Skip to main content

Advertisement

Log in

Prognostic value of multiple biomarkers for cardiovascular mortality in adult congenital heart disease: comparisons of single-/two-ventricle physiology, and systemic morphologically right/left ventricles

  • Original Article
  • Published:
Heart and Vessels Aims and scope Submit manuscript

Abstract

Although there are many biomarkers for heart failure, limited data are available regarding their prognostic value in adult congenital heart disease (ACHD). We investigated the potential of various biomarkers to predict ACHD mortality in a single-center, retrospective cohort study. Blood levels of neurohormones [angiotensin II, endothelin-1 (ET-1), norepinephrine (NE), aldosterone, and plasma renin activity]; inflammatory biomarkers [high-sensitivity C-reactive protein (hs-CRP), high-sensitivity tumor necrosis factor, soluble TNF receptor type I and II (sTNF-RI and sTNF-RII), and interleukin-6 (IL-6)]; and brain natriuretic peptide (BNP) were measured in 103 ACHD patients (median age 28 years). Subjects were divided into patients with single-ventricle physiology (SV group, n = 61) and those with two-ventricle physiology (TV group, n = 42); and into patients with a systemic right ventricle (SRV group, n = 25) and those with a systemic left ventricle (SLV group, n = 78). During a median follow-up period of 6.5 years, 12 patients (11 %) died of acute decompensated heart failure (ADHF). Predictive biomarkers, which are related to the New York Heart Association class and cardiothoracic ratio, were as follows: elevated levels of BNP, ET-1, sTNF-RI, NE, and IL-6 in the overall patient group; IL-6, NE, hs-CRP, BNP, and ET-1 in the TV group; BNP and ET-1 in the SV group; BNP, NE, hs-CRP, sTNF-RI, IL-6, and ET-1 in the SLV group. Elevated levels of ET-1 in SRV groups were slightly although not significantly associated with these. Various clinical biomarkers are associated with ADHF mortality in ACHD patients. The most prominent mortality predictors in biomarker profiles may vary according to differences in ventricular physiology and systemic ventricle morphology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Braunwald E (2008) Biomarkers in heart failure. N Engl J Med 358:2148–2159

    Article  CAS  PubMed  Google Scholar 

  2. Ohuchi H, Diller GP (2014) Biomarkers in adult congenital heart disease heart failure. Heart Fail Clin 10:43–56

    Article  PubMed  Google Scholar 

  3. Giannakoulas G, Dimopoulos K, Bolger AP, Tay EL, Inuzuka R, Bedard E, Davos C, Swan L, Gatzoulis MA (2010) Usefulness of natriuretic Peptide levels to predict mortality in adults with congenital heart disease. Am J Cardiol 105:869–873

    Article  CAS  PubMed  Google Scholar 

  4. Inai K, Nakanishi T, Nakazawa M (2005) Clinical correlation and prognostic predictive value of neurohumoral factors in patients late after the Fontan operation. Am Heart J 150:588–594

    Article  PubMed  Google Scholar 

  5. Diller GP, Alonso-Gonzalez R, Kempny A, Dimopoulos K, Inuzuka R, Giannakoulas G, Castle L, Lammers AE, Hooper J, Uebing A, Swan L, Gatzoulis M, Wort SJ (2012) B-type natriuretic peptide concentrations in contemporary Eisenmenger syndrome patients: predictive value and response to disease targeting therapy. Heart 98:736–742

    Article  CAS  PubMed  Google Scholar 

  6. Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, Yamagata K, Tomino Y, Yokoyama H, Hishida A, Collaborators developing the Japanese equation for estimated GFR (2009) Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 53:982–992

  7. Felker GM, Allen LA, Pocock SJ, Shaw LK, McMurray JJ, Pfeffer MA, Swedberg K, Wang D, Yusuf S, Michelson EL, Granger CB, Investigators CHARM (2007) Red cell distribution width as a novel prognostic marker in heart failure: data from the CHARM Program and the Duke Databank. J Am Coll Cardiol 50:40–47

    Article  PubMed  Google Scholar 

  8. Akobeng AK (2007) Understanding diagnostic test 3: ROC curves. Acta Paediatr 96:644–647

  9. Bolger AP, Sharma R, Li W, Leenarts M, Kalra PR, Kemp M, Coats AJ, Anker SD, Gatzoulis MA (2002) Neurohormonal activation and the chronic heart failure syndrome in adults with congenital heart disease. Circulation 106:92–99

    Article  CAS  PubMed  Google Scholar 

  10. Bolger AP, Coats AJ, Gatzoulis MA (2003) Congenital heart disease: the original heart failure syndrome. Eur Heart J 24:970–976

    Article  PubMed  Google Scholar 

  11. Venugopalan P, Agarwal AK (2003) Plasma catecholamine levels parallel severity of heart failure and have prognostic value in children with dilated cardiomyopathy. Eur J Heart Fail 5:655–658

