Comparative analysis of diagnostic significance of biomarkers’ panels in cardiac recipients in the long term period after transplantation

Aim. To perform comparative analysis of the diagnostic efficacy of sCD40L, PDGF-BB, VEGF-A and ST2 in recipients with cardiac rejection in different periods after transplantation. Materials and methods. The study included 144 cardiac recipients aged from 12 to 71 (mean age 44 ± 14) years old, among those 112 were men. Venous blood plasma taken on the same day with endomyocardial biopsy was used for the study. The concentrations of soluble CD40 ligand (sCD40L), vascular endothelial growth factor (VEGF-A), platelet-derived growth factor (PDGF-BB) were measured using xMAP technology. The concentrations of ST2 were measured by ELISA. Results. Men had significantly higher levels of ST2 and VEGF-A compared to women (p = 0.03). No correlation was found between the levels of biomarkers (sCD40L, PDGF-BB, VEGF-A, ST2) and age, diagnosis before transplantation, presence of arterial hypertension and diabetes mellitus. Comparative analysis of the biomarkers’ levels didn’t show significant difference between patients with heart transplant rejection and without it in the first month and in the first year after transplantation. The ST2 level was significantly higher in patients with heart rejection (p = 0.01) in the long term period (1–5 years) after transplantation compared to patients without rejection. Relative risk of cardiac transplant rejection was significantly higher in patients with high (>22.8 ng/ml) ST2 level (RR = 2.59 ± 0.33; Se – 35%, Sp – 93%). However, its combination with other biomarkers improved their diagnostic value. Relative risk for panel including ST2, VEGF-A and PDGF-BB 3.47 ± 0.55, Se – 57%, Sp – 91%; relative risk for panel including ST2, sCD40L and PDGF-BB was 3.75 ± 0.59, Se – 50%, Sp – 92%. The highest diagnostic efficacy for the heart transplant rejection was reached by a panel of biomarkers that included ST2 and PDGF-BB (RR = 5.0 ± 0.56 [95% CI 1.68–14.92], Se – 63%, Sp – 94%). Conclusion. ST2 had the biggest diagnostic value for heart transplant rejection in the long term period after heart transplantation. Its usage as a part of complex tests with other biomarkers improves the sensitivity of noninvasive diagnosis of the cardiac rejection. The highest diagnostic significance for cardiac transplant rejection in the long term period was shown by a panel of ST2 and PDGF-BB.

heart transplantation, rejection, biomarkers, sCD40L, VEGF-A, PDGF-BB, ST2

1. Насырова АА, Шевченко АО. Функциональные показатели магистральных артерий и риск отторжения трансплантированного сердца. Трансплантология: итоги и перспективы. Том VII. 2015 год. Под ред. С.В. Готье. М.–Тверь: Триада, 2016: 431–450. Nasyrova AA, Shevchenko AO. Funktsional’nye pokazateli magistral’nykh arteriy i risk ottorzheniya transplantirovannogo serdtsa. Transplantologiya: itogi i perspektivy. Tom VII. 2015 god. Pod red. S.V. Gautier. M.–Tver’: Triada, 2016: 431–450.

2. Labarrere CA, Jaeger BR. Biomarkers of heart transplant rejection: the good, the bad, and the ugly! Transplantional Research. 2012; 159 (4): 238–251.

3. Долгов ВВ, Шевченко ОП, Шевченко АО. Биомаркеры в лабораторной диагностике. М.–Тверь: Триада, 2014: 288. Dolgov VV, Shevchenko OP, Shevchenko AO. Biomarkery v laboratornoy diagnostike. M.–Tver’: Triada, 2014: 288.

4. Martinez-Dolz L, Almenar L, Reganon E et al. What is the best biomarker for diagnosis of rejection in heart transplantation? Clinical Transplantation. 2009; 23: 672–680.

5. Starling RC, Stehlik J, Baran DA et al. Multicenter analysis of immune biomarkers and heart transplant outcomes: results of the clinical trials in organ transplantation-05 study. American Journal of Transplantation. 2016; 16: 121–136.

6. Kramer F, Milting H. Novel biomarkers in human terminal heart failure and under mechanical circulatory support. Biomarkers: Biochemical Indicators of Exposure, Response, and Susceptibility to Chemicals. 2011; 16: 31–41.

7. Frangogiannis NG. Biomarkers: hopes and challenges in the path from discovery to clinical practice. Transplantional Research. 2012; 159 (4): 197–204.

8. McMinn JF, Lang NN, McPhadden A et al. Biomarkers of acute rejection following cardiac transplantation. Biomarkers in Medicine. 2014; 8 (6): 815–832.

9. Savic-Radojevic A, Pljesa-Ercegovac M, Matic M et al. Novel biomarkers of heart failure. Advances In Clinical Chemistry. 2017; 79: 93–152.

10. Rywik TM, Janas J, Klisiewicz A et al. Prognostic value of novel biomarkers compared with detailed biochemical evaluation in patients with heart failure. Polskie Archiwum Medycyny Wewnetrznej. 2015; 125 (6): 434–442.

11. Schmitter D, Cotter G, Voors AA. Clinical use of novel biomarkers in heart failure: towards personalized medicine. Heart Failure Reviews. 2014; 19 (3): 369–381.

12. Ghashghaei R, Arbit B, Maisel AS. Current and novel biomarkers in heart failure: bench to bedside. Current Opinion in Cardiology, 2016; 31 (2): 191–195.

13. Breen EJ, Polaskova V, Khan A. Bead-based multiplex immune-assays for cytokines, chemokines, growth factors and other analytes: median fluorescence intensities versus their derived absolute concentration values for statistical analysis. Cytokine. 2015; 71 (2): 188–198.

14. Jungbauer CG, Riedlinger J, Block D et al. Panel of emerging cardiac biomarkers contributes for prognosis rather than diagnosis in chronic heart failure. Biomarkers in Medicine. 2014; 8 (6): 777–789.

15. Стаханова ЕА, Шевченко ОП. Роль мультиплексного анализа биомаркеров неоангиогенеза и воспаления при трансплантации сердца. Трансплантология: итоги и перспективы. Том VII. 2015 год. Под ред. С.В. Готье. М.–Тверь: Триада, 2016: 422–442. Stakhanova EA, Shevchenko OP. Rol’ mul’tipleksnogo analiza biomarkerov neoangiogeneza i vospaleniya pri transplantatsii serdtsa. Transplantologiya: itogi i perspektivy. Tom VII. 2015 god. Pod red. S.V. Gautier. M.–Tver’: Triada, 2016: 422–442.

16. Stewart S, Winters GL, Fishbein MC et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. Journal of Heart and Lung Transplantation. 2005; 24 (11): 1710–1720.

17. Coglianese EE, Larson MG, Vasan RS et al. Distribution and clinical correlates of the interleukin receptor family member soluble ST2 in the framingham heart study. Clin. Chem. 2012; 58 (12): 1673–1681.