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Aim: To evaluate the dynamics of specific biomarkers for cardiotoxicity, endothelial dysfunction, fibrosis, systemic inflammation, and morpho-functional alterations in the left ventricular (LV) myocardium in patients with newly diagnosed lymphomas during 6 courses of polychemotherapy (PCT)., Material and Methods: The study included 30 patients with newly diagnosed lymphomas. All patients were evaluated for laboratory markers of cardiotoxicity at baseline and after 6 courses of chemotherapy (6 months), including N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin I (hsTnI), endothelin-1 (ET-1), circulating cardiac biomarker ST-2, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and LV structural and functional echocardiographic (EchoCG) parameters., Results: The changes in NT-proBNP and hsTnI concentrations during 6 courses of PCT were not statistically significant. Comparison of the baseline values with those after 6 courses of PCT showed increases in the median concentrations of ET-1 (3.38 and 5.5 pg/ml, respectively; p=0.438) and ST-2 (12.21 and 26.75 ng/ml, respectively; p=0.687). Markers of systemic inflammation were significantly decreased after 6 courses of PCT: the median CRP decreased from 15.2 to 0.72 mg/ml (p=0.006), and the median IL-6 decreased from 12.2 to 5.1 pg/ml (p=0.034). EchoCG data revealed a statistically significant impairment of the LV diastolic function parameters (E/A; E/e' lateral; E/e' average; left atrial volume index; isovolumic relaxation time). A moderate direct correlation was found between the ET-1 concentration and the isovolumic relaxation time at baseline and after 6 courses of PCT, respectively (r1 = 0.387, p=0.047 and r2 = 0.391, p=0.035). No changes in the LV systolic function were observed., Conclusion: The study showed that patients with lymphoproliferative diseases had no signs of cardiotoxicity during PCT according to the accepted criteria. This study described and highlighted for the first time the interrelation of endothelial dysfunction, profibrotic status, and LV diastolic dysfunction as manifestations of cardiovascular toxicity in patients with lymphoproliferative diseases. It is advisable to supplement the integrated strategies for the prevention and monitoring of PCT cardiovascular toxicity with a thorough evaluation of instrumental parameters of diastolic dysfunction for timely initiation/correction of cardioprotective therapy.

Aim: To discuss two aspects that can be used to improve the adherence to therapy in patients with arterial hypertension (AH): 1) which of the angiotensin II receptor blockers (ARBs) provides the highest adherence rates; 2) how various factors influence adherence rates., Material and Methods: An analysis of one of the world's largest clinical practice databases, Truven Health Analytics MarketScan (currently Merative MarketScan), was performed. The analysis included data on patients of both sexes aged 30 to 65 years who had been diagnosed with uncomplicated AH (at least once between March 1, 2012 and January 1, 2018) and prescribed monotherapy with one of ARBs. The exclusion criteria were heart failure and the treatment with two or more ARBs (simultaneously or sequentially) during the treatment period. Ultimately, the study included 717,099 patients with uncomplicated AH, who were divided into four groups based on the prescribed drug: azilsartan (n=4276), candesartan (n=6023), losartan (n=586,857), and valsartan (n=119,943). Adherence to treatment was evaluated by two parameters: duration of continuous therapy and medication possession ratio (MPR). The individual effect of each factor (specific ARB used for therapy, patient gender, age, initial ARB dose, patient co-payment per day of treatment) on the adherence to treatment was assessed using a regression analysis., Results: The adherence to the ARB therapy was generally high. The MPR was the lowest in the azilsartan group and the highest in the candesartan group. However, the parameters that potentially influenced both the MPR and the duration of continuous therapy (patient's gender and age, initial ARB dose, co-payment size) differed significantly between the groups receiving different ARBs. The regression analysis showed that both adherence parameters and the duration of continuous therapy were higher in patients receiving candesartan than in patients receiving azilsartan, losartan or valsartan, when the effect on the adherence of other factors available for study (age, gender, initial dose of the drug, and the absolute size of co-payment for a day of therapy) was excluded. The lowest adherence to therapy was observed in the azilsartan treatment group (p<0.01)., Conclusion: The study provided data for comparing the adherence of patients with uncomplicated AH to the therapy with different ARBs. Further study of adherence to treatment will provide additional data that will allow an optimal selection of drugs for the treatment of AH in patients with potentially poor adherence.

