Serum level of apelin-13 negatively correlated with NT-proBNP in heart failure patients

Open access


Background: Apelin is a potent endogenous inotropic peptide with a major role in counteracting the aldosterone and angiotensin II and their negative effects on the cardiovascular system. The exact role of apelin in the patho-physiology of this disease is not well understood. We aimed to investigate the possible associations of apelin-13 with clinical and paraclinical characteristics in HF patients as well as studying its dynamics during the course of the heart failure.

Method: We performed a prospective observational cohort single-center study. We compared the baseline serum levels of apelin-13 and NT-proBNP level in 53 heart failure patients (acute heart failure, chronic compensated heart failure and chronic decompensated heart failure). We divided the patients according to the apelin-13 level: above and below the median, and we analyzed the relationship between serum apelin-13 and the clinical, echocardiographic, electrocardiographic and biological parameters. Twenty patients were followed-up (after an average time interval of 9 months), investigating the same parameters.

Results: The median of apelin-13 was 495pg/mL (IQR 276-845pg/mL). We found strong, negative correlation between the serum levels of apelin-13 and NT-proBNP (Spearman rho= −0.83, p<0.001). For the reassessed patients the median apelin level was significantly higher at follow-up (460 pg/mL, IQR 342-871 pg/mL) as compared with the baseline level (395 pg/mL, IQR 270-603 pg/mL), p=0.019, and maintained the negative correlation with NT-proBNP level (Spearman’s rho −0.7, p<0.001. The Low Apelin-13 group have higher NT-proBNP levels and also contains all the patients in NYHA IV class heart failure, 71% of the acute HF patients, and 7 of 8 patients who died before follow-up.

Conclusion: Apelin-13 was negatively correlated with NT-proBNP. The Low Apelin-13 group contained the majority of the patients with a negative outcome (death before follow-up), most of the patients who presented with acute HF and all the patients in NYHA IV class.

1. Stewart S, MacIntyre K, Hole DJ, Capewell S, McMurray JJ. More ‘malignant’ than cancer? Five-year survival following a first admission for heart failure. Eur J Heart Fail. 2001;3(3):315-22. DOI: 10.1016/S1388-9842(00)00141-0.

2. Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart. 2007;93(9):1137-46. DOI: 10.1136/hrt.2003.025270.

3. Hernandez AF, Greiner MA, Fonarow GC, Hammill BG, Heidenreich PA, Yancy CW, et al. Relationship between early physician follow-up and 30-day read-mission among Medicare beneficiaries hospitalized for heart failure. JAMA. 2010;303(17):1716-22. DOI: 10.1001/jama.2010.533.

4. Bui AL, Horwich TB, Fonarow GC. Epidemiology and risk profile of heart failure. Nat Rev Cardiol. 2011;8(1):30-41. DOI: 10.1038/nrcardio.2010.165.

5. Aalbers J. New ESC heart failure guidelines with South African expert comment. Cardiovasc J Afr. 2012;23(5):295-6.

6. Roger VL. Epidemiology of heart failure. Circ Res. 2013;113(6):646-59. DOI: 10.1161/CIRCRESAHA.113.300268.

7. Goidescu CM, Vida-Simiti LA. The Apelin-APJ System in the Evolution of Heart Failure. Clujul Med. 2015;88(1):3-8. DOI: 10.15386/cjmed-380.

8. Malyszko J, Malyszko JS, Pawlak K, Wolczynski S, Mysliwiec M. Apelin, a novel adipocytokine, in relation to endothelial function and inflammation in kidney allograft recipients. Transplant Proc. 2008;40(10):3466-9. DOI: 10.1016/j.transproceed.2008.03.163.

9. Malyszko J, Malyszko JS, Pawlak K, Mysliwiec M. Visfatin and apelin, new adipocytokines, and their relation to endothelial function in patients with chronic renal failure. Adv Med Sci. 2008;53(1):32-6. DOI: 10.2478/v10039-008-0024-x.

10. Vida-Simiti L, Todor I, Stoia M, Gherman C, Goidescu C. Plasma levels of resistin predicts cardiovascular events. RRML. 2014;22(1):35-47. DOI: 10.2478/rrlm-2014-0011.

11. Vida-Simiti LA, Todor I, Stoia MA, Goidescu CM, Anton FP, Farcas AD. Better prognosis in overweight/obese coronary heart disease patients with high plasma levels of leptin. Clujul Med. 2016;89(1):65-71. DOI: 10.15386/cjmed-524.

