Siberian Journal of Clinical and Experimental Medicine
Peer-rewieved scientific medical journal
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Controversial and unresolved issues in the classification of surgically implanted biological heart valve prostheses (problem lecture)
One of the significant areas of cardiac surgery is the replacement of damaged or faulty heart valves. Biological heart valve prostheses created from biological tissues represent a significant achievement in this area, providing effective treatment and improving the quality of life of patients. Aim: To analyze and discuss unresolved issues in the classification of surgically implanted biological heart valve prostheses. Various approaches to the classification of biological heart valve prostheses are presented, including from the standpoint of their historicity. Particular attention is paid to the prospects for the development of combined technologies in the creation of heart valve prostheses. Thus, the rapid development of biological and engineering technologies makes significant adjustments to the very concept of “biological heart valve prosthesis”. A transformation in the production of these medical devices is expected, which is already associated with the development and implementation of bioengineering technologies in clinical practice, which may lead to the abandonment of existing methods of production and use of biopolymers (collection from animals and fixation /sterilization /storage in glutaraldehyde or a similar agent). It is obvious that in the near future, synthetic, combined bioprostheses and valves created on the basis of promising tissue engineering technologies will appear. Innovative tissue and cell prostheses already include structures created from patient cells or using bioprinting. In general, these technologies are aimed at creating prostheses that can have an ideal match to the patient's anatomy and minimize the risk of rejection. Such valves are likely to be stronger, less likely to cause complications and easier to implant.
Diagnostic value of the fractional flow reserve: attention, blood rheology!
Assessment of hemodynamic significance of coronary artery stenosis has become crucial in determining the treatment strategy for coronary artery disease (CAD). Consequently, invasive methods for evaluating the functional significance of stenosis have become widely used. Additionally, diagnostic technologies that combine coronary angiography and mathematical modeling of coronary flow have also been employed for this purpose. This paper presents an analytical review of the assessment of the functional significance of coronary artery stenosis using the fractional flow reserve (FFR) method. The review covers the fundamental aspects of the FFR method, its practical application, and its diagnostic value. Significant attention is given to blood rheology, particularly dynamic viscosity. Since dynamic viscosity is a key determinant of hemodynamic resistance to blood flow, especially in microcirculation, this factor can influence the interpretation of the results in coronary stenosis assessment.
Context-specific endothelial heterogeneity (literature review)
The analytical review considers morphological and functional aspects of endothelial heterogeneity depending on various vascular pathologies using atherosclerosis, thrombosis, arterial hypertension and microcirculatory vasospastic angina as examples. Among the universal mechanisms of endothelial dysfunction, the most important are impaired nitric oxide biosynthesis, dysregulation of molecular mechanisms of mechanotransduction, endothelial-mesenchymal transition, proinflammatory and prothrombotic activation. Besides, the very process of physiological aging of endothelial cells in the form of increased permeability, lipid retention, adhesion and cellular transmigration is also of great importance in the pathogenesis of these diseases. Taking into account the current state of the issue of endothelial heterogeneity, promising areas for further study of its pathophysiology are briefly listed, including developments in the field of studying the transcriptome and proteome of cells of atheroprotective conduits used in coronary artery bypass grafting, and molecular-cellular analogies between oncopathology and atherosclerosis.
Risk factors for cognitive impairments in children and adolescents with type 1 diabetes mellitus: pathophysiological aspects (literature review)
Type 1 diabetes mellitus (T1DM) in children and adolescents is associated not only with metabolic disturbances but also with the development of cognitive impairments, which may initially present subclinically. These impairments reflect central nervous system involvement driven by a variety of pathophysiological mechanisms. Recent studies have demonstrated that the cognitive status of children with T1DM is influenced by both acute and chronic factors, including episodes of hypoand hyperglycemia, diabetic ketoacidosis, disease duration, and poor glycemic control. Aim. Summarize current literature on the mechanisms underlying cognitive impairment in T1DM, as well as the possibilities for early diagnosis and prevention. The roles of neuroinflammation, oxidative stress, altered glucose transporter function, impaired neurogenesis, microvascular complications, gut dysbiosis, and psychiatric comorbidities in the pathogenesis of cerebral dysfunction are discussed. Particular attention is given to the methodological challenges of assessing cognitive status in the pediatric population, the potential use of laboratory and neuroimaging markers, and their clinical applicability. The review also highlights the impact of cognitive impairment on learning, social adaptation, and quality of life in patients. The data presented emphasize the need for the development of personalized strategies for prevention and intervention. Cognitive disturbances in T1DM are increasingly recognized as a major factor influencing long-term prognosis and the adaptive capacity of young patients.
The relationship between overexpression of somatostatin receptor type 2 in the infarcted myocardium and serum biomarkers of inflammation in the early post-infarction period
Introduction. Radionuclide imaging of somatostatin receptor type 2 (SSTR-2) shows great promise as a novel marker of cardiovascular inflammation. However, it is still unclear whether local inflammation and high levels of macrophages in the infarct area that overexpress SSTR-2 are positive or negative factors for myocardial healing. Aim: To assess the relationship between inflammatory biomarkers as indicators of the systemic response to ischemic injury and the local inflammatory response in the myocardium, as measured by SSTR-2-targeted imaging, during the early post-infarction period. Material and Methods. Twenty-three patients with acute primary anterior wall myocardial infarction and ST-segment elevation myocardial infarction (STEMI) were included in the study. On the first day (before percutaneous intervention) and on the fifth day after acute myocardial infarction (AMI), venous blood was collected from all patients to determine hsCRP and IL-6 levels. Five to six days after the acute coronary event, all patients underwent single-photon emission computed tomography (SPECT)/computed tomography (CT) with 99mTc-Tektrotyd. Seven days after the acute coronary event, they underwent myocardial perfusion scintigraphy with 99mTcMIBI at rest. Results. The results of the study indicated a negative correlation between hs-CRP and IL-6 levels on days 1 and 5 with left ventricular ejection fraction (LVEF) and a positive correlation with the summed rest score (SRS). Concurrently, SUVmax exhibited no correlation with hsCRP and IL-6 levels. At the same time SUVmax exhibited a moderate correlation with SRS (r = 0.517, p = 0.011). In the context of univariate linear regression, SUVmax demonstrated no statistically significant impact on hs-CRP and IL-6 levels. Concurrently, the total resting perfusion defect score (SRS) exerted an influence on the alteration in the levels of inflammatory biomarkers. It is also noteworthy that no regression relationship was identified between SUVmax and SRS Conclusion. The findings indicated that the intensity of accumulation of somatostatin analog 99mTc-Tectrotyd in the left ventricular myocardium during the early postinfarction period is not associated with the levels of inflammatory biomarkers. Our findings indicate the activation of cellular and biochemical pathways of the inflammatory cascade. Conversely, the study identified a potential antiinflammatory function of somatostatin receptor type 2 hyperexpression.
