Complex Issues of Cardiovascular Diseases
Federal State Budgetary Institution “Research Institute for Complex Issues of Cardiovascular Diseases”
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CAROTID ATHEROSCLEROSIS AS AN ADDITIONAL PREDICTOR OF CARDIOVASCULAR RISK: ANALYSIS USING THE SCORE IN THE POPULATION AGED 40–64 YEARS
Highlights Total carotid plaque thickness ≥ 1.4 mm (TPT14) and the maximum stenosis percentage > 25% showed added prognostic information in assessing the 10-year risk of fatal cardiovascular events in the population of apparently healthy men aged 40–64 years. Integration of the TPT14 parameter into the SCORE significantly changed the risk structure and improves risk stratification, especially in clinically significant ranges where the transition between moderate, high and very high risk categories may influence medical decision-making. No effect of ultrasound parameters on cardiovascular risk was found in women, which is probably due to the peculiarities of the risk structure and the lower prevalence of carotid atherosclerosis in this population. Absract Aim. To research predictive value of ultrasound carotid plaque parameters in assessing 10-year cardiovascular risk (CVR) once added to SCORE in apparently healthy population and developing a risk recalculation table for actual parameters. Methods. We analyzed data from 777 members of representative sample of unorganized population aged 40–64 years, formed as part of the ESSE-RF study (299 men, 478 women). Cardiac screening, carotid ultrasound, CVR assessment by SCORE, and 10-year prospective follow-up were performed. All participants signed a voluntary informed consent to participate in the study. Statistical analysis included Weibull regression, estimation of the added value of parameters (likelihood ratio, AIC, AUC), calibration, risk recalculation by relative risk and Bayesian methods, reclassification analysis (NRI). Results. In men, total carotid plaque thickness ≥ 1.4 mm and maximum stenosis > 25% showed independent prognostic value once added to SCORE. When integrating the first parameter into SCORE, risk reclassification affected 54.9% of men (NRI = 0.41; p = 0.022), especially in intermediate categories (moderate, high risk). Specifically, the risk category increased in 22% and decreased in 32.9% of men. In women, there was no significant relationship between ultrasound parameters and CVR, assumed due to the risk distribution features and low overall risk level. The table of SCORE-specific CVR recalculation was developed based on total plaque thickness ≥ 1.4 mm parameter. Conclusion. The study emphasizes importance of taking subclinical atherosclerosis into account when assessing CVR, especially in men with intermediate SCORE values. Adding specific ultrasound parameters improves risk stratification and can influence clinical decisions. The proposed risk recalculation system provides a practical tool that facilitates personification of therapeutic and preventive measures. Overall, the work demonstrates potential of ultrasound atherosclerosis parameters in improving existing risk assessment methods and may be of particular interest for development of personalized approaches to CVD prevention, however, additional studies are needed to confirm the properties of the model proposed.
CYTOCHROME C IS A MITOCHONDRIAL DAMAGE MARKER: ASSOCIATIONS WITH CLINICAL PARAMETERS AND QUALITY OF LIFE OF HEART FAILURE PATIENTS WITH CORONARY ARTERY DISEASE
Highlights The association of cytochrome C concentration, a marker of mitochondrial damage, with the left ventricular ejection fraction (LVEF), exercise tolerance and quality of life in heart failure (HF) patients with reduced and mildly reduced LVEF of ischemic etiology has been shown. The obtained results emphasize the importance of mitochondrial dysfunction in the pathogenesis of HF. Abstract Background. A feature of the pathogenesis of chronic heart failure (HF) in patients with coronary artery disease (CAD) is the development of myocardial dysfunction against the background of repeated episodes of ischemia/reperfusion. Damage to the mitochondria of cardiomyocytes leads to stimulation of cell death and the release of mitochondrial DNA and mitochondrial enzymes into the interstitium and blood. Cytochrome C is one of the mitochondrial proteins released into the systemic circulation, but the clinical significance of cytochrome C in HF remains poorly understood. Aim. The aim of this study was to search for associations between cytochrome C concentration and clinical characteristics of HF of ischemic etiology, including quality of life, as well as to analyze the dynamics of cytochrome C in the postoperative period after coronary artery bypass grafting (CABG). Methods. The study included 30 patients aged 67 (58; 71) years with HF with reduced (HFrEF) and mildly reduced (HFmrEF) left ventricular ejection fraction (LVEF), who were scheduled for CABG. All patients underwent collection of complaints, anamnesis, standard laboratory and instrumental dates. Quality of life was assessed using the Kansas Cardiomyopathy Questionnaire (KCCQ). Blood samples for determination of cytochrome C concentration were taken before CABG and on days 3 and 10 after surgery. Statistical processing of the results was performed using IBM SPSS 21.0. Results. The cytochrome C concentration before CABG in the study cohort was 24.1 (17.1; 31.1) ng/ml. Patients were divided into two equal groups (n = 15) depending on the cytochrome C level: group 1 included patients with cytochrome C concentration less than or equal to the median value, group 2 – with cytochrome C concentration values ​​greater than the median. Patients in group 2 had lower values ​​of distance in the six-minute walk test: 341 (232; 370) m, compared with group 1 – 400 (310; 440) m (p = 0.048). Lower values ​​of quality of life were recorded in patients of group 2 (p = 0.046). The value of LVEF was also statistically significantly different in the analyzed groups: 44.5 (36.5; 48.3) % and 30 (28; 44) %, respectively, in groups 1 and 2 (p = 0.029). In addition, it was shown that in group 1, on the third day after CABG, a statistically significant increase in the concentration of cytochrome C was recorded (p = 0.05), while in group 2, no pronounced dynamics of this indicator in the perioperative period were revealed. Conclusion. Elevated blood cytochrome C concentrations in patients with HFrEF and HFmrEF and coronary artery disease are associated with lower LVEF values, a shorter six-minute walk distance, and worse quality of life. Cytochrome C dynamics after CABG depended on the initial concentration of this marker.
