Advertisement

Cardiac troponin T and NT-proBNP as diagnostic and prognostic biomarkers of primary cardiac involvement and disease severity in systemic sclerosis: A prospective study

Published:October 23, 2018DOI:https://doi.org/10.1016/j.ejim.2018.10.013

      Highlights

      • Subclinical heart involvement is common in Systemic Sclerosis.
      • Primary heart involvement portend a dismal prognosis.
      • hs-cTnT and NT-proBNP are biomarkers of early cardiac damage.
      • hs-cTnT and NT-proBNP are predictors of poor outcome.
      • hs-cTnT and NT-proBNP should be measured in all patients with Systemic Sclerosis.

      Abstract

      Objectives

      The aim of our study was to define the role of high-sensitive cardiac troponin T (hs-cTnT) and NT-proBNP in identifying Systemic Sclerosis (SSc) patients with cardiac involvement and at higher risk of cardiac death.

      Methods

      Plasma hs-cTnT and NT-proBNP concentrations were measured in 245 SSc-patients.

      Results

      hs-cTnT and NT-proBNP levels were higher in SSc-patients than in healthy controls. Hs-cTnT levels were higher than 0.014 ng/ml in 32.3% SSc-patients, while NT-proBNP was above 125 pg/ml in 31.8% of them, irrespective of classical cardiovascular risk factor and of pulmonary arterial hypertension. Elevated hs-cTnT and NT-proBNP were associated with diffuse skin involvement and directly correlated with the skin score. Patients with increased cardiac markers presented a lower left-ventricular ejection fraction (LVEF) and a higher rate of right bundle branch block (RBBB) on electrocardiogram (ECG) compared to patients with normal cardiac enzymes.
      During the follow-up, 12 SSc-patients experience a disease-related death; 9 of these were directly related to cardiac involvement (sudden cardiac death or heart failure) and the majority of them occurred among patients with increase of at least one cardiac biomarker. Long-term survival was worse in patients with increase of both cardiac biomarkers.

      Conclusions

      Evaluation of hs-cTnT and NT-proBNP levels may provide a tool to screen non-invasively SSc-patients for heart involvement. A higher incidence of impaired systolic function, ECG abnormalities and a poor outcome in SSc-patients with elevated cardiac enzymes suggests that they may be valuable screening biomarkers to detect a cardiac damage at early stages and to improve risk stratification.

      Keywords

      Abbreviations:

      SSc (Systemic Sclerosis), cTnT (cardiac troponin T), hs (high sensitive), LVEF (left ventricular ejection fraction), ECG (electrocardiogram), NT-proBNP (N-terminal of the prohormone brain natriuretic peptide), PAH (pulmonary)
      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:

      Subscribe to European Journal of Internal Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Denton C.P.
        • Khanna D.
        Systemic sclerosis.
        Lancet. 2017; 390: 1685-1699
        • Heine J.
        Uber ein eigenartiges Krankheitsbild von deiffuser Sklerosis der haut and innerer organe.
        Virchows Arch. 1926; 262: 1
        • Weiss S.E.
        • Warren J.
        Scleroderma heart disease, with a consideration of certain other visceral manifestations of cardiopulmonary disease in progressive systemic sclerosis.
        Arch Intern Med. 1943; 71: 749-776
        • Meune C.
        • Vignaux O.
        • Kahan A.
        • Allanore Y.
        Heart involvement in systemic sclerosis: evolving concept and diagnostic methodologies.
        Arch Cardiovasc Dis. 2010; 103: 46-52
        • Champion H.C.
        The heart in scleroderma.
        Rheum Dis Clin N Am. 2008; 34: 181-190
        • Ferri C.
        • Giuggioli D.
        • Sebastiani M.
        • Colaci M.
        • Emdin M.
        Heart involvement and systemic sclerosis.
        Lupus. 2005; 14: 702-707
        • Pieroni M.
        • De Santis M.
        • Zizzo G.
        • Bosello S.
        • Smaldone C.
        • Campioni M.
        • et al.
        Recognizing and treating myocarditis in recent-onset systemic sclerosis heart disease: potential utility of immunosuppressive therapy in cardiac damage progression.
        Semin Arthritis Rheum. 2014; 43: 526-535
        • De Luca G.
        • Bosello S.
        • Leone A.M.
        • Gabrielli F.
        • Pelargonio G.
        • Inzani F.
        • et al.
        Life-threatening arrhythmias in a scleroderma patient: the role of myocardial inflammation in arrhythmic outburst.
        Scand J Rheumatol. 2017; 46: 78-80
        • Kahan A.
        • Coghlan G.
        • McLaughlin V.
        Cardiac complications of systemic sclerosis.
        Rheumatology (Oxford). 2009; 48: 8-45
        • Bulkley B.H.
        • Ridolfi R.L.
        • Salyer W.R.
        • Hutchins G.M.
        Myocardial lesions of progressive systemic sclerosis. A cause of cardiac dysfunction.
        Circulation. 1976; 53: 483-490
        • Tyndall J.A.
        • Bannert B.
        • Vonk M.
        • Airò P.
        • Cozzi F.
        • Carreira P.E.
        • et al.
        Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database.
        Ann Rheum Dis. 2010; 69: 1809-1815
        • Allanore Y.
        • Wahbi K.
        • Borderie D.
        • Weber S.
        • Kahan A.
        • Meune C.
        N-terminal pro-brain natriuretic peptide in systemic sclerosis: a new cornerstone of cardiovascular assessment?.
        Ann Rheum Dis. 2009; 68: 1885-1889
        • Mathai S.C.
        • Bueso M.
        • Hummers L.K.
        • Boyce D.
        • Lechtzin N.
        • Le Pavec J.
        • et al.
        Disproportionate elevation of N-terminal pro-brain natriuretic peptide in scleroderma-related pulmonary hypertension.
        Eur Respir J. 2010; 35: 95-104
        • Montagnana M.
        • Lippi G.
        • Volpe A.
        • Salvagno G.L.
        • Biasi D.
        • Caramaschi P.
        • et al.
        Evaluation of cardiac laboratory markers in patients with systemic sclerosis.
        Clin Biochem. 2006; 39: 913-917
        • Borderie D.
        • Allanore Y.
        • Meune C.
        • Devaux J.Y.
        • Ekindjian O.G.
        • Kahan A.
        High ischemia-modified albumin concentration reflects oxidative stress but not myocardial involvement in systemic sclerosis.
        Clin Chem. 2004; 50: 2190-2193
        • Foocharoen C.
        • Pussadhamma B.
        • Mahakkanukrauh A.
        • Suwannaroj S.
        • Nanagara R.
        Asymptomatic cardiac involvement in Thai systemic sclerosis: prevalence and clinical correlations with non-cardiac manifestations preliminary report.
        Rheumatology (Oxford). 2015; 54: 1616-1621
        • Avouac J.
        • Meune C.
        • Chenevier-Gobeaux C.
        • Borderie D.
        • Lefevre G.
        • Kahan A.
        • et al.
        Cardiac biomarkers in systemic sclerosis: contribution of high-sensitivity cardiac troponin in addition to N-terminal pro-brain natriuretic peptide.
        Arthritis Care Res. 2015; 67: 1022-1030
        • Bosello S.
        • De Luca G.
        • Ferraccioli G.
        Troponin in Stable Ischemic Heart Disease and Diabetes.
        N Engl J Med. 2015; 373: 1977-1978
        • Barsotti S.
        • Stagnaro C.
        • D'Ascanio A.
        • Parma A.
        • Emdin M.
        • Conti U.
        • et al.
        High sensitivity troponin might be a marker of subclinical scleroderma heart involvement: a preliminary study.
        J Scleroderma Relat Disord. 2017; 2: 183-187
        • Kolto G.
        • Vuolteenaho O.
        • Szodoki I.
        • Faludi R.
        • Tornyos A.
        • Ruskoaho H.
        • et al.
        Prognostic value of N-terminal natriuretic peptides in systemic sclerosis: a single centre study.