Multiple myeloma (MM) is an incurable malignancy of clonal plasma cells. Various diagnostic methods are used in parallel to accurately determine stage and severity of the disease. Identifying a biomarker or a panel of biomarkers could enhance the quality of medical care that patients receive by adopting a more personalized approach. Metabolomics utilizes high-throughput analytical platforms to examine the levels and quantities of biochemical compounds in biosamples. The aim of this review was to conduct a systematic literature search for potential metabolic biomarkers that may aid in the diagnosis and prognosis of MM. The review was conducted in accordance with PRISMA recommendations and was registered in PROSPERO. The systematic search was performed in PubMed, CINAHL, SciFinder, Scopus, The Cochrane Library and Google Scholar. Studies were limited to those involving people with clinically diagnosed MM and healthy controls as comparators. Articles had to be published in English and had no restrictions on publication date or sample type. The quality of articles was assessed according to QUADOMICS criteria. A total of 709 articles were collected during the literature search. Of these, 436 were excluded based on their abstract, with 26 more removed after a thorough review of the full text. Finally, 16 articles were deemed relevant and were subjected to further analysis of their data. A number of promising candidate biomarkers was discovered. Follow-up studies with large sample sizes are needed to determine their suitability for clinical applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The most important component of cardio-oncology is the assessment of the risk of development and diagnosis of cardiovascular toxicity of the antitumor therapy, the detection of which is largely based on visualization of the cardiovascular system. The article addresses up-to-date methods of non-invasive visualization of the heart and blood vessels, according to the 2022 European Society of Cardiology Clinical Guidelines on cardio-oncology. Also, the article discusses promising cardiovascular imaging techniques that are not yet included in the guidelines: assessment of coronary calcium using multislice computed tomography and positron emission computed tomography with 18F-labeled 2-deoxy-2-fluoro-d-glucose.

Aim: Assessment of WNT1, WNT3a, and LRP6 concentrations in patients with ischemic heart disease (IHD) and obstructive and non-obstructive coronary artery (CA) disease., Material and Methods: This cross-sectional observational study included 50 IHD patients (verified by coronary angiography, CAG), of which 25 (50%) were men, mean age 64.9±8.1 years; 20 patients had non-obstructive CA disease (stenosis <50%), and 30 patients had hemodynamically significant stenosis. Concentrations of WNT1, WNT3a and LRP6 were measured in all patients., Results: The concentrations of WNT1 and WNT3a proteins were significantly higher in patients with IHD and obstructive CA disease (p < 0.001), while the concentration of LRP6 was higher in the group with non-obstructive CA disease (p = 0.016). Data analysis of the group with obstructive CA disease showed a moderate correlation between WNT1 and LRP6 (ρ=0.374; p=0.042). Correlation analysis of all groups of patients with CA disease revealed a moderate association between the concentrations of WNT1 and uric acid (ρ=0.416; p=0.007). Regression analysis showed that risk factors for the development of IHD, such as increased body mass index, age, smoking, dyslipidemia, and hypertension, did not significantly influence the type of CA disease in IHD patients. According to ROC analysis, the obstructive form of IHD was predicted by a WNT3a concentration higher than 0.155 ng/ml and a LRP6 concentration lower than 12.94 ng/ml., Conclusion: IHD patients with non-obstructive CA disease had the greatest increase in LRP6, while patients with obstructive CA disease had significantly higher concentrations of the canonical WNT cascade proteins, WNT1 and WNT3a. According to the ROC analysis, a WNT3a concentration >0.155 ng/ml can serve as a predictor for the presence of hemodynamically significant CA stenosis in IHD patients (sensitivity 96.7%; specificity 70%), whereas a LRP6 concentration >12.94 ng/ml can predict the development of non-obstructive CA disease (sensitivity 76.7%; specificity 65%).

Aim: To assess the levels of matrix metalloproteinases (MMP), vascular endothelial growth factor (VEGF), and miRNA-34a expression in patients with ischemic heart disease (IHD) and obstructive and nonobstructive coronary artery (CA) disease., Material and Methods: This cross-sectional observational study included 64 patients with IHD (diagnosis verified by coronary angiography or multislice computed tomography coronary angiography), of which 33 (51.6%) were men aged 64.9±8.1 years. 20 patients had nonobstructive CA disease (stenosis <50%), and 44 had hemodynamically significant stenoses. The control group consisted of 30 healthy volunteers. MMP-1, -9, -13, and -14, miRNA-34a, and VEGF were measured in all patients., Results: The concentration of MMP-1 was significantly higher in patients with ischemia and nonobstructive CA disease (INOCAD) (p=0.016), and the concentration of MMP-9 was the highest in the group with obstructive CA disease (p<0.001). The concentrations of MMP-13 and MMP-14 did not differ significantly between the groups. The highest VEGF concentrations were observed in the INOCAD group (p<0.001). The expression of miRNA-34a significantly differed between the IHD groups with different types of CA disease and controls (p <0.001). Patients with hemodynamically significant stenosis showed moderate relationships between the concentrations of MMP-14 and VEGF (ρ=0.418; p=0.024), as well as between VEGF and miRNA-34a (ρ=0.425; p=0.022). Patients with INOCAD had a significant negative correlation between the concentrations of MMP-13 and VEGF (ρ= -0.659; p=0.003). Correlation analysis showed in all IHD patients a moderate relationship of the concentrations of MMP-1 and MMP-14 with VEGF (ρ=0.449; p=0.002 and p=0.341; p=0.019, respectively). According to ROC analysis, a MMP-9 concentration above 4.83 ng/ml can be a predictor for the presence of hemodynamically significant CA obstruction in IHD patients; a VEGF concentration higher than 27.23 pg/ml suggests the absence of hemodynamically significant CA stenosis., Conclusion: IHD patients with INOCAD had the greatest increase in MMP-1, whereas patients with obstructive CA disease had the highest level of MMP-9. According to our data, concentrations of MMP-9 and VEGF can be used to predict the degree of CA obstruction. The expression of miRNA-34a was significantly higher in IHD patients with INOCAD and CA obstruction than in the control group, which suggested a miRNA-34a contribution to the development and progression of coronary atherosclerosis. In the future, it may be possible to use this miRNA as a diagnostic marker for IHD.

