Biomarkers are quantitative indicators of biological processes performed by an organ or system. In recent years, natriuretic peptides (NPs) have emerged as important tools in the diagnosis and therapeutic monitoring of heart diseases. Research has shown that serum and plasma levels of N-terminal pro brain NP (NT-proBNP) in dogs and cats are the only biomarkers that afford to diagnose and monitor congestive processes and, indirectly, the myocardial function of small animals. The present review discusses the peer-reviewed specialized literature about NT-proBNP and presents and compares the potential clinical applications of this NP in veterinary medicine of small animals, considering diagnosis, follow-up, and prognosis of myocardial or systemic diseases. The relevance of NT-proBNP is associated with sample stability, easy determination in laboratory, sensitivity, accuracy, and the possibility to analyze myocardial function. These advantages are specially important when NT-proBNP is compared with other cardiac biomarkers, mostly those that indicate the integrity of the myocardial cell. Fast NT-proBNP assays are marketed today and may be used in association with complementary tests. Together, these methods are an important source of information in differential diagnosis of heart and lung diseases as well in the early diagnosis of cardiopathy in dogs and cats, proving valuable tools in treatment and prognosis.

Keywords: cardiac biomarkers, cats, congestive heart failure, dogs, NT-proBPN.

1. Oyama, M.A. and Sisson, D.D. (2004) Cardiac troponin-I concentration in dogs with cardiac disease. J. Vet. Intern. Med., 18(6): 831-839. [Crossref]

2. Boswood, A. (2009) Biomarkers in cardiovascular disease: Beyond natriuretic peptides. J. Vet. Intern. Med., 11: S23-S32. [Crossref]

3. Mobasheri, A. and Cassidy, J. (2010) Biomarkers in veterinary medicine: Towards targeted, individualized therapies for companion animals. Vet. J., 185: 1-3. [Crossref]

4. Yonezawa, L.A., Silveira, V.F., Machado, L.P. and Kohayagawa, A. (2010) Cardiac markers in veterinary medicine. Cienc. Rural, 40(1): 222-230. [Crossref]

5. Vanderheyden, M., Bartunek, J. and Goethals, M. (2004) Brain and other natriuretic peptides: Molecular aspects. Eur. J. Heart Fail., 6: 261-268. [Crossref] [PubMed]

6. Anjos, D.S., Cintra, C.A., Rocha, J.R. and Junior, D.P. (2015) Cardiac biomarkers - an ally in the prognosis of heart disorders in small animals . Rev. Investig. Med. Vet., 14(6): 38-45.

7. Freitas, M.V., Ferreira, F.S., Barretto, F.L., Correa, E.S. and Carvalho, C.B. (2013) Creatine phosphokinase isoenzime-MB mass (CK-MB mass) and Troponin I (cTnI) in dogs. MEDVEP Rev. Cient. Med. Vet.Pequenos Anim. Anim. Estim., 11(38): 156-165.

8. Alves, A.C., Sousa, V.R.F., Silva, E.P., Nespoli, P.E.B., Silva, F.G. and Almeida, A.B.P.F. (2015) Biomarkers CK-NAC, CK-MB and troponin I in dogs with heart disease. . Arch. Vet. Sci., 20(2): 103-108.

9. Ferreira, F.S., Barretto, F.L., Fabres, A., Silveira, L.S. and Carvalho, C.B. (2016) Cardiac markers in five different breeds of rabbits (Oryctolaguscuniculus Linnaeus, 1758) used for cardiovascular research. Pesq. Vet. Bras. 36(8): 737-742. [Crossref]

10. Kishimoto, I., Makino, H., Ohata, Y., Tamanaha, T., Tochiya, M., Kusano, K., Anzai, T., Toyoda, K., Yasuda, S., Minematsu, K. and Ogawa, H. (2015) Impact of B-type natriuretic peptide (BNP) on development of atrial fibrillation in people with Type 2 diabetes. Diab. Med., 33(8): 1118-1124. [Crossref] [PubMed]

11. Solter, P.F. (2007) Clinical Biomarkers of Cardiac Injury and Disease. Proceedings of the ACVP/ASVCP Annual Meetings, Savannah, Georgia.

