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Aim. To evaluate the expression of leptin receptor isoforms in local fat depots in patients with coronary artery disease (CAD) and acquired heart defects (AHDs).Material and methods. The study included 120 patients with CAD. The comparison group consisted of 96 patients with degenerative aortic stenosis (AS). Expression of six leptin receptor isoforms (LEPR1, LEPR2, LEPR2/2, LEPR3, LEPR3/2, LEPR4) was assessed using quantitative real-time polymerase chain reaction in subcutaneous (SAT), epicardial (EAT) and perivascular (PVAT) adipose tissue. Statistical processing was carried out using the Statistica 10.0 and SPSS 17.0 for Windows software package.Results. In EAT, minimal expression of LEPR1, LEPR2, LEPR2/2, LEPR3, LEPR3/2, LEPR4 was detected relative to SAT and PVAT in the group of CAD patients. In patients with CAD, mRNA levels of six LEPR isoforms were lower than in patients with AS. In indi­viduals with AHDs, a decrease in the expression of LEPR1, LEPR2, LEPR2/2, LEPR3, LEPR3/2, LEPR4 in SAT relative to EAT and PVAT was recorded. However, only the LEPR1 and LEPR2 isoforms were significantly lower in SAT in patients with AS when com­pared with patients with CAD. In PVAT, the maximum mRNA levels of six LEPR isoforms were found in both groups. There were no significant differences in LEPR1, LEPR2, LEPR2/2, LEPR3, LEPR3/2, LEPR4 expression between patients with CAD and AHDs.Conclusion. Patients with CAD are characterized by a marked decrease in the expression of six LEPR isoforms in EAT. A decrease in the expression of studied LEPR isoforms in EAT is associated with impaired adipogenesis, adipocyte hypertrophy, insulin resistance, increased proinflammatory factors, hyperleptinemia, and progression of atherosclerosis. The identified features of EAT in patients with СФВ can probably have both local and systemic negative effects on the cardiovascular system.

Aim. The aim of this review was to analyze publications describing studies focusing on the pathophysiological mechanisms of calcification of bioprosthetic heart valves, and to substantiate new and promising methods of calcification prevention for the implantable medical devices.Material and methods. Databases and electronic libraries such as PubMed, Google Scholar and eLibrary were used for searching relevant articles. Search queries included the following word combinations: “bioprosthetic heart valves”, “structural valve degeneration”, “calcification”, “cyclic loading”, “inflammation”, “proteolysis”, “proteolytic enzymes”, “decellularization”, “anticalcification treatment”. The references in relevant articles were used for the search as well. Preference was given to works published from January 2013 to January 2023.Results. We have considered the key aspects of bioprosthetic heart valves calcification and the main strategies of calcification prevention. Calcification of bioprosthetic heart valves incorporates a complex set of mechanisms that includes, but is not limited to: 1) binding of calcium in chemically stabilized biomaterial by free groups of the preservative; 2) precipitation of calcium on residual donor cells and cell debris; 3) pro-calcifying changes in biological material due to proteolysis, mechanical and oxidative stress; 4) cell-mediated biomineralization. Despite modern advances in biopreservation, such as treatment with chemical agents that prevent the deposition of calcium, the problem of bioprosthetic heart valves calcification still prevails. The cause of it lies in the heterogeneity of the pathophysiological mechanisms behind the mineralization of biomaterial: the currently developed methods of calcification prevention cannot block all ways of bioprosthetic heart valves calcification.Conclusion. Calcification of bioprosthetic heart valves leaflets is a complex process that underlies the main cause of dysfunction of the medical devices. Supposedly, a new innovative approach that involves polymer hydrogel filler in biomaterials can completely prevent its calcification.