RELATIONSHIP BETWEEN HEART RATE VARIABILITY AND LEFT VENTRICULAR EJECTION FRACTION IN PATIENTS WITH CORONARY HEART DISEASE AND CHRONIC HEART FAILURE
Highlights The study deepens the understanding of the relationship between HRV and LV in patients with coronary heart disease and CHF, which may contribute to a more accurate diagnosis and classification of the severity of the disease. Determining the average VLF power values allows using this indicator for early diagnosis of neurohumoral disorders. The study highlights differences in vegetative balance in patients with different levels of HF, which may help in the development of more effective approaches to the treatment of CHF. Abstract Aim. To determine the relationship between heart rate variability indices and left ventricular ejection fraction in patients suffering from coronary heart disease with chronic heart failure. Methods. The study included 94 outpatients (47 men and 47 women) with coronary heart disease and chronic heart failure, aged 42 to 83 years. According to the classification of chronic heart failure, depending on the left ventricular ejection fraction, the patients were divided into groups: Group 1 (CHFpEF) – preserved EF (≥ 50%), Group 2 (CHFmrEF) – moderately reduced EF (41–49%); Group 3 (CHFrEF) – reduced EF (≤ 40%). The ejection fraction was determined based on the results of echocardiography (using the Simpson method), and the heart rate variability indices were calculated based on the data of Holter ECG monitoring. The dependence of quantitative indices of the heart rate variability power and the left ventricular ejection fraction (%) was also analyzed. Result. In groups of patients with a lower left ventricular ejection fraction, a significantly lower value of the power of temporal (SDNN, SDANN) and spectral (VLF) indices of heart rate variability was noted (p < 0,05). In group 1 (CHFpEF), the nHF power (22 ± 9) was higher than in group 2 (CHFmrEF) (17 ± 5). However, in group 3 (CHFrEF) (40 ± 27), the nHF power demonstrated significantly higher values ​​than in groups 1 and 2. At the same time, in group 3, a very low value of HF, VLF and LF powers was revealed relative to groups 1 and 2. A quantitative analysis of the left ventricular ejection fraction (%) relative to the power of the spectral indices of heart rate variability revealed a noticeable direct correlation with VLF (r = 0,617; p < 0,001). Quantitative statistical assessment of the power of time indices of heart rate variability and left ventricular ejection fraction (%) revealed a direct correlation for avNN (r = 0,207; p = 0,046), SDNN (r = 0,304; p = 0,003), SDNNidx (r = 0,213; p = 0,039), SDANN (r = 0,296; p = 0,004). Conclusion. In patients with coronary heart disease, a decrease in the overall power of heart rate variability is associated with the severity of chronic heart failure by left ventricular ejection fraction. The autonomic balance in different groups of chronic heart failure by left ventricular ejection fraction is different. Thus, group 1 (CHFpEF) of patients was characterized by heart rate variability power indicators, which indicated a slight deviation in the balance of the autonomic nervous system. In group 2 (CHFmrEF), heart rate variability indicators characterized sympathicotonia. In group 3 (CHFrEF), the predominance of the parasympathetic division of the autonomic nervous system was revealed (p < 0,05). The average values ​​of VLF power (ms2) were determined, which can be used for early diagnosis and classification of the severity of neurohumoral disorders in CHF: CHFpEF – 1622 ± 417; CHFmrEF – 1059 ± 307; CHFrEF – 589 ± 152 (p < 0,001).
THE RELATIONSHIP OF INDICATORS OF ENDOTHELIAL FUNCTION AND MYOCARDIAL FIBROSIS WITH THE SEVERITY OF CORONARY ATHEROSCLEROSIS IN PATIENTS WITH CHRONIC HEART FAILURE WHO HAVE HAD A MYOCARDIAL INFARCTION
Highlights The severity of coronary atherosclerosis associated with a deterioration in the deformational properties of the myocardium, disturbances in microcirculation, as well as an increase in inflammatory and profibrotic biomarkers. Abstract Aim. To study the relationship between the severity of coronary atherosclerosis, endothelial dysfunction and myocardial fibrosis in patients with chronic heart failure who have had a myocardial infarction. Methods. 96 patients with chronic heart failure hospitalized in the acute period of myocardial infarction were included. All participants underwent: echocardiographic examination with assessment of left ventricular ejection fraction (LVEF) and global longitudinal strain, laser doppler flowmetry, assessment of biomarker levels (CRP, sST2, NTproBNP, VEGF), coronary angiography. Results. According to coronary angiography results, multivessel coronary artery disease was identified in 58 (60.4%) patients, and left main coronary artery (LMCA) involvement was found in 20 (20.8%). The severity of coronary atherosclerosis was associated with a decrease in LVEF (R = –0.31, p = 0.002), global longitudinal strain (R = –0.73, p < 0.001), amplitude-frequency parameters of microcirculation, volume of regulatory mechanisms, and coefficient of variation of microcirculation (R = –0.3, p = 0.003), as well as an increase in the degree of left ventricular diastolic dysfunction (R = 0.31, p = 0.002), capillary blood flow reserve (R = 0.29, p = 0.005), concentrations of CRP (R = 0.32, p = 0.002), NT-proBNP (R = 0.71, p < 0.001), and sST2 (R = 0.77, p < 0.001). Inverse relationships were identified between the number of affected coronary arteries and LVEF (R = –0.23; p = 0.027), coefficient of variation of microcirculation (R = –0.36, p < 0.001), and amplitude of microcirculation oscillations in the neurogenic range (R = –0.24, p = 0.019). Patients with LMCA stenosis had lower LVEF, amplitudes of oscillations in the neurogenic and myogenic ranges, as well as higher capillary blood flow reserve values. Conclusion. The results of the study indicate a relationship between the severity of coronary atherosclerosis and changes in hemodynamics at the microcirculatory level, fibrotic remodeling of the myocardium, and concentrations of biomarkers such as CRP, NT-proBNP, and sST2.