12. Freitas, M.V., Ferreira, F.S., Barretto, F.L., Correa, E.S. and Carvalho, C.B. (2015) Creatinephosphokinase isoenzyme-MB mass (CK-MB MASS) and troponin I (cTnI) in dogs (Canisfamiliaris). Cienc. Anim. Bras., 16(3): 369-376. [Crossref]

13. Oyama, M.A. (2015) Using cardiac biomarkers in veterinary practice. Clin. Lab. Med., 35: 555-566. [Crossref] [PubMed]

14. Hori, Y., Ohshima, N., Chikazawa, S., Kanai, K., Hoshi, F., Itoh, N. and Higushi, S. (2012) Myocardial injury-related changes in plasma NT-proBNP and ANP concentrations in a canine model of ischemic myocardial injury. Vet. J., 191: 46-51. [Crossref] [PubMed]

15. Reynolds, C. and Oyama, M. (2008) Biomarkers in the diagnosis of canine heart disease. Vet. Focus, 18(3): 2-6. [Crossref]

16. Baisan, R.A., Rosa, A., Loria, A.L., Vulpe, V. and Piantedosi, E. (2016) Cardiac biomarkers in clinical practice of dog and cat-a review. HVM Bioflux., 8(1): 50-58.

17. Woodard, G.E. and Rosado, J.A. (2007) Recent advances in natriuretic peptide research. J. Cell. Mol. Med., 11(6): 1263-1271. [Crossref] [PubMed] [PMC]

18. Kosic,L.S.,Trailovic, D.R. and Matunovic, R. (2012) Resting and dobutamine stress test induced serum concentrations of brain natriuretic peptide in German Shepherd dogs. Res. Vet. Sci., 93: 1446-1453. [Crossref] [PubMed]

19. Katzung, B.G. (2014) Farmacologia Basica e Clinica. 12th ed. AMGH, Porto Alegre.

20. Silva, L.B., Ferreira, C.A., Blacher, C., Leaes, P. and Haddad, H. (2003) Type-B Natriuretic Peptide and Cardiovascular Diseases. Arq. Bras. Cardiol., 81(5): 529-534. [Crossref] [PubMed]

21. Ware, A.W. (2011) Cardiovascular Disease in Small Animal Medicine. Manson Publishing, United Kingdom. [Crossref]

22. Baerts, L., Gomez, N., Vanderheyden, M., de Meester, I. and McEntee, K. (2012) Possible mechanisms for brain natriuretic peptide resistance in heart failure with a focus on interspecies differences and canine BNP biology. Vet. J., 194: 34-39. [Crossref]

23. Solter, P.F., Oyama, M.A., Machen, M.C., Trafny, D.J. and Sisson, D.D. (2015) Detection by ELISA of C-terminal proBNP in plasma from cats with cardiomyopathy. Vet. J., 206: 213-217. [Crossref] [PubMed]

24. Smith, K.F., Quinn, R.L. and Rahilly, L.J. (2015a) Biomarkers for differentiation of causes of respiratory distress in dogs and cats: Part 2-lower airway, thromboembolic, and inflammatory diseases. J. Vet. Emerg. Crit. Care., 25(3): 330-348. [Crossref] [PubMed]

25. Jaffe, A.S. (2007) Cardiovascular biomarkers: The state of the art in 2006. Clin. Chim. Acta., 381: 9-13. [Crossref] [PubMed]

26. Tarnow, I., Olsen, L.H., Kvart, C., Hoglung, K., Moesgaard S.G., Kamstrup, T.S., Pedersen, H.D. and Haggstrom, J. (2009) Predictive value of natriuretic peptides in dogs with mitral valve disease. Vet. J., 180: 195-201. [Crossref] [PubMed]

27. Atkinson, K.J., Fine, D.M., Thombs, L.A., Gorelick, J.J. and Durhan, H.E. (2009) Evaluation of pimobendanand N-terminal probrain natriuretic peptide in the treatment of pulmonary hypertension secondary to degenerative mitral valve disease in dogs. J. Vet. Intern. Med., 23: 1190-1196. [Crossref] [PubMed]