Experience in using a cell-free vascular matrix in smalldiameter arterial surgery
Introduction. Modern vascular surgery faces a need for reliable biocompatible models for small-diameter vessel prosthetics, as traditional methods are limited due to donor material shortages and risks of complications such as thrombosis and infection. In this context, the use of prostheses made from decellularized aorta (DCA) – a natural biological scaffold preserving the extracellular matrix that stimulates vascular wall regeneration – is studied. Aim: To evaluate the manufacturability and biocompatibility of DCA prostheses made from rat aorta, when transplanted into the abdominal aorta of animals, with investigation of patency and vascular wall response over 4 weeks. Material and Methods. Chemical and physical decellularization of the aorta using SDS, Triton X-100, and enzymes was performed; prostheses were implanted into 20 Wistar rats. Patency was assessed immediately and 30 minutes post-operation, with morphological control including ultrasound with Doppler performed at 4 weeks. Histological analysis used cross-sections stained with hematoxylin and eosin. Results. Prosthesis transplantation occurred without technical complications. The DCA showed sufficient strength and elasticity. After 4 weeks, normal capillary perfusion in hind limb tissues was noted. Doppler imaging revealed a decrease in mean linear blood flow velocity (about 25%, p < 0.001) in the prosthesis region. Thrombosis or stenosis developed in 60% of animals, aneurysms in 30%. Histology revealed lymphocytic infiltration and intimal hyperplasia in most animals, explaining impaired vessel patency. Conclusion. Decellularized aortic prostheses demonstrate unique biocompatibility and structural similarity to native vessels but carry a high risk of complications such as thrombosis, stenosis, and aneurysms. Modifications, possibly including synthetic coatings or endothelial cell cultivation, are needed to improve stability and thromboresistance.
A multimarker approach to the diagnosis of heart failure with preserved ejection fraction
Background. Against the background of a steady increase in the incidence of heart failure with preserved ejection fraction (HFpEF), the highly laborious diagnosis of the disease hinders the timely implementation of therapeutic and preventive measures, which determines the relevance of our study. Aim: To evaluate the significance of biomarkers, indices of myocardial strain and diastolic function in the diagnosis of HFpEF. Material and Methods. According to a diastolic stress test (DST), 88 patients (65.9±5.4 years; 47.7% men) with left ventricular ejection fraction ≥50% were divided into 2 groups: 1 (n = 49) – with HFpEF, 2 (n = 39) – without HFpEF. All patients underwent echocardiography (ECHOCG) at rest and DST, evaluation of left atrial reservoir strain (LASr), left atrial stiffness index (LASI), diastolic function index E/e΄; biomarkers of immune inflammation; neurohumoral (NT-proBNP) and sympathoadrenal systems; fibrosis; growth factors; insulin resistance were studied: triglycerides/glucose (TyG) index; renal function; anemia, iron (Fe) status with assessment of percentage of transferrin iron saturation (%TIS); cortisol; progesterone (PGN). Factors associated with HFpEF were identified using simple or multivariate logistic regression, and 2 mathematical models of the disease were created. ROC analysis was used to identify cut-off points for indicators and HFpEF models were estimated. Results. In group 1, women predominated (63.3 vs 38.5%; p = 0.021), mainly with functional class II according to the New York classification, with a higher body mass index (BMI) (32.4 ± 4.0 vs 29.9 ± 3.9 kg/m²; p = 0.003), the incidence of obesity (67.3 vs 43.6%; p = 0.025), iron deficiency (43.9 vs 34.6%; p = 0.033) and the use of β-blockers (73.5 vs 51.3%; p = 0.032). In multivariate analysis, HFpEF was associated with LASr: OR (95% CI) 0.722 (0.540–0.965) (p = 0.028) and E/e΄ at DST: OR (95% CI) 9.263 (1.912–44.885) (p = 0.006). Due to the unavailability of DST in practical healthcare, the following were included in 1 model without DST: gender, BMI > 30.4 kg/m², NT-proBNP > 360 pg/ml, LA volume index > 30 ml, E/e΄ > 9.8 at rest, LASr < 26%, TyG > 8.7 units, %TIS interaction < 27.7%, PGN < 1.7 nmol/l. The area under the ROC curve (AUC) was 0.879 (95% CI 0.806–0.951) and p < 0.001, specificity was 75.7%, sensitivity – 86.2% and the overall predictive value was 79.5%. Due to the secondary nature of the fibrotic process with the development of diastolic dysfunction, the following were included in model 2 without ECHOCG: gender, BMI > 30.4 kg/m², NT-proBNP > 360 pg/ml, cardiotrophin 1 > 587.0 pg/ml, TyG > 8.7 units, %TIS < 27.7%, PGN < 1.7 nmol/l. The AUC of the model was 0.830 (95% CI 0.734–0.927) and p < 0.001, specificity – 75.7%, sensitivity – 80.4%, overall predictive value – 78.3%. Conclusion. Multimarker analysis revealed the diagnostic significance in HFpEF of a decrease in PGN level less than 1.7 nmol/l due to age-related hormonal remodeling, an increase in NT-proBNP level more than 360 pg/ml with neurohumoral activation, a decrease in transferrin iron saturation percentage less than 27.7% as a marker of iron deficiency, an increase in TyG insulin resistance index more than 8.7 units associated with obesity, LASr less than 26%, LASI more than 0.38 units, E/e΄ ratio more than 9.8 units at rest and more than 12.1 units during DST. Using a panel of laboratory markers including the previously mentioned levels of sST2, NT-proBNP, %LVAT, and hsTnT allows for a more precise assessment of the disease or its high risk of development, even without performing resting echocardiography or DST.
