Research Article|Articles in Press

Assessment of Biomarkers of Myocardial injury, Inflammation, and Renal Function in Heart Failure With Reduced Ejection Fraction: The VICTORIA Biomarker Substudy


      • COMPETENCY IN MEDICAL KNOWLEDGE: This prospectively planned secondary analysis of the VICTORIA study preselected 5 biomarkers measured at baseline and 16 weeks thought to reflect the potentially beneficial nonvasodilatory mechanisms of action of vericiguat, a sGC stimulator, in patients with heart failure with a reduced ejection fraction.
      • COMPETENCY IN PATIENT CARE: In this population with a high event rate, baseline hs-cTnT, GDF-15, and IL-6 were prognostic in a comprehensive adjustment model inclusive of NT-proBNP levels.
      • TRANSLATIONAL OUTLOOK: This study is one of the first to identify that progressively lower baseline levels of hs-cTnT could distinguish participants deriving increasing benefit from a specific heart failure treatment to decrease cardiovascular death.



      Circulating biomarkers may be useful in understanding prognosis and treatment efficacy in heart failure with reduced ejection fraction. In the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, vericiguat, a soluble guanylate cyclase stimulator, decreased the primary outcome of cardiovascular death or heart failure hospitalization in heart failure with reduced ejection fraction. We evaluated biomarkers of cardiac injury, inflammation, and renal function for associations with outcomes and vericiguat treatment effect.

      Methods and Results

      High-sensitivity cardiac troponin T (hs-cTnT), growth differentiation factor-15 (GDF-15), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), and cystatin C were measured at baseline and 16 weeks. Associations of biomarkers with the primary outcome and its components were estimated. Interaction with study treatment was tested. Changes in biomarkers over time were examined by study treatment. One or more biomarkers were measured in 4652 (92%) of 5050 participants at baseline and 4063 (81%) at 16 weeks. After adjustment, higher values of hs-cTnT, growth differentiation factor-15, and interleukin-6 were associated with the primary outcome, independent of N-terminal pro-B-type natriuretic peptide. Higher hs-cTnT values were associated with a hazard ratio per log standard deviation of 1.21 (95% confidence interval 1.14–1.27). A treatment interaction with vericiguat was evident with hs-cTnT and cardiovascular death (P = .04), but not HF hospitalization (P = .38). All biomarkers except cystatin C decreased over 16 weeks and no relationship between treatment assignment and changes in biomarker levels was observed.


      hs-cTnT, growth differentiation factor-15, and interleukin-6 levels were associated with risk of the primary outcome in VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction). Uniquely, lower hs-cTnT was associated with a lower rate of cardiovascular death but not HF hospitalization after treatment with vericiguat.