28. Oyama, M.A., Boswood, A., Connolly, D.J., Ettinger, S.J., Fox, P.R., Gordon, S.G.,Rush, J.E.,Sisson, D.D.,Stepien, R.L.,Wess, G. and Zannad, F. (2013) Clinical usefulness of an assay for measurement of circulating N-terminal pro-B-type natriuretic peptide concentration in dogs and cats with heart disease. J. Am. Vet. Med. Assoc., 243(1): 71-82. [Crossref] [PubMed]

29. Kobayashi, K., Hori, Y. and Chimura, S. (2014) Plasma N-terminal pro B-type natriuretic peptide concentrations in dogs with pulmonic stenosis. J. Vet. Med. Sci., 76(6): 827-831. [PMC]

30. Cahill, R.J., Pigeon, K., Strong-Townsend, M.I., Drexel, J.P., Clark, G.H. and Buch, J.S. (2015) Analytical validation of a second-generation immunoassay for the quantification of N-terminal pro-B-type natriuretic peptide in canine blood. J. Vet. Diagn. Investig., 27(1): 61-67. [Crossref] [PubMed]

31. Hezzell, M.J., Boswood, A., Lotter, N. and Elliott, J. (2015) The effects of storage conditions on measurements of canine N-terminal pro-B-type natriuretic peptide. J. Vet. Cardiol., 17:34-41. [Crossref] [PubMed]

32. Harris, A.N., Estrada, A.H., Gallagher, A.E., Winter, B., Lamb, K.E., Bohannon, M., Hanscom J. and Mainville A.C. (2017) Biologic variability of N-terminal pro-brain natriuretic peptide in adult healthy cats. J. Feline Med. Surg., 19(2): 216-233. [Crossref] [PubMed]

33. Smith, K.F., Quinn, R.L. and Rahilly, L.J. (2015b) Biomarkers for differentiation of causes of respiratory distress in dogs and cats: Part 1-cardiac diseases and pulmonary hypertension. J. Vet. Emerg. Crit. Care., 25(3): 311-329. [Crossref] [PubMed]

34. Wolf, J.G.N., Gerlach, N., Weber, K., Klima, A. and Wess, G. (2012) Lowered N-terminal pro-B-type natriuretic peptide levels in response to treatment predict survival in dogs with symptomatic mitral valve disease. J. Vet. Cardiol., 14: 399-408. [Crossref]

35. Oyama, M.A. (2013) Using cardiac biomarkers in veterinary practice. Vet. Clin. Small. Anim. Pract., 43: 1261-1272.

36. Kanno, N., Hori, Y., Hidaka, Y., Chikazawa, S., Kanai, K., Hoshi, F. and Itoh, N. (2016) Plasma atrial natriuretic peptide and N-terminal pro B-type natriuretic peptide concentrations in dogs with right-sided congestive heart failure. J. Vet. Med. Sci., 78(4): 535-542. [Crossref] [PubMed] [PMC]

37. Nicolson, G.P., McGrath, A., Webster, R.A., Li, J., Kaye, S.M., Malik, R. and Beijerink, N.J. (2016) NT-proBNP and cardiac troponin I concentrations in dogs with tick paralysis caused by Ixodesholocyclus. Aust. Vet. J., 94: 274-279. [Crossref] [PubMed]

38. Hsu, A., Kittleson, M.D. and Paling, A. (2009) Investigation into the use of plasma NT-proBNP concentration to screen for feline hypertrophic cardiomyopathy. J. Vet. Cardiol., 11Suppl 1: S63-S70. [Crossref]

39. Kluser, L., Holler, P.J., Simak, J., Tater, G., Smets, P., Rugamer, D., Kuchenhoff, H. and Wess, G. (2016) Predictors of Sudden cardiac death in doberman pinschers with dilated cardiomyopathy. J. Vet. Intern. Med., 30: 722-732. [Crossref] [PubMed] [PMC]

40. Miller, W.L. and Jaffe, A.S. (2016) Biomarkers in heart failure: The importance of inconvenient details. ESC Heart Fail., 3: 3-10. [Crossref] [PubMed] [PMC]