Aim: To study the long-term effect of enhanced external counterpulsation (EECP) therapy on exercise tolerance, quality of life (QoL), and indicators of the structural and functional state of the cardiovascular system in patients with stable ischemic heart disease (IHD) complicated by chronic heart failure (CHF)., Material and Methods: This open randomized EXCEL study included 120 patients with verified IHD complicated by NYHA II-III functional class CHF with reduced or mid-range left ventricular (LV) ejection fraction. Patients were randomized into group 1 (n=40), optimal drug therapy (ODT) and EECP (35 hours, 2 courses per year); group 2 (n=40), ODT and EECP (35 hours, 1 course per year); and group 3 (control; n=40), ODT and placebo counterpulsation (35 h, 1 course per year). All patients underwent a 6-minute walk test (6MWT), evaluation of clinical status, QoL with the MLHFQ and SF-36 questionnaires, structural and functional state of large blood vessels and microvasculature, measurement of brain natriuretic peptide precursor (NT-proBNP), and echocardiography at baseline and after 12 months., Results: In groups 1 and 2 after 12 months, the 6MWT distance increased statistically significantly (44.5 and 24.9%, respectively) and the following indexes improved: QoL (SF-36, MLHFQ), the condition of large blood vessels (phase shift, radial augmentation index, central aortic systolic pressure (CASP)) and microvasculature (occlusion index, percentage of perfused capillaries, percentage of capillary recovery), and the LV systolic function (from 40.6±7.5 to 47.5±10.2% and from 41.3± 6.8 to 43.9±10.3%, respectively). The proportion of patients with a >20% increase in the 6MWT at 12 months was 97.5, 72.5, and 7.7%, respectively. A statistically significant decrease in NT-proBNP was observed in all groups. In group 3, the incidence of hospitalizations for CHF and the risk of the composite endpoint were significantly higher., Conclusion: For the 12-month study period, the effects of EECP in patients with IHD complicated by CHF included improvements in exercise tolerance, QoL, vascular and cardiac functional parameters, and a decrease in the incidence of adverse outcomes.

MicroRNAs and the WNT signaling cascade regulate the pathogenetic mechanisms of atherosclerotic coronary artery disease (CAD) development., Objective: To evaluate the expression of microRNAs (miR-21a, miR-145, and miR-221) and the role of the WNT signaling cascade (WNT1, WNT3a, WNT4, and WNT5a) in obstructive CAD and ischemia with no obstructive coronary arteries (INOCA)., Method: The cross-sectional observational study comprised 94 subjects. The expression of miR-21a, miR-145, miR-221 (RT-PCR) and the protein levels of WNT1, WNT3a, WNT4, WNT5a, LRP6, and SIRT1 (ELISA) were estimated in the plasma of 20 patients with INOCA (66.5 [62.8; 71.2] years; 25% men), 44 patients with obstructive CAD (64.0 [56.5; 71,0] years; 63.6% men), and 30 healthy volunteers without risk factors for cardiovascular diseases (CVD)., Results: Higher levels of WNT1 (0.189 [0.184; 0.193] ng/mL vs. 0.15 [0.15-0.16] ng/mL, p < 0.001) and WNT3a (0.227 [0.181; 0.252] vs. 0.115 [0.07; 0.16] p < 0.001) were found in plasma samples from patients with obstructive CAD, whereas the INOCA group was characterized by higher concentrations of WNT4 (0.345 [0.278; 0.492] ng/mL vs. 0.203 [0.112; 0.378] ng/mL, p = 0.025) and WNT5a (0.17 [0.16; 0.17] ng/mL vs. 0.01 [0.007; 0.018] ng/mL, p < 0.001). MiR-221 expression level was higher in all CAD groups compared to the control group ( p < 0.001), whereas miR-21a was more highly expressed in the control group than in the obstructive ( p = 0.012) and INOCA ( p = 0.003) groups. Correlation analysis revealed associations of miR-21a expression with WNT1 (r = -0.32; p = 0.028) and SIRT1 (r = 0.399; p = 0.005) protein levels in all CAD groups. A positive correlation between miR-145 expression and the WNT4 protein level was observed in patients with obstructive CAD (r = 0.436; p = 0.016). Based on multivariate regression analysis, a mathematical model was constructed that predicts the type of coronary lesion. WNT3a and LRP6 were the independent predictors of INOCA ( p < 0.001 and p = 0.002, respectively)., Conclusions: Activation of the canonical cascade of WNT-β-catenin prevailed in patients with obstructive CAD, whereas in the INOCA and control groups, the activity of the non-canonical pathway was higher. It can be assumed that miR-21a has a negative effect on the formation of atherosclerotic CAD. Alternatively, miR-145 could be involved in the development of coronary artery obstruction, presumably through the regulation of the WNT4 protein. A mathematical model with WNT3a and LRP6 as predictors allows for the prediction of the type of coronary artery lesion.