Adipokine status and gene expression of leptin and adiponectin from epicardial and subcutaneous adipose tissue in cardiac surgery patients with mitral valve disease: a cross-sectional study
The level of adipokine gene expression in adipose tissue and the concentration of proand anti-inflammatory adipokines in the blood are potentially promising for predicting the severity of patients with cardiovascular diseases, the dynamics of their inflammatory status and cardiac remodeling. However, the assessment of the adipokine status in the cohort of patients with valvular heart diseases remains poorly studied. Aim: To study the relationship between the severity of epicardial and visceral obesity with the adipokine status and the level of adiponectin and leptin gene expression from epicardial and subcutaneous adipose tissue in patients with indications for surgical correction of mitral valve disease. Material and Methods. The study included 51 patients with acquired mitral valve disease of non-infectious genesis, who had indications for surgical correction. All patients were divided into groups depending on visceral/epicardial obesity, with subsequent assessment of the level of expression of leptin and adiponectin genes in adipose tissue, blood concentrations of leptin, adiponectin, resistin. Results. Patients with visceral obesity have been shown to exhibit higher serum levels of the pro-inflammatory adipokine leptin and lower levels of the anti-inflammatory adipokine adiponectin compared to individuals without obesity. Blood leptin levels are significantly higher in patients with epicardial obesity compared to those without. The present study found no association between the level of adipokines in the blood serum and the level of expression of adipokine genes in samples of epicardial and subcutaneous adipose tissue. Conclusions. Patients with visceral and epicardial obesity are characterized by adipokine imbalance in the form of increased leptin levels and decreased adiponectin levels in the blood serum. The lack of association between the level of adipokines in the blood serum and the level of adipokine gene expression in samples of epicardial and subcutaneous adipose tissue can be explained by the disrupted relationship between adiponectin and leptin and their receptors in obesity, which leads to resistance of receptors to adipokines and the development of leptin and adiponectin resistance. As a result, despite the increased level of adipokines in the blood serum, the expression of their genes continues, which leads to the lack of association between the expression of adipokine genes and their serum content.
Identification of clinically significant variants in genes of cardiovascular embryonic development in sporadic ascending aortic aneurysm and “bovine aortic arch”
Introduction. Aortic arch anomalies, especially the “bovine arch”, can cause the development of an ascending aortic aneurysm. There is a high coefficient of heritability of this pathology, however, genetic studies are rare. Since the “bovine arch” is one of the variants of the development of the aortic arch and large vessels during embryogenesis, this pathology may be associated with genes encoding proteins involved in the embryonic development of the cardiovascular system. Aim: To identify rare, clinically significant variants of genes of cardiovascular embryonic development in patients with sporadic ascending aortic aneurysm and a “bovine arch”. Material and Methods. The study included 42 patients with a sporadic form of ascending aortic aneurysm, including 11 patients with a “bovine arch”. Analysis of the clinical exome was performed based on DNA sequencing data using Clinical Exome Solution (Sophia Genetics, Switzerland) and NextSeq 500 genetic sequencer (Illumina, USA). The search for rare, clinically significant variants (minor allele frequency <1%) was carried out in exons and adjacent introns of 120 genes of embryonic development of the cardiovascular system. Validation of identified variants was performed using Sanger sequencing. Results. In patients with aortic aneurysm and “bovine arch”, the following clinically significant variants were identified: the pathogenic variant c.610-2A>G of the CCDC39 gene, which is a single-nucleotide substitution leading to the loss of the acceptor splice site (ΔScore = 0.97 Spliceailookup) and a variant of uncertain clinical significance (VUS) c.2564T>C in the ANKS6 gene, which has high pathogenicity rates on the CADD (Phred = 28.3) and AlphaMissense (0.972) scales. A likely pathogenic variant c.1151T>C of the ACVR2B gene was identified in the group of patients with aortic aneurysm without supraaortic vessels anomaly (AlphaMissense = 0.966). Among the 38 genes whose sequences revealed VUS in both groups of patients, the protein products of 17 (44.7%) are involved in the functioning of cilia and microtubules, and the proteins encoded by the genes MKS1, CCDC40, DNAAF1, ANKS6, CCDC39, DNAH5, DNAAF3 are also responsible for the development of the cardiovascular system. Conclusion. Rare, clinically significant variants in the CCDC39 and ANKS6 genes, which are crucial for primary cilia function, contribute to the development of sporadic ascending aortic aneurysm in combination with a “bull’s arch.” When a normal aortic arch is present, variants in the ACVR2B gene, belonging to the TGF-beta signaling protein superfamily, play an important role.
Whole transcriptome analysis of alternative ribonucleic acid splicing events in severe and moderate forms of fetal growth retardation
Background. Fetal growth retardation (FGR) remains one of the leading causes of perinatal morbidity and a major risk factor for longterm adverse health outcomes in children, including an increased likelihood of neurological, metabolic, and cardiovascular disorders. Despite extensive research interest, the molecular mechanisms underlying FGR are still insufficiently understood. In particular, little is known about the role of post-transcriptional regulation in the development of this condition. Alternative splicing is of special interest. It determines transcriptome diversity and expands the functional capacities of cells. Through this mechanism, cells gain the ability to adapt to pathological stimuli. At the same time, it influences their susceptibility to disease, including obstetric complications. Aim: To characterize alternative splicing profiles in placental decidual cells (DCs) that determine the severity of fetal growth retardation. Material and Methods. The study was conducted on placental tissue samples from patients with moderate and severe forms of FGR. Whole-transcriptome analysis was performed on decidual cells isolated by laser microdissection from stained thin tissue sections. Whole-genome ribonucleic acid (RNA) sequencing was performed using the SMARTer Stranded Total RNA-Seq kit v2 (Takara BIO). Alternative splicing events were analyzed with the MAJIQ package under a Linux operating system. Results. In the analyzed samples, 13,688 alternative splicing (AS) events were detected across 4,002 genes expressed in decidual cells. More than 52% of these events were identical between both groups. In severe FGR, both annotated and de novo events demonstrated a statistically significant decrease in the frequency of the alternative first exon (χ2 = 8.48, p = 0.004; χ2 = 6.15, p = 0.014, respectively). The alternatively spliced genes specific to severe FGR were involved in the following biological processes: catalytic activity acting on nucleic acids (pFDR = 0.020), regulation of GTPase activity (pFDR = 0.021), regulation of nucleoside triphosphatase activity (pFDR = 0.021), and peptide N-acetyltransferase activity (pFDR = 0.028). Comparison of the moderate and severe FGR groups identified 84 differentially spliced genes (0.200 < deltaPSI < 0.648; p < 0.05). These genes were significantly associated with biological and signaling pathways including multiple types of DNA repair, the ligand-gated ion channel pathway, vesicular transport to the plasma membrane, regulation of mRNA metabolism, peroxisome organization, lysosome organization, morphogenesis, the SMAD signaling pathway, sulfur metabolism, and ATP-dependent chromatin remodeling. Conclusion. The data indicate a specific set of AS-related molecular changes characteristic of FGR, regardless of its severity. AS patterns unique to severe FGR are associated with disruptions of fundamental cellular regulatory systems. Functional annotation of differentially spliced genes suggests that AS affects post-transcriptional control, cellular architecture, and intercellular signaling interactions in severe FGR.
