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Proteomics of pediatric heart failure: from traditional biomarkers to new discovery strategies*

Published online by Cambridge University Press:  17 September 2015

Mingguo Xu
Department of Pediatrics, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America Department of Internal Cardiology, Shen Zhen Children’s Hospital, Shen Zhen, China
Genaro A. Ramirez-Correa
Department of Pediatrics, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
Anne M. Murphy*
Department of Pediatrics, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
Correspondence to: A. M. Murphy, MD, Department of Pediatrics, Division of Cardiology, 720 Rutland Avenue/Ross Building 1144, Baltimore, MD 21205, United States of America. Tel: +410 614 0703; Fax: +410 614 0699; E-mail:


Heart failure in children is a complex clinical syndrome with multiple aetiologies. The underlying disorders that lead to heart failure in children differ significantly from those in adults. Some clinical biomarkers for heart failure status and prognosis appear to be useful in both age groups. This review outlines the use and the present status of biomarkers for heart failure in paediatric cardiology. Furthermore, clinical scenarios in which development of new biomarkers might address management or prognosis are discussed. Finally, strategies for proteomic discovery of novel biomarkers and application to practice are described.

Original Articles
© Cambridge University Press 2015 

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Presented at Johns Hopkins All Children’s Heart Institute, International Pediatric Heart Failure Summit, Saint Petersburg, Florida, United States of America, 4–5 February, 2015.