The failure of heart valve bioprostheses, requiring repeated intervention to replace them, is a serious drawback that narrows the scope of such devices. The present study demonstrates the experimental investigation of a medical device designed to partially solve the problem of repeated interventions on heart valves, primarily with an emphasis on reducing the duration and trauma of such procedures due to the sutureless balloon implantation method of the «valvein- valve» method.Material and methods. The paper presents a series of in silico, in vitro and in vivo experiments to evaluate various aspects of the device under development. Numerical modeling of the final shape setting to the supporting frame of the heart valve prosthesis to select the most promising concept for prototyping was carried out in the Abaqus/CAE (Dassault Systèmes, France) based on the finite element method. The selected optimal support frame model was prototyped in the form of a series of prosthesis samples of four standard sizes for hydrodynamic studies of quantitative characteristics in vitro. The study was carried out in the Vivitro Labs unit (Vivitro Labs, Canada), imitating the physiological mode of the heart, the prostheses were examined for the mitral position. The developed prototypes of the device were supplemented with related products, an implant holder and a balloon catheter, after which the proposed method of sutureless fixation was validated in an in vitro implantation procedure on a bovine heart model and a series of in vivo (n = 3) chronic experiments on animals.Results. In the course of numerical simulation, it was shown that in Model No. 3 of the supporting frame of the prosthesis, the smallest stresses occur – with an amplitude of up to 490 MPa. For other concepts (Models No. 1 and No. 2), this indicator was significantly higher, 543 and 514 MPa, respectively. Prototypes obtained on the basis of the selected shape of the support frame demonstrated satisfactory hydrodynamic characteristics: effective hole area 190-261 mm2, regurgitation volume 6–9 ml/cycle, average transprosthetic gradient 4.4–6.4 mmHg, depending on size. The study of the technology of sutureless balloon implantation in an in vitro model of the heart and the subsequent chronic experiment on sheep confirmed the main idea of the system – the possibility of a significant reduction in the duration of repeated prosthetics. It has been shown that the time of suture implantation of the “classic” frame prosthesis of the mitral valve is 23–29 minutes, with a total access time of 41–52 minutes. When implanting the experimental device, the sutureless prosthesis itself took 4–6 minutes, access time 24–29 minutes. At the same time, one-month results of an echocardiographic study of the operation of the prosthesis demonstrated satisfactory hemodynamics.Conclusions. This work demonstrates a consistent series of tests of the system being developed for repeated heart valve replacement, which substantiates some design solutions, confirms the effectiveness and viability of the chosen approach to sutureless minimally invasive implantation.

As a clinical case, we present the "portrait" of a woman patient with acquired mitral valve (MV) defect against the background of infective endocarditis which was diagnosed during the third trimester of pregnancy. The patient underwent mitral valve replacement surgery with biological prosthesis "KemKor" followed by two successful deliveries. In 18 years after the correction of the mitral valve defect, she developed valve prosthesis dysfunction therefore, she underwent endovascular transcatheter implantation of bioprosthesis by method "prosthesis-into-prosthesis" in the mitral position.This clinical case is unique in terms of the reasoning the biological prosthesis choice to correct acquired MV defect in a patient of reproductive age, the long-term period of the bioprosthesis functioning and the correction of further developed valve dysfunction using the techniques of transcatheter implantation.

Aim. To assess gene expression of enzymes of the sphingomyelinase pathway of ceramide biosynthesis and degradation in fat depots of various localization in patients with cardiovascular diseases.Material and methods. A total of 38 patients were examined: 20 with coronary artery disease (CAD) and 18 with aortic stenosis/insufficiency. Biopsies of subcutaneous, epicardial, perivascular adipose tissue (AT) (SAT, EAT, PVAT, respectively) were obtained during surgery. The gene expression of sphingomyelinase pathway enzymes (acid and neutral sphingomyelinase SMPD1 and SMPD3) and the degradation of ceramides (acid ceramidase ASAH1; sphingomyelin synthase 1 and 2 SGMS1 and SGMS2) was assessed using a quantitative polymerase chain reaction. Analysis of the level of corresponding proteins was carried out using immunoblotting (western blotting). Statistical processing was performed using GraphPad Prism 8 (GraphPad Software).Results. In CAD, the maximum expression of SMPD1 was observed in subcutaneous and epicardial adipocytes. In acquired heart defects (AHD), the level of SMPD1 mRNA in the SAT was higher than in the PVAT. Expression of the SMPD1 gene in the EAT of patients with CAD was more pronounced than in patients with heart defects. PVAT was characterized by minimal expression of SMPD1 regardless of disease. Expression of SMPD3 had no tissue features in studied groups, while SMPD1 was more expressed in cardiac AT adipocytes than SMPD3. ASAH1 in the EAT of patients with CAD was maximal relative to adipocytes of other localizations. Persons with AHD were characterized by a high expression of ASAH1, regardless of AT localization, exceeding the values of patients with CAD. In CAD, the level of SGMS1 in EAT was higher than in SAT and PVAT, while no differences were found in patients with AHD depending on AT location. SGMS1 gene expression in EAT of patients with CAD was higher than in the group of AHD. Expression of SGMS2 significantly exceeded SGMS1 in both study groups and was maximal in SAT and PVAT adipocytes compared to EAT in the CAD group and in PVAT in the AHD group. Coronary pathology was characterized by a higher level of SGMS2 mRNA in SAT and EAT. The level of ceramide metabolism enzymes in AT of patients corresponded to the expression of their genes.Conclusion. In coronarogenic disease, cardiac AT (mainly epicardial) is characterized not only by increased expression of gene ceramide synthesis enzymes via the sphingomyelinase pathway, but also by activation of ceramide utilization with sphingosine formation. The observed changes may contribute to the accumulation of ceramides and sphingomyelin associated with atherosclerotic processes.

