Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow

Aim      To study changes in markers for myocardial direct injury and dysfunction and endothelial dysfunction (ED) indexes in patients with indolent lymphoma during the antitumor treatment.

Material and methods  Current antitumor therapy for lymphoma is often associated with cardio- and vasculotoxicity, studying of which is a relevant scientific direction. Markers for myocardial direct injury and dysfunction and ED indexes were studied in patients with indolent lymphomas receiving polychemotherapy (PCT). The study included 77 patients with newly diagnosed indolent type lymphoma. The main group (n=52): mean age, 63.4±2.8 years, 15 (28.8 %) men who had received one course of PCT. The comparison group (n=25): mean age, 61.8±3.7 years, 8 (32 %) men who had not received PCT. Troponin I (TnI), high-sensitivity troponin I (hs-сTnI), heart-type fatty acid binding protein (h-FAВР), and N-terminal pro-B-type natriuretic peptide (NT-prоBNP) were measured in patients of both groups. ED was evaluated by measuring the level of vascular cell adhesion molecule (VCAM) and by assessing the structure and function condition of small blood vessels using photoplethysmography. In both groups, the study parameters were determined at the start of the study (T1) and following the PCT course in the main group; if the PCT schedule included anthracycline antibiotics, the second point (T2) was assessed at 6 h following the drug administration.

Results In both groups, the level of NT-proBNP was increased. This increase was significantly more pronounced in the comparison group (49.896±23.228 vs 20.877±8.534 pmol/l, respectively, p=0.011) whereas a tendency to its increase was observed after the PCT course. Before the start of the treatment, laboratory and instrumental signs of ED were noticed: the level of VCAM was 4951±1297 and 3225±757 ng/ml in the comparison group and the main group, respectively (р=0.246); reflection index was <1.8 in 23 (44.2%) patients of the main group and in 16 (64%) patients of the comparison group (р=0.098). During the PTC course, the endothelial function significantly improved; the level of VCAM decreased by 748 ng/ml (p=0.016), which was associated with significant decreases in erythrocyte sedimentation rate by 2.71 mm/h (р=0.027) and lactate dehydrogenase level by 62.38 U/l (р=0.026). Statistically significant decreases in other inflammatory markers (alpha-2-globulin, fibrinogen, C-reactive protein, neutrophil count) were not observed.

Conclusion      The level of NT-proBNP showed the highest sensitivity in assessing the cardiotoxic effect of PCT. The dynamics of VCAM level suggested a possible role of the disease itself in the development of ED in this patient group.

1. Davel AP, Wenceslau CF, Akamine EH, Xavier FE, Couto GK, Oliveira HT et al. Endothelial dysfunction in cardiovascular and endocrine-metabolic diseases: an update. Brazilian Journal of Medical and Biological Research. 2011;44(9):920–32. DOI: 10.1590/S0100-879X2011007500104

2. Godo S, Shimokawa H. Endothelial Functions. Arteriosclerosis, Thrombosis, and Vascular Biology. 2017;37(9):e108–14. DOI: 10.1161/ATVBAHA.117.309813

3. Dzau VJ, Antman EM, Black HR, Hayes DL, Manson JE, Plutzky J et al. The Cardiovascular Disease Continuum Validated: Clinical Evidence of Improved Patient Outcomes: Part II: Clinical Trial Evidence (Acute Coronary Syndromes Through Renal Disease) and Future Directions. Circulation. 2006;114(25):2871–91. DOI: 10.1161/CIRCULATIONAHA.106.655761

4. Ferraro M, Gimeno E, Ble M, Subirana I, Gómez M, Díaz J et al. Usefulness of n-terminal brain natriuretic peptide levels and fresco scale for the prediction of anthracycline-induced cardiomyotoxicity in patients with hodgkin lymphoma. Hematological Oncology. 2017;35:174–5. DOI: 10.1002/hon.2438_35

5. Gimeno E, Gómez M, González JR, Comín J, Alvarez-Larrán A, Sánchez-González B et al. NT-proBNP: A cardiac biomarker to assess prognosis in non-Hodgkin lymphoma. Leukemia Research. 2011;35(6):715–20. DOI: 10.1016/j.leukres.2011.01.018

6. Sawaya H, Sebag IA, Plana JC, Januzzi JL, Ky B, Cohen V et al. Early detection and prediction of cardiotoxicity in chemotherapy-treated patients. The American Journal of Cardiology. 2011;107(9):1375–80. DOI: 10.1016/j.amjcard.2011.01.006

7. Knudsen CW, Clopton P, Westheim A, Klemsdal TO, Wu AHB, Duc P et al. Predictors of Elevated B-Type Natriuretic Peptide Concentrations in Dyspneic Patients Without Heart Failure: An Analysis From the Breathing Not Properly Multinational Study. Annals of Emergency Medicine. 2005;45(6):573–80. DOI: 10.1016/j.annemergmed.2005.01.027

8. Anwaruddin S, Lloyd-Jones DM, Baggish A, Chen A, Krauser D, Tung R et al. Renal Function, Congestive Heart Failure, and Amino-Terminal Pro-Brain Natriuretic Peptide Measurement: Results From the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study. Journal of the American College of Cardiology. 2006;47(1):91–7. DOI: 10.1016/j.jacc.2005.08.051