      Graphical Abstract

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Cardiac Failure
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Aimo A
        • Januzzi Jr., JL
        • Vergaro G
        • Ripoli A
        • Latini R
        • Masson S
        • et al.
        Prognostic value of high-sensitivity troponin t in chronic heart failure: an individual patient data meta-analysis.
        Circulation. 2018; 137: 286-297
        • Anand IS
        • Latini R
        • Florea VG
        • Kuskowski MA
        • Rector T
        • Masson S
        • et al.
        C-reactive protein in heart failure: prognostic value and the effect of valsartan.
        Circulation. 2005; 112: 1428-1434
        • Bouabdallaoui N
        • Claggett B
        • Zile MR
        • McMurray JJV
        • O'Meara E
        • Packer M
        • et al.
        Growth differentiation factor-15 is not modified by sacubitril/valsartan and is an independent marker of risk in patients with heart failure and reduced ejection fraction: the PARADIGM-HF trial.
        Eur J Heart Fail. 2018; 20: 1701-1709
        • Gao C
        • Zhong L
        • Gao Y
        • Li X
        • Zhang M,
        • Wei S.
        Cystatin C levels are associated with the prognosis of systolic heart failure patients.
        Arch Cardiovasc Dis. 2011; 104: 565-571
        • Markousis-Mavrogenis G
        • Tromp J
        • Ouwerkerk W
        • Devalaraja M
        • Anker SD
        • Cleland JG
        • et al.
        The clinical significance of interleukin-6 in heart failure: results from the BIOSTAT-CHF study.
        Eur J Heart Fail. 2019; 21: 965-973
        • Rørth R
        • Jhund PS
        • Kristensen SL
        • Desai AS
        • Køber L
        • Rouleau JL
        • et al.
        The prognostic value of troponin T and N-terminal pro B-type natriuretic peptide, alone and in combination, in heart failure patients with and without diabetes.
        Eur J Heart Fail. 2019; 21: 40-49
        • Januzzi Jr., JL
        • Canty JM
        • Das S
        • DeFilippi CR
        • Gintant GA
        • Gutstein DE
        • et al.
        Gaining efficiency in clinical trials with cardiac biomarkers: JACC review topic of the week.
        J Am Coll Cardiol. 2021; 77: 1922-1933
        • Masuyama H
        • Tsuruda T
        • Sekita Y
        • Hatakeyama K
        • Imamura T
        • Kato J
        • et al.
        Pressure-independent effects of pharmacological stimulation of soluble guanylate cyclase on fibrosis in pressure-overloaded rat heart.
        Hypertens Res. 2009; 32: 597-603
        • Sandner P
        • Berger P
        • Zenzmaier C.
        The potential of SGC modulators for the treatment of age-related fibrosis: a mini-review.
        Gerontology. 2017; 63: 216-227
        • Sharkovska Y
        • Kalk P
        • Lawrenz B
        • Godes M
        • Hoffmann LS
        • Wellkisch K
        • et al.
        Nitric oxide-independent stimulation of soluble guanylate cyclase reduces organ damage in experimental low-renin and high-renin models.
        J Hypertens. 2010; 28: 1666-1675
        • Armstrong PW
        • Pieske B
        • Anstrom KJ
        • Ezekowitz J
        • Hernandez AF
        • Butler J
        • et al.
        Vericiguat in patients with heart failure and reduced ejection fraction.
        N Engl J Med. 2020; 382: 1883-1893
        • Ezekowitz JA
        • O'Connor CM
        • Troughton RW
        • Alemayehu WG
        • Westerhout CM
        • Voors AA
        • et al.
        N-terminal pro-B-type natriuretic peptide and clinical outcomes: Vericiguat Heart Failure With Reduced Ejection Fraction Study.
        JACC Heart Fail. 2020; 8: 931-939
        • Armstrong PW
        • Roessig L
        • Patel MJ
        • Anstrom KJ
        • Butler J
        • Voors AA
        • et al.
        A multicenter, randomized, double-blind, placebo-controlled trial of the efficacy and safety of the oral soluble guanylate cyclase stimulator: the VICTORIA trial.
        JACC Heart Fail. 2018; 6: 96-104
        • Fitzgerald RL
        • Hollander JE
        • Peacock WF
        • Limkakeng AT
        • Breitenbeck N
        • Blechschmidt K
        • et al.
        Analytical performance evaluation of the Elecsys® Troponin T Gen 5 STAT assay.
        Clinica Chimica Acta. 2019; 495: 522-528
      1. Elecysis Troponin Gen 5 Stat. Available at: Accessed August 3, 2022

        • Kempf T
        • Horn-Wichmann R
        • Brabant G
        • Peter T
        • Allhoff T
        • Klein G
        • et al.
        Circulating concentrations of growth-differentiation factor 15 in apparently healthy elderly individuals and patients with chronic heart failure as assessed by a new immunoradiometric sandwich assay.
        Clin Chem. 2007; 53: 284-291
        • Pearson TA
        • Mensah GA
        • Alexander RW
        • Anderson JL
        • Cannon RO
        • Criqui M
        • et al.
        Markers of inflammation and cardiovascular disease.
        Circulation. 2003; 107: 499-511
      2. Fact sheet for healthcare providers. Advia Centaur IL-6 assay – Siemens Healthcare Diagnostics. Available at: Accessed August 3, 2022

