Factors of Interleukin-6 Signaling in COVID-19 Patients with Lung Damage of Varying Degrees: A Pilot Study.

Specific features of IL-6 signal transduction were studied in 89 patients with lung damage of varying degrees during the first COVID-19 pandemic wave. The levels of IL-6 signaling components (IL-6, sIL-6R, and sgp130) and highly sensitive C-reactive protein (hsCRP) were examined in patients with intact lungs (CT-0), mild (CT-1), moderate (CT-2), moderate to severe (CT-3), and severe (CT-4) lung damage. Seventy patients were re-examined 3-7 months after discharge from the hospital. The IL-6 and hsCRP levels increased several times with severing lung damage severity. In patients with CT-3, sIL6-R increased statistically significantly and remained high in CT-4 patients. sgp130 levels were lower in CT-1 and CT-2 patients and higher in CT-3 and CT-4 patients compared to CT-0 patients. We revealed a positive correlation between IL-6 and hsCRP levels in CT-1, CT-2, and CT-3 patients. In CT-3 patients, sIL-6R levels positively correlated with IL-6 concentration. The studied parameters decreased considerably in all patients 3-7 months after discharge. It can be suggested that IL-6 classic-signaling is predominant in CT-1 and CT-2, while trans-signaling prevails in CT-3. Disorders in regulatory mechanisms of IL-6 signaling occur in CT-4, which prevents physiological elimination of IL-6 hyperactivity. The results obtained are preliminary and require a broader study.

Ratios between the Levels of IL-18, Free IL-18, and IL-1ß-Binding Protein Depending on the Severity and Outcome of COVID-19.

In 89 patients with COVID-19, the ratios between IL-18, free IL-18, and IL-18-binding protein (IL-18BP) were analyzed depending on severity and outcome of the disease. At admission to the hospital, the levels of IL-18 and free IL-18 were significantly higher than 3 months after discharge from the hospital, the levels IL-18BP of being almost the same. In patients with more severe lung injury (computed tomography data), the levels of IL-18 and free IL-18 were higher and IL-18BP levels were lower than in patients with mild and moderate COVID-19. Three months after discharge from the hospital, no differences between these parameters were found. In 9 patients who died in the hospital, free IL-18 levels were significantly higher and IL-18BP levels were lower than in survivors. Thus, high levels of bioactive free IL-18 in combination with low levels of IL-18BP can be indicative of severe inflammatory phase of COVID-19 and the risk of worse clinical outcomes.

Retrospective Analysis of Lipid-Lowering and Antiplatelet Therapy Regimen by Clinical Decision Support Service Based on Real-World Data from Electronic Medical Records "Intellect 3 Study".

Aim      To evaluate prescription of lipid-lowering and antithrombotic therapy in clinical practice and to compare differences in recommendations using the clinical decision support service (CDSS).Material and methods  Electronic medical records (EMR) of 300 patients from the Chazov National Medical Research Center of Cardiology, as well as from medical organizations controlled by the Department of Health of the Lipetsk Region and the Ministry of Health of the Voronezh Region, were analyzed for the period of August - December 2022, during the pilot implementation of CDSS. Retrospective information about the prescription of lipid-lowering and antithrombotic therapy from the EMR was compared with the CDSS guidelines under the expert supervision based on digitized clinical and laboratory profiles of patients. The study primary endpoint was a change in the initially prescribed lipid-lowering and / or antithrombotic therapy as per CDSS guidelines.Results Overall 292 patients were included in the final analysis; 46 (15.7 %) were from the primary prevention group and 246 (84.3 %) from the secondary prevention group. In group 1, the lipid-lowering therapy recommended by the CDSS differed by 50 % (p<0.001) from the baseline therapy recorded in the EMR. In the secondary prevention group, 78.9 % (p<0.001) differences were found in the lipid-lowering therapy recommended in the CDSS guidelines compared to the prescriptions in the EMR. In 76.8 % (p<0.001) of patients, antithrombotic therapy was significantly different from the baseline therapy in the EMR.Conclusion      The use of CDSS may improve the practice of choosing lipid-lowering and antithrombotic therapy for prevention of cardiovascular complications.

Reactivity of skin microcirculation as a biomarker of cardiovascular events. Pilot study.