EFFECT OF IMMERSION HYPOTHERMIA ON VELOCITY INDICATORS OF CORTICO-CEREBRAL BLOOD FLOW IN RATS
Highlights The velocity of cortico-cerebral blood flow during general progressive hypothermia of the body, measured by ultrasound Dopplerography in anesthetized rats, changes nonlinearly. The beginning of body cooling (reduction of rectal temperature to 35 °C) is characterized by an increase in peak systolic velocity, mean velocity per cardiac cycle and end diastolic velocity, while the STI index shows a tendency to increase, which together increases the risk of cerebral hemodynamic disorders. A mild stage of hypothermia (rectal temperature 32–35 °C) with stable peak systolic and mean per cardiac cycle velocities and a decrease in the resistance index RI and pulsatility index PI seems to be the most preferable in terms of use in clinical practice. The most significant decrease in the velocity of cortico-cerebral blood flow occurs during severe and deep hypothermia. Abstract Aim. Determination and analysis of linear velocities and indices of blood flow in the cortex and subcortical structures of the cerebral hemispheres during immersion hypothermia of rats using Doppler ultrasound. Methods. Anesthetized (urethane, intraperitoneal, 1 000 mg/kg) Wistar rats weighing 300–320 g (n = 11) underwent craniotomy and removal of the dura mater. While the animals were cooling in water with the addition of ice (the temperature of the mixture was about 10 °C), using Doppler ultrasound the velocity indicators of cerebral blood flow were measured, and the parameters of mean arterial pressure, respiratory rate and heart rate were continuously recorded. Rats were cooled to a rectal temperature of 17 °C in ~80 min with an average cooling rate of 0.25 °C/min. Results. Multidirectional changes in cerebral blood flow velocity parameters were detected. At the beginning of cooling, the perfusion of the frontal and occipital areas of the cerebral hemispheres increases due to an increase in peak systolic velocity (by 15%, p = 0,005) and mean velocity per cardiac cycle (by 41,5%, p = 0,001). In mild to moderate hypothermia, increased perfusion is maintained by maintaining a high peak systolic velocity in the parietal area. At the stages of severe and deep hypothermia of the body, there is a significant decrease in cerebral blood supply, as indicated by a decrease in the values of peak systolic and mean velocity per cardiac cycle, occurring in all studied areas. Conclusion. At various stages of progressive immersion hypothermia in rats, changes in the velocity indicators of cortico-cerebral blood flow are observed, which are nonlinear: at the initial stage of cooling, the blood flow velocity increases, and with further cooling its decrease is observed.
ENDOTHELIAL CELLS OF THE PULMONARY ARTERY IN VITRO: HOW TO OVERCOME THE DEFICIENCY OF A MODEL OBJECT IN THE STUDY OF PULMONARY ARTERIAL HYPERTENSION?
Highlights The endothelial cells of the pulmonary artery are a deficient model object. Our task was to work out the method of cell isolation from the Swan-Ganz catheter described in the literature. However, no cells were obtained using this technique. We have developed an alternative technique for isolating cells from blood obtained from the lumen of the pulmonary artery during right heart catheterization, and demonstrated the suitability of this technique for routine production of endothelial cell cultures from patients with pulmonary arterial hypertension. Abstract Aim. Obtaining cultures of pulmonary artery endothelial cells as a model object. The endothelium ensures the integrity of the vascular wall, and disorders of endothelial function play an important role in the development of various pathological processes. Obtaining endothelial cell cultures from fragments of various human vessels is a fairly well–developed and widely used method. However, it has limitations that relate to the availability of biological material for certain groups of patients. Thus, when studying the pathogenesis of pulmonary hypertension, fragments of the pulmonary artery are practically inaccessible to the researcher, since surgical intervention for this pathology is not a routine method of treatment. Methods. The cells were obtained from the balloon of the Swan-Ganz catheter in accordance with the descriptions in the literature, alternative tissue dissociators and different adhesive media were additionally tested. The isolation of cells from the blood from the lumen of the pulmonary artery and from the peripheral (cubital) vein was carried out by dividing the blood into fractions and washing the cells of interest according to the protocols described in the literature. Results. In this work, we tested the production of pulmonary artery endothelial cells in patients with pulmonary arterial hypertension by removing cells from the balloon of the Swan-Ganz catheter during right heart catheterization. The catheter removal method has shown its unsuitability for use in routine laboratory practice. As an alternative, we have developed a method for obtaining endothelial cells from blood taken from the lumen of the pulmonary artery during catheterization. Conclusion. Isolation of endothelial cells from blood taken from the lumen of the pulmonary artery during right heart catheterization showed the suitability of this method for routine production of endothelial cell cultures from patients with pulmonary arterial hypertension.
TEN-YEAR DYNAMICS OF SURGICAL AND ENDOVASCULAR TREATMENT OF ISCHEMIC HEART DISEASE IN THE RUSSIAN FEDERATION (2014–2023). PART 1.