    Article  CAS  PubMed  Google Scholar 

  12. Nagaya N, Nishikimi T, Uematsu M, Satoh T, Kyotani S, Sakamaki F, Kakishita M, Fukushima K, Okano Y, Nakanishi N, Miyatake K, Kangawa K (2000) Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation 102:865–870

    Article  CAS  PubMed  Google Scholar 

  13. Monge JC (1998) Neurohormonal markers of clinical outcome in cardiovascular disease: is endothelin the best one? J Cardiovasc Pharmacol 32:S36–S42

    CAS  PubMed  Google Scholar 

  14. Kinugawa T, Kato M, Ogino K, Osaki S, Igawa O, Hisatome I, Shigemasa C (2003) Plasma endothelin-1 levels and clinical correlates in patients with chronic heart failure. J Card Fail 9:318–324

    Article  CAS  PubMed  Google Scholar 

  15. Drawnel FM, Archer CR, Roderick HL (2013) The role of the paracrine/autocrine mediator endothelin-1 in regulation of cardiac contractility and growth. Br J Pharmacol 168:296–317

    Article  CAS  PubMed  Google Scholar 

  16. Ratnasamy C, Kinnamon DD, Lipshultz SE, Rusconi P (2008) Associations between neurohormonal and inflammatory activation and heart failure in children. Am Heart J 155:527–533

    Article  CAS  PubMed  Google Scholar 

  17. Lemmer J, Heise G, Rentzsch A, Boettler P, Kuehne T, Dubowy KO, Peters B, Lemmer B, Hager A, Stiller B, German Competence Network for Congenital Heart Defects (2011) Right ventricular function in grown-up patients after correction of congenital right heart disease. Clin Res Cardiol 100:289–296

  18. Eindhoven JA, van den Bosch AE, Jansen PR, Boersma E, Roos-Hesselink JW (2012) The usefulness of brain natriuretic peptide in complex congenital heart disease: a systematic review. J Am Coll Cardiol 60:2140–2149

    Article  CAS  PubMed  Google Scholar 

  19. Kantor PF, Lougheed J, Dancea A, McGillion M, Barbosa N, Chan C, Dillenburg R, Atallah J, Buchholz H, Chant-Gambacort C, Conway J, Gardin L, George K, Greenway S, Human DG, Jeewa A, Price JF, Ross RD, Roche SL, Ryerson L, Soni R, Wilson J, Wong K, Children’s Heart Failure Study Group (2013) Presentation, diagnosis, and medical management of heart failure in children: Canadian cardiovascular society guidelines. Can J Cardiol 29:1535–1552

  20. Nishiyama M, Park IS, Yoshikawa T, Hatai Y, Ando M, Takahashi Y, Mori K, Murakami Y (2009) Efficacy and safety of carvedilol for heart failure in children and patients with congenital heart disease. Heart Vessels 24:187–192

    Article  PubMed  Google Scholar 

  21. Taniguchi R, Sato Y, Nishio Y, Kimura T, Kita T (2006) Measurements of baseline and follow-up concentrations of cardiac troponin-T and brain natriuretic peptide in patients with heart failure from various etiologies. Heart Vessels 21:344–349

    Article  PubMed  Google Scholar 

  22. Rauchhaus M, Doehner W, Francis DP, Davos C, Kemp M, Liebenthal C, Niebauer J, Hooper J, Volk HD, Coats AJ, Anker SD (2000) Plasma cytokine parameters and mortality in patients with chronic heart failure. Circulation 102:3060–3067

    Article  CAS  PubMed  Google Scholar 

  23. Marti CN, Khan H, Mann DL, Georgiopoulou VV, Bibbins-Domingo K, Harris T, Koster A, Newman A, Kritchevsky SB, Kalogeropoulos AP, Butler J, Health ABC Study (2014) Soluble tumor necrosis factor receptors and heart failure risk in older adults: Health, aging, and body composition (Health ABC) study. Circ Heart Fail 7:5–11

  24. Afify MF, Mohamed GB, El-Maboud MA, Abdel-Latif EA (2009) Serum levels of ghrelin, tumor necrosis factor-alpha and interleukin-6 in infants and children with congenital heart disease. J Trop Pediatr 55:388–392

    Article  PubMed  Google Scholar 

  25. Sharma R, Bolger AP, Li W, Davlouros PA, Volk HD, Poole-Wilson PA, Coats AJ, Gatzoulis MA, Anker SD (2003) Elevated circulating levels of inflammatory cytokines and bacterial endotoxin in adults with congenital heart disease. Am J Cardiol 92:188–193

    Article  CAS  PubMed  Google Scholar 

  26. Mahle WT, Wang A, Quyyumi AA, McConnell ME, Book WM (2009) Impact of spironolactone on endothelial function in patients with single ventricle heart. Congenit Heart Dis 4:12–16

    Article  PubMed  PubMed Central  Google Scholar 

  27. Okazaki S, Sakaguchi M, Miwa K, Furukado S, Yamagami H, Yagita Y, Mochizuki H, Kitagawa K (2014) Association of interleukin-6 with the progression of carotid atherosclerosis: a 9-year follow-up study. Stroke 45:2924–2929

