search for more papers by this author , Chien-Wei ChenChien-Wei Chen Novartis Institutes for Biomedical Research, Cambridge, MA (L.Z., J.J., M.M.M., D.P.Y., M.H., C.-W.C., G.M.T., N.L.P.-M., F.Z., M.T.B., J.M.L., W.C.). Search for more papers by this author , Gordon M. TurnerGordon M. Turner https://orcid.org/0000-0001-9156-7499 Novartis Institutes for Biomedical Research, Cambridge, MA (L.Z., J.J., M.M.M., D.P.Y., M.H., C.-W.C., G.M.T., N.L.P.-M., F.Z., M.T.B., J.M.L., W.C.). Search for more papers by this author , Natasha L. Patel-MurrayNatasha L. Patel-Murray https://orcid.org/0000-0001-5230-3626 Novartis Institutes for Biomedical Research, Cambridge, MA (L.Z., J.J., M.M.M., D.P.Y., M.H., C.-W.C., G.M.T., N.L.P.-M., F.Z., M.T.B., J.M.L., W.C.). Search for more papers by this author , Faye ZhaoFaye Zhao Novartis Institutes for Biomedical Research, Cambridge, MA (L.Z., J.J., M.M.M., D.P.Y., M.H., C.-W.C., G.M.T., N.L.P.-M., F.Z., M.T.B., J.M.L., W.C.). Search for more papers by this author , Michael T. BesteMichael T. Beste Novartis Institutes for Biomedical Research, Cambridge, MA (L.Z., J.J., M.M.M., D.P.Y., M.H., C.-W.C., G.M.T., N.L.P.-M., F.Z., M.T.B., J.M.L., W.C.). Search for more papers by this author , Jason M. LaramieJason M. Laramie https://orcid.org/0000-0002-1473-7105 Novartis Institutes for Biomedical Research, Cambridge, MA (L.Z., J.J., M.M.M., D.P.Y., M.H., C.-W.C., G.M.T., N.L.P.-M., F.Z., M.T.B., J.M.L., W.C.). Search for more papers by this author , William T. AbrahamWilliam T. Abraham https://orcid.org/0000-0003-4805-1037 Ohio State University Wexner Medical Center, Columbus (W.T.A.). Search for more papers by this author , Pardeep S. JhundPardeep S. Jhund https://orcid.org/0000-0003-4306-5317 British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom (P.S.J., J.J.V.M.). Search for more papers by this author , Lars KoberLars Kober https://orcid.org/0000-0002-6635-1466 Rigshospitalet Copenhagen University Hospital, Denmark (L.K.). Search for more papers by this author , Milton PackerMilton Packer https://orcid.org/0000-0003-1828-2387 Baylor University Medical Center, Dallas, TX (M.P.). Search for more papers by this author , Jean RouleauJean Rouleau Montreal Heart Institute and Université de Montréal, Canada (J.R.). Search for more papers by this author , Michael R. ZileMichael R. Zile https://orcid.org/0000-0001-7076-221X Ralph H. Johnson Department of Veterans Affairs Medical Center and Medical University of South Carolina, Charleston (M.R.Z.). Search for more papers by this author , Margaret F. PrescottMargaret F. Prescott Novartis, East Hanover, NJ (M.F.P., M.L.). Search for more papers by this author , Martin LefkowitzMartin Lefkowitz Novartis, East Hanover, NJ (M.F.P., M.L.). Search for more papers by this author , John J.V. McMurrayJohn J.V. McMurray https://orcid.org/0000-0002-6317-3975 British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom (P.S.J., J.J.V.M.). Search for more papers by this author , Scott D. SolomonScott D. Solomon Correspondence to: Scott D. Solomon, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115; or William Chutkow, MD, PhD, Novartis Institute for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139. Email E-mail Address: [email protected] or E-mail Address: [email protected] https://orcid.org/0000-0003-3698-9597 Brigham and Women’s Hospital, Boston, MA (J.W.C., B.L.C., S.D.S.). †S.D. Solomon and W. Chutkow contributed equally. Search for more papers by this author and William ChutkowWilliam Chutkow Novartis Institutes for Biomedical Research, Cambridge, MA (L.Z., J.J., M.M.M., D.P.Y., M.H., C.-W.C., G.M.T., N.L.P.-M., F.Z., M.T.B., J.M.L., W.C.). †S.D. Solomon and W. Chutkow contributed equally. Search for more papers by this author Originally published27 Aug 2022https://doi.org/10.1161/CIRCULATIONAHA.122.061481Circulation. 