Proinflammatory cytokines IL-6, IL-1β, TNF-α in infective endocarditis

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Abstract

Aim. To study the features of macrophages in the tissues of resected valves in operated patients with infective endocarditis (IE), their significance and interaction with inflammatory markers to improve the effectiveness of IE diagnosis.

Materials and methods. Prospectively the research included 25 adult patients with active IE (Duke criteria 2015) and 24 patients with heart defects without IE, hospitalized in a cardiosurgical hospital in Moscow (2021–2022). A standard laboratory and instrumental examination was carried out for the diagnosis of IE, including etiological diagnosis with microbiological and molecular biological methods, and echocardiographic examination of heart. Additionally, the neutrophil-to-lymphocyte ratio (NLR) was calculated. The study of macrophages was carried out in the tissues of resected valves with the determination of the expression of pro- and anti-inflammatory cytokine genes, macrophage markers (CD 68+) using real-time PCR.

Results. Increased expression of proinflammatory cytokines IL-1β, TNF-α and IL-6 was revealed in the group of operated patients with IE with significant differences in IL-1β (CI [IQR] 0.00367 [0.00047–0.01553] vs 0.00018 [0.00012–0.00262]; p<0.05) and IL-6 (CI [IQR] 0.00367 [0.00047–0.01553] vs 0.00018 [0.00012–0.00262]; p<0.05) and IL-6 (CI [IQR] 0.00338 [0.00066–0.01674] vs 0.00054 [0.00044–0.00378]; p<0.05). The expression of anti-inflammatory cytokines in valve tissues prevailed in the control group without significant differences from patients with IE. The macrophage marker CD 68+ was revealed in all examined patients with a significant quantitative predominance in the group of patients with IE. There were no differences in the expression of pro- and anti-inflammatory cytokines depending on the presence of embolic events, intracardiac complications, etiological affiliation to S. aureus, as well as hospital mortality and combined endpoint (death from all causes or recurrence of IE 6 months after surgery) in patients with IE with or without events. Cytokines IL-1β and IL-6 positively correlated with each other, with leukocytes and NLR. ROC analysis determined that IL-1β and NLR had the most favorable features for the diagnosis of IE [IL-1β AUC 0.816 (p=0.02), NLR AUC 0.807 (p=0.03)]. IL-6 did not show a diagnostic value in IE. The threshold value for IL-1β was 0.00029 (sensitivity 86.4%, specificity 60.0%, prognostic value of negative result 75.0% and positive 76.0%, AUC 0.761; p=0.008).

Conclusion. The valve macrophages of patients with IE express elevated levels of proinflammatory cytokines IL-1β and IL-6, regardless of etiological affiliation or complicated course of IE. IL-1β has a high diagnostic value for determining the inflammatory activity in IE.

About the authors

Elizaveta O. Kotova

Patrice Lumumba Peoples’ Friendship University of Russia; Vinogradov Clinical Hospital; Central Research Institute of Epidemiology

Author for correspondence.
Email: kotova_eo@pfur.ru
ORCID iD: 0000-0002-9643-5089

д-р мед. наук, доц., доц. каф. внутренних болезней с курсом кардиологии и функциональной диагностики им. акад. В.С. Моисеева Медицинского института, врач-кардиолог, консультант организационно-методического отд. административно-управленческого подразделения

Russian Federation, Moscow; Moscow; Moscow

Alexandra Yu. Moiseeva

Patrice Lumumba Peoples’ Friendship University of Russia

Email: kotova_eo@pfur.ru
ORCID iD: 0000-0003-0718-5258

канд. мед. наук, ассистент каф. внутренних болезней с курсом кардиологии и функциональной диагностики им. акад. В.С. Моисеева Медицинского института

Russian Federation, Moscow

Zhanna D. Kobalava

Patrice Lumumba Peoples’ Friendship University of Russia; Vinogradov Clinical Hospital

Email: kotova_eo@pfur.ru
ORCID iD: 0000-0002-5873-1768

чл.-кор. РАН, д-р мед. наук, проф., зав. каф. внутренних болезней с курсом кардиологии и функциональной диагностики им. акад. В.С. Моисеева Медицинского института, врач-кардиолог

Russian Federation, Moscow; Moscow

Anastasiya V. Lokhonina

Patrice Lumumba Peoples’ Friendship University of Russia; Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery

Email: kotova_eo@pfur.ru
ORCID iD: 0000-0001-8077-2307

канд. биол. наук, доц. каф. гистологии, цитологии и эмбриологии Медицинского института, науч. сотр.

Russian Federation, Moscow; Moscow

Alexandra S. Pisaryuk

Patrice Lumumba Peoples’ Friendship University of Russia; Vinogradov Clinical Hospital

Email: kotova_eo@pfur.ru
ORCID iD: 0000-0003-4103-4322

канд. мед. наук, доц. каф. внутренних болезней с курсом кардиологии и функциональной диагностики им. акад. В.С. Моисеева Медицинского института, врач-кардиолог отд-ния реанимации и интенсивной терапии

Russian Federation, Moscow; Moscow

Tatyana A. Gusarova

Vinogradov Clinical Hospital

Email: kotova_eo@pfur.ru
ORCID iD: 0000-0003-1827-2197

зав. патологоанатомическим отд-нием

Russian Federation, Moscow

Timur Kh. Fatkhudinov

Patrice Lumumba Peoples’ Friendship University of Russia; Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery

Email: kotova_eo@pfur.ru

д-р мед. наук, доц., зав. каф. гистологии, цитологии и эмбриологии Медицинского института, доц.

Russian Federation, Moscow; Moscow

Elvira A. Domonova

Central Research Institute of Epidemiology

Email: kotova_eo@pfur.ru
ORCID iD: 0000-0001-8262-3938

канд. биол. наук, рук. научной группы разработки новых методов диагностики оппортунистических и папилломавирусных инфекций отд. молекулярной диагностики и эпидемиологии

Russian Federation, Moscow

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Supplementary files

Supplementary Files
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1. JATS XML
2. Fig. 1. Comparison of pro-inflammatory cytokine expression by macrophages in valve tissues in operated patients with IE and with valvular malformations without IE (control).

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3. Fig. 2. Comparison of expression of anti-inflammatory cytokines by macrophages in valve tissues in operated patients with IE and with valvular malformations without IE.

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4. Fig. 3. Comparison of CD68+ macrophage marker expression in valve tissues in operated patients with IE and with valvular malformations without IE.

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5. Fig. 4. ROC curve of the diagnostic characteristics of IL-1β, WBC, NLI and IL-6 when comparing operated patients with IE and with valvular malformations without IE (control): a – diagnostic characteristics of markers for the detection of infectious endocarditis; b – IL-1β threshold.

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