    Article  CAS  PubMed  Google Scholar 

  28. Reardon LC, Williams RJ, Houser LS, Miner PD, Child JS, Aboulhosn JA (2012) Usefulness of serum brain natriuretic peptide to predict adverse events in patients with the Eisenmenger syndrome. Am J Cardiol 110:1523–1526

    Article  CAS  PubMed  Google Scholar 

  29. Ohuchi H, Negishi J, Ono S, Miyake A, Toyota N, Tamaki W, Miyazaki A, Yamada O (2011) Hyponatremia and its association with the neurohormonal activity and adverse clinical events in children and young adult patients after the Fontan operation. Congenit Heart Dis 6:304–312

    Article  PubMed  Google Scholar 

  30. Shah A, Feraco AM, Harmon C, Tacy T, Fineman JR, Bernstein HS (2009) Usefulness of various plasma biomarkers for diagnosis of heart failure in children with single ventricle physiology. Am J Cardiol 104:1280–1284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lowenthal A, Camacho BV, Lowenthal S, Natal-Hernandez L, Liszewski W, Hills NK, Fineman JR, Bernstein HS (2012) Usefulness of B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide as biomarkers for heart failure in young children with single ventricle congenital heart disease. Am J Cardiol 109:866–872

    Article  CAS  PubMed  Google Scholar 

  32. Heng EL, Bolger AP, Kempny A, Davlouros PA, Davidson S, Swan L, Uebing A, Pennell DJ, Gatzoulis MA, Babu-Narayan SV (2015) Neurohormonal activation and its relation to outcomes late after repair of tetralogy of Fallot. Heart 101:447–454

    Article  CAS  PubMed  Google Scholar 

  33. Tomkiewicz-Pajak L, Wojcik T, Chłopicki S, Olszowska M, Pajak J, Podolec J, Sitek B, Musiałek P, Rubis P, Komar M, Podolec P (2015) Aspirin resistance in adult patients after Fontan surgery. Int J Cardiol 181:19–26

    Article  PubMed  Google Scholar 

  34. Cordina RL, Nakhla S, O’Meagher S, Leaney J, Graham S, Celermajer DS (2015) Widespread endotheliopathy in adults with cyanotic congenital heart disease. Cardiol Young 25:511–519

    Article  PubMed  Google Scholar 

  35. Winter MM, Bouma BJ, van Dijk AP, Groenink M, Nieuwkerk PT, van der Plas MN, Sieswerda GT, Konings TC, Mulder BJ (2008) Relation of physical activity, cardiac function, exercise capacity, and quality of life in patients with a systemic right ventricle. Am J Cardiol 102:1258–1262

    Article  PubMed  Google Scholar 

  36. Koch AM, Zink S, Singer H (2008) B-type natriuretic peptide in patients with systemic right ventricle. Cardiology 110:1–7

    Article  CAS  PubMed  Google Scholar 

  37. Garg R, Raman SV, Hoffman TM, Hayes J, Daniels CJ (2008) Serum markers of systemic right ventricular function and exercise performance. Pediatr Cardiol 29:641–648

    Article  PubMed  Google Scholar 

  38. Nakazawa M, Okuda H, Imai Y, Takanashi Y, Takao A (1986) Right and left ventricular volume characteristics after external conduit repair (Rastelli procedure) for cyanotic congenital heart disease. Heart Vessels 2:106–110

    Article  CAS  PubMed  Google Scholar 

  39. Koch AM, Zink S, Singer H, Dittrich S (2008) B-type natriuretic peptide levels in patients with functionally univentricular hearts after total cavopulmonary connection. Eur J Heart Fail 10:60–62

    Article  CAS  PubMed  Google Scholar 

  40. Schuuring MJ, Vis JC, van Dijk AP, van Melle JP, Vliegen HW, Pieper PG, Sieswerda GT, de Bruin-Bon RH, Mulder BJ, Bouma BJ (2013) Impact of bosentan on exercise capacity in adults after the Fontan procedure: a randomized controlled trial. Eur J Heart Fail 15:690–698

    Article  CAS  PubMed  Google Scholar 

  41. Heck PB, Müller J, Weber R, Hager A (2013) Value of N-terminal pro brain natriuretic peptide levels in different types of Fontan circulation. Eur J Heart Fail 15:644–649

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Yoshiyuki Furutani, Department of Pediatric Cardiology, Tokyo Women’s Medical University, for interpretation of the discussion and help to the general revision to the text.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kenji Miyamoto.

Ethics declarations

Conflict of interest

The authors of this work have no conflicts of interest to disclose.

Additional information

K. Miyamoto and D. Takeuchi contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Miyamoto, K., Takeuchi, D., Inai, K. et al. Prognostic value of multiple biomarkers for cardiovascular mortality in adult congenital heart disease: comparisons of single-/two-ventricle physiology, and systemic morphologically right/left ventricles. Heart Vessels 31, 1834–1847 (2016). https://doi.org/10.1007/s00380-016-0807-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00380-016-0807-0

Keywords

Navigation