Role of intercellular aggregates and oxidative stress markers in assessment of cardiovascular outcomes in patients after coronary artery bypass grafting
Aim: To compare the levels of C-reactive protein (CRP), circulating cell aggregates (including P-selectin-expressing aggregates), lipid profiles, and platelet chemiluminescence activity in patients with and without adverse cardiovascular events following coronary artery bypass grafting (CABG). Material and Methods. The study enrolled 102 patients with angina pectoris (functional class II–IV) who underwent CABG. Prior to CABG, comprehensive blood analysis and lipid profile assessment were performed. Both preand postoperatively, platelet chemiluminescence and flow cytometry analyses were conducted. Composite endpoints (worsening angina class, progression of heart failure, myocardial infarction, stroke, cardiovascular death, or repeat revascularization) were evaluated during hospitalization (8–10 days post-CABG) and at 23.3 ± 7.6 months postoperatively. Results. Composite endpoints occurred in 16 patients. Significant differences were observed between groups (no events vs. adverse outcomes). Pre-CABG: monocyte-platelet aggregates: 13.4% [5.9; 24.2] vs. 34.9% [19.05; 50.25], p = 0.001; Mean fluorescence intensity (MFI) of P-selectin-expressing neutrophil-platelet aggregates: 4.85 AU [2.99; 8.79] vs. 12.5 AU [5.09; 15.3], p = 0.005; MFI of P-selectin-expressing monocyte-platelet aggregates: 4.27 AU [2.6; 7.76] vs. 9.53 AU [6.68; 14.8], p = 0.006. Post-CABG: P-selectin-expressing neutrophil-platelet aggregates: 75.7% [62.36; 90.54] vs. 92.3% [80; 99.29], p = 0.027. The median time to peak lucigenin-enhanced platelet chemiluminescence pre-CABG was significantly shorter in patients with adverse events compared to event-free patients (212 s [53; 621] vs. 885 s [257.75; 2087], p = 0.032). Similarly, the median time to peak spontaneous neutrophil chemiluminescence with lucigenin was reduced in the adverse events group (847 s [565; 1018] vs. 1355 s [1065.5; 1898.5], p = 0.017). Conclusion. Patients with composite adverse cardiovascular events exhibited significantly different MFI and platelet-leukocyte aggregate counts (preand post-CABG), pre-operative platelet/neutrophil chemiluminescence peak times, and cardiopulmonary bypass durations compared to event-free patients. These parameters may serve as predictive biomarkers for post-CABG cardiovascular risk and warrant further investigation.
Association of lipoprotein-associated phospholipase A2 levels with epicardial adipose tissue adipocyte size and metabolic parameters in patients with coronary artery disease
Introduction. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is considered to be an independent marker of vascular inflammation and atherosclerosis progression. Epicardial adipose tissue (EAT) actively participates in the pathogenesis of coronary artery disease (CAD) through modulation of metabolism. The potential links between Lp-PLA2 levels, metabolic parameters, and EAT morphology in patients with CAD remain unexplored. Aim: To investigate the relationships between blood Lp-PLA2 content, lipid and glucose metabolism, and morphometric parameters of the epicardial fat depot assessed at the cellular and tissue levels in patients with established chronic CAD. Material and Methods. The study included 217 patients with CAD. Blood concentrations of Lp-PLA2, sortilin, glucagon, C-peptide, glucose, HbA1c, and lipid profile were determined. EAT thickness was measured. In 42 patients, EAT adipocyte size and the degree of their hypertrophy were assessed. Patients were divided into two groups according to Lp-PLA2 level: group 1 (n = 205), with concentrations not exceeding the 95th percentile; group 2 (n = 12), with concentrations above the 95th percentile. Results. Patients in group 2 had higher levels of sortilin and glucagon, increased EAT thickness, and a predominance of hypertrophied adipocytes. In group 1, Lp-PLA2 concentration correlated significantly with total cholesterol, C-LDL, glucose, HbA1c, mean EAT adipocyte size, and the proportion of hypertrophied cells. In men in group 1 with type 2 diabetes, Lp-PLA2 concentration was associated with BMI and EAT morphometry, whereas in women in group 1 with type 2 diabetes it was associated with lipid and glucose metabolism parameters. Group 1 patients with a mean EAT adipocyte size greater than 89 μm had higher blood levels of Lp-PLA2 and C-peptide compared with those with a mean EAT adipocyte size below 89 μm. Conclusion. Lp-PLA2 level is closely related to the morphometric characteristics of the epicardial fat depot at both the cellular and tissue levels, as well as to lipid and glucose metabolism indices in patients with chronic CAD. Extremely high Lp-PLA2 concentrations are associated with increased EAT thickness, hypertrophy of EAT adipocytes, and elevated sortilin and glucagon levels. Among patients with moderate Lp-PLA2 values, the presence of large EAT adipocytes was accompanied by higher C-peptide levels, and sex differences were observed: in women, Lp-PLA2 concentration was linked to lipid and glucose metabolism parameters, whereas in men it was linked to EAT morphometry. These findings underscore the importance of comprehensive assessment of systemic and local metabolic markers, including Lp-PLA2, for cardiovascular risk stratification in CAD.