Background: Progressive myocardial remodeling (MR) in chronic heart failure (CHF) leads to aggravation of systolic dysfunction (SD) and clinical manifestations. Identification of metabolomic markers of these processes may help in the search for new therapeutic approaches aimed at achieving reversibility of MR and improving prognosis in patients with CHF., Methods: To determine the relationship between plasma acylcarnitine (ACs) levels, MR parameters and clinical characteristics, in patients with CHF of ischemic etiology (n = 79) and patients with coronary heart disease CHD (n = 19) targeted analysis of 30 ACs was performed by flow injection analysis mass spectrometry., Results: Significant differences between cohorts were found for the levels of 11 ACs. Significant positive correlations (r > 0.3) between the medium- and long-chain ACs (MCACs and LCACs) and symptoms (CHF NYHA functional class (FC); r = 0.31-0.39; p < 0.05); negative correlation (r = -0.31-0.34; p < 0.05) between C5-OH and FC was revealed. Positive correlations of MCACs and LCACs (r = 0.31-0.48; p < 0.05) with the left atrium size and volume, the right atrium volume, right ventricle, and the inferior vena cava sizes, as well as the pulmonary artery systolic pressure level were shown. A negative correlation between C18:1 and left ventricular ejection fraction (r = -0.31; p < 0.05) was found. However, a decrease in levels compared to referent values of ACs with medium and long chain lengths was 50% of the CHF-CHD cohort. Carnitine deficiency was found in 6% and acylcarnitine deficiency in 3% of all patients with chronic heart disease., Conclusions: ACs may be used in assessing the severity of the clinical manifestations and MR. ACs are an important locus to study in terms of altered metabolic pathways in patients with CHF of ischemic etiology and SD. Further larger prospective trials are warranted and needed to determine the potential benefits to treat patients with CV diseases with aberrate AC levels.

Over the past few decades, due to the extensive implementation of cancer screening programs, up-to-date early diagnostic methods, and effective combinations of antitumor therapy, it has become possible to significantly improve survival of cancer patients. At the same time, despite the effective treatment of malignancies, most patient face adverse and often life-threatening effects of specific treatment on the heart and blood vessels. All this resulted in active development of a new field in cardiology, cardio-oncology. In recent years, based on the experience of leading experts, data from large studies, and meta-analyses, both international and Russian Consensuses, conciliation documents, have been formed and published. These documents regulate principal methodological approaches to management and control of the cardiovascular conditions in cancer patients. Finally, 2022 was marked by issuing the first official European Guidelines on Cardio-Oncology in the history of medicine. This article highlights the most relevant, in our opinion, positions of these guidelines as well as controversial and unresolved issues.

Aim      To evaluate functional changes in the heart in the long-term following COVID-19 in patients with chronic heart failure (CHF).Material and methods  Case reports of 54 patients aged 69.1±9.7 years who had COVID-19 from January 2021 through January 2022 and had been previously diagnosed with NYHA functional class II-III CHF were studied. Two comparison groups were isolated: HF with LV EF &gt;50 % (n=39) and &lt;50 % (n=15). Echocardiography was used to evaluate changes in LV EF and pulmonary artery systolic pressure (PASP) 5-6 months following COVID-19.Results In all CHF patients after COVID-19 at 5.8 months on average, LV EF decreased (median difference, 2.5 %; 95 % confidence interval (CI): 6.99×10-5- 4.99) and PASP increased (median difference, 8 mm Hg; 95 % CI: 4.5-12.9). In the HF group with LV EF &lt;50 %, the decrease in EF was greater than in the group with LV EF &gt;50 % (6.9 and 0.7 %, respectively; p=0.037); furthermore, the CHF phenotype did not influence the change in PASP (p=0.4). The one-factor regression analysis showed that the dynamics of LV EF decrease was significantly influenced by the baseline decrease in LV EF, whereas the change in PASP was influenced by the dynamics of LV EF decrease, presence of dyslipidemia, and statin treatment. Furthermore, the multifactorial analysis showed that prognostically significant factors for long-term changes in LV EF following COVID-19 were male gender (odds ratio (OR), 5.92; 95 % CI: 1.31-26.75; p=0.014), LV EF at baseline &lt;50 % (OR, 0.88; 95 % CI: 0.8-0.96; p&lt;0.001); changes in PASP depended on the presence of dyslipidemia (OR, 0.08; 95 % CI: 0.01-0.84; p=0.018).Conclusion      This study showed that COVID-19 in the long term can influence the course of CHF; in this process, HF patients with EF &lt;50 % have progression of systolic dysfunction and PASP, whereas patients with EF &gt;50 % have an isolated increase in PASP.

