S.N. SHILOV¹, E.N. BEREZIKOVA¹, S.D. MAYANSKAYA², I.V. PANKOVA¹, A.A. POPOVA¹, S.V. TRETYAKOV¹

 ¹Novosibirsk State Medical University, Novosibirsk

²Kazan State Medical University, Kazan

Contact details:

Shilov S.N. — MD, Professor of the Department of Pathological Physiology and Clinical Pathophysiology

Address: 52 Krasniy prospekt, Novosibirsk, Russian Federation, 630091, tel.: +7-913-986-69-82, e-mail: newsib54@gmail.com

 The purpose — to study the effect of cytomegalovirus (CMV) infection on the production of pro-inflammatory cytokines (tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) and its relationship with functional status in patients with chronic heart failure (CHF) of ischemic genesis.

Material and methods. We examined 187 patients with CHF of ischemic etiology, hospitalized in the cardiology department for decompensated heart failure (functional class (FC) CHF II-IV). Subsequently, patients were prospectively monitored for 24 months. The end point was a combined one and was defined as an increase by 1 or more in the FC of CHF (according to NYHA), hospitalization for decompensation of CHF, progressive deterioration of the structural and functional parameters of the left ventricle during the study period, the occurrence of adverse clinical events (cardiovascular death, non-fatal myocardial infarction or acute cerebrovascular accident, pulmonary embolism) during 24 months of prospective observation. After stabilization of patients upon inclusion in the study, plasma concentrations of TNF-α and IL-1β were determined by enzyme-linked immunosorbent assay. Qualitative determination of cytomegalovirus DNA in blood was carried out using the polymerase chain reaction method.

Results. Based on the results of quantitative determination of CMV DNA, patients were divided into two groups: group 1 — seropositive (CMV+) (n = 128) and group 2 — seronegative (CMV-) (n = 59). In seropositive patients, functional class IV of CHF was significantly more often recorded (p < 0.035), as well as higher levels of TNF-α (p < 0.001) and IL-1β (p < 0.001) regardless of the FC of CHF. In the group of patients with positive CMV serostatus, adverse cardiovascular events were recorded significantly more often during 24 months of observation compared to seronegative patients: there was a significantly higher number of hospitalizations due to decompensation of CHF (p = 0.023), development of acute coronary syndrome (p = 0.031) and pulmonary embolism (p = 0.042), and lethal cases (p = 0.018).

Conclusion. High levels of proinflammatory cytokines in patients with CHF correlate with carriage of CMV infection. Seropositive patients have an increased risk of adverse cardiovascular events compared to seronegative patients with CHF.

Key words: cytomegalovirus, herpes virus, heart failure, prognosis, cytokines.

REFERENCES

1. Moro-Garcia M.A., Echeverria A., Galan-Artimez M.C. et al. Immunosenescence and inflammation character rize chronic heart failure patients with more advanced disease. Int J Cardiol, 2014, vol. 174, pp. 590–599.
2. Girerd N., Cleland J., Anker S.D. et al. Inflammation and remodeling pathways and risk of cardiovascular events in patients with ischemic heart failure and reduced ejection fraction. Sci Rep, 2022, vol. 12 (1), p. 8574.
3. Kallikourdis M., Martini E., Carullo P. et al. T cell costimulation blockade blunts pressure overload-induced heart failure. Nat Commun, 2017, vol. 8, p. 4680.
4. Alonso Arias R., Moro-Garcia M.A., Echeverria A. et al. Intensity of the humoral response to cytomegalovirus is associated with the phenotypic and functional status of the immune system. J Virol, 2013, vol. 87, pp. 4486–4495.
5. Paulus W.J., Zile M.R. From Systemic Inflammation to Myocardial Fibrosis: The Heart Failure with Preserved Ejection Fraction Paradigm Revisited. Circ Res, 2021, vol. 128 (10), pp. 1451–1467.
6. Levine B., Kalman J., Mayer L. et al. Elevated Circulating Levels of Tumor Necrosis Factor in Severe Chronic Heart Failure. N Engl J Med, 1990, vol. 323 (4), pp. 236–241.
7. Nishida K., Otsu K. Sterile Inflammation and Degradation Systems in Heart Failure. Circ J, 2017, vol. 81 (5), pp. 622–628.
8. Sangali T.D., Souza G.C., Ribeiro E.C.T., Perry I.D.S. Sarcopenia: inflammatory and humoral markers in older heart failure patients. Arq Bras Cardiol, 2023, vol. 120 (7), p. e20220369.
9. Mocan M., Hognogi L.D.M., Anton F.P. et al. Biomarkers of inflammation in left ventricular diastolic dysfunction. Dis Markers, 2019, vol. 2019, p. 7583690.
10. Wu C.K., Yang C.Y., Lin J.W. et al. The relationship among central obesity, systemic inflammation, and left ventricular diastolic dysfunction as determined by structural equation modeling. Obesity, 2012, vol. 20 (4), pp. 730–737.
11. Eskandari V., Amirzargar A.A., Mahmoudi M.J. et al. Gene expression and levels of IL-6 and Tnfa in PBMCs Correlate with severity and functional class in patients with chronic heart failure. Ir J Med Sci, 2018, vol. 187 (2), pp. 359–368.
12. Rauchhaus M., Doehner W., Francis D.P. et al. Plasma cytokine parameters and mortality in patients with chronic heart failure. Circulation, 2000, vol. 102 (25), pp. 3060–3067.
13. Vasilieva E., Gianella S., Freeman M.L. Novel strategies to combat CMV-related cardiovascular disease. Pathog Immun, 2020, vol. 5 (1), pp. 240–274.
14. Li D., Li B., Yang L., Wang J. Human cytomegalovirus infection is correlated with atherosclerotic plaque vulnerability in carotid artery. J Gene Med, 2020, vol. 22 (10), p. e3236.
15. Gong K., Zhang Z., Sun X. et al. The nonspecific anti-inflammatory therapy with methotrexate for patients with chronic heart failure. Am Heart J, 2006, vol. 151 (5), p. e5.
16. Sommerer C., Schmitt A., Huckelhoven-Krauss A. et al. Peptide vaccination against cytomegalovirus induces specific T cell response in responses in CMV seronegative end-stage renal disease patient. Vaccines, 2021, vol. 9 (2), p. 133.
17. Griffiths P., Reeves M. Pathogenesis of human cytomegalovirus in the immunocompromised host. Nat Rev Microbiol, 2021, vol. 19 (12), pp. 759–773.
18. Mogensen T.H., Paludan S.R. Molecular pathways in virus-induced cytokine production. Microbiol Mol Biol Rev, 2001, vol. 65 (1), pp. 131–150.
19. Stowe R.P., Kozlova E.V., Yetman D.L. et al. Chronic herpesvirus reactivation occurs in aging. Exp Gerontol, 2007, vol. 42 (6), pp. 563–570.