Association of mitochondrial DNA C7028T, G3010A, G9055A polymorphisms and the severity of chronic heart failure of ischemic genesis
Introduction. Common mitochondrial DNA (mtDNA) polymorphisms can affect the intensity of cellular respiration and the production of reactive oxygen species. Excessive amounts of reactive oxygen species lead to oxidative stress, which contributes to the development of multifactorial diseases. It can be expected that mtDNA polymorphisms can act as candidate risk loci for the development or progression of cardiovascular pathology. Aim: To evaluate the association of mtDNA polymorphisms C7028T, G3010A and G9055A with the severity of chronic heart failure (CHF) in patients with ischemic heart disease. Material and Methods. The sample included 97 patients aged 63 (58; 68) years. A history of myocardial infarction was diagnosed in 74 (76.3%) patients. Standard clinical and instrumental research methods were performed. The mtDNA polymorphisms were determined using polymerase chain reaction followed by restriction fragment length polymorphism analysis. Results. It was found that among patients with a moderately reduced ejection fraction, the 7028T allele was found 2 times more often than among patients with preserved and reduced ejection fraction (EF) (78.9% versus 34.3% and 34.9%, p = 0.002). In patients with low EF and right atrial dilation, the frequency of the 7028C allele was 8 (44.4%), the 7028T allele – 10 (55.6%); without dilation – 20 (80.0%) and 5 (20.0%) (p = 0.024). There was no association between the G3010A polymorphism and parameters characterizing the severity of CHF. However, the frequency of 3010A substitution was lower among patients requiring diuretic therapy than among those not taking diuretics (8.6% vs. 30.8%, p = 0.005). Only 3 patients (3.1%) were identified with the 9055A allele. Conclusion. Among patients with CHF of ischemic genesis, an association of mtDNA C7028T polymorphism with a heart failure phenotype with a moderately reduced left ventricular EF and in group with low EF with right atrial dilation was revealed. The mtDNA G3010A polymorphism was associated with a diuretic prescription.
Influence of diabetes mellitus on the development of pulmonary dysfunction in community-acquired pneumonia
Aim: To determine the influence of type 2 diabetes mellitus (DM 2) on the functional state of alveolar-capillary permeability (ACP) and inflammatory process intensity in community-acquired pneumonia (CAP). Material and Methods. Patients hospitalized with CAP and DM 2 (n = 24), CAP (n = 24) and DM 2 (n = 32) were enrolled in a singlecenter cross-sectional study. All patients underwent: ventilation scintigraphy to assess the state of ACP, biochemical study of oxidative processes in blood plasma using spectrophotometry. The examination was performed on the 1st-3rd day from the beginning of their hospitalization. Results. A statistically significant increase in ACP at the 30th minute of the examination was observed in both the affected lung (39.2%) and the intact lung (34.1%) in CAP + DM2 patients vs. 30.9% and 28.2% in CAP patients and 23.2% in DM 2 patients. The highest production of trypsin-like proteinases (TLPs, 153.3 BAEE/min·mL), elastase-like proteinases (ELPs, 130.7 BAEE/min·mL), thiobarbituric acid (TBARS, 8.4 μmol/mL), and bityrosine (12*10–3 units) was observed in CAP + DM 2 patients with the minimum activity of α1-proteinase inhibitor (α1PI) of 28.5 IU/mL vs. all comparison groups. The correlation analysis revealed strong direct relations between the ACP value and the activity of TLPs, ELPs, TBARS and negative relations with α1PI. Conclusion. The peculiarity of pulmonary dysfunction manifestation in CAP+DM 2 patients consists in increased ACP both in the affected and intact lungs. The inflammatory process in CAP + DM 2 patients is characterized by the minimum activity of the inhibitor and the maximum activity of proinflammatory enzymes. These correlations testify to a systemic inflammation being more pronounced when the two nosologies occur simultaneously, which affects the state of ACP.
Radiomics in assessing neurosonographic changes in newborns with diabetic fetopathy: analysis of ultrasound images
Introduction. Early noninvasive assessment of brain changes in newborns is a significant challenge in pediatrics. This article presents an approach to noninvasive assessment of brain changes in newborns using radiomics analysis of ultrasound images. Radiomics analysis allows characterization of the morphological structure of neurosonographic ultrasound images using a set of texture parameters and the identification of changes invisible to the naked eye. Aim: To investigate the feasibility of using radiomics analysis of ultrasound images to detect brain changes in diabetic fetopathy in newborns. Material and Methods. Data were collected from brain ultrasound images of 89 full-term neonates (gestational age greater than 37 weeks), including 45 (51%) healthy neonates (control group) and 44 (49%) with diabetic fetopathy (study group). Data were extracted using specialized projections to display four locations: Frontal lobe (F0 scan at the level of the anterior sections of both frontal lobes): 45 healthy and 37 patients. Parasagittal section in the choroid plexus area (S2 scan in the parasagittal plane): 41 healthy and 40 patients. Sagittal section in the corpus callosum area (S0 scan in the midsagittal plane): 44 healthy and 40 patients. Frontal section in the periventricular region (F4 scanning in the area of the parietal and temporal lobes, as well as the cerebellum): 45 healthy and 44 patients. Results. When conducting B-mode neurosonography, the same frequency of subependymal cysts and lateral ventricular dilation was observed in both groups (7% vs. 5%; p = 0.53), but intraventricular hemorrhages and periventricular edema were observed only in the main group (7% vs. 0%; p < 0,05). As a result of radiomics analysis of ultrasound images of the brain, radiomics predictors of texture changes in newborns with diabetic fetopathy were established in four localizations. Classification models were built and ROC analysis was performed. The best results were shown by Model 1 for the frontal lobe (accuracy – 0.71, AUC = 0,69) and Model 4 for the periventricular region (accuracy – 0.89, AUC = 0,85). The established textural changes in the brain of newborns with diabetic fetopathy manifest as follows: an uneven, chaotic distribution of echogenicity with multiple hyperechoic areas is observed in the frontal lobe. The periventricular zone exhibits a marked, diffuse increase in echogenicity, creating a homogenized effect on the image. Radiomics analysis of ultrasound images can reveal changes in brain texture that are not detectable with standard neurosonography. Conclusions. Multiparametric analysis of ultrasound images using a radiomics approach demonstrated the ability to detect structural changes in the brain of newborns with diabetic fetopathy. The results confirm the effectiveness of radiomics analysis in identifying subtle neuroanatomical changes.