Bioprosthetic valve dysfunction represent a serious drawback that limits the wider clinical use of these medical devices for valvular heart disease surgery. Modern studies describe the view of pathophysiologists on this problem as a multifactorial multi-stage process that causes irreversible changes in bioprosthesis components, ultimately leading to its dysfunction. However, in addition to under- standing the causes and manifestations of prosthetic valve dys- function, an applied question arises about the treatment strategies — determining the most attenuated and accessible low-risk method/ device. The aim of this review was to analyze and systematize current literature data on methods and designs used in repeated surgical and transcatheter interventions on heart valves.

Aim. To compare the expression of enzymes of the ceramide de novo synthesis pathway in cardiac adipose tissue (AT) and blood vessels of patients with coronary artery disease (CAD) and acquired heart defects.Material and methods. The study included 20 patients with CAD and 18 patients with aortic stenosis/regurgitation. Biopsies of subcutaneous, epicardial, perivascular AT (SCAT, EAT, PVAT, respectively) were obtained during surgery. Quantitative PCR test was used to evaluate the gene expression of de novo ceramide synthesis enzymes (serine palmitoyltransferase C1 and C2: SPTLC1, SPTLC2; ceramide synthase 1-6: CERS1-6; dihydroceramide desaturase: DEGS1). Statistical analysis was performed using GraphPad Prism 8 (GraphPad Software).Results. Patients with CAD were characterized by a higher level of mRNA SPTLC1 in SCAT and EAT, SPTLC2, CERS1, producing C18 ceramides, CERS5 and CERS6, generating C14-C16 ceramides in EAT, CERS2 — in SCAT, producing long-chain ceramides C20-C24, CERS4, synthesizing very long-chain ceamides C18-C20. In PVAT, a high expression of CERS4 and CERS3, which synthesizes very long-chain ceramides C26 and higher, was revealed. DEGS1 expression was highest in SCAT and EAT. In patients with heart defects, there was a high expression of CERS3 in PVAT, CERS4 in EAT and PVAT, DEGS1 in EAT. The mRNA level of SPTLC1 in SCAT and EAT, SPTLC2 in EAT, CERS2 in all studied AT, CERS4 and 5 in EAT, DEGS1 in SCAT and EAT among patients with CAD was higher than in the comparison group.Conclusion. Regional fat depots of the heart differed in the level of expression of enzymes of the ceramide de novo synthesis pathway. The results obtained indicate the activation of ceramide synthesis along this pathway in predominantly epicardial adipocytes in coronary pathology, which may contribute to the accumulation of long-chain ceramides in the AT of this localization.

Aim. The aim of this study is to compare hospital and long-term outcomes in patients with low surgical risk after aortic stenosis correction in surgical aortic valve replacement (SAVR) and transcatheter aortic valve implantation (TAVI).Materials and methods. Patients with aortic stenosis (AS) were included in the study. The main criterion for inclusion - the presence of indications for surgical correction of an isolated aortic valve defect. The first group included patients after TAVI (n = 11). As a control group, patients who underwent surgical correction aortic stenosis (n = 23). The TAVI group used non-repositories CoreValve (Medtronic) and repositioned Lotus (Boston Scientific) valves. Biological prosthesis Uniline (KemKor) was used in the group of surgical patients. The efficacy of the interventions was evaluated at the hospital and annual follow-up, based on the analysis of the combined endpoint, and major adverse cardiovascular events.Results. The mean age of the patients was 66.9±5.7 years in the SAVR group and 75.3±4.1 years in the TAVI group (р=0,003). The average score for EuroSCORE II was 3.49±0.3 in the SAVR group and 3.93±1.2 in the TAVI group (р=0,31). Repositionable and non-repositionable valves were implanted in 2 and 9 cases, respectively. The combined endpoint was noted in one patient in the TAVI group and in four patients in the SAVR group according to the annual observation results. There are three (13%) fatal outcomes in the surgical prosthesis group.Conclusion. The possibility of using TAVI in low-risk patients with aortic stenosis was demonstrated on the basis of comparable results of evaluating efficacy and safety with SAVR in 1-year follow-up.