Highlights Over the period from 2014 to 2023, the number of coronary artery angioplasties (with and without stenting) in the Russian Federation increased by 153%, and mortality increased from 2.1 to 4.3%. The number of coronary artery bypass grafting surgeries increased by 6.4%, without changing mortality (1.8 and 1.9%). Absract Aim. To assess the dynamics of the number of operations for coronary heart disease (CHD) and mortality in the Russian Federation in 2014–2023; possibilities for modifying the accounting and analysis of data. Methods. The data obtained from Rosstat upon request from table 2000 of the federal statistical observation form (FSOS) No. 14 were used. The data contained information on the number of operations for CHD performed in hospitals of the Russian Federation and the number of deaths after operations for the year from 2014 to 2023. Results. The number of operations for CHD in 2023 increased by 46.7% compared to 2014, with a period of decline during the COVID-19 pandemic (in 2020 compared to 2019 by 14.1% and recovery in 2022). In 2023, the absolute number of coronary artery angioplasties increased by 153% compared to 2014 (from 112,574 or 108 per 100,000 population in 2014; to 309,063 or 276 per 100,000 in 2023, or from 7 to 22.5 per 100 hospitalizations for coronary artery disease). The number of angioplasty operations without stenting decreased by 5%, and with stenting increased by 2.7 times. The number of coronary artery bypass grafting (CABG) surgeries increased by 6.4% (from 30,128 to 32,056; from 25 to 27.7 per 100 thousand population or from 1.7 to 2.2 per 100 hospitalizations for coronary artery disease; their share of the total number of operations for coronary artery disease decreased from 17.8% to 8.8%). The ratio between the number of angioplasties and CABG in 2014 was 4:1; in 2023, 10:1. The proportion of deaths from the number of CABG surgeries performed has not changed significantly over the past 10 years; the maximum was registered in 2021 (2.1%), the minimum in 2017 (1.6%). The proportion of deaths from the number of endovascular surgeries increased (in 2014 – 2.1%; in 2023 – 4.3%; p < 0.001). Conclusions. A trend towards a significant increase in the number of coronary artery stenting (and mortality after them) against the background of stagnation in CABG surgeries was revealed. The lack of personalized databases does not allow for a correct assessment of the causes of the identified changes; it is necessary to change approaches to organizing accounting.
METHOD OF “DRY” STORAGE OF BIOLOGICAL PROSTHESES FOR CARDIOVASCULAR SURGERY
Highlights The technology of pre-implantation storage of bioprostheses plays a key role in the prevention of postoperative complications in cardiovascular surgery. The developed method of “dry storage” using glycerol allows to exclude the aqueous phase, thereby reducing the risk of damage to the collagen matrix during storage and transportation of the biomaterial. Glycerolization preserves the basic physical, mechanical and hemocompatible characteristics of the biotissue, without having a negative effect on its biocompatibility. Absract Aim. Development of a technology for “dry storage” of biological tissue using glycerol and evaluation of the effectiveness of the technology in an experiment. Methods. Xenopericardial patches preserved with ethylene glycol diglycidyl ether, provided by NeoCor JSC, were immersed in a 57% glycerol solution for 24 hours, then kept in a vacuum chamber at a negative pressure of 700 mbar for 6 hours. After complete drying, the xenopericardial flaps were sterilized with ethylene oxide at a temperature of 37 °C. The following were assessed: physicomechanical, hemocompatible, cytotoxic properties, calcium-binding potential of the biomaterial after the glycerolization stage, as well as cycle resistance and hydrodynamic characteristics in dynamics up to 200 million cycles. Results. The glycerolization process did not have a negative effect on the properties of the biomaterial. Relative elongation of the biomaterial increased by 27.6% (p = 0.02), while the rigidity of the biotissue did not change. During subcutaneous implantation of the biomaterial in rats at implantation periods of up to 60 days, no calcification foci were found in the samples treated with glycerol. The amount of hemolysis of erythrocytes after contact with glycerolized samples did not exceed 0.2%, with an acceptable rate of 2%. The process of glycerolization and subsequent drying does not have a negative effect on platelets and made it possible to significantly reduce the cytotoxic effect, provided that the biomaterial is briefly washed in saline for 5 minutes. The Uniline heart valve bioprostheses of sizes 25 and 30 have successfully passed tests of 200 million cycles. At the same time, for both size 19 prostheses, initially relatively high values of the average transprosthetic gradient were noted, which increased by 3–4.7 times to the 200 ml cycles mark. Conclusion. The developed technology of “dry” storage, based on glycerolization of biomaterial, does not have a negative effect on the physical and mechanical, bio- and hemocompatible properties of bioprostheses, does not cause calcification of biotissue in an experiment on laboratory animals and does not reduce resistance to cyclic loads in dynamics up to 200 million cycles.
SENSITIVITY OF VARIOUS METHODS FOR ASSESSING THE CYTOTOXICITY OF MEDICAL DEVICES
Highlights There is no universal method for assessing the cytotoxicity of a material. A valid result can be obtained using several fundamentally different research methods. It is also necessary to take into account the features of the tested material. Resume Background. Despite the prevalence and frequency of use, the issues of standardization of methods for determining the cytotoxicity of materials for medical devices remain unresolved. The wide variability of approaches to assessing cytotoxicity in vitro requires the researcher to carefully plan the test to according with characteristics of the object being studied. Aim. To conduct a comparative analysis of the sensitivity of different cell cultures and methods for assessing cytotoxicity materials for creating cardiovascular prostheses using preserved xenopericardium as an example. Methods. The experiment was carried out on three cell cultures: fibroblasts, HUVEC, Ea.hy926, with the specific culture medium for each case. We used xenopericardium samples stored in a paraben solution as an object with a cytotoxic effect. We analyzed reaction of cells in direct and indirect contact with xenopericardium samples, as well as in the presence of its extract. An MTT test was carried out, cell growth dynamics were studied using the xCelligence cell analyzer and cell proliferative activity was assessed using a commercial Click-IT kit. Results. According to the results of the MTT test, in all cases the presence of xenopericardium extract in the culture medium led to a pronounced decrease in cell viability and population density. According to the assessment of growth dynamics, in groups with pericardial samples, complete cell death was noted. The addition of preserved xenopericardium extract did not have a noticeable effect on the change in the cellular growth index of the fibroblast culture, however, in the presence of xenopericardium samples, there was a pronounced decrease in it. In HUVEC culture, the addition of both the extract and xenopericardium samples caused the death of a significant portion of the cells in a short time. In the Ea.hy926 culture, a decrease in the rate of proliferation was observed, but throughout the experiment the positive dynamics of cell culture growth continued. In the presence of the extract, the absence of proliferating cells in the fibroblast culture and a decrease in their number in the Ea.hy926 culture were noted. Conclusion. Experimental conditions, test culture and evaluation methods must be selected individually based on the characteristics of the material being tested. To obtain reliable results, it is necessary to use several fundamentally different research methods to more fully characterize the effect of cytotoxic agents on cell culture.