2022;146:1411–1414Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: August 27, 2022: Ahead of Print Systematically characterizing associations between circulating proteins and risk for hospitalization and death may identify novel biological pathways and improve risk prediction in heart failure (HF). Large-scale assays now enable broad proteomic investigation in clinical trials.1We measured serum levels of 4076 unique proteins at baseline in a subset of patients from the ATMOSPHERE (Efficacy and Safety of Aliskiren and Aliskiren/Enalapril Combination on Morbidity-Mortality in Patients With Chronic Heart Failure; n=1258, 487 events, 12.2 events per 100 patient-years) and PARADIGM-HF (This Study Will Evaluate the Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure; n=1257, 287 events, 10.4 events per 100 patient-years) trials of chronic HF with reduced ejection fraction using the SomaScan modified aptamer-based proteomics assay. After quality control filters, we excluded 19 ATMOSPHERE samples and 22 PARADIGM-HF samples, and then used global median normalization to account for batch effects between assay plates. Baseline protein levels associated with the trial primary end point of HF hospitalization or cardiovascular death were identified in the ATMOSPHERE discovery cohort by Cox regression (false discovery rate <0.05), and replicated in PARADIGM-HF (Bonferroni-corrected P<0.05). We used 2 covariate models: a minimal model including age, sex, treatment arm, and anticoagulant usage, and a second model adjusted for 13 additional covariates. Study protocols were approved by local institutional review boards. All subjects provided informed consent. The data, analytic methods, and study materials will not be made available to other researchers for purposes of reproducing the results.In minimally adjusted models, 377 proteins were associated with risk of HF hospitalization or cardiovascular death (false discovery rate <0.05) in the discovery cohort (ATMOSPHERE), and of these, 167 were replicated in PARADIGM-HF (Bonferroni-adjusted P<0.05). Baseline protein levels marking the largest increased risk included a novel HF biomarker Sushi, von Willebrand factor type A, EGF and pentraxin domain containing 1 (SVEP1; hazard ratio, 1.60 [95% CI, 1.44–1.79] per SD, P=2.0×10-17) and known HF biomarkers GDF15 (growth differentiation factor 15), ANGPT2 (angiopoietin-2), NT-proBNP (N-terminal pro-B-type natriuretic peptide), and thrombospondin-2 (Figure [A]). After adjustment for 13 additional risk factors, 64 proteins remained significantly associated with the primary end point in both trials (Figure [B and C]). Target-specific binding of the assay for SVEP1 was supported by the measurement of 2 aptamers that were highly correlated (r=0.98, P<2.2×10-16), and the presence of a strong SVEP1 cis-protein quantitative trait locus in deCODE using the same platform (P<10-250).2Download figureDownload PowerPointFigure. Serum proteins associated with risk of heart failure hospitalization and cardiovascular death. A, Top 10 proteins most strongly associated with risk of heart failure hospitalization or cardiovascular death. Cox regression model adjusted for age, sex, anticoagulant use, and treatment group. The order of the table was determined by P value in the ATMOSPHERE discovery cohort. B and C, Proteins associated with heart failure hospitalization or cardiovascular death in the cardiovascular risk–adjusted model. Proteins with significant associations at false discovery rate <0.05 in both trials are indicated by red dots (positive associations) and blue dots (negative associations) and are labeled. Faintly colored dots indicate proteins meeting false discovery rate <0.05 in only 1 trial. Gray dots indicate associations that were not statistically significant at false discovery rate <0.05. The cardiovascular risk factor–adjusted model is adjusted for age, sex, anticoagulant use, treatment group, previous myocardial infarction, body mass index, diabetes, current smoking, time since heart failure diagnosis, previous heart failure hospitalization, systolic blood pressure, low- and high-density lipoprotein concentrations, estimated glomerular filtration rate, atrial fibrillation, New York Heart Association functional class, and left ventricular ejection fraction. D, Proteomic risk score discrimination compared with current clinical standards. In the PARADIGM-HF validation cohort, the proteomic risk score derived in ATMOSPHERE