BACKGROUND: The role of microcirculatory disorders is progressively being accepted in the pathogenesis of cardiovascular diseases. OBJECTIVE: The purpose of current study is to assess whether we can consider skin microcirculation disorders as a biomarker of cardiovascular events. METHODS: Group 1 consisted of healthy volunteers (n = 31); group 2 (n = 42) consisted of patients with diseases that increase the risk of cardiovascular events; group 3 (n = 39) included patients with the history of cardiovascular events. Skin microcirculation measurement was performed using laser Doppler flowmetry during the heating test. RESULTS: LDF parameters reflecting the rapid response of microcirculation to heating ("Slope 120 s" and "Slope 180 s") significantly differed in three groups (p <  0.05). A decrease in the "Slope 180 s" parameter less than 0.5 PU/s is associated with cardiovascular events (sensitivity 69.2%, specificity 66.7%; the area under the ROC curve, 0.667; 95% confidence interval [CI], 0.545-0.788, p = 0.01). Multivariable logistic regression analysis revealed that "Slope 180 s≤0.5 PU/s" was significantly related to cardiovascular events (adjusted odds ratio = 3.9, p = 0.019, CI 95% 1.2-12). CONCLUSIONS: Reduced reactivity of the skin microcirculation may be useful as a biomarker of severe damage to the cardiovascular system and is promising as a risk factor for cardiovascular events.

Clinical Characteristics and Factors Associated with Poor Outcomes in Hospitalized Patients with Novel Coronavirus Infection COVID-19.

Aim      To evaluate the clinical picture and factors associated with unfavorable outcomes in admitted patients with COVID-19.Material and methods This study included all patients admitted to the COVID Center of the National Research Center of Cardiology of the Russian Ministry of Health Care from May 1 through May 31, 2020. Clinical demographic, laboratory, and instrumental indexes and associated factors were studied with one-way and multivariate logistic regression analysis.Results This study included 402 patients aged 18 to 95 years (mean age, 62.9±14.6 years); 43.0 % of them were older than 65 years. COVID-19 was frequently associated with chronic comorbidities, including arterial hypertension (74.4 %), obesity (41.6 %), history of ischemic heart disease (12.9 %), atrial fibrillation (18.9 %), type 2 diabetes mellitus (DM) (13.0 %), and oncological diseases (9.2 %). 13.0 % of patients were smokers; less than 10% had chronic lung diseases. 3.9% of patients had a combination of COVID-19 and acute coronary pathology, including acute myocardial infarction (MI) in 3.2 % (13) and unstable angina in 0.7 % (3). The most frequent clinical manifestation of COVID-19 were four symptoms: cough (81.1 %), weakness (80.3 %), shortness of breath (71.6 %), and fever (62.7 %). 46.5% of patients had shortage of breath and chest pain/compression, 40.3% had headache, 31.1% had myalgia, 28.8% had anosmia, and 25.5% had ageusia. Arterial oxygen saturation was <93.0 % in 55.7 % of cases. According to laboratory blood tests the patients had anemia (58.2 %), lymphopenia (34.8 %), neutropenia (19.2 %), thrombocytopenia (11.9 %), and increased levels of high-sensitivity C-reactive protein (hsCRP, 87.3 %), interleukin-6 (89.3 %), ferritin (62.1 %), and D-dimer (49.2 %). 56.2% of patients required various regimens of oxygen support. 83 (20.6%) patients were admitted to intensive care and resuscitation units; invasive artificial ventilation was performed only for 34 (8.5 %) patients. In-hospital mortality was 7.7 % (31 / 402). One-way regression analysis identified major factors associated with death during the stay in the hospital: age >55 years, NEWS scale score >4.0, oxygen saturation <92.0 %, blood glucose >5.4 mmol/l, hs-CRP >25.7 mg/l, and creatinine clearance <72.0 ml/min. Furthermore, the risk increased with increasing degree of changes in each factor. According to results of the multivariate regression analysis, three most significant predictors of the hard endpoint, all-cause death during the stay in the hospital, were more than 5-fold increases in aspartate aminotransferase and/or alanine aminotransferase compared to normal levels (relative risk (RR) 16.8 at 95 % confidence interval (CI) 5.0-56.3, р<0.001), pronounced changes in the lungs consistent with a CT-4 picture as shown by computed tomography (CT) (RR 13.4; 95 % CI 3.9-45.5, р<0.001), and MI/unstable angina during the stay in the hospital (RR 11.3; 95 % CI 1.4-90.6, р=0.023). The probability of death was also considerably increased by chronic obstructive pulmonary disease, impaired kidney function (creatinine clearance estimated by Cockcroft-Gault <60.0 ml/min), type 2 DM, oncological diseases, and dementia.Conclusion      This study established factors associated with unfavorable outcomes in admitted patients with COVID-19. This will allow identifying in advance patients with a high risk of complications that require increased attention to take more active diagnostic and therapeutic measures at prehospital and hospital stages.

[Factors Affecting Duration of Stay in IntensiveCare Unit After Coronary Artery Bypass Surgery].

We studied predictors of prolonged stay in intensive care unit (ICU) after coronary surgery without cardiopulmonary bypass. Factors significantly associated with duration of ICU stay were elevated levels of glucose and lactate in venous blood, types of conduits used, and type of bypass surgery. Results of this study can be used for elaboration of a quantitative scale for prediction of duration of postoperative treatment in ICU.