NON-PHARMACOLOGICAL METHODS IN STROKE MANAGEMENT IN PATIENTS WITH ATRIAL FIBRILLATION: FROM INTERVENTIONAL METHODS TO SURGERY
Highlights Prevention of ischaemic stroke development in atrial fibrillation is an important public health concern. Pharmacological strategies for the prevention of thromboembolic events have a number of limitations and contraindications. Therefore, invasive methods aimed at isolation of the auricle of the left atrium as the main source of thrombosis in patients with non-valvular atrial fibrillation began to be developed. The aim of our review was to provide comprehensive information on the efficacy and safety of interventional and surgical approaches to left atrial auricle isolation. Since 2010, new direct oral anticoagulants (NOACs) have become the leading pharmacotherapy for stroke prevention in patients with AF. Abstract Atrial fibrillation (AF) is associated with a high risk of systemic thromboembolic (TE) events. Prevention of ischaemic stroke development in AF is an important task and depends on primary screening, adequate and timely assessment of the patient's risk of stroke development. Medium-term adherence to NOAC medication remains very low, with only 60% continuing anticoagulants 1.3 years after AF diagnosis. In addition, there are patients who continue to have a high incidence of TE events despite regular administration of NOACs. These results, together with the information that in isolated AF, approximately 90% of thrombi are localised in the left atrial appendage (LAA), have prompted the development, testing and subsequent clinical implementation of invasive strategies to isolate the LAA from the systemic blood flow. Thus, among the methods of isolation of LAA are (1) open surgical; (2) endovascular; and (3) minimally invasive video-assisted. The main purpose of this literature review is to present the latest evidence on the efficacy and safety of the main strategies for the prevention of thromboembolic events in patients with AF.
MORPHOFUNCTIONAL SYSTEM CONDUIT-ARTERY IN ACUTE CORONARY SYNDROME
Highlights The analytical review proposes to consider the morphofunctional conduit-artery system in the context of acute coronary syndrome, which is one of the leading problems of modern angiology. Based on the data of currently available fundamental and clinical studies, possible pathophysiological scenarios are shown that potentially occur in the elements of this system. Abstract The review considers the autobionic morphofunctional conduit-artery system, formed surgically during coronary artery bypass grafting, including such elements as the afferent (conduit) and receiving (coronary artery) vessels, as well as blood, from the position of its functioning in conditions of an acute coronary event. For a fundamental understanding of the current status of open myocardial revascularization, which has many unresolved issues, including the timing of surgery, volume, drug therapy, etc., various pathophysiological aspects reflecting the response of the system and its elements to a vascular catastrophe are shown. In this context, new horizons are opened for further study of surgical revascularization, which will help optimize the approach to this type of treatment in patients with acute coronary syndrome.
PATHOPHYSIOLOGICAL SIGNIFICANCE OF ENDOTHELIAL HETEROGENEITY
Highlights Acquisition and maintenance of organ-specific endothelial signatures depend on the flow- and matrix-derived biophysical stimuli, juxtracrine, paracrine and endocrine biochemical cues, and comorbid conditions. Being tailored to the organ-specific needs, capillary endothelial cells have significant heterogeneity and high molecular plasticity. Whilst endothelial heterogeneity in vivo is evident, molecular heterogeneity of arterial, venous, and microvascular endothelial cells in vitro and its pathophysiological significance still remain unclear. Abstract In this review, we consider molecular and pathophysiological heterogeneity of distinct endothelial cell (EC) lineages and organ-specific ECs. Recent single-cell sequencing studies showed a significant endothelial heterogeneity at physiological and pathological conditions and found that molecular heterogeneity of arterial, venous, and microvascular ECs is lower than in ECs of different organs, also showing higher heterogeneity of vascular as compared with lymphatic ECs. Acquisition and maintenance of organ-specific endothelial signatures depend on organ-specific biophysical setup (i.e., shear stress, cyclic loading, and extracellular matrix stiffness); 3) biochemical profile of circulating blood (including blood gas composition and molecular profile); 3) juxtacrine and paracrine molecular signals from adjacent cell populations and surrounding extracellular matrix; 4) concomitant pathological conditions within the organ such as inflammation, hypoxia, and fibrosis. Because of tailoring to the organ-specific needs, capillary endothelial cells have significant heterogeneity and molecular plasticity, exhibiting the highest adaptation potential in comparison with arterial and venous ECs. Whilst capillary ECs lack common molecular signatures, arterial and venous ECs have specific markers in the embryonic state (COUP-TFII transcription factor and ephrin type-B receptor 4 (EPHB4) in venous ECs; HEY1, HEY2, and HES1 transcription factors, gap junction proteins GJA4 и GJA5, semaphorin 3G, and ephrin B2 (EFNB2) in arterial ECs). Nevertheless, molecular heterogeneity of distinct EC specifications in vitro and its pathophysiological significance in the absence of confounding biophysical and biochemical factors remains obscure.
A CLINICAL CASE OF PROSTHETICS OF THE EXCRETORY RIGHT VENTRICLE IN A CHILD USING A VALVE-CONTAINING XENOPERICARDIAL CONDUIT “PYLON”
Highlights The relevance of the clinical case is related to the high incidence of Fallot's tetrad and the need for complex cardiac surgery, including prosthetics of the excretory right ventricle. The development and application of high-quality conduits, such as Pylon, is important for improving surgical outcomes in children. Abstract Resume Tetrad of Fallot (TF), the most common type of cyanotic congenital heart disease (CHD), has an incidence rate of 0.34 per 1,000 infants. When performing radical correction, transannular plastic surgery is often required. Later, such children need prosthetics of the excretory right ventricle. This clinical case demonstrates the adequacy of the chosen conduit during the procedure.