1. Wilkinson, JD, Landy, DC, Colan, SD, et al. The pediatric cardiomyopathy registry and heart failure: key results from the first 15 years. Heart Fail Clin 2010; 6: 401413.Google Scholar
2. Rossano, JW, Shaddy, RE. Heart failure in children: etiology and treatment. J Pediatr 2014; 165: 228233.Google Scholar
3. Kantor, PF, Lougheed, J, Dancea, A, et al. Presentation, diagnosis, and medical management of heart failure in children: Canadian Cardiovascular Society guidelines. Can J Cardiol 2013; 29: 15351552.Google Scholar
4. Biomarker. NCI dictionary of cancer terms. National Cancer Institute.Google Scholar
5. Braunwald, E. Biomarkers in heart failure. N Eng J Med 2008; 358: 21482159.Google Scholar
6. Ohuchi, H, Diller, GP. Biomarkers in adult congenital heart disease heart failure. Heart Fail Clin 2014; 10: 4356.Google Scholar
7. Bhatia, V, Nayyar, P, Dhindsa, S. Brain natriuretic peptide in diagnosis and treatment of heart failure. J Postgrad Med 2003; 49: 182185.Google Scholar
8. Ho, JE, Liu, C, Lyass, A, et al. Galectin-3, a marker of cardiac fibrosis, predicts incident heart failure in the community. J Am Coll Cardiol 2012; 60: 12491256.Google Scholar
9. Tromp, J, van der Pol, A, Klip, IT, et al. Fibrosis marker syndecan-1 and outcome in patients with heart failure with reduced and preserved ejection fraction. Circulation 2014; 7: 457462.Google Scholar
10. Schmitter, D, Cotter, G, Voors, AA. Clinical use of novel biomarkers in heart failure: towards personalized medicine. Heart Fail Rev 2014; 19: 369381.Google Scholar
11. Ma, TK, Kam, KK, Yan, BP, Lam, YY. Renin-angiotensin-aldosterone system blockade for cardiovascular diseases: current status. Br J Pharmacol 2010; 160: 12731292.Google Scholar
12. Ross, RD, Daniels, SR, Schwartz, DC, Hannon, DW, Kaplan, S. Return of plasma norepinephrine to normal after resolution of congestive heart failure in congenital heart disease. Am J Cardiol 1987; 60: 14111413.Google Scholar
13. Ross, RD, Daniels, SR, Schwartz, DC, Hannon, DW, Shukla, R, Kaplan, S. Plasma norepinephrine levels in infants and children with congestive heart failure. Am J Cardiol 1987; 59: 911914.Google Scholar
14. Eisenman, A. Troponin assays for the diagnosis of myocardial infarction and acute coronary syndrome: where do we stand? Expert Rev Cardiovasc Ther 2006; 4: 509514.Google Scholar
15. Brown, JL, Hirsh, DA, Mahle, WT. Use of troponin as a screen for chest pain in the pediatric emergency department. Pediatr Cardiol 2012; 33: 337342.Google Scholar
16. Hirsch, R, Landt, Y, Porter, S, et al. Cardiac troponin I in pediatrics: normal values and potential use in the assessment of cardiac injury. J Pediatr 1997; 130: 872877.Google Scholar
17. Lipshultz, SE, Miller, TL, Scully, RE, et al. Changes in cardiac biomarkers during doxorubicin treatment of pediatric patients with high-risk acute lymphoblastic leukemia: associations with long-term echocardiographic outcomes. J Clin Oncol 2012; 30: 10421049.Google Scholar
18. Checchia, PA, Sehra, R, Moynihan, J, Daher, N, Tang, W, Weil, MH. Myocardial injury in children following resuscitation after cardiac arrest. Resuscitation 2003; 57: 131137.Google Scholar
19. Diaz-Miron, JL, Dillon, PA, Saini, A, et al. Left main coronary artery dissection in pediatric sport-related chest trauma. J Emerg Med 2014; 47: 150154.Google Scholar
20. Liesemer, K, Casper, TC, Korgenski, K, Menon, SC. Use and misuse of serum troponin assays in pediatric practice. Am J Cardiol 2012; 110: 284289.Google Scholar
21. Dyer, AK, Barnes, AP, Fixler, DE, et al. Use of a highly sensitive assay for cardiac troponin T and N-terminal pro-brain natriuretic peptide to diagnose acute rejection in pediatric cardiac transplant recipients. Am Heart J 2012; 163: 595600.Google Scholar
22. Siaplaouras, J, Thul, J, Kramer, U, Bauer, J, Schranz, D. Cardiac troponin I: a marker of acute heart rejection in infant and child heart recipients? Pediatr Transplant 2003; 7: 4345.Google Scholar
23. Potapov, EV, Ivanitskaia, EA, Loebe, M, et al. Value of cardiac troponin I and T for selection of heart donors and as predictors of early graft failure. Transplantation 2001; 71: 13941400.Google Scholar
24. Lin, KY, Sullivan, P, Salam, A, et al. Troponin I levels from donors accepted for pediatric heart transplantation do not predict recipient graft survival. J Heart Lung Transplant 2011; 30: 920927.Google Scholar
25. Korley, FK, Jaffe, AS. Preparing the United States for high-sensitivity cardiac troponin assays. J Am Coll Cardiol 2013; 61: 17531758.Google Scholar
26. Potter, JM, Koerbin, G, Abhayaratna, WP, Cunningham, RD, Telford, RD, Hickman, PE. Transient troponin elevations in the blood of healthy young children. Clin Chim Acta 2012; 413: 702706.Google Scholar
27. Korley, FK, Schulman, SP, Sokoll, LJ, et al. Troponin elevations only detected with a high-sensitivity assay: clinical correlations and prognostic significance. Acad Emerg Med 2014; 21: 727735.Google Scholar
28. Price, JF, Thomas, AK, Grenier, M, et al. B-type natriuretic peptide predicts adverse cardiovascular events in pediatric outpatients with chronic left ventricular systolic dysfunction. Circulation 2006; 114: 10631069.Google Scholar
29. Rusconi, PG, Ludwig, DA, Ratnasamy, C, et al. Serial measurements of serum NT-proBNP as markers of left ventricular systolic function and remodeling in children with heart failure. Am Heart J 2010; 160: 776783.Google Scholar