[Evaluation of Direct and Indirect Expenditures for Management of Patients With Stable Ischemic Heart Disease After Stenting of Coronary Arteries].

Assessment of cost of management of patients during 1 year after stenting of coronary arteries has shown that priority should be given to active introduction into practical health care of technologies increasing duration of life and lowering probability of invalidization. We stress the need for evaluation of indirect expenditures on patients care because of their substantial share in the total cost. We also consider essential to elaborate measures of state regulation of medication supply irrespective of type of treatment for shifting expenditures from hospital to ambulatory sector and improvement of effectiveness of pharmacotherapy.

[Fundamental bases for the use of silk fibroin-based bioresorbable microvehicles as an example of skin regeneration in therapeutic practice].

AIM: To assess whether silk fibroin-based microvehicles (MVs) may be used to grow fibroblasts (FBs) and keratinocytes (KCs), key cellular components in skin regeneration after injury. SUBJECTS AND METHODS: Cryogrinding was applied to derive MVs from fibroin-based and fibroin- and 30% gelatin-containing composite matrices. To examine the structure of the matrices and MVs, confocal microscopy was used to conjugate the polymer with the dye tetramethylrhodamine isothiocyanate. Microparticle size distribution was estimated by granulometric analysis. 3T3 mouse FBs and cultured primary mouse KCs expressing green fluorescent protein (GFP) were used to study whether fibroin-based MVs might be suitable for growing the cells involved in skin regeneration. KC growth was analyzed by confocal laser scanning microscopy from cellular GFP expression. The proliferation rate of FBs and KCs was estimated by a MTT assay. RESULTS: There were two derived MV types: fibroin-based and fibroin and 30% gelatin-containing composite ones. On day 1, 3T3 mouse FBs on the fibroin-based gelatin-free MVs actively proliferated and the presence of gelatin in MVs diminished the proliferation of these cells. Fibroin-based MVs were shown to be suitable for the effective in vitro growth of KCs expressing cytokeratins 5 and 14, the major markers of KCs in the basal layer. Gelatin did not give rise to accelerated KC growth. The investigation has demonstrated that is possible to regulate FB proliferation on MVs, which is of great importance in delivering the cells into the site of injury since intensive proliferation of FBs may lead to the development of fibrosis and the formation of scar tissue. Balanced FB growth is essential to the creation of optimal conditions for KC growth in composite tissue-engineering constructions. CONCLUSION: The use of fibroin-based MVs is promising for the design of novel therapeutic materials and injectable cell therapy for different diseases.

[Change in the blood cytokine spectrum in patients with pulmonary sarcoidosis].

AIM: To assess cytokine spectrum changes in different types of pulmonary sarcoidosis (PS). SUBJECTS AND METHODS: Twenty-seven PS patients without signs of pulmonary fibrosis and 14 patients with sarcoidosis complicated by pulmonary fibrosis were examined. Baseline serum Th1 and Th2 cytokine concentrations were studied. A control group comprised 30 healthy donors. RESULTS: A higher interleukin (IL)-4/IL-2 ratio was found in the peripheral blood of the patients with pulmonary fibrosis-complicated sarcoidosis than in the other patients (326.4 +/- 122.6 and 88.2 +/- 28.6%, respectively; p = 0.002). The sarcoidosis patients with signs of pulmonary fibrosis and no symptoms of disease inflammatory activity had elevated blood IL-1 levels whereas an IL-1 receptor antagonist was decreased. CONCLUSION: In the patients with PS, the development and progression of pulmonary fibrosis occur with a shift in the Th1/Th2 balance towards Th2, which manifests itself as a higher IL-4/IL-2 ratio in the peripheral blood. At the same time, the signs of systemic inflammatory activity remain.

[Catalytic autoantibodies in autoimmune myocarditis: clinical and pathogenetic implications].

AIM: To evaluate pathogenetic and clinical significance of autoantibodies (AAB) with catalytic activity in the serum of patients with autoimmune myocarditis (AM). MATERIAL AND METHODS: The study was made on the sera from 99 patients with AM of different course: malignant, benign, myocardiosclerosis (MCS). In addition to standard immunological parameters, the study was made of serum levels of anticardiomyosine-antiCM (protabzymes) and anti-DNA (DNA-abzymes) of AAB. After obtaining anti-CM and anti-DNA IgG-AT, we determined non-specific and specific proteolytic activity of anti-CM. RESULTS: Maximal specific activity of protabzymes was seen in 73% patients with malignant AM, it correlated with blood levels of anti-CM AAB, DNA-abzymes activity was very high in 45% patients. In MCS proteolytic activity of autoAT was absent in 61% patients. In benign AM occurrence of protabzymes was confirmed in 35% cases. Elevated DNA-hydrolyzing activity of DNA-abzymes occurred in 13% cases. The activity had no significant correlation with serum titers of AB. In MCS proteolytic activity of AAB was absent in 61% cases, but high activity of anti-CM AAB was in 28%. The activity of DNA-abzymes in 44% ranged considerably which, in seropositive cases, detected significant correlation with serum titers of DNA-binding autoAT. CONCLUSION: Evaluation of catalytic activity of AAB may be considered as a criterial test assessing the stage, clinical variants and severity of AM. It also permits formulation of the disease prognosis and its possible outcomes.