NEURAL NETWORK ANALYSIS AS A WAY TO ASSESS SOME PATHOGENETIC ASPECTS OF NEUROINFLAMMATION IN HYPERTENSIVE DISEASE
Highlights Cardiovascular diseases are the leading cause of death in the population. The most common cardiovascular disease is hypertension, which can lead to damage to target organs, including the brain. Several studies have examined the role of specific neuroinflammatory molecules and tumor necrosis factor family proteins in the progression and outcome of vascular-related cerebral damage. The article highlights the possibilities of neural network analysis, which can be used to determine the ranked contribution of certain biomarkers to the pathogenesis of neuroinflammation that develops in hypertension. Abstract Background. Hypertensive disease is accompanied by involvement of target organs, including the brain, in the pathological process, leading to the development of acute and chronic cerebrovascular diseases. The development of modern methods for predicting the development and course of angio-cerebral pathology can be used to create new methods for managing patients at risk. Aim. Using the capabilities of neural network analysis, we determined the ranked contribution of biomarkers of neuroinflammation and proteins of the tumor necrosis factor family to the pathogenesis of neuroinflammation in the context of hypertension. Methods. The study involved 80 participants. The control group consisted of healthy individuals. The first group included patients with stage II–III hypertension, achieved target blood pressure levels, and a 3–4 risk of developing cardiovascular complications. The second group consisted of patients with stage II–III hypertension, unachieved target blood pressure levels, and a 3–4 risk of developing cardiovascular complications. Group 3 included patients with a verified diagnosis of ischemic (atherothrombotic) stroke. The data obtained from the study were used to train a multilayer perceptron and create a mathematical model that determines the ranked contribution of biomarkers of neuroinflammation and proteins of the tumor necrosis factor family to the pathogenesis of neuroinflammation in the context of hypertension. Results. According to the results of the conducted multiplex analysis and statistical data processing, similar shifts in the neuroimmune status were identified in both patients with ischemic stroke and individuals with hypertension. Modern developments in the field of predicting the development and course of angiocerebral pathology can be used to create new methods for managing patients at risk. Conclusion. The data obtained as a result of the conducted study indicate changes in the neuroimmune status of patients with hypertension. It is noteworthy that the content of biomarkers associated with neuroinflammation in patients with unattained target blood pressure levels is as close as possible to that of patients with ischemic stroke. At the same time, in the group of patients with achieved target blood pressure levels, there is also a shift in the studied indicators, but to a lesser extent, which may indicate the presence of a neuroinflammatory process that is present even in the presence of antihypertensive therapy and blood pressure control. The mathematical model developed using neural network analysis allowed us to determine the ranked contribution of the studied parameters to the pathogenesis of neuroinflammation in patients with hypertension. These results can be further used for a more personalized approach to patient treatment by influencing specific aspects of the pathogenesis, thereby moderating the ongoing process and influencing the future course of the disease.
PATHOMORPHOLOGICAL PATTERNS OF DYSFUNCTIONS OF XENOPERICARDIAL BIOPROSTHESES OF HEART VALVES OF THE “UNILINE” MODEL
Highlights Prosthetic endocarditis (PE) was the main cause of dysfunctions of biological prosthetic heart valves of the UniLine model that occurred during the first 4 years of operation. The main factor in the development of PD insolvency in the later time period was structural valvular degeneration (SKD). The key macroscopic signs of SCD included calcification and ruptures of the valve apparatus. At the microscopic level, PD with SCD was characterized by moderate cellular infiltration with a predominance of macrophages. In turn, for valves with PE, thickening of the valves and the formation of vegetation were noted, the development of which was accompanied by aggressive invasion of neutrophils. The results of cluster analysis of data on 46 key clinical and pathomorphological features supported the division of the studied PD sample into 2 stable clusters corresponding to the patterns of CD and PE. Abstract Aim. This study aimed to comprehensively evaluate the pathomorphological changes in “Uniline” bioprosthetic heart valves (BHVs) explanted due to dysfunction. Methods. A total of 44 “Uniline” BHVs, retrieved from an equal number of recipients during valve re-replacement procedures were examined. To determine cellular composition and assess biomaterial microstructure, valve leaflets were sectioned and stained using hematoxylin and eosin, Russell-Movat pentachrome, Oil Red O, and Alizarin Red S. Bacterial colonies were identified using Gram staining. Immunohistochemistry was performed with the NovoLink Polymer DS detection system and antibodies against the pan-leukocyte marker (CD45), T-lymphocytes (CD3), B-lymphocytes (CD19), macrophages (CD68), neutrophils (MPO), and platelets (CD62p). Stained sections were scanned on an MT5300L microscope, and the resulting histological slides were analyzed using QuPath and Fiji software. Cluster analysis was performed to identify pathomorphological patterns of BHV dysfunction. Results. Clinical and pathomorphological data confirmed PE and SVD as the underlying causes of dysfunction within the cohort. Patients in the PE and SVD groups showed no significant clinical or demographic differences. The mean duration of BHV function was 30 months for PE and 74 months for SVD. Valves explanted due to SVD exhibited leaflet calcification and tears. Most BHVs with PE were characterized by the presence of vegetations on the leaflets. SVD-affected valves displayed moderate macrophage infiltration, whereas PE cases showed aggressive neutrophil invasion. Cluster analysis algorithms identified two stable patterns of dysfunction: the first was characterized by features typical of SVD, including chronic inflammation and calcification, while the second corresponded to persistent acute inflammation associated with PE. Conclusion. PE and SVD are key pathomorphological patterns of dysfunction in “Uniline” BHVs, treated with ethyleneglycol diglycidyl ether. The identified patterns are the same as the main causes of degeneration in BHVs treated with glutaraldehyde. This underscores fundamental limitations in using chemically cross-linked xenopericardium for BHV manufacturing and, consequently, highlights the necessity for developing new materials and methods aimed at improving the durability of artificial heart valves.