        Clin Exp Rheumatol. 2014; 32: S75-S81
        • Alpert J.S.
        • Thygesen K.
        • Antman E.
        • Bassand J.P.
        Myocardial infarction redefined--a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction.
        J Am Coll Cardiol. 2000; 36: 959-969
        • Wu A.H.
        • Jaffe A.S.
        • Apple F.S.
        • Jesse R.L.
        • Francis G.L.
        • Morrow D.A.
        • NACB Writing Group
        • et al.
        National Academy of Clinical Biochemistry laboratory medicine practice guidelines: use of cardiac troponin and B-type natriuretic peptide or N-terminal proB-type natriuretic peptide for etiologies other than acute coronary syndromes and heart failure.
        Clin Chem. 2007; 53: 2086-2096
        • Vafaie M.
        • Biener M.
        • Mueller M.
        • Schnabel P.A.
        • André F.
        • Steen H.
        • et al.
        Analytically false or true positive elevations of high sensitivity cardiac troponin: a systematic approach.
        Heart. 2014; 100: 508-514
        • Everett B.M.
        • Brooks M.M.
        • Vlachos H.E.
        • BARI 2D Study Group
        Troponin and Cardiac Events in Stable Ischemic Heart Disease and Diabetes.
        N Engl J Med. 2015 Aug 13; 373: 610
        • Van den Hoogen F.
        • Khanna D.
        • Fransen J.
        • Johnson S.R.
        • Baron M.
        • Tyndall A.
        • et al.
        2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative.
        Ann Rheum Dis. 2013; 72: 1747-1755
        • Leroy E.C.
        • Black C.
        • Fleishmajer R.
        • Jablonska S.
        • Krieg T.
        • Medsger Jr., T.A.
        • et al.
        Scleroderma (systemic sclerosis): classification, subset and pathogenesis.
        J Rheumatol. 1988; 15: 202-205
        • Valentini G.
        • Silman A.J.
        • Veale D.
        Assessment of disease activity.
        Clin Exp Rheumatol. 2003; 21: S39-S41
        • Medsger Jr., T.A.
        • Bombardieri S.
        • Czirjak L.
        • Scorza R.
        • Della Rossa A.
        • Bencivelli W.
        Assessment of disease severity and prognosis.
        Clin Exp Rheumatol. 2003; 21: S42-S46
        • The Criteria Committee of the New York Heart Association
        Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels.
        9th ed. Little, Brown & Co, Boston, Mass1994: 253-256
        • Saenger A.K.
        • Beyrau R.
        • Braun S.
        • Cooray R.
        • Dolci A.
        • Freidank H.
        • et al.
        Multicenter analytical evaluation of a high-sensitivity troponin T assay.
        Clin Chim Acta. 2011; 412: 748-754
        • Gustafsson F.
        • Steensgaard-Hansen F.
        • Badskjaer J.
        • Poulsen A.H.
        • Corell P.
        • Hildebrandt P.
        Diagnostic and prognostic performance of N-terminal ProBNP in primary care patients with suspected heart failure.
        J Card Fail. 2005; 11: S15-S20
        • Perkins N.J.
        • Schisterman E.F.
        The inconsistency of “optimal” cutpoints obtained using two criteria based on the receiver operating characteristic curve.
        Am J Epidemiol. 2006; 163: 670-675
        • De Luca G.
        • Bosello S.
        • Berardi G.
        • Rucco M.
        • Canestrari G.
        • Correra M.
        • et al.
        Tumor associated antigens in Systemic Sclerosis patients with interstitial lung disease: association with lung involvement and cancer risk.
        Rheumatology (Oxford). 2015 Jun 22; : kev204
        • Mueller K.A.
        • Mueller I.I.
        • Eppler D.
        • Zuern C.S.
        • Seizer P.
        • Kramer U.
        • et al.
        Clinical and histopathological features of patients with systemic sclerosis undergoing endomyocardial biopsy.
        PLoS One. 2015; 10e0126707
        • Vasta B.
        • Flower V.
        • Bucciarelli-Ducci C.
        • Brown S.
        • Korendowych E.
        • McHugh N.J.
        • et al.
        Abnormal cardiac enzymes in systemic sclerosis: a report of four patients and review of the literature.
        Clin Rheumatol. 2014; 33: 435-438
        • Draeger H.T.
        • Assassi S.
        • Sharif R.
        • Gonzalez E.B.
        • Harper B.E.
        • Arnett F.C.
        • et al.
        Right bundle branch block: a predictor of mortality in early systemic sclerosis.
        PLoS One. 2013; 8e78808
        • Heresi G.A.
        • Tang W.H.
        • Aytekin M.
        • Hammel J.
        • Hazen S.L.
        • Dweik R.A.
        Sensitive cardiac troponin I predicts poor outcomes in pulmonary arterial hypertension.
        Eur Respir J. 2012; 39: 939-944
        • Sato Y.
        • Kita T.
        • Takatsu Y.
        • Kimura T.
        Biochemical markers of myocyte injury in heart failure.
        Heart. 2004; 90: 1110-1113
        • Peacock 4th, W.F.
        • De Marco T.
        • Fonarow G.C.
        • Diercks D.
        • Wynne J.
        • Apple F.S.
        • et al.