provided greater risk discrimination compared with a clinical risk score derived in ATMOSPHERE, NT-proBNP (N-terminal pro-B-type natriuretic peptide), or high-sensitivity troponin individually, and similar discrimination to a combination of these. P values for differences in c-statistic compared with the proteomic score were calculated by the Somers’ D method. ATMOSPHERE indicates Efficacy and Safety of Aliskiren and Aliskiren/Enalapril Combination on Morbidity-Mortality in Patients With Chronic Heart Failure; and PARADIGM, This Study Will Evaluate the Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure.A 64-protein proteomic risk score was derived in ATMOSPHERE using Cox LASSO regression, externally validated in PARADIGM-HF, and compared with current clinical risk prediction metrics. We refit a clinical risk score for the primary end point in ATMOSPHERE using variables from the MAGGIC score, which was developed to predict mortality.3 In PARADIGM-HF, the ATMOSPHERE-derived proteomic score provided marginally greater discrimination (c-statistic 0.70) compared with the clinical risk score (c-statistic 0.64), NT-proBNP (c-statistic 0.65), or hs-cTnT (high-sensitivity cardiac troponin T) (c-statistic 0.65) (P=0.001 for all) alone, and similar discrimination to a combination of the clinical score, NT-proBNP, and hs-cTnT (c-statistic 0.70) (Figure [D]). Adding the clinical score, NT-proBNP, and hs-cTnT to the proteomic score did not significantly improve discrimination (P=0.28), suggesting the proteomic score contained most relevant information from these metrics. The proteomic score alone modestly improved 2-year continuous net reclassification index compared with each of the clinical score (net reclassification index 0.16, P=0.03), NT-proBNP (net reclassification index 0.21, P<0.001), and hs-cTnT (0.16, P=0.01) alone, but not the combination of the clinical score, NT-proBNP, and hs-cTnT (net reclassification index 0.04, P=0.55). Improvements in c-statistic compared with models including hs-cTnT may be understated because hs-cTnT was not measured in ATMOSPHERE; therefore, hs-cTnT model coefficients were derived from and evaluated in PARADIGM-HF. Patients with lower proteomic risk scores had greater reductions in the primary end point with sacubitril/valsartan compared with enalapril in PARADIGM-HF (P-interaction=0.01).The discovery of a novel HF biomarker, SVEP1, illustrates the value of our broad proteomic discovery approach. The magnitude of the association between baseline serum SVEP1 levels and the risk of HF hospitalization or cardiovascular death was as strong as for NT-proBNP, independent of other clinical risk factors, and consistent across the 2 trials and 2 aptamers. SVEP1 is an extracellular matrix protein expressed in vascular smooth muscle cells that promotes inflammation and atherosclerosis through integrin, notch, and fibroblast growth factor receptor signaling in animal studies.4 The mechanism linking circulating SVEP1 and HF outcomes merits further investigation.Improvements in discrimination and reclassification with the 64-protein score compared with the clinical score, NT-proBNP, or hs-cTnT may not be clinically significant. However, the proteomic score performed as well as these 3 metrics combined, and may be more convenient for clinicians than risk scores requiring online calculators.The SomaScan proteomics platform has not been validated for all proteins in the panel. However, many have been validated by mass spectrometry or presence of cis-protein quantitative trait loci, which support aptamer specificity.2In conclusion, broad proteomic investigation in 2 HF clinical trials characterized associations between serum proteins and risk of HF hospitalization or cardiovascular death and identified SVEP1 as a new HF biomarker.Article InformationThe originally submitted version of this article is available on medRxiv (https://medrxiv.org/cgi/content/short/2022.07.27.22276826v1).Sources of FundingThe PARADIGM-HF and ATMOSPHERE trials, and this proteomic study, were funded by Novartis.Disclosures Drs Zhang, Mendelson, Serrano-Fernandez, Kaiser, Yates, Chen, Turner, Patel-Murray, Beste, Laramie, Prescott, Lefkowitz, and