SYNTHESIS OF PRO-INFLAMMATORY CYTOKINES BY HUMAN AORTIC VALVE, INTERNAL THORACIC ARTERY, SAPHENOUS VEIN, AND ADIPOSE TISSUE-DERIVED MICROVASCULAR ENDOTHELIAL CELLS
Highlights The list of cytokines produced by the primary human valvular, arterial, venous, and microvascular endothelial cells (ECs) is restricted to MIF, IL-6, IL-8/CXCL8, MCP-1/CCL2, RANTES/CCL5, MIP-3α/CCL20, GM-CSF, G-CSF, GRO-α/CXCL1, ENA-78/CXCL5, IP-10/CXCL10, and PTX3. These cytokines can be classified into those with a high (MCP-1/CCL2, IL-8/CXCL8, GROα/CXCL1, MIF, and pentraxin-3), moderate (IL-6), and low expression (GM-CSF, G-CSF, RANTES/CCL5, MIP-3α/CCL20, ENA-78/CXCL5, and IP-10/CXCL10). Human internal thoracic artery endothelial cells show the highest inflammatory activity in comparison with saphenous vein endothelial cells, adipose tissue-derived microvascular endothelial cells, and aortic valve endothelial cells. Abstract Aim. To define pro-inflammatory cytokines secreted by distinct primary endothelial cells (ECs) into the cell culture medium. Methods. Primary human aortic valve endothelial cells (HAVEC) were obtained from the patients with aortic stenosis (n = 3). Primary human saphenous vein endothelial cells (HSaVEC, n = 3), internal thoracic artery endothelial cells (HITAEC, n = 3), and subcutaneous adipose tissue-derived microvascular endothelial cells (HMVEC, n = 3) were isolated from the patients with coronary artery disease. Expression of MIF, IL6, CXCL8, CCL2, CCL5, CCL20, CSF2, CSF3, CXCL1, CXCL5, CXCL10, PTX3, SERPINE1, VCAM1, ICAM1, SELE, and SELP genes was performed by reverse transcription-quantitative polymerase chain reaction. The levels of 109 pro-inflammatory cytokines in the serum-free cell culture medium were measured by the semi-quantitative dot blot profiling with the chemiluminescent detection and densitometry. Statistical analysis was carried out using Kruskal-Wallis test with the further Dunn’s multiple comparisons test. Results. MIF, IL-6, IL-8/CXCL8, MCP-1/CCL2, RANTES/CCL5, GM-CSF, GROα/CXCL1, ENA-78/CXCL5, and PTX3 were detected in the cell culture supernatant from all EC lines, whilst G-CSF, MIP-3α/CCL20, and IP-10/CXCL10 were exclusively observed in the cell culture supernatant from HITAEC. As compared with other cell lines, HITAEC had significantly elevated expression of CCL2, CCL20, CSF2, CSF3, and CXCL10 genes and showed a trend to the increased expression of CXCL5 and SERPINE1 genes. In contrast, HSaVEC and HMVEC did not demonstrate significant increase in the expression of any of the genes encoding pro-inflammatory cytokines. CCL2, CXCL8, CXCL1, MIF, PTX3, and IL6 genes had higher expression in comparison to other cytokine-encoding genes regardless of the EC line. Count of the expression ranks per each of these pro-inflammatory cytokines showed a significant relative distance between HITAEC and other EC lines. Conclusion. We defined a list of endothelial pro-inflammatory cytokines (MIF, IL-6, IL-8/CXCL8, MCP-1/CCL2, RANTES/CCL5, MIP-3α/CCL20, GM-CSF, G-CSF, GRO-α/CXCL1, ENA-78/CXCL5, IP-10/CXCL10, and PTX3) and suggested a higher pro-inflammatory status of HITAEC as compared with HAVEC, HSaVEC, and HMVEC.
ATHEROSCLEROSIS SEVERITY AFFECTS ARTERIAL REMODELING AFTER THE CAROTID ANGIOPLASTY
Highlights In the examined human stented internal carotid artery sample, we identified significant differences in remodeling patterns between the initially intact intima and atherosclerotic plaque area. Severe restenosis in the initially intact intima was characterized by intensive neutrophilic infiltration, proliferation of vascular smooth muscle cells and fibroblasts, active extracellular matrix remodeling, and immature microvessels. Moderate restenosis in the atherosclerotic plaque area was characterized by the absence of neutrophils, notable macrophage infiltration, and mature microvessels. Abstract Aim. To perform a histological analysis of arterial remodeling after the carotid angioplasty depending on the extent of atherosclerosis before the surgery. Methods. Here we examined human internal carotid artery excised during carotid endarterectomy which has been performed because of severe in-stent restenosis. The artery was sectioned into segments with initially intact intima (n = 3) and segments with atherosclerotic plaque (n = 3). Visualization was performed using backscattered scanning electron microscopy (EM-BSEM) after staining the segments with heavy metals, embedding them into epoxy resin, grinding and polishing of embedded specimens, and sputter coating the samples with carbon. We further assessed neointimal thickness, extracellular matrix state, microvessel parameters (total and mean lumen area, vessel density by area and quantity, presence of blood cells within and surrounding vessels), cellular composition, and immune cell infiltration patterns. Results. Significant differences in patterns of arterial remodeling were observed between the initially intact intima and atherosclerotic plaque area. Restenotic neointima in initially intact regions was thick, loose and disorganized and was notable for high cellular density, severe neutrophilic infiltration, and immature microvessels (i.e., signs of acute inflammation). In contrast, atherosclerotic plaque areas had moderate degree of restenosis, dense neointima, mature microvessels, and macrophage infiltration, altogether suggestive of chronic inflammation. Morphometric analysis revealed a trend toward increased neointimal thickness in the initially intact intima; however, microvascular parameters did not differ significantly between the intact and atherosclerotic areas. Conclusion. The initial state of the carotid artery wall affects the neointimal composition, extracellular matrix remodeling, angiogenesis and inflammation patterns. Initially intact intima exhibited high reactivity associated with a severe restenosis, loose neointima formation, and acute inflammation. In contrast, plaque areas demonstrate more stable neointimal structure and features of chronic inflammation.