[Achievements and prospects of clinical abzymology].

Catalytic autoantibodies (abzymes) are autoantibodies that are potentially ready to realize certain effects in the organism, first of all antibody-mediated catalysis and cytotoxicity. Natural abzymes with protolytic (protabzymes) and DNA-hydrolyzing DNA-abzymes) activity are of the greatest interest. The most impressive example of the catalytic activity of protabzymes is hydrolysis of specific proteins, revealed in patients with autoimmune diseases, such as bronchial asthma (vasoactive intestinal neuropeptide), autoimmune thyroiditis (thyroglobulin), multiple sclerosis (myelin basic protein), and autoimmune myocarditis (cardiomyosin). The pathogenic role of DNA-abzymes is not quite clear yet. However, it has been proven that they present a powerful regulator of apoptosis and other cytotoxicity mechanisms in systemic autoimmune diseases and tumors. The most promising is use of abzymes as illness activity markers, and as therapeutic agents capable of catalyzing specific proteins or activating antitumoral chemotherapeutic preparations.

[Cytokines as a diagnostic and therapeutic tool in patients with myocarditis].

One of the leading causes of autoimmune myocardial lesion in patients with myocarditis is disbalance between pro-inflammatory and anti-inflammatory cytokines, leading to the loss of functional tolerance to certain myocardial autoantibodies, and activation of autoreactive T-lymphocytes, which are able of myocardial cytotoxicity. The authors have conducted studies, which have shown that malignant myocarditis is characterized by abrupt increase of TNF-alfa and IFN-alfa basal serum levels, while at the same stage of the disease in patients with benign myocarditis only moderate increase of TNF-alfa level is observed, and IFN-alfa concentration is within normal limits. Abrupt increase of the cytotoxic activity of lymphocytes, activated by IL-2 (LAK-cells), is a feature of malignant myocarditis. In this category of patients the studies have found pronounced disbalance between cytokine serum levels, with abruptly increased levels of both cytokines which activate cytotoxic reactions (TNF-alfa, IFN-alfa, IL-1 alfa, IL-1 beta, IL-12), and cytokines which stimulate humoral immunity (IL-4 and IL-6), and increase of antimyocardial autoantibody concentration. Further research into the role of cytokines in myocarditis pathogenesis would allow grounded cytokinotherapy and application of immunomodulators, activating cytokine production.

[Tumor necrosis factor alpha and interferon alpha in patients with myocarditis.]. / Faktor nekroza opukholi a i interferona-a u bol'nykh miokarditom.

AIM: To elucidate the role of tumor necrosis factor alpha (TNF alpha) and interferon alpha (INF alpha) in pathogenesis of infectious-immune myocarditis (M) and myocarditic cardiosclerosis (MCS). MATERIAL AND METHODS: Patients with infectious-immune myocarditis (n=27) and myocarditic cardiosclerosis with symptoms of heart failure (n=19). Blood levels of TNF alpha and INF alpha were measured by immune enzyme analysis. RESULTS: Mean levels of INF alpha and TNF alpha in patients with M (75+/-47 and 304+/-102 rg/ml respectively) were significantly higher than in patients with MCS and healthy donors (31+/-14 and 83+/-39; 38+/-18 95+/-58 rg/ml, respectively, p<0.05). Levels of INF alpha and TNF alpha significantly differed between patients with benign and malignant course of M (99+/-46 and 354+/-100; 39+/-10 227+/-42 rg/ml, p<0.05). Phytohemagglutinine induced TNF alpha production by leucocytes in patients with malignant M (1432+/-515 rg/ml) was higher (p<0.05) while in patients with benign M (131+/-54 rg/ml) lower (p<0.01) than in healthy donors (255+/-98 rg/ml). Patients with malignant compared with those with benign course of myocarditis had lower ejection fraction (25.9+/-12.1 and 42.5+/-11,2%, respectively, p<0.003) and higher inhospital mortality (16.6 and 0%, respectively). CONCLUSION: It is most probable that factors of regulation of INF alpha and TNF alpha production occupy an import place among mechanisms of malignant transformation of myocarditis.