Antibacterial and antimycotic activity of benzophenazine derivatives: an in vitro study
Introduction. Today, one of the urgent health problems is the increasing antibiotic resistance of pathogenic microorganisms. In this regard, there is an increasing need to find new antimicrobial agents for medical use. Benzophenazine derivatives may be an example of promising antimicrobial agents. This article presents a study of the antimicrobial properties of newly synthesized compounds of the benzophenazine group. Aim: To evaluate the antibacterial and antifungal potential of benzophenazine derivatives under experimental conditions in vitro. Material and Methods. The antimicrobial activity of a panel of benzophenazine derivatives – unsubstituted benzophenazin-5-ol (VN-13), o-methylated benzophenazin-5-ol (VN-16-3), 4,5-difluorobenzophenazin-5-ol (VN-11), and o-methylated 4,5-difluorobenzophenazin5-ol (VN-35-3) – was assessed by titration in sterile 96-well plates, followed by plating on solid media. The antimicrobial activity of the compounds was evaluated against pathogens of infectious diseases such as Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 29213, Streptococcus agalactiae, Pseudomonas aeruginosa, MRSA (methicillin-resistant Staphylococcus aureus), VRE (vancomycin-resistant Enterococcus), CRAB (carbapenem -resistant Acinetobacter baumannii), Burkholderia cenocepacia, Candida albicans. The antibacterial and antifungal potential of the compounds was assessed by the presence or absence of microbial colony growth at various concentrations of the benzophenazines (from 2000 μg/ml to 0.016 μg/ml). Results. The study results demonstrated that all tested benzophenazine derivatives exhibited antibacterial activity against Streptococcus agalactiae and Burkholderia cenocepacia. Against other tested strains, including multidrug-resistant ones, only unsubstituted benzophenazine-5-ol (VN-13) showed activity. Pseudomonas aeruginosa and Escherichia coli ATCC 25922 were resistant to all studied compounds. Conclusion. Benzophenazine derivatives demonstrate bactericidal or bacteriostatic activity against a number of bacteria, including polyresistant strains, as well as fungi of the genus Candida. Based on the results obtained, it is possible to assume the relevance of further research in the direction of studying the efficacy and safety of benzophenazines as promising antimicrobial agents.
Experimental investigation of the diterpenoid alkaloid songorine regarding its antinociceptive activity and potential adverse effects
Introduction. Opioid and cannabinoid receptors are involved in the antinociceptive effects of songorine, a diterpene alkaloid isolated from the above-ground parts of Aconitum barbatum, as demonstrated in various models of chemical and thermal pain. The involvement of opioid receptors in songorine is antinociceptive mechanism necessitates studying its potential side effects, characteristic of narcotic analgesics. TRPA1 receptor involvement in songorine is analgesic mechanism is possible, requiring further investigation in models of mechanical hyperalgesia with formalin. Aim: To study the antinociceptive activity of the diterpenoid alkaloid songorine at a dose of 25 μg/kg in the Randall-Selitto test against formalin-induced hyperalgesia and its potential opioid-like side effects. Material and Methods. The study was performed on outbred male CDI and mice male CBA mice obtained from the Department of Experimental Biological Models at the E.D. Goldberg Research Institute of Pharmacology and Regenerative Medicine Tomsk NRMC. Songorine, a diterpene alkaloid of the atizine series, was administered orally to the animals at a previously established effective dose of 25 μg/kg. Tramadol (KRKA) at a dose of 20 mg/kg and ketorolac (Dr. Reddy´s Laboratories Ltd.) at a dose of 6 mg/kg were used as reference drugs. Antinociceptive activity was studied using the Randall-Selitto test with a Ugo Basile (Italy) analgesy-meter on a mechanical pain model, with and without formalin-induced hyperalgesia. To study the effect of songorine on the frequency of breathing in non-narcotized mice, the number of respiratory movements per minute was recorded after 5-fold administration of the alkaloid and the reference drug tramadol. The withdrawal syndrome was assessed using the non-selective opioid receptor antagonist naloxone (Sigma). The effect of the alkaloid on gastrointestinal smooth muscle was studied in the “charcoal meal” test. Results. Songorine is antinociceptive effect in the Randall-Selitto test upon single administration is comparable to ketorolac and tramadol, but less prolonged than the latter. Songorine is pronounced analgesic activity in formalin-induced hyperalgesia suggests the possible involvement of TRPA1 receptors in its mechanism of action. The study of possible undesirable effects of the course per os administration of the diterpene alkaloid songorine at a dose of 25 μg/kg showed that it does not cause the development of respiratory depression, withdrawal syndrome and drug-induced obstipation. Conclusion. In the Randall-Selitto test, TRPA1 receptor involvement in the antinociceptive activity of songorine was established against a background of formalin hyperalgesia. The diterpene alkaloid songorine at subchronic administration at a dose of 25 μg/kg does not show the side effects characteristic of morphine-like drugs.
Development of HPLC-methodology of determination of amiodarone and desethylamiodarone in human blood plasma
Background. Amiodarone is widely used as an antiarrhythmic drug, but its effectiveness is not entirely predictable, and its side effects are not completely controllable. To determine the effective concentration of amiodarone in the blood, a method for quantitative analysis of the drug in the presence of a biological matrix is needed. Objective. To develop a procedure for quantitative determination of amiodarone (AMI) and desethylamiodarone (DEA) in blood plasma by high-performance liquid chromatography (HPLC). Materials and Methods. The procedure was developed using an Agilent 1260 Infinity chromatograph with diode array detector (Agilent, USA) on a Tsunami C18 Pharm column (250×4.6 mm, 5 μm) with proprietary stationary phase. Agilent Zorbax SB C8 precolumn (9.4×15 mm, 7 μm) was used to protect the column from mechanical contaminants. Validation was performed according to OFS.1.1.0012.15 “Validation of Analytical Methods” for the following parameters: selectivity, matrix effect, linearity, accuracy, precision, stability and limits of detection and quantification. Results. The QuEChERS sample preparation was modified to achieve optimal conditions for the extraction of AMI and DEA from the biological matrix. Mobile phase A was phosphate buffer (pH 3, 7.5 mM), mobile phase B was 100% acetonitrile. The separation was performed in gradient mode. Up to 7.00 minutes – the B phase content was 55%, from 7.00 to 7.15 minutes – an increase in B phase content to 85% in order to elute the more hydrophobic components, from 7.15 to 15.00 minutes – the B phase content did not change, followed by a return to the original 50% at 15.15 min. The total analysis time was 18 minutes. Column thermostat temperature was set to 30 °C, flow rate – 1.2 mL/min; injection volume – 80 µL; selective wavelength was 241 nm. The value of retention factor for AMI was 2.25; for DEA – 1.44. Conclusion. The authors have developed and validated the new HPLC procedure for quantitative identification of AMI and DEA in human blood plasma.