9. Melanson SEF, Laposata M, Camargo CA, Chen AA, Tung R, Krauser D et al. Combination of D-dimer and amino-terminal pro-B-type natriuretic Peptide testing for the evaluation of dyspneic patients with and without acute pulmonary embolism. Archives of Pathology & Laboratory Medicine. 2006;130(9):1326–9. DOI: 10.1043/1543-2165(2006)130[1326:CODAAP]2.0.CO;2

10. Nagaya N, Nishikimi T, Uematsu M, Satoh T, Kyotani S, Sakamaki F et al. Plasma Brain Natriuretic Peptide as a Prognostic Indicator in Patients With Primary Pulmonary Hypertension. Circulation. 2000;102(8):865–70. DOI: 10.1161/01.CIR.102.8.865

11. Maisel A, Hollander JE, Guss D, McCullough P, Nowak R, Green G et al. Primary results of the Rapid Emergency Department Heart Failure Outpatient Trial (REDHOT). Journal of the American College of Cardiology. 2004;44(6):1328–33. DOI: 10.1016/j.jacc.2004.06.015

12. O’Donoghue M, Chen A, Baggish AL, Anwaruddin S, Krauser DG, Tung R et al. The Effects of Ejection Fraction on N-Terminal ProBNP and BNP Levels in Patients With Acute CHF: Analysis From the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study. Journal of Cardiac Failure. 2005;11(5):S9–14. DOI: 10.1016/j.cardfail.2005.04.011

13. Belenkov Yu.N., Privalova E.V., Danilogorskaya Yu.A., Shchendrygina A.A. Structural and functional changes in capillary microcirculation in patients with cardiovascular diseases (arterial hypertension, coronary heart disease, chronic heart failure) observed during computer videocapillaroscopy. Cardiology and cardiovascular surgery. 2012;5(2):49–56.

14. Nuver J, Smit AJ, Sleijfer DTh, van Gessel AI, van Roon AM, van der Meer J et al. Microalbuminuria, decreased fibrinolysis, and inflammation as early signs of atherosclerosis in long-term survivors of disseminated testicular cancer. European Journal of Cancer. 2004;40(5):701–6. DOI: 10.1016/j.ejca.2003.12.012

15. Vaughn DJ, Palmer SC, Carver JR, Jacobs LA, Mohler ER. Cardiovascular risk in long-term survivors of testicular cancer. Cancer. 2008;112(9):1949–53. DOI: 10.1002/cncr.23389

16. Blix ES, Husebekk A. Raiders of the lost mark – endothelial cells and their role in transplantation for hematologic malignancies. Leukemia & Lymphoma. 2016;57(12):2752–62. DOI: 10.1080/10428194.2016.1201566

17. Zsary A, Szucs S, Keltai K, Pasztor E, Schneider T, Rosta A et al. Endothelin-1 and Cardiac Function in Anthracyclinetreated Patients: A 1-year Follow-up: Journal of Cardiovascular Pharmacology. 2004;44(Suppl 1):S372–5. DOI: 10.1097/01.fjc.0000166300.48561.07

18. Koptev V.D., Pospelova T.I., Tsirendorzhiev D.D. Functional state of vascular endothelium in patients with hematological malignancies before and after polychemotherapy. Siberian journal of Oncology. 2010;4:20–4.

19. Fukuda Y. Clinical significance of serum CD44 measurement in malignant lymphoma. The Kurume Medical Journal. 2001;48(1):65–9. DOI: 10.2739/kurumemedj.48.65

20. Syrigos KN, Salgami E, Karayiannakis AJ, Katirtzoglou N, Sekara E, Roussou P. Prognostic significance of soluble adhesion molecules in Hodgkin’s disease. Anticancer Research. 2004;24(2C):1243–7. PMID: 15154654

21. Yang J, Li W, He X, Zhang G, Yue L, Chai Y. VEGF Overexpression Is a Valuable Prognostic Factor for Non-Hodgkin’s Lymphoma Evidence from a Systemic Meta-Analysis. Disease Markers. 2015;2015:786790. DOI: 10.1155/2015/786790

22. Fox ED, Heffernan DS, Cioffi WG, Reichner JS. Neutrophils from critically ill septic patients mediate profound loss of endothelial barrier integrity. Critical Care. 2013;17(5):R226. DOI: 10.1186/cc13049

23. Ajikumar A, Long MB, Heath PR, Wharton SB, Ince PG, Ridger VC et al. Neutrophil-Derived Microvesicle Induced Dysfunction of Brain Microvascular Endothelial Cells In Vitro. International Journal of Molecular Sciences. 2019;20(20):5227. DOI: 10.3390/ijms20205227

24. Shah N, Cabanillas F, McIntyre B, Feng L, McLaughlin P, Rodriguez MA et al. Prognostic value of serum CD44, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 levels in patients with indolent non-Hodgkin lymphomas. Leukemia & Lymphoma. 2012;53(1):50–6. DOI: 10.3109/10428194.2011.616611