41. Misbach, C., Chetboul, V., Concordet, D., Gruet, P., Speranza, C., Hoffmann, A.C., Rocha, A., Balouka, D., Petit, A.M., Trehiou-Sechi, E., Pouchelon, J.L. and Lefebvre, H.P. (2013) Basal plasma concentrations of N-terminal pro-B-type natriuretic peptide in clinically healthy adult small size dogs: Effect of body weight, age, gender and breed, and reference intervals. Res. Vet. Sci., 95: 879-885. [Crossref]

42. Sjostrand, K., Wess, G., Ljungvall, I., Haggstron, J., Merveille, A.C., Wiberg. M.,Gouni, V., Lundgren, W.J., Hanas, S., Lequarre, A.S., Mejer, S.L., Wolf, J., Tiret, L., Kierczak, M., Forsberg, S., McEntee, K., Battaille, G., Seppala, E., Lindblad-Toh, K., Georges, M., Lohi, H., Chetboul, V., Fredholm, M. and Hoglund, K. (2014) Breed differences in natriuretic peptides in healthy dogs. J. Vet. Intern. Med., 28: 451-457. [Crossref] [PubMed] [PMC]

43. Couto, K.M., Iazbik, M.C., Marin, L.M., Zaldivar-Lopez, S., Beal, M.J., Gomez Ochoa, P. and Couto, C.G. (2015) Plasma N-terminal pro-B-type natriuretic peptide concentration in healthy retired racing greyhounds. Vet. Clin. Pathol. 44(3): 405-409. [Crossref] [PubMed]

44. Singletary, G.E., Morris, N.A., Lynne O'Sullivam, M., Gordon, S.G. and Oyama, M.A. (2012a) Prospective evaluation of NT-proBNP assay to detect occult dilated cardiomyopathy and predict survival in Doberman pinschers. J. Vet. Intern. Med., 26: 1330-1336. [Crossref] [PubMed]

45. Ruaux, C., Scollan, K., Suchodolsky, J.S., Steiner, J.M. and Sisson, D. (2015) Biologic variability in NT-proBNP and cardiac troponin-I in healthy dogs and dogs with mitral valve degeneration. Vet. Clin. Pathol., 44(3): 420-430. [Crossref] [PubMed]

46. Singh, M.K., Cocchiaro, M.F. and Kittleson, M.D. (2010) NT-proBNP measurement fails to reliably identify subclinical hypertrophic cardiomyopathy in Maine Coon cats. J. Feline Med. Surg., 12: 942-947. [Crossref] [PubMed]

47. Boswood, A., Dukes-McEwan, J., Loureiro, J., James, R.A., Martin, M., Stafford-Johnson, M., Smith, P.,Little, C. and Attree, S. (2008) The diagnostic accuracy of different natriuretic peptides in the investigation of canine cardiac disease. J. Small Anim. Pract. 49: 26-32. [PubMed]

48. Fox, P.R., Oyama, M.A., Hezzel, M.J., Rush, J.E., Nguyenba, T.P., Defrancesco, T.C.,Lehmkuhl, L.B.,Kellihan, H.B., Bulmer, B., Gordon, S.G., Cunningham, S.M., MacGregor, J., Stepien, R.L.,Lefbom, B.,Adin, D. and Lamb, K.(2015) Relationship of plasma n-terminal pro-brain natriuretic peptide concentrations to heart failure classification and cause of respiratory distress in dogs using a 2ndgeneration ELISA assay. J. Vet. Intern. Med., 29: 171-179. [Crossref] [PubMed] [PMC]

49. Winter, R.L., Saunders, A.B., Gordon, S.G., Buch, J.S. and Miller, M.W. (2017) Biologic variability of N-terminal pro-brain natriuretic peptide in healthy dogs and dogs with myxomatous mitral valve disease. J. Vet. Cardiol., 19(2): 124-131. [Crossref] [PubMed]

50. Wolf, J., Gerlach, N., Weber, K., Klima, A. and Wess, G. (2013) The diagnostic relevance of NT-proBNP and proANP 31-67 measurements in staging of myxomatous mitral valve disease in dogs. Vet. Clin. Pathol., 42(2): 196-206. [Crossref] [PubMed]