Modification of a high-performance liquid chromatography method for quantitative determination of rivaroxaban concentration in blood
Introduction. Achieving therapeutic concentrations of direct oral anticoagulants (DOAC) and, accordingly, personalization of anticoagulant therapy in certain groups of patients are becoming increasingly important. To optimize drug monitoring in routine clinical practice, it is necessary to develop and test sensitive and selective methods that can quantitatively determine the content of DOAC in the blood, including rivaroxaban. Aim: To modify the method for determining the concentration of rivaroxaban in the blood using high-performance liquid chromatography (HPLC), as well as testing the selected conditions for determining the concentration of the drug in the whole venous blood of patients. Material and Methods. For the first stage of the work, the samples for the study were blood samples (n = 20) from healthy volunteers (n = 5) not taking medications. Blood was collected from a peripheral vein using a vacuum system in a volume of 6 ml. Blood collection tubes with four different fillings were used. Before preparation, the samples were divided into 6 parts and each was supplemented with a solution of rivaroxaban of different concentrations, prepared from the pure substance Rivaroxaban (India). Next, liquid extraction of rivaroxaban with acetonitrile from a sample of whole venous blood was carried out with parallel elimination of the interfering effect of proteins by precipitation with nickel chloride. The separation of the sample components was performed by reversed-phase highperformance liquid chromatography on a liquid chromatograph (1260 Infinity II LC). The analytical signal on a diode-array detector (1260 DAD WR, Agilent Technologies) was recorded at two wavelengths of 254 nm and 280 nm. For the second stage of the work, the samples for the study were whole venous blood samples from patients taking rivaroxaban (n = 54). Blood is collected in the morning, on an empty stomach, 12 hours after taking the last dose of the drug. Results. The authors investigated and established the factors influencing the decrease in the detection limit of rivaroxaban (Bayer, Germany) in the blood when determining it by HPLC using an Agilent 1260 liquid chromatograph with a diode array detector (Agilent Technologies, Germany). To assess the degree of rivaroxaban extraction and select the working wavelength, calibration dependences of the anticoagulant in the initial acetonitrile solutions and graphs of changes in the peak areas of rivaroxaban from its content in the blood were constructed: at a wavelength of 254 nm (r2 = 0.98) and 280 nm (r2 = 0.99). The dependence function at a wavelength of 254 nm has a larger slope, which makes it possible to reduce the detection limit of the substance being determined. The silicon dioxide content in the tube does not significantly affect the analytical signal of rivaroxaban (minimum detection limits 0.25 µg/ml, minimum determination limits 0.77 µg/ ml), and does not introduce additional error into the accuracy of the method. The median concentration of rivaroxaban was 0.32 µg/ ml (0.26; 0.49) 12 hours after taking the drug. Conclusion. The use of a modified HPLC method with a wavelength of 254 nm selected for detecting the analytical signal makes it possible to reduce the detection limit of the substance being determined and increase the range of concentrations being determined. And the use of tubes with silicon dioxide can be recommended for decreasing the influence of the matrix effect on the quantitative determination of rivaroxaban in blood and increasing the accuracy of the method.
Metabolic and functional disorders in rats with cadmium intoxication and their pathogenetic correction
Introduction. The relevance of the study is due to the high prevalence of diseases caused by exposure to harmful substances, such as cadmium, which is an environmental and professional hazard. Modeling the intoxication syndrome in animals and developing strategies for its correction allow us to identify effective methods of prevention and therapy, which is especially important for combating toxic effects and preventing the development of severe pathologies of the liver, kidneys and cardiovascular system. Aim: To study influence of cadmium sulfate on the changes in metabolic and functional parameters of blood and organs and their pathogenetic correction. Material and Methods. The intoxication syndrome was modeled on 65 rats, by exposure to cadmium sulfate in an amount of 1 mg/ kg of body weight intramuscularly. After creating systematic daily intoxication lasting 30 days, L-arginine (10 mg/kg of animal body weight) was injected intramuscularly and kudesan (10 mg/kg) orally. Results. The applied drugs had an inhibitory effect on the activity of oxidative stress, decreased the level of malonate dialdehyde in the blood and in the cortex and medulla of the renal tissue, compared with the results indicating cadmium intoxication. The severity of lipid peroxidation was also reduced in the liver parenchyma. At the same time, positive dynamics of the antioxidant system activity and an increase in the activity of SOD, as well as total metabolites of nitric oxide – NOx were revealed. The use of corrective drugs – L-arginine and kudesan provided a lower level of LDL-C with an increase in HDL-C. From the side of the main processes of urine formation, an increase in SCF, water and sodium transport in the renal tubules was shown due to a higher activity of Na, K-ATPase in the cortex and medulla of the kidneys. A negative correlation was found between the decrease in MDA content, the increase in NOx concentration and the activation of Na, K-ATPase (r = –0.67, p < 0.05; r = –0.69, p < 0.05). A decrease in the activity level of organspecific enzymes in blood plasma indicates an improvement in liver function. Conclusion. Cadmium intoxication is characterized by the development of oxidative stress, decreased NOx levels as a major vasodilator, and increased atherogenic lipoprotein levels in the blood plasma. These biochemical changes disrupt microcirculatory hemodynamics and the functional capacity of renal and hepatic tissue. Corrective therapy with the medicinal agents L-arginine and kudesan for cadmium intoxication effectively suppressed oxidative stress and improved cholesterol and nitric oxide metabolism. The combination of these metabolic parameters in the intoxication syndrome was accompanied by increased renal and hepatic function, improved parameters of key urine formation processes, and decreased levels of organ-specific enzymes in the blood plasma. This approach to pathogenetic correction opens up prospects for clinical application in toxicology and preventive medicine.