Chutkow, M. Healey, and F. Zhao are employees of Novartis. Dr Claggett reports consulting fees from Amgen, Boehringer-Ingelheim, Cardurion, Corvia, MyoKardia, and Novartis outside the submitted work. Dr Jacob reports salary support from Novartis and Moderna. Dr Abraham reports consulting fees from Abbott, ARCA Biopharma, Boehringer Ingelheim, Cardionomic, CVRx, Edwards Lifesciences, Respicardia, Sensible Medical, and Vectorious, and salary support from V-Wave Medical. Dr Jhund reports consulting fees, advisory board fees, and lecture fees from Novartis; advisory board fees from Cytokinetics; and grant support from Boehringer Ingelheim. Dr Kober reports speaker honoraria from Novo Nordisk, Novartis, AstraZeneca and Boehringer Ingleheim; support from AstraZeneca; and personal fees from Novartis and Bristol Myers Squibb as a speaker. Dr Packer reports consulting fees from AbbVie, Akcea, Actavis, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Gilead, Johnson & Johnson, Novo Nordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance. Dr Rouleau reports grants and consulting fees from Novartis and consulting fees from Abbott, AstraZeneca, MyoKardia, and Sanofi. Dr. Zile has received research funding from Novartis; and has been a consultant for Novartis, Abbott, Boston Scientific, CVRx, EBR, Endotronics, Ironwood, Merck, Medtronic, MyoKardia, and V Wave. Dr McMurray has received funding to his institution, Glasgow University, for his work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cardurion, Cytokinetics, GlaxoSmithKline, Novartis, Pfizer, and Theracos; and has received personal lecture fees from Corpus, Abbott, Hickma, Sun Pharmaceuticals, and Medscape. Dr Solomon reports grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and Us2.aI outside the submitted work; consulting fees from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, DaiichiSankyo, GSK, Lilly, Merck, MyoKardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, and Sarepta; and participation on a Data Safety Monitoring Board or Advisory Board for Janssen. The other author reports no conflicts.Footnotes*L. Zhang and J.W. Cunningham contributed equally.†S.D. Solomon and W. Chutkow contributed equally.Circulation is available at www.ahajournals.org/journal/circFor Sources of Funding and Disclosures, see page 1413.Correspondence to: Scott D. Solomon, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115; or William Chutkow, MD, PhD, Novartis Institute for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139. Email [email protected]harvard.edu or william.[email protected]comReferences1. Gold L, Ayers D, Bertino J, Bock C, Bock A, Brody EN, Carter J, Dalby AB, Eaton BE, Fitzwater T, et al. Aptamer-based multiplexed proteomic technology for biomarker discovery.PLoS One. 2010; 5:e15004. doi: 10.1371/journal.pone.0015004CrossrefMedlineGoogle Scholar2. Ferkingstad E, Sulem P, Atlason BA, Sveinbjornsson G, Magnusson MI, Styrmisdottir EL, Gunnarsdottir K, Helgason A, Oddsson A, Halldorsson BV, et al. Large-scale integration of the plasma proteome with genetics and disease.Nat Genet. 2021; 53:1712–1721. doi: 10.1038/s41588-021-00978-wCrossrefMedlineGoogle Scholar3. Pocock SJ, Ariti CA, McMurray JJV, Maggioni A, Køber L, Squire IB, Swedberg K, Dobson J, Poppe KK, Whalley GA, et al; Meta-Analysis Global Group in Chronic Heart Failure. Predicting survival in heart failure: a risk score based on 39 372 patients from 30 studies.Eur Heart J. 2013; 34:1404–1413. doi: 10.1093/eurheartj/ehs337CrossrefMedlineGoogle Scholar4. Jung I-H, Elenbaas JS, Alisio A, Santana K, Young EP, Kang CJ, Kachroo P, Lavine KJ, Razani B, Mecham RP, et al. SVEP1 is a human coronary artery disease locus that promotes atherosclerosis.Sci Transl Med. 2021; 13:eabe0357. doi: 10.1126/scitranslmed.abe0357CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails November 1, 2022Vol 146, Issue 18 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.122.061481PMID: 36029463 Originally publishedAugust 27, 2022 Keywordsbiomarkersproteomicsheart failureSVEP1 protein, humanPDF download Advertisement SubjectsHeart FailureProteomics