51. Oyama, M.A., Fox, P.R., Rush, J.E., Rozanski, E.A. and Lesser, M. (2008) Clinical utility of serum N-terminal pro-B-type natriuretic peptide concentration for identifying cardiac disease in dogs and assessing disease severity. J. Am. Vet. Med. Assoc., 232: 1496-1503. [Crossref]

52. Hariu, C.D., Saunders, A.B., Gordon, S.G., Norby, B. and Miller, M.W. (2013) Utility of N-terminal pro-brain natriuretic peptide for assessing hemodynamic significance of patent ductus arteriosus in dogs undergoing ductal repair. J. Vet. Cardiol., 15: 197-204. [Crossref]

53. Kellihan, H.B., Mackie, B.A. and Stepien, R.L. (2011) NT-proBNP, NT-proANP and cTnI concentrations in dogs with pre-capillary pulmonary hypertension. J. Vet. Cardiol., 13: 171-182. [Crossref] [PubMed]

54. Lobetti, R., Dvir, E. and Pearson, J. (2002) Cardiac troponins in canine babesiosis. J. Vet. Intern. Med., 16: 63-68. [Crossref] [PubMed]

55. Cenk, E.R. and Mahmut, O.K. (2015) Levels of cardiac biomarkers and coagulation profiles in dogs with parvoviral enteritis. Kafkas Univ. Vet. Fak. Derg., 21(3): 383-388.

56. Silva, V.B.C.,Sousa, M.G., Araujo, C.R.A.,Lima, A.B.G.andCarareto, R.(2016) Cardiac biomarkers in dogs with visceral leishmaniasis. Arch. Med. Vet., 48: 269-275. [Crossref]

57. Singletary, G.E., Rush, J.E., Fox, P.R., Stepien, R.L. and Oyama, M.A. (2012b) Effect of NT-proBNP assay on accuracy and confidence of general practitioners in diagnosing heart failure or respiratory disease in cats with respiratory signs. J. Vet. Intern. Med., 26(3): 542-546. [Crossref] [PubMed]

58. Meurs, K.M., Norgard, M.M., Ederer, M.M., Hendrix, K.P. and Kittleson, M.D. (2007) A substitution mutation in the myosin binding protein C gene in ragdoll hypertrophic cardiomyopathy. Genomics, 90: 261-264. [Crossref] [PubMed]

59. Hagstromm, J., Luis Fuentes,V. and Wess, G. (2015) Screening for hypertrophic cardiomyopathy in cats. J. Vet. Cardiol., 17: S134-S149. [Crossref]

60. Borgeat, K., Conolly, D.J. and Luis Fuentes, V. (2015) Cardiac biomarkers in cats. J. Vet. Cardiol., 17: S74-S86. [Crossref]

61. Connolly, D.J., Magalhaes, R.J., Syme, H.M., Boswood, A., Fuentes, V.L., Chu, L.andMetcalf, M. (2008) Circulating natriuretic peptides in cats with heart disease. J. Vet. Intern. Med., 22(1): 96-105. [Crossref] [PubMed]

62. Machen, M.C., Oyama, M.A., Gordon, S.G., Rush, J.E., Achen, S.E., Stepien, R.L., Fox, P.R.,Saunders, A.B. and Cunningham, S.M.(2014) Multi-centered investigation of a point-of care NT-proBNP ELISA assay to detect moderate to severe occult (pre-clinical) feline heart disease in cats referred for cardiac evaluation. J. Vet. Cardiol. 16: 245-255. [Crossref]

63. Hassdenteufel, E., Henrich, E., Hildebrandt, N., Stosic, A. and Schneider, M. (2013) Assessment of circulating N-terminal pro B-type natriuretic peptide concentration to differentiate between cardiac from noncardiac causes of pleural effusion in cats. J. Vet. Emerg. Crit. Care, 23(4): 416-422. [Crossref] [PubMed]

64. Humm, K., Hazzell, M.J., Sargent, J., Connolly, D.J. and Boswood, A. (2013) Differentiating between feline pleural effusions of cardiac and non-cardiac origin using pleural fluid NT-proBNP concentrations. J. Small Anim. Pract., 54: 656-661. [Crossref] [PubMed]