30. Wong, DT, George, K, Wilson, J, et al. Effectiveness of serial increases in amino-terminal pro-B-type natriuretic peptide levels to indicate the need for mechanical circulatory support in children with acute decompensated heart failure. Am J Cardiol 2011; 107: 573578.Google Scholar
31. Lowenthal, A, Camacho, BV, Lowenthal, S, et al. 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 2012; 109: 866872.Google Scholar
32. Atz, AM, Zak, V, Breitbart, RE, et al. Factors associated with serum brain natriuretic peptide levels after the Fontan procedure. Congenit Heart Dis 2011; 6: 313321.Google Scholar
33. Book, WM, Hott, BJ, McConnell, M. B-type natriuretic peptide levels in adults with congenital heart disease and right ventricular failure. Am J Cardiol 2005; 95: 545546.Google Scholar
34. Chow, PC, Cheung, EW, Chong, CY, et al. Brain natriuretic peptide as a biomarker of systemic right ventricular function in patients with transposition of great arteries after atrial switch operation. Int J Cardiol 2008; 127: 192197.Google Scholar
35. Koch, AM, Zink, S, Singer, H. B-type natriuretic peptide in patients with systemic right ventricle. Cardiology 2008; 110: 17.Google Scholar
36. Kim, HN, Januzzi, JL Jr. Natriuretic peptide testing in heart failure. Circulation 2011; 123: 20152019.Google Scholar
37. Lipshultz, SE, Simbre, VC 2nd, Hart, S, et al. Frequency of elevations in markers of cardiomyocyte damage in otherwise healthy newborns. Am J Cardiol 2008; 102: 761766.Google Scholar
38. Nir, A, Bar-Oz, B, Perles, Z, Brooks, R, Korach, A, Rein, AJ. N-terminal pro-B-type natriuretic peptide: reference plasma levels from birth to adolescence. Elevated levels at birth and in infants and children with heart diseases. Acta Paediatr 2004; 93: 603607.Google Scholar
39. Friedland-Little, JM, Hirsch-Romano, JC, Yu, S, et al. Risk factors for requiring extracorporeal membrane oxygenation support after a Norwood operation. J Thorac Cardiovasc Surg 2014; 148: 266272.Google Scholar
40. Agirbasli, M, Undar, A. Monitoring biomarkers after pediatric heart surgery: a new paradigm on the horizon. Artif Organs 2013; 37: 1015.Google Scholar
41. Kamp, AN, Von Bergen, NH, Henrikson, CA, et al. Implanted defibrillators in young hypertrophic cardiomyopathy patients: a multicenter study. Pediatr Cardiol 2013; 34: 16201627.Google Scholar
42. O’Mahony, C, Elliott, PM. Prevention of sudden cardiac death in hypertrophic cardiomyopathy. Heart 2014; 100: 254260.Google Scholar
43. Adabag, AS, Maron, BJ, Appelbaum, E, et al. Occurrence and frequency of arrhythmias in hypertrophic cardiomyopathy in relation to delayed enhancement on cardiovascular magnetic resonance. J Am Coll Cardiol 2008; 51: 13691374.Google Scholar
44. Burns, KM, Byrne, BJ, Gelb, BD, et al. New mechanistic and therapeutic targets for pediatric heart failure: report from a National Heart, Lung, and Blood Institute working group. Circulation 2014; 130: 7986.Google Scholar
45. Kantor, PF, Rusconi, P, Lipshultz, S, Mital, S, Wilkinson, JD, Burch, M. Current applications and Future Needs for Biomarkers in Pediatric Cardiomyopathy and Heart Failure: Summary from the Second International Conference on Pediatric Cardiomyopathy. Prog Pediatr Cardiol 2011; 32: 1114.Google Scholar
46. Agnetti, G, Husberg, C, Van Eyk, JE. Divide and conquer: the application of organelle proteomics to heart failure. Circ Res 2011; 108: 512526.Google Scholar
47. Gregorich, ZR, Chang, YH, Ge, Y. Proteomics in heart failure: top-down or bottom-up? Pflugers Arch 2014; 466: 11991209.Google Scholar
48. Mebazaa, A, Vanpoucke, G, Thomas, G, et al. Unbiased plasma proteomics for novel diagnostic biomarkers in cardiovascular disease: identification of quiescin Q6 as a candidate biomarker of acutely decompensated heart failure. Eur Heart J 2012; 33: 23172324.Google Scholar
49. Ramirez-Correa, GA, Martinez-Ferrando, MI, Zhang, P, Murphy, AM. Targeted proteomics of myofilament phosphorylation and other protein posttranslational modifications. Proteomics Clin Appl 2014; 8: 543553.Google Scholar
50. Holewinski, RJ, Jin, Z, Powell, MJ, Maust, MD, Van Eyk, JE. A fast and reproducible method for albumin isolation and depletion from serum and cerebrospinal fluid. Proteomics 2013; 13: 743750.Google Scholar
51. Kooij, V, Holewinski, RJ, Murphy, AM, Van Eyk, JE. Characterization of the cardiac myosin binding protein-C phosphoproteome in healthy and failing human hearts. J Mol Cell Cardiol 2013; 60: 116120.Google Scholar
52. Schechter, MA, Hsieh, MK, Njoroge, LW, et al. Phosphoproteomic profiling of human myocardial tissues distinguishes ischemic from non-ischemic end stage heart failure. PloS One 2014; 9: e104157.Google Scholar
53. Marchionni, L, Afsari, B, Geman, D, Leek, JT. A simple and reproducible breast cancer prognostic test. BMC Genomics 2013; 14: 336.Google Scholar
54. Marchionni, L, Wilson, RF, Wolff, AC, et al. Systematic review: gene expression profiling assays in early-stage breast cancer. Ann Intern Med 2008; 148: 358369.Google Scholar
55. Zhang, P, Kirk, JA, Ji, W, et al. Multiple reaction monitoring to identify site-specific troponin I phosphorylated residues in the failing human heart. Circulation 2012; 126: 18281837.Google Scholar
56. Ahmad, T, Fiuzat, M, Pencina, MJ, et al. Charting a roadmap for heart failure biomarker studies. JACC 2014; 2: 477488.Google Scholar
57. Schoenhoff, FS, Fu, Q, Van Eyk, JE. Cardiovascular proteomics: implications for clinical applications. Clin Lab Med 2009; 29: 8799.Google Scholar