Aim    To compare serum concentrations of tryptophane (Trp) and its metabolites in subjects with no cardiovascular disease (CVD) and patients with СVD, including arterial hypertension (AH) and ischemic heart disease (IHD).Material and methods    This study included 131 participants; 58 participants (11 of them with documented peripheral atherosclerosis) were included into the AH group, 46 participants were included into the IHD group, and 27 participants with no signs of CVD were included into the control group. Plasma concentrations of Trp and its metabolites were measured by high-performance liquid chromatography in combination with a triple quadrupole analyzer.Results    Comparison of the three study groups revealed significant differences in concentrations of Trp (р=0.029), kynurenine (p&lt;0.001), kynurenine/Trp ratio (p&lt;0.001), quinolinic acid (р=0.007), kynurenic acid (р=0.003), serotonin (p&lt;0.001), and 5‑hydroxyindoleacetic acid (5‑HIAA) (р=0.011). When the AH group was subdivided into subgroups without and with documented peripheral atherosclerosis, the intergroup differences remained for concentrations of kynurenine, kynurenine/Trp ratio, quinolinic acid, kynurenic acid, serotonin, and 5‑HIAA. Also, correlations were found between concentrations of Trp metabolites and laboratory and instrumental data, primarily inflammatory markers. Conclusion    Analysis of serum concentrations of Trp and its metabolites in CVD patients showed increases in kynurenine, kynurenine/Trp ratio, quinolinic acid, kynurenic acid, and 5‑HIAA along with decreases in concentrations of Trp and serotonin in the groups of AH, AH with documented peripheral atherosclerosis, and IHD.

Metabolomics is a promising technology for the application of translational medicine to cardiovascular risk. Here, we applied a liquid chromatography/tandem mass spectrometry approach to explore the associations between plasma concentrations of amino acids, methylarginines, acylcarnitines, and tryptophan catabolism metabolites and cardiometabolic risk factors in patients diagnosed with arterial hypertension (HTA) (n = 61), coronary artery disease (CAD) (n = 48), and non-cardiovascular disease (CVD) individuals (n = 27). In total, almost all significantly different acylcarnitines, amino acids, methylarginines, and intermediates of the kynurenic and indolic tryptophan conversion pathways presented increased (p < 0.05) in concentration levels during the progression of CVD, indicating an association of inflammation, mitochondrial imbalance, and oxidative stress with early stages of CVD. Additionally, the random forest algorithm was found to have the highest prediction power in multiclass and binary classification patients with CAD, HTA, and non-CVD individuals and globally between CVD and non-CVD individuals (accuracy equal to 0.80 and 0.91, respectively). Thus, the present study provided a complex approach for the risk stratification of patients with CAD, patients with HTA, and non-CVD individuals using targeted metabolomics profiling.

Aim      To determine the neuregulin-1β concentration in patients with chronic heart failure with preserved ejection fraction (HFpEF) and the association of this biomarker with the functional status of patients, echocardiographic parameters of the structural and functional condition of the heart, and the risk of unfavorable outcome.Material and methods  This observational, prospective study included 47 patients with HFpEF; 32 (68%) of them were females. Mean age was 70 [66-77] years, EF was 57 [56; 58] %. The group of healthy volunteers consisted of 40 people; 32 (55 %) of them were females; mean age was 56 [53-61] years. For all patients, the functional status was evaluated (6-min walk test, 6MWT); standard echocardiography (EchoCG) was performed; and concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) and neuregulin-1β were measured. The follow-up period was two years. Cases of cardiovascular (CV) death and hospitalizations for decompensated chronic heart failure (CHF) were recorded.Results Median concentration of neuregulin-1β was 0.969 [0.348; 1.932] ng/ml in the HFpEF group, which was significantly higher than 0.379 [0.195; 0.861] ng/ml in the group of healthy volunteers (р=0.003). Significant correlations between the neuregulin-1β concentration and the distance walked in 6MWT or with EchoCG parameters of left ventricular diastolic function were not found. Mean observation time was 456 [244; 730] days. 21 outcomes were observed, including 2 CV deaths and 19 hospitalizations for CHF. Patients with high concentrations of neuregulin-1β (≥Me) had a greater frequency of hospitalizations for CHF (Log-rank, p=0.046) and a higher risk of this outcome (risk ratio, 1.30; 95 % confidence interval, 1.01-1.66; p=0.037).Conclusion      Patients with HFpEF had increased concentrations of neuregulin-1β. High levels of neuregulin-1β were associated with a higher risk of hospitalization for decompensated CHF.