Aim. To study a bone mineral density (BMD) in recipients with calcium degeneration and preserved morphofunctional state of heart valve bioprotheses (BP).Material and methods. The experimental groups included the patients with structural dysfunctions of BP associated with the calcification of the xenomaterial, confirmed by light and electron microscopy data (group I, n=22) and the patients with normal functional state of the implanted valves according to the results of echocardiographic tests (group II, n=48). BMD was assessed by dual energy absorptiometry in the absolute count of mineralized bone and indicators of T­test.Results. When interpreting the T­test of a femoral neck the severity of osteopenic syndrome prevailed in patients with calcium degeneration of BP (­1,83 [­2,66; ­1,25] in group I vs ­1,47 [­2,51; ­0,86] in group II, р=0,055). At that the mean values of this indicator in patients with the development of calcium­associated BP dysfunctions in the first four years after a surgical correction of the defects reached the diagnostic criteria of the osteoporosis (­2,73 [­3,40; ­2,09] vs ­1,67 [­2,92; ­0,42], р>0,05). According to the result of absorptiometry of the lumbar spine the worst Т­score indicators were also recorded in recipients with the calcification of BP within the first four years of follow­up (­1,75 [­1,83; ­1,43] vs ­0,81 [­0,96; ­0,66] in patients without the signs of calcification, р=0,021). The state of BMD reflects the physiological and pathological processes of calcium redistribution in organism. The existence of the pathogenetic parallels between the activity of bone resorption processes and calcification of the elements of cardiovascular system allows to consider the osteopenia and pathological mineralization of the soft tissues within the framework of a single continuum. The results of the presented work in their turn testify to the determining significance of the severity of osteopenic syndrome manifestations in the development of the “early” calcium degeneration of BP.Conclusion. Extension of the concepts of the mechanisms and processes which form the pathogenetic basis of mineralization will allow to determine the effective strategies for managing the risk of calcium­associated BP dysfunctions.

Aim: to evaluate the manipulative properties of the system being developed for cardiac valve re-operation on an in vitro bovine heart model.Material and methods. The prototype of the prosthesis being developed, mounted on the implant holder, as well as the dilatation balloon of its own design, were used as the objects of the study. The bioprosthesis «UniLine» of 21 mm size for the aortic position was chosen as the target site of implantation, which was established by the «classical» suture method. After that, the implantation of the tested device was carried out as a «valve in valve» and the quality of the installation and the combined operation of all the components of the re-prosthesis system were evaluated.Results. The test implantation demonstrated the consistency of the proposed method on the basis of balloon seamless fi xation, as well as high ergonomic characteristics: the average time of seamless implantation of the developed prototype on an in vitro animal heart model was 3 minutes versus the implantation of the «UniLine» bioprosthesis – 11 min, Implantation provided a reliable prosthesis The breaking force was 12.9 N, which is equivalent to a pressure of 279 mm Hg.

The aim of the study was to perform a series of in vitro tests of a prototype of the developing heart valve prosthesis to evaluate its functional characteristics. Materials and methods. In this work we have used the frames and full prototypes of the prosthesis, consisting of a stent-like stainless steel support frame with mounted biological leaflets and cover. The authors evaluated the calculated and experimental forces necessary for the displacement of the sutureless implanted prosthesis using the test machine under uniaxial tension. The risk of defects and damages to the supporting framework as a result of implantation was evaluated by scanning electron microscopy. The hydrodynamic characteristics of the prosthesis were investigated under physiological conditions and «valvein-valve» implantation. Evaluation of the ergonomics and applicability of the proposed construction on the cadaver heart model of cattle was carried out. Results. As a result of the forces assessment, it was found that the force required to shear the prosthesis was 3.12 ± 0.37 N, while the calculated value was 1.7 N, which is significantly lower than the obtained value. The comparison of the images obtained with small and large magnifications demonstrated the absence of critical surface defects. Additional analysis under the super-large magnifications also did not reveal problem areas. During the hydrodynamic study, it was shown that the average transplant gradient increased slightly from 2.8–3.4 to 3.2–4.5 mm Hg for the initial prosthesis and the «valve-in-valve» complex, respectively. The decrease of the effective orifice area was 6–9% relative to the initial one. Evaluation of the implantation technique demonstrated the consistency of the approach: the use of the developed holder in combination with the balloon implantation system made it possible to position the prosthesis throughout the procedure. Conclusion. The series of tests demonstrates the consistency of the developed design, intended for the replacement of a failed prosthetic valve of the heart with the «valve-in-valve» implantation.