65. Hezzell, M.J., Rush, J.E., Humm, K., Rozansky, E.A., Sargent, J., Connolly, D.J., Boswood, A. and Oyama, M.A.(2016) Differentiation of cardiac from noncardiac pleural effusions in cats using second generation quantitative and point-of-care NT-proBNP Measurements. J. Vet. Intern. Med., 30: 536-542. [Crossref]

66. Maisel, A.S., Bhalla, V. and Braunwald, E. (2006) Cardiac biomarkers: A contemporary status report. Nat. Clin. Pract. Cardiovasc. Med., 3(1): 24-34. [Crossref] [PubMed]

67. Noszczyk-Nowak, A. (2011) NT-proBNP and troponin I as predictors of mortality in dogs with heart failure. Pol. J. Vet. Sci., 14: 551-556. [Crossref] [PubMed]

68. Kalil, R.F., Hajjar, L.A., Bacal, F., Hoff, P.M.G., Diz, M.P.E., Galas, F.R.B.G., Fukushima, J.T., Almeida, J.P., Nakamura, R.E., Trielli, T.R., Bittar, C.S., Santos, M.H., Galdeano, F.G., Junior, J.O.C.A., Silvestrini, A.A., Alencar, A., Mota, A.C.A., Gusmao, C.A.B., Almeida, D.R., Simoes, C.M., Bocchi, E.A., Lima, E.M., Fernandes, F., Silveira, F.S., Vilas-Boas, F., Neto, L.B.S., Rohde, L.E.P., Montera, M.W., Barbosa, M., Mano, M.S., Riechelmann, R.S., Arai, R.J., Martins, S.M., Ferreira, S.M.A., Santos, V. (2011) I Brazilian guideline of cardio-oncology of the Brazilian society of cardiology. Arq. Bras. Cardiol., 962 Suppl1: 1-52. [Crossref]

69. Gallay-Lepoutre, J., Belanger, M.C. and Nadeau, M.E. (2016) Prospective evaluation of Doppler echocardiography, tissue Doppler imaging and biomarkers measurement for the detection of doxorubicin-induced cardiotoxicity in dogs: A pilot study. Res. Vet. Sci., 105: 153-159. [Crossref]

70. Crivellente, F., Tontodonati, M., Fasdelli, N., Casartelli, A., Dorigatti, R., Faustineli, A. and Cristofori, P.(2011)NT-proBNP as a biomarker for the assessment of a potential cardiovascular drug-induced liability in beagle dogs. Cell Biol. Toxicol., 27: 425-438. [Crossref] [PubMed]

71. DeFrancesco, T.C., Rush, J.E., Rozanski, E.A., Hanse, B.D., Keene, B.W, Moore, D.T.andAtkins, C.E. (2007) Prospective clinical evaluation of an ELISA B-type natriuretic peptide assay in the diagnosis of congestive heart failure in dogs presenting with cough or dyspnea. J. Vet. Intern. Med., 21: 243-250. [Crossref]

72. Lobetti, R., Kirberger, R., Keller, N., Kettner, F. and Dvir, E. (2012) NT-ProBNP and cardiac troponin I in virulent canine babesiosis. Vet. Parasitol., 190: 333-339. [Crossref] [PubMed]

73. Fox, P.R., Rush, J.E., Reynolds, C.A., Defrancesco, T.C., Keene, B.W., Atkins, C.E.,Gordon, S.G.,Schober, K.E., Bonagura, J.D.,Stepien, R.L., Kellihan, H.B., Macdonald, K.A.,Lehmkuhl, L.B.,Nguyenba, T.P.,Sydney, M.N.,Lefbom, B.K.,Hogan, D.F. and Oyama, M.A. (2011) Multicenter evaluation of plasma N-terminal probrain natriuretic peptide (NT-pro BNP) as a biochemical screening test for asymptomatic (occult) cardiomyopathy in cats. J. Vet. Intern. Med., 25: 1010-1016. [Crossref]

74. Hori, Y., Uchide, T., Saitoh, R., Thoei, D., Uchida, M., Yoshioka, K., Chikazawa, S. and Hoshi, F. (2012) Diagnostic utility of NT-proBNP and ANP in a canine model of chronic embolic pulmonary hypertension. Vet. J., 194: 215-221. [Crossref] [PubMed]