Aim      To evaluate in a pilot study time-related changes in the clinical state, indexes of the acute phase of inflammation, parameters of blood lipid profile, intracardiac hemodynamics, and disorders of cardiac rhythm/conduction in patients who are not candidates for autologous hemopoietic stem cell transplantation, during three bortezomib-containing chemotherapy courses (VCD) followed by a correlation analysis.Material and methods  This pilot study included 20 patients diagnosed with myeloma, who were not candidates for autologous hemopoietic stem cell transplantation and who had undergone three courses of VCD chemotherapy (bortezomib, cyclophosphamide and dexamethasone). In addition to mandatory examinations, measurement of blood lipid profile, transthoracic echocardiography (EchoCG), and 24-h Holter electrocardiogram (ECG) monitoring were performed for all participants before and after a specific therapy.Results Following three bortezomib-containing courses of chemotherapy, patients of the study group had significant increases in the neutrophil-lymphocyte ratio (NLR) (1.6±0.2 and 2.5±0.4; р=0.05), cholesterol concentration (4.8±1.1 and 5.6±1.1 mmol/l, р=0.05), and low-density lipoprotein concentration (2.8±0.4 and 3.5±0.8 mmol/l, р=0.02). In comparing the changes in parameters of intracardiac hemodynamics, criteria for genuine cardiotoxicity were not met, however, a tendency to emergence/progression of myocardial diastolic dysfunction was noted. No clinically significant disorders of cardiac rhythm/conduction were observed. The correlation analysis performed prior to the start of chemotherapy, showed significant strong, direct correlations between the C-protein concentration and left atrial (LA) volume (r=0.793; p=0.006), right atrial (RA) volume (r=0.857; p=0.002), left ventricular (LV) end-diastolic dimension (EDD) (r=0.589; p=0.043), and LV end-diastolic volume (EDV) (r=0.726; p=0.017). Following the specific treatment, significant, medium-power and strong correlations were found between NLR and EDV (r= -0.673; p=0.033), NLR and end systolic volume (ESV) (r= -0.710; p=0.021), respectively. Significant direct correlations were found between the bortezomib dose per one injection and the serum concentration of triglycerides following the treatment (r=0.78; p=0.05); a single bortezomib dose and parameters of intracardiac hemodynamics: LA (r=0.71; p=0.026), RA (r=0.74; p=0.014), EDD (r=0.837; p=0.003), EDV (r=0.749; p=0.013), ESV (r=0.553; p=0.049).Conclusion      For the first time, a comprehensive evaluation was performed in patients with multiple myeloma, including the dynamics of blood lipid profile, intracardiac hemodynamics and disorders of cardiac rhythm/conduction during bortezomib-containing antitumor therapy, with an analysis of correlation with levels of acute inflammation phase markers. Although in the observation window for genuine cardiotoxicity, clinically significant cardiovascular complications were not detected, the found correlations may evidence a potential role of systemic inflammation activity in myocardial remodeling in the studied patient cohort.

Aim    To study true prevalence of atrial fibrillation (AF) in a representative sample from the European part of the Russian Federation; to describe characteristics of patients with AF; and to provide the frequency of anticoagulant treatment.Material and methods    Cross-sectional data of the EPOCH epidemiological study (2017) were used. Data were collected in 8 constituent entities of the Russian Federation; the sample size was 11 453 people. The sample included all respondents who had given their consent for participation and were older than 10 years. Statistical tests were performed in the R system for statistical data analysis.Results    The prevalence of AF in the representative sample from the European part of the Russian Federation was 2.04 %. The AF prevalence increased with age and reached a maximum value of 9.6% in the age group of 80 to 89 years. The AF prevalence among females was 1.5 times higher than among men. With age standardization, the AF prevalence was 18.95 and 21.33 per 1,000 people for men and women, respectively. The AF prevalence increased in the presence of concurrent cardiovascular diseases (CVDs) or diabetes mellitus as well as with an increased number of comorbidities in the same person and reached 70.3 and 60.0 % in patients with 4 and 5 comorbidities, respectively. Patients with AF had a greater number of comorbidities and higher CHA2DS2VASc scores (5.0 vs. 2.0, p&lt;0.001) compared to patients with CVDs without AF. Only 22.6 % of patients with CVD and AF took anticoagulants. Only 23.9% of patients with absolute indications for the anticoagulant treatment received anticoagulants.Conclusion    The AF prevalence in the European part of the Russian Federation was 2.04 %; it increased with age and in patients with concurrent CVDs or diabetes mellitus. Most of AF patients (93.2 %) required a mandatory treatment with oral anticoagulants.

Aim: assessment of risk factors, cardiovascular status and intracardiac hemodynamics in patients with multiple myeloma before the start of specific antitumor therapy. Materials and methods: The study included 2 equal groups of patients: the first group - 25 patients with a newly diagnosed diagnosis of multiple myeloma (MM), the comparison group - 25 patients with proven cardiovascular diseases (CVD) (hypertension (HD) and coronary heart disease (CHD)). All patients included in the study underwent standard laboratory diagnostics, instrumental research methods (ECG, Echo-KG, 24-hour Holter monitoring); proven CVD risk factors were also evaluated. Results: When comparing the two groups, it was reliably shown that the state of CVD in patients with MM is comparable to that in patients with proven CVD. In patients from the main group, were revealed significant positive correlations of average strength between indicators of systemic inflammation, the lipid spectrum and intracardiac hemodynamics: between the levels of CRP and triglycerides (r=0,415, p&lt;0,05); between the values of CRP and LDL (r=0,345, p=0,09); CRP and LA volume (r=0,434, p&lt;0,05); CRP and final diastolic volume (r=0,30, p&lt;0,05). At the beginning, a high risk of developing CV- events in patients with MM may be due to cardiac remodeling associated with the activity of systemic inflammation., Conclusion: in view the use of potentially cardiovasculartoxicity drugs for the treatment of multiple myeloma, the assessment of the CV status and consultation with a cardiologist/cardiologist with the selection of the necessary therapy should be obligatory step before starting specific treatment.