        ADHERE investigators. Cardiac troponin and outcome in acute heart failure.
        N Engl J Med. 2008; 358: 2117-2126
        • Kühl U.
        • Noutsias M.
        • Seeberg B.
        • Schultheiss H.P.
        Immunohistological evidence for a chronic intramyocardial inflammatory process in dilated cardiomyopathy.
        Heart. 1996; 75: 295-300
        • Bouzas-Mosquera A.
        • Peteiro J.
        • Constanso I.P.
        • Álvarez-García N.
        • Vázquez-Rodríguez J.M.
        Association of troponin levels below the 99th percentile with outcomes in patients with acute chest pain.
        Eur J Intern Med. 2016 May; 30: e9-e10https://doi.org/10.1016/j.ejim.2015.12.006
        • Mair J.
        • Lindahl B.
        • Hammarsten O.
        • Müller C.
        • Giannitsis E.
        • Huber K.
        • et al.
        European Society of Cardiology (ESC) Study Group on Biomarkers in Cardiology of the Acute Cardiovascular Care Association (ACCA). How is cardiac troponin released from injured myocardium?.
        Eur Heart J Acute Cardiovasc Care. 2017; 1 (2048872617748553)
        • De Luca G.
        • Cavalli G.
        • Campochiaro C.
        • Tresoldi M.
        • Dagna L.
        Myocarditis: an interleukin-1-mediated disease?.
        Front Immunol. 2018 Jun 13; 9: 1335https://doi.org/10.3389/fimmu.2018.01335
        • De Luca G.
        • Campochiaro C.
        • Dinarello C.
        • Dagna L.
        • Cavalli G.
        Treatment of Dilated Cardiomyopathy with Interleukin-1 Inhibition.
        Ann Intern Med. 2018; https://doi.org/10.7326/L18-0315
        • Tomelleri A.
        • Cavalli G.
        • De Luca G.
        • Campochiaro C.
        • D'Aliberti T.
        • Tresoldi M.
        • et al.
        Treating heart inflammation with interleukin-1 blockade in a case of Erdheim-Chester disease.
        Front Immunol. 2018 Jun 1; 9: 1233https://doi.org/10.3389/fimmu.2018.01233
        • James T.N.
        De subitaneis mortibus. VIII. Coronary arteries and conduction system in scleroderma heart disease.
        Circulation. 1974; 50: 844-856
        • De Luca G.
        • Bosello S.
        • Gabrielli F.A.
        • Berardi G.
        • Parisi F.
        • Rucco M.
        • et al.
        Prognostic role of ventricular ectopic beats in systemic sclerosis: a prospective Cohort Study shows ECG indexes predicting the worse outcome.
        PLoS One. 2016; 11e0153012
        • De Luca G.
        • Bosello S.L.
        • Canestrari G.
        • Cavalli G.
        • Dagna L.
        • Ferraccioli G.
        QTc interval prolongation in Systemic Sclerosis: Correlations with clinical variables and arrhythmic risk.
        Int J Cardiol. 2017; 239: 33
        • De Luca G.
        • Campochiaro C.
        • Cavalli G.
        • Dagna L.
        Relationship between Ventricular Arrhythmias, Conduction Disorders, and Myocardial Fibrosis in patients with Systemic Sclerosis: the Role of Cardiac magnetic Resonance.
        J Clin Rheumatol. 2018 Apr 16; https://doi.org/10.1097/RHU.0000000000000792
        • De Luca G.
        • Campochiaro C.
        • Cavalli G.
        • Dagna L.
        Cardiac magnetic resonance in systemic sclerosis patients with cardiac symptoms: do we really need it?.
        Eur Rev Med Pharmacol Sci. 2018 Apr; 22: 2189-2190https://doi.org/10.26355/eurrev_201804_14801
        • Reinstadler S.J.
        • Feistritzer H.J.
        • Reindl M.
        • Klug G.
        • Metzler B.
        Utility of NT-proBNP in predicting infarct scar and left ventricular dysfunction at a chronic stage after myocardial infarction.
        Eur J Intern Med. 2016 Apr; 29: e16-e18https://doi.org/10.1016/j.ejim.2015.12.018
        • De Sa D.D.
        • Chen H.H.
        The role of natriuretic peptides in heart failure.
        Curr Cardiol Rep. 2008; 10: 182-189
        • Williams M.H.
        • Handler C.E.
        • Akram R.
        • Smith C.J.
        • Das C.
        • Smee J.
        • et al.
        Role of N-terminal brain natriuretic peptide (NT-proBNP) in scleroderma-associated pulmonary arterial hypertension.
        Eur Heart J. 2006; 27: 1485-1494
        • Choi H.J.
        • Shin Y.K.
        • Lee H.J.
        • Kee J.Y.
        • Shin D.W.
        • Lee E.Y.
        • et al.
        The clinical significance of serum N-terminal pro-brain natriuretic peptide in systemic sclerosis patients.
        Clin Rheumatol. 2008; 27: 437-442
        • Chighizola C.
        • Meroni P.L.
        • Schreiber B.E.
        • Coghlan J.G.
        • Denton C.P.
        • Ong V.H.
        Role of N-terminal pro-brain natriuretic peptide in detecting clinically significant cardiac involvement in systemic sclerosis patients.
        Clin Exp Rheumatol. 2012; 30: S81-S85
        • Hammarsten O.
        • Mair J.
        • Möckel M.
        • Lindahl B.
        • Jaffe A.S.
        Possible mechanisms behind cardiac troponin elevations.
        Biomarkers. 2018 Jul; 6: 1-26https://doi.org/10.1080/1354750X.2018.1490969