Aim. To study calcium-phosphor homeostasis and proinflammatory status of the cardiac valves bioprostheses (BP) recipients related to their interference with calcium degeneration of biomaterials.Material and methods. A retrospective assessment was performed of the calcium-phosphor metabolism and markers of non-specific inflammatory response in recipients of BP in mitral position: with histologically confirmed calcification — group I (n=22) and with normal morphology and prosthesis function — group II (n=48).Results. In patients with BP degeneration, comparing to the recipients of biological prostheses with normal function at the background of moderate hypovitaminosis D (34,0 [21,0; 49,4] versus 40 [27,2; 54,0] pmol/L, р>0,05), osteoprotegerine deficiency (82,5 [44,2; 115,4] versus 113,5 [65,7; 191,3] pg/ml, р>0,05) and osteopontine (4,5 [3,3; 7,7] versus 5,2 [4,1; 7,2] ng/ml, р>0,05) there was statistically significant decrease of the bone isoenzyme of alkaline phosphatase (17,1 [12,2; 21,4] versus 22,3 [15,5; 30,5] E/L, р=0,01), and significant decrease of IL-8 (9,74 [9,19; 10,09] pg/ml versus 13,17 [9,72; 23,1] pg/ml, р=0,045) with general increase of proinflammatory serum markers activity.Conclusion. Into the group of probable predictors determining the tempos of BP calcification, the following could be included: specifics of recipient metabolic status defined by the activity of bone resorption processes, and local and systemic inflammation.

Background Whereas the risk factors for structural valve degeneration (SVD) of glutaraldehyde‐treated bioprosthetic heart valves (BHVs) are well studied, those responsible for the failure of BHVs fixed with alternative next‐generation chemicals remain largely unknown. This study aimed to investigate the reasons behind the development of SVD in ethylene glycol diglycidyl ether–treated BHVs. Methods and Results Ten ethylene glycol diglycidyl ether–treated BHVs excised because of SVD, and 5 calcified aortic valves (AVs) replaced with BHVs because of calcific AV disease were collected and their proteomic profile was deciphered. Then, BHVs and AVs were interrogated for immune cell infiltration, microbial contamination, distribution of matrix‐degrading enzymes and their tissue inhibitors, lipid deposition, and calcification. In contrast with dysfunctional AVs, failing BHVs suffered from complement‐driven neutrophil invasion, excessive proteolysis, unwanted coagulation, and lipid deposition. Neutrophil infiltration was triggered by an asymptomatic bacterial colonization of the prosthetic tissue. Neutrophil elastase, myeloblastin/proteinase 3, cathepsin G, and matrix metalloproteinases (MMPs; neutrophil‐derived MMP‐8 and plasma‐derived MMP‐9), were significantly overexpressed, while tissue inhibitors of metalloproteinases 1/2 were downregulated in the BHVs as compared with AVs, together indicative of unbalanced proteolysis in the failing BHVs. As opposed to other proteases, MMP‐9 was mostly expressed in the disorganized prosthetic extracellular matrix, suggesting plasma‐derived proteases as the primary culprit of SVD in ethylene glycol diglycidyl ether–treated BHVs. Hence, hemodynamic stress and progressive accumulation of proteases led to the extracellular matrix degeneration and dystrophic calcification, ultimately resulting in SVD. Conclusions Neutrophil‐ and plasma‐derived proteases are responsible for the loss of BHV mechanical competence and need to be thwarted to prevent SVD.

Currently, an ultrastructural analysis of cardiovascular tissues is significantly complicated. Routine histopathological examinations and immunohistochemical staining suffer from a relatively low resolution of light microscopy, whereas the fluorescence imaging of plaques and bioprosthetic heart valves yields considerable background noise from the convoluted extracellular matrix that often results in a low signal-to-noise ratio. Besides, the sectioning of calcified or stent-expanded blood vessels or mineralised heart valves leads to a critical loss of their integrity, demanding other methods to be developed. Here, we designed a conceptually novel approach that combines conventional formalin fixation, sequential incubation in heavy metal solutions (osmium tetroxide, uranyl acetate or lanthanides, and lead citrate), and the embedding of the whole specimen into epoxy resin to retain its integrity while accessing the region of interest by grinding and polishing. Upon carbon sputtering, the sample is visualised by means of backscattered scanning electron microscopy. The technique fully preserves calcified and stent-expanded tissues, permits a detailed analysis of vascular and valvular composition and architecture, enables discrimination between multiple cell types (including endothelial cells, vascular smooth muscle cells, fibroblasts, adipocytes, mast cells, foam cells, foreign-body giant cells, canonical macrophages, neutrophils, and lymphocytes) and microvascular identities (arterioles, venules, and capillaries), and gives a technical possibility for quantitating the number, area, and density of the blood vessels. Hence, we suggest that our approach is capable of providing a pathophysiological insight into cardiovascular disease development. The protocol does not require specific expertise and can be employed in virtually any laboratory that has a scanning electron microscope.