Aim      To study the dynamics of serum markers for vascular remodeling in patients with arterial hypertension (AH), including AH associated with type 2 diabetes mellitus (DM2) during the 12-month treatment with the angiotensin-converting enzyme (ACE) inhibitor, perindopril A.Material and methods  The study included patients with grade 1-2 AH with or without type 2 DM (30 and 32, respectively). Perindopril A 10 mg/day was administered for the outpatient correction of previous, ineffective antihypertensive therapy. The following biomarkers were measured for all patients at baseline and at 12 months: matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), E-selectin, endothelin 1, transforming growth factor β-1 (TGF-β1), and von Willebrand factor (WF). Laboratory tests were performed with enzyme immunoassay.Results After 12 months of the perindopril A (perindopril arginine) 10 mg/day treatment, both groups achieved the goal blood pressure. Evaluation of biomarker dynamics during the perindopril A treatment showed significant decreases in MMP-9, TIMP-1, and endothelin 1 in the AH group; then the level of TIMP-1 returned to normal values (р&lt;0.05). In the AH+DM2 group, the MMP-9 concentration was significantly decreased (р&lt;0.05); the other values did not show any significant differences. In both groups, MMP-9 was significantly decreased (28.6 % (р=0.01) in group 1 and 33.2 % (р=0.00) in group 2. Notably, in none of these groups, did this index reach normal values. Also, there were no significant differences in this index between the groups (р=0.66). It should be noted that the decreases in TIMP-1 were significantly different between the groups (р=0.001). Thus, this biomarker did not significantly decrease in patients with AH and DM2 (р=0.26) whereas in group 1 (AH without DM2), the level of TIMP-1 decreased by 39.3 % and reached the normal range (р=0.005).Conclusion      Concentrations of biomarkers were decreased in both groups. However, in the AH group, there were statistically significant decreases in the markers that reflect processes of fibrosis and vasoconstriction. At the same time in the AH+DM2 group, there was no significant dynamics of the biomarkers, which was most likely due to more pronounced damage of blood vessels. However, the decrease in MMP-9 may indicate an alleviation of fibrotic processes in arterial walls. These results allow a conclusion that the long-term treatment with the ACE inhibitor, perindopril A, may reverse remodeling of the vascular changes that are called "early vascular ageing".r aging".

Aim      To evaluate the effect of perindopril on the endothelial function and levels of endothelial dysfunction markers in groups of patients with heart failure with preserved (HFpEF) and mid-range (intermediate) left ventricular ejection fraction (HFmrEF).Material and methods  40 patients with HFpEF (n=20) and HFmrEF (n=20) were evaluated. At baseline, parameters of the morpho-functional state of large blood vessels and of microvessels were evaluated with photoplethysmography, and levels of E-selectin and endothelin-1 (ET-1) were measured. The patients were prescribed perindopril, and after 12 months of treatment, photoplethysmographic parameters and endothelial dysfunction markers were determined again.Results After 12 months of the perindopril treatment, improvements in the endothelial function of both large blood vessels and microvessels were noted. The phase shift increased from 10.1 to 10.9 ms in the HFpEF group (р=0.001) and from 8.35 to 9.65 ms in the HFmrEF group (р=0.002). Furthermore, the occlusion index increased from 1.45 to 1.75 in patients with HFpEF (р=0.004) and from 1.5 to 1.75 in patients with HFmrEF (р=0.010). The Е-selectin concentration decreased in both groups, from 57.25 to 42.4 ng/ml (р=0.00008) and from 40.5 to 35.7 ng/ml (р=0.010) in patients with HFpEF and HFmrEF, respectively. The ET-1 concentration decreased from pg/ml (р=0.010) in patients with HFpEF whereas in patients with HFmrEF, there was no significant change in the ET-1 concentration after 12 months of the perindopril treatment.Conclusion      At 12 months, the endothelial function improved and E-selectin and ET-1 levels decreased in patients with HFpEF and HFmrEF.