        • Shlipak MG
        • Katz R
        • Fried LF
        • Jenny NS
        • Stehman-Breen C
        • Newman AB
        • et al.
        Cystatin-C and mortality in elderly persons with heart failure.
        J Am Coll Cardiol. 2005; 45: 268-271
        • Finney H
        • Newman DJ,
        • Price CP.
        Adult reference ranges for serum cystatin C, creatinine and predicted creatinine clearance.
        Ann Clin Biochem. 2000; 37: 49-59
        • Berg DD
        • Docherty KF
        • Sattar N
        • Jarolim P
        • Welsh P
        • Jhund PS
        • et al.
        Serial assessment of high-sensitivity cardiac troponin and the effect of dapagliflozin in patients with heart failure with reduced ejection fraction: an analysis of the DAPA-HF trial.
        Circulation. 2022; 145: 158-169
        • Butler J
        • Anstrom KJ,
        • Armstrong PW.
        Comparing the benefit of novel therapies across clinical trials: insights from the VICTORIA trial.
        Circulation. 2020; 142: 717-719
        • Lok SI
        • Winkens B
        • Goldschmeding R
        • van Geffen AJP
        • Nous FMA
        • van Kuik J
        • et al.
        Circulating growth differentiation factor-15 correlates with myocardial fibrosis in patients with non-ischaemic dilated cardiomyopathy and decreases rapidly after left ventricular assist device support.
        Eur J Heart Fail. 2012; 14: 1249-1256
        • Cleland JG
        • McMurray JJ
        • Kjekshus J
        • Cornel JH
        • Dunselman P
        • Fonseca C
        • et al.
        Plasma concentration of amino-terminal pro-brain natriuretic peptide in chronic heart failure: prediction of cardiovascular events and interaction with the effects of rosuvastatin: a report from CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure).
        J Am Coll Cardiol. 2009; 54: 1850-1859
        • Kjekshus J
        • Apetrei E
        • Barrios V
        • Böhm M
        • Cleland JGF
        • Cornel JH
        • et al.
        Rosuvastatin in older patients with systolic heart failure.
        N Engl J Med. 2007; 357: 2248-2261
        • Gravning J
        • Askevold ET
        • Nymo SH
        • Ueland T
        • Wikstrand J
        • McMurray JJ
        • et al.
        Prognostic effect of high-sensitive troponin T assessment in elderly patients with chronic heart failure: results from the CORONA trial.
        Circ Heart Fail. 2014; 7: 96-103
        • Heggermont W
        • Auricchio A,
        • Vanderheyden M.
        Biomarkers to predict the response to cardiac resynchronization therapy.
        Europace. 2019; 21: 1609-1620
        • Zile MR
        • O'Meara E
        • Claggett B
        • Prescott MF
        • Solomon SD
        • Swedberg K
        • et al.
        Effects of sacubitril/valsartan on biomarkers of extracellular matrix regulation in patients with HFrEF.
        J Am Coll Cardiol. 2019; 73: 795-806
        • Packer M
        • Januzzi JL
        • Ferreira JP
        • Anker SD
        • Butler J
        • Filippatos G
        • et al.
        Concentration-dependent clinical and prognostic importance of high-sensitivity cardiac troponin T in heart failure and a reduced ejection fraction and the influence of empagliflozin: the EMPEROR-Reduced trial.
        Eur J Heart Fail. 2021; 23: 1529-1538
        • Latini R
        • Masson S
        • Anand IS
        • Missov E
        • Carlson M
        • Vago T
        • et al.
        Prognostic value of very low plasma concentrations of troponin T in patients with stable chronic heart failure.
        Circulation. 2007; 116: 1242-1249
        • Gori M
        • Senni M
        • Claggett B
        • Liu J
        • Maggioni AP
        • Zile M
        • et al.
        Integrating high-sensitivity troponin T and sacubitril/valsartan treatment in HFpEF: the PARAGON-HF trial.
        JACC Heart Fail. 2021; 9: 627-635
        • Liu CY
        • Heckbert SR
        • Lai S
        • Ambale-Venkatesh B
        • Ostovaneh MR
        • McClelland RL
        • et al.
        Association of elevated NT-proBNP with myocardial fibrosis in the Multi-Ethnic Study of Atherosclerosis (MESA).
        J Am Coll Cardiol. 2017; 70: 3102-3109
        • Seliger SL
        • Hong SN
        • Christenson RH
        • Kronmal R
        • Daniels LB
        • Lima JAC
        • et al.
        High-sensitive cardiac troponin T as an early biochemical signature for clinical and subclinical heart failure: MESA (Multi-Ethnic Study of Atherosclerosis).
        Circulation. 2017; 135: 1494-1505
        • Cohn JN
        • Archibald DG
        • Ziesche S
        • Franciosa JA
        • Harston WE
        • Tristani FE
        • et al.
        Effect of vasodilator therapy on mortality in chronic congestive heart failure.
        N Engl J Med. 1986; 314: 1547-1552
        • Voors AA
        • Mulder H
        • Reyes E
        • Cowie MR
        • Lassus J
        • Hernandez AF
        • et al.
        Renal function and the effects of vericiguat in patients with worsening heart failure with reduced ejection fraction: insights from the VICTORIA (Vericiguat Global Study in Subjects with HFrEF) trial.
        Eur J Heart Fail. 2021; 23: 1313-1321
        • Kramer F
        • Voss S
        • Roessig L
        • Igl B-W
        • Butler J
        • Lam CSP
        • et al.
        Evaluation of high-sensitivity C-reactive protein and uric acid in vericiguat-treated patients with heart failure with reduced ejection fraction.
        Eur J Heart Fail. 2020; 22: 1675-1683

      Linked Article

      • Leveraging biomarkers for precision medicine in heart failure
        Journal of Cardiac Failure
        • Preview
          Over the past decade, the number of therapies for heart failure (HF) with clinical trial evidence of benefit has multiplied. Physicians treating HF today are faced with the challenges of selecting and prioritizing among drugs to optimize therapy for each patient. The current paradigm centers around four first-line therapies—beta blockers, angiotensin-receptor-neprilysin inhibitors, mineralocorticoid-receptor antagonists and sodium–glucose cotransporter 2 (SGLT2) inhibitors—that showed the largest relative effects in broad patient populations (1).
        • Full-Text
        • PDF