THE EFFICACY OF INTRAVASCULAR IMAGING METHODS IN THE MANAGEMENT OF PATIENTS WITH “FALSE” LEFT MAIN BIFURCATION LESIONS: 12-MONTH FOLLOW-UP RESULTS
Highlights Despite the longstanding use of intravascular imaging methods, patients presenting with “false” bifurcation lesions of the left main coronary artery have traditionally been excluded from observational studies. The study presents results on the safety and efficacy outcomes of percutaneous coronary intervention guided by intravascular imaging in this patient cohort. Over a 12-month follow-up period, intravascular ultrasound and optical coherence tomography demonstrated comparable safety and efficacy profiles, while post-procedural fractional flow reserve measurement showed additional clinical utility. Abstract Aim. To evaluate the efficacy and safety of percutaneous coronary interventions using intravascular methods in patients with “false” bifurcation lesions of the left main coronary artery. Methods. The study enrolled 162 patients with angiographically confirmed “false” bifurcation lesions of the LMCA. Participants were randomized into two groups using the envelope method, based on the selected imaging technique. In Group 1 (n = 81), intravascular ultrasound (IVUS) was performed, while Group 2 (n = 81) underwent optical coherence tomography (OCT). Following imaging and per inclusion criteria, 128 patients were ultimately included in the analysis. Patients with a minimal lumen area (MLA) < 6 mm² in the distal LMCA underwent myocardial revascularization. In cases where MLA > 6 mm² and fractional flow reserve (FFR) > 0.8 (n = 36), revascularization was deferred, and medical therapy was recommended. Provisional stenting was performed in both groups, with subsequent FFR measurement in both the main and side branches, as well as stent assessment using IVUS or OCT. If FFR in a native branch was < 0.8, a second stent was deployed using either the "reverse-crush" or "reverse-Culotte" technique. If FFR was > 0.8, the procedure was considered complete. Results. At 12-month follow-up, in-stent restenosis occurred in 2.0% and 4.8% of patients in Groups 1 and 2, respectively (p = 0.590). Restenosis in the side branch was observed in 6.0% and 4.8% of patients (p = 1.000). Target lesion revascularization was performed in 2.0% of Group 1 patients (p = 0.489). Myocardial infarction (MI) was recorded in 8.0% of patients in Group 1 (p = 0.122), with stent thrombosis at the target lesion site being the cause in 4.0% (p = 0.498), and 2.0% of these cases proving fatal. Other MIs were attributable to lesions in non-target coronary arteries. Cardiac mortality was exclusively observed in Group 1, at 4.0% (p = 0.186). The cumulative incidence of major adverse cardiac events (MACE) was higher in Group 1 compared to Group 2, at 10.0% and 2.4%, respectively (p = 0.214). Conclusion. The use of IVUS or OCT demonstrates equivalent efficacy in optimizing clinical outcomes for patients with “false” bifurcation lesions of the LMCA. Postprocedural FFR measurement facilitates the timely detection of residual ischemia and enables dynamic intraoperative decision-making, significantly enhancing the safety and effectiveness of PCI.
Highlights Implantation of an artificial heart serves as a temporary solution for patients with end-stage heart failure. The literature review presents the history of the completely artificial heart, its different models, and clinical applications. Abstract Cardiovascular disease is one of the leading causes of death worldwide. Many patients with end-stage heart failure die due to a shortage of donor hearts. A total artificial heart (TAH) is an implantable device that replaces the heart. To date, it has been successfully implanted in more than 2,000 patients as a bridge to heart transplantation. However, after several decades of research, a TAH suitable for targeted therapy has yet to be developed. High complication rates, bulky devices, poor durability, poor biocompatibility and poor quality of life for patients are some of the major drawbacks of existing TAH devices that need to be addressed before they can be used as targeted therapy. Rapidly emerging innovations in battery technology, wireless energy transfer, biocompatible materials, and soft robotics offer promising opportunities for TAH development and may help address the shortcomings of existing devices [1]. This review describes the major milestones in the history of TAH design and development. The differences in the mechanisms of operation of these devices are described, and current challenges and requirements for the next generation of TAHs are discussed. Thus, despite significant progress, modern TAHs remain predominantly a temporary solution. The key challenges for transitioning to long-term targeted therapy are improving device durability, addressing the need for pulsatile flow, and miniaturizing the systems for a broad patient population.
THE USE OF PCSK9-TARGETED THERAPY IN PATIENTS WITH CORONARY HEART DISEASE AND AORTIC VALVE STENOSIS AFTER SURGERY (CLINICAL EXAMPLES OF AN EXPLORATORY RESEARCH STUDY)
Highlights The relevance of the clinical case is related to the high incidence of Fallot's tetrad and the need for complex cardiac surgery, including prosthetics of the excretory right ventricle. The development and application of high-quality conduits, such as Pylon, is important for improving surgical outcomes in children. Abstract In this paper, using clinical examples of two patients from an exploratory scientific study with an established diagnosis of coronary heart disease and operated aortic valve stenosis, an analysis of the efficacy and safety of using a PCSK9 inhibitor (alirocumab) as part of a combination lipid-lowering therapy prescribed for the correction of dyslipidemia over 4 months of treatment is presented. It is shown that over 4 months of the exploratory scientific study, despite the high safety of the prescribed treatment, the reduction in low-density lipoprotein cholesterol in this category of patients remains suboptimal and is not accompanied by the achievement of its target values, which justifies the need for additional optimization of lipidological treatment as part of cardiovascular risk management.