12. Szokodi I, Tavi P, Foldes G, Voutilainen-Myllyla S, Ilves M, Tokola H, et al. Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility. Circ Res. 2002;91(5):434-40. DOI: 10.1161/01.RES.0000033522.37861.69.

13. Foldes G, Horkay F, Szokodi I, Vuolteenaho O, Ilves M, Lindstedt KA, et al. Circulating and cardiac levels of apelin, the novel ligand of the orphan receptor APJ, in patients with heart failure. Biochem Biophys Res Commun. 2003;308(3):480-5. DOI: 10.1016/S0006-291X(03)01424-4.

14. Emam MN, Abo El gheit RE. Promoting effect of adipocytokine, apelin, on hepatic injury in caerulein-induced acute pancreatitis in rats: Apelin on AP-induced hepatic injury. Alexandria Journal of Medicine. DOI: 10.1016/j.ajme.2015.11.003. DOI: 10.1016/j.ajme.2015.11.003.

15. Chong KS, Gardner RS, Morton JJ, Ashley EA, McDonagh TA. Plasma concentrations of the novel peptide apelin are decreased in patients with chronic heart failure. Eur J Heart Fail. 2006;8(4):355-60. DOI: 10.1016/j.ejheart.2005.10.007.

16. Zhang J, Ren CX, Qi YF, Lou LX, Chen L, Zhang LK, et al. Exercise training promotes expression of apelin and APJ of cardiovascular tissues in spontaneously hypertensive rats. Life Sci. 2006;79(12):1153-9. DOI: 10.1016/j.lfs.2006.03.040.

17. Koguchi W, Kobayashi N, Takeshima H, Ishikawa M, Sugiyama F, Ishimitsu T. Cardioprotective effect of apelin-13 on cardiac performance and remodeling in end-stage heart failure. Circ J. 2012;76(1):137-44. DOI: 10.1253/circj.CJ-11-0689.

18. Soliman M, Arafah M. Apelin protect against multiple organ injury following hemorrhagic shock and decrease the inflammatory response. Int J Appl Basic Med Res. 2015;5(3):195-9. DOI: 10.4103/2229-516X.165377.

19. Tasci I, Erdem G, Ozgur G, Tapan S, Dogru T, Genc H, et al. LDL-cholesterol lowering increases plasma apelin in isolated hypercholesterolemia. Atherosclerosis. 2009;204(1):222-8. DOI: 10.1016/j.atherosclerosis.2008.08.030.

20. Heinonen MV, Laaksonen DE, Karhu T, Karhunen L, Laitinen T, Kainulainen S, et al. Effect of diet-induced weight loss on plasma apelin and cytokine levels in individuals with the metabolic syndrome. Nutr Metab Cardiovasc Dis. 2009;19(9):626-33. DOI: 10.1016/j.numecd.2008.12.008.

21. Leal VO, Lobo JC, Stockler-Pinto MB, Farage NE, Calixto A, Geloneze B, et al. Apelin: a peptide involved in cardiovascular risk in hemodialysis patients? Ren Fail. 2012;34(5):577-81. DOI: 10.3109/0886022X.2012.668490.

22. Wang M, Gupta RC, Rastogi S, Kohli S, Sabbah MS, Zhang K, et al. Effects of acute intravenous infusion of apelin on left ventricular function in dogs with advanced heart failure. J Card Fail. 2013;19(7):509-16. DOI: 10.1016/j.cardfail.2013.05.004.

23. Dai T, Ramirez-Correa G, Gao WD. Apelin increases contractility in failing cardiac muscle. Eur J Pharmacol. 2006;553(1-3):222-8. DOI: 10.1016/j.ejphar.2006.09.034.

24. Jia ZQ, Hou L, Leger A, Wu I, Kudej AB, Stefano J, et al. Cardiovascular effects of a PEGylated apelin. Peptides. 2012;38(1):181-8. DOI: 10.1016/j.peptides.2012.09.003.

25. Japp AG, Cruden NL, Barnes G, van Gemeren N, Mathews J, Adamson J, et al. Acute cardiovascular effects of apelin in humans: potential role in patients with chronic heart failure. Circulation. 2010;121(16):1818-27. DOI: 10.1161/CIRCULATIONAHA.109.911339.