Aim    Dilated cardiomyopathy (DCMP) is a major cause for severe heart failure. Development of a combination (drug and surgery) treatment of this disease is relevant. This prospective observational study was aimed at evaluating short- and long-term results of extracardiac mesh implantation in DCMP patients with heart failure resistant to the optimum drug therapy.Material and methods    The extracardiac mesh ACOR-1 was implanted in 15 patients with DCMP. All meshes were produced individually for each patient and made of Gelweave (great Britain) vascular graft strips. The mesh size corresponded to the heart diastolic size, which was measured after achieving a maximum possible clinical improvement for the patient. Long-term results were followed for up to 4 years. Mean age of patients was 43.1±10.8 years (from 28 to 62 years). One patient was followed up for 18 years. Data of that patient were presented as a clinical case report.Results    From October, 2003 through October, 2007, 15 DCMP patients received mesh implants. Cases of in-hospital death were absent. In 3 mos. after the surgery, left ventricular volumes decreased (end-diastolic volume decreased from 251.7±80.7 to 229.0±61.3 ml; end-systolic volume decreased from 182.3±73.6 to 167.7±46.2 ml), and the left ventricular pump function improved (ejection fraction increased from 25.2±6.0 to 27.1±5.1 %; cardiac index increased from 2.0±0.5 to 2.4±0.7 ml /min /m2). The functional state of patients improved by one NYHA class, from 3.7±0.3 to 2.8±0.6. In some cases, the left ventricular size and the systolic function completely normalized. There were no episodes of circulatory decompensation in the long term after surgery. Actuarial survival for the observation period was 100%.Conclusion    Implantation of extracardiac mesh prevented progression of heart dilatation and, in combination with drug therapy, it may represent an effective method for treatment of DCMP.

Aim      To study the effect of regular drug therapy for cardiovascular and other diseases preceding the COVID-19 infection on severity and outcome of COVID-19 based on data of the ACTIVE (Analysis of dynamics of Comorbidities in paTIents who surVived SARS-CoV-2 infEction) registry.Material and methods  The ACTIVE registry was created at the initiative of the Eurasian Association of Therapists. The registry includes 5 808 male and female patients diagnosed with COVID-19 treated in a hospital or at home with a due protection of patients' privacy (data of nasal and throat smears; antibody titer; typical CT imaging features). The register territory included 7 countries: the Russian Federation, the Republic of Armenia, the Republic of Belarus, the Republic of Kazakhstan, the Kyrgyz Republic, the Republic of Moldova, and the Republic of Uzbekistan. The registry design: a closed, multicenter registry with two nonoverlapping arms (outpatient arm and in-patient arm). The registry scheduled 6 visits, 3 in-person visits during the acute period and 3 virtual visits (telephone calls) at 3, 6, and 12 mos. Patient enrollment started on June 29, 2020 and was completed on October 29, 2020. The registry completion is scheduled for October 29, 2022. The registry ID: ClinicalTrials.gov: NCT04492384. In this fragment of the study of registry data, the work group analyzed the effect of therapy for comorbidities at baseline on severity and outcomes of the novel coronavirus infection. The study population included only the patients who took their medicines on a regular basis while the comparison population consisted of noncompliant patients (irregular drug intake or not taking drugs at all despite indications for the treatment).Results The analysis of the ACTIVE registry database included 5808 patients. The vast majority of patients with COVID-19 had comorbidities with prevalence of cardiovascular diseases. Medicines used for the treatment of COVID-19 comorbidities influenced the course of the infectious disease in different ways. A lower risk of fatal outcome was associated with the statin treatment in patients with ischemic heart disease (IHD); with angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor antagonists and with beta-blockers in patients with IHD, arterial hypertension, chronic heart failure (CHF), and atrial fibrillation; with oral anticoagulants (OAC), primarily direct OAC, clopidogrel/prasugrel/ticagrelor in patients with IHD; with oral antihyperglycemic therapy in patients with type 2 diabetes mellitus (DM); and with long-acting insulins in patients with type 1 DM. A higher risk of fatal outcome was associated with the spironolactone treatment in patients with CHF and with inhaled corticosteroids (iCS) in patients with chronic obstructive pulmonary disease (COPD).Conclusion      In the epoch of COVID-19 pandemic, a lower risk of severe course of the coronavirus infection was observed for patients with chronic noninfectious comorbidities highly compliant with the base treatment of the comorbidity.

On December 18, 2020, an expert council was held with the participation of members of the Russian Society of Cardiology, the Eurasian Association of Ther-apists, the National Society for Atherothrombosis, the National Society for Evi-dence-Based Pharmacotherapy, and the Russian Heart Failure Society. The event was devoted to the discussion of the correct use of research data of "real clinical practice" in decision making.

Aim    To study the etiology and the dynamics of prevalence and mortality of CHF; to evaluate the treatment coverage of such patients in a representative sample of the European part of the Russian Federation for a 20-year period. Material and methods    A representative sample of the European part of the Russian Federation followed up for 2002 through 2017 (n=19 276); a representative sample of the population of the Nizhny Novgorod region examined in 1998 (n=1922).Results    During the observation period since 2002, the incidence of major CHF symptoms (tachycardia, edema, shortness of breath, weakness) tended to decrease while the prevalence of cardiovascular diseases has statistically significantly increased. During the period from 1998 through 2017, the prevalence of I-IV functional class (FC) CHF increased from 6.1 % to 8.2 % whereas III-IV FC CHF increased from 1.8 % to 3.1 %. The main causes for the development of CHF remained arterial hypertension and ischemic heart disease; the role of myocardial infarction and diabetes mellitus as causes for CHF was noted. For the analyzed period, the number of treatment components and the coverage of basic therapy for patients with CHF increased, which probably accounts for a slower increase in the disease prevalence by 2007-2017