The influence of preterm birth on the development of intracardiac nerve fibers in the postnatal ontogenesis: an immunohistochemical study
Rationale. At the time of birth, the innervation of the rat heart is not complete: differentiation of neurons of the autonomic ganglia, growth of axons, and development of nerve fibers sheaths continue in the postnatal period of ontogenesis. Whether preterm birth affects the innervation of the heart has not been sufficiently studied. Aim: To perform immunohistochemical study of cardiac nerve fibers of preterm rats in the postnatal period of ontogenesis. Material and Methods. A morphological study of the development of intracardiac nerve fibers in the right and left ventricles, as well as the interventricular septum of the heart in full-term and 24-hour preterm Wistar rats on the 7th, 56th and 180th days of the postnatal period of ontogenesis was carried out. Immunohistochemical detection of PGP9.5 and tyrosine hydroxylase was carried out. The relative area of nerve fibers (PGP9.5-positive staining) and sympathetic postganglionic nerve fibers (tyrosine hydroxylase-positive staining) was determined dynamically, as well as the proportion of sympathetic nerve fibers from nerve fibers total number in the wall of the right and left ventricles, as well as the interventricular septum of the heart of full-term and 24-hour preterm rats. Results. It has been shown that on the 7th day of the postnatal period of ontogenesis in the right, left ventricle and interventricular septum of the heart in 24-hour preterm rats, the relative area of nerve fibers is reduced, compared with that in full-term animals, the differences are leveled out by the 56th day. The relative area of sympathetic postganglionic nerve fibers in the interventricular septum of 24-hour preterm rats on the 7th day of the postnatal period of ontogenesis remains lower, on the 56th day – is higher than in fullterm animals. The relative area of sympathetic postganglionic nerve fibers in the right ventricle of the heart of 24-hour preterm rats throughout the experiment remains lower, while in the left ventricle – does not differ from the parameters of full-term animals. Conclusion. There were revealed structural features of the development of intracardiac nerve fibers of the right and left ventricles of the heart, as well as the interventricular septum in 24-hour preterm rats in the postnatal period of ontogenesis, which may be the cause of a violation of the autonomic regulation of the heart.
Additional parameters of myocardial perfusion imaging in the detection of multivessel coronary artery lesions (case report)
Myocardial perfusion imaging is included in the diagnostic algorithm in management of chronic coronary syndromes. However, in patients with multivessel coronary artery disease (CAD) this method can demonstrate false-negative result, which, in case of low pretest probability of CAD and mild symptomatology, can lead to errors in diagnostic tactics. The presented clinical case demonstrates the significance of analysis of additional parameters of myocardial perfusion imaging on the example of a patient with multivessel coronary artery disease and the phenomenon of balanced ischemia, in which the left ventricular perfusion has an almost normal perfusion. A 58-year-old patient has main complaints of dyspnea and blood pressure elevations up to 170/100 mmHg. The calculated pre-test probability of coronary heart disease was 20%. Rest ECG, echocardiography showed no significant abnormalities. According to the guidelines for diagnostics and treatment of patients with stable ischemic heart disease, the patient was referred for noninvasive stress testing myocardial perfusion scintigraphy. According to the study results, the size of reversed perfusion defect was 3% of the left ventricle, which is defined as a moderate risk of adverse cardiovascular events. However, extended analysis of myocardial perfusion data, such as transient ischemic dilatation index, stress-induced dynamics of left ventricular ejection fraction, wall motion and mechanical dyssynchrony of the left ventricle, as well as the presence of coronary calcium allowed to suspect multivessel coronary artery disease in the patient, which was the reason for coronarography and subsequent revascularization.
False aneurysm and arteriovenous fistula between the popliteal artery and popliteal vein one year after a shrapnel wound: surgical reconstruction in a military field hospital in a special military operation zone
A 41-year-old serviceman. A year ago, while performing a combat mission in the Special Military Operations (SMO) zone, he sustained a blind shrapnel wound to his right lower extremity as a result of a shell explosion. The metal fragment was not removed due to its deep location in the tissue of the lower leg. The wound healed by primary intention, and he returned to military service 10 days after seeking medical attention. Six months later, he felt the development of a tumor-like rounded mass in his right popliteal region, which continued to grow. A year after the injury, he developed numbness in his foot and decreased sensation in his fingers. An ultrasound examination revealed a false aneurysm of the popliteal artery (PA) and an arteriovenous fistula (AVF) between the PA and popliteal vein (PV). Due to the risks of transporting the patient to a specialized hospital during active combat operations and the progression of tibial nerve neuropathy symptoms, a decision was made to perform reconstructive surgery at a military field hospital in the SMO zone. The following surgery was performed: removal of the PA false aneurysm, removal of the AVF between the PA and PV, and autologous vein grafting of the PA with a reversed great saphenous vein. The postoperative period was uneventful. Symptoms of tibial nerve neuropathy regressed 14 days after surgery. The patient was discharged and returned to military service 30 days after surgery.
Machine learning algorithms for prediction of side effects development in patients with pharmacoresistance to antipsychotics and antidepressants
Rationale. Artificial intelligence and machine learning allow for development of predictive models using pharmacogenetic testing (PGT) data. It helps to predict the development of side effects (SE) in patients treated with antipsychotics (AP) and antidepressants (AD) and provides personalized approach for the treatment of patients with treatment resistance to antipsychotics and antidepressants. Aim: To compare machine learning algorithms for prediction of side effects development in patients with pharmacoresistance (PR) to antipsychotics and antidepressants. Material and Methods. A retrospective study utilized PGT data of 144 patients (72 males and 72 females, mean age 33±8.4 years) with PR to AP and AD, treated on an outpatient basis for the period from 2016 to 2024. PGT assessed CYP2D6, CYP2C19, CYP1A2, and MDR1 (C3435T) gene polymorphisms conducted in medical laboratories in St. Petersburg (MedLab, Invitro). Machine learning algorithms Lasso, Ridge, Extra Tree (ET), k-Nearest Neighbors (KNN), Naive Bayes (NB), Random Forest (RF), and eXtreme Gradient Boosting (XGB) were used to build the predictive model for SE development. Results. RF algorithm demonstrated the best performance as the predictive model in test sample parameters: ROC-AUC 75.5% [59.6; 89.9], sensitivity 72.2% [55.0; 88.9], and specificity 58.3% [33.3; 81.8]. The main predictors included age, sex, CYP2C19, CYP2D6, CYP1A2, MDR1 C3435T genotypes and alleles, smoking, presence of neurological diseases and substance abuse. Conclusion. Random Forest model machine learning algorithm has demonstrated high efficiency in predicting side effects probability in treatment resistant patients to AP and AD. The model can serve as the basis for future research and development of personalized treatment approach for the patients treated with AP and AD, with the possibility of further integration into Medical Decision Support System.