26. Barnes GD, Alam S, Carter G, Pedersen CM, Lee KM, Hubbard TJ, et al. Sustained cardiovascular actions of APJ agonism during renin-angiotensin system activation and in patients with heart failure. Circ Heart Fail. 2013;6(3):482-91. DOI: 10.1161/CIRCHEARTFAILURE.111.000077.

27. Masri B, Knibiehler B, Audigier Y. Apelin signalling: a promising pathway from cloning to pharmacology. Cell Signal. 2005;17(4):415-26. DOI: 10.1016/j.cell-sig.2004.09.018.

28. Masri B, Morin N, Pedebernade L, Knibiehler B, Audigier Y. The apelin receptor is coupled to Gi1 or Gi2 protein and is differentially desensitized by apelin fragments. J Biol Chem. 2006;281(27):18317-26. DOI: 10.1074/jbc.M600606200.

29. Zhen EY, Higgs RE, Gutierrez JA. Pyroglutamyl apelin-13 identified as the major apelin isoform in human plasma. Anal Biochem. 2013;442(1):1-9. DOI: 10.1016/j.ab.2013.07.006.

30. Maguire JJ, Kleinz MJ, Pitkin SL, Davenport AP. [Pyr1] apelin-13 identified as the predominant apelin isoform in the human heart: vasoactive mechanisms and inotropic action in disease. Hypertension. 2009;54(3):598-604. DOI: 10.1161/HYPERTENSIONAHA.109.134619.

31. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2012;14(8):803-69. DOI: 10.1093/eurjhf/hfs105.

32. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015;28(1):1-39 e14.

33. Foppa M, Duncan BB, Rohde LE. Echocardiography-based left ventricular mass estimation. How should we define hypertrophy? Cardiovasc Ultrasound. 2005;3:17. DOI: 10.1186/1476-7120-3-17.

34. Armstrong AC, Gidding S, Gjesdal O, Wu C, Bluemke DA, Lima JA. LV mass assessed by echocardiography and CMR, cardiovascular outcomes, and medical practice. JACC Cardiovasc Imaging. 2012;5(8):837-48. DOI: 10.1016/j.jcmg.2012.06.003.

35. R Core Team. R: A Language and Environment for Statistical Computing [Internet]. Vienna, Austria; 2015. Available from:

36. Miettinen KH, Magga J, Vuolteenaho O, Vanninen EJ, Punnonen KR, Ylitalo K, et al. Utility of plasma apelin and other indices of cardiac dysfunction in the clinical assessment of patients with dilated cardiomyopathy. Regul Pept. 2007;140(3):178-84. DOI: 10.1016/j.regpep.2006.12.004.

37. Pitkin SL, Maguire JJ, Kuc RE, Davenport AP. Modulation of the apelin/APJ system in heart failure and atherosclerosis in man. Br J Pharmacol. 2010;160(7):1785-95. DOI: 10.1111/j.1476-5381.2010.00821.x.

38. Liu HT, Chen M, Yu J, Li WJ, Tao L, Li Y, et al. Serum apelin level predicts the major adverse cardiac events in patients with ST elevation myocardial infarction receiving percutaneous coronary intervention. Medicine (Baltimore). 2015;94(4):e449. DOI: 10.1097/MD.0000000000000449.

39. Kuklinska AM, Sobkowicz B, Sawicki R, Musial WJ, Waszkiewicz E, Bolinska S, et al. Apelin: a novel marker for the patients with first ST-elevation myocar-dial infarction. Heart Vessels. 2010;25(5):363-7. DOI: 10.1007/s00380-009-1217-3.

40. Chandrasekaran B, Kalra PR, Donovan J, Hooper J, Clague JR, McDonagh TA. Myocardial apelin production is reduced in humans with left ventricular systolic dysfunction. J Card Fail. 2010;16(7):556-61. DOI: 10.1016/j.cardfail.2010.02.004.

Revista Romana de Medicina de Laborator

Romanian Journal of Laboratory Medicine

Journal Information

IMPACT FACTOR 2017: 0.400
5-year IMPACT FACTOR: 0.320

CiteScore 2017: 0.31

SCImago Journal Rank (SJR) 2017: 0.144
Source Normalized Impact per Paper (SNIP) 2017: 0.195

Cited By


All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 266 266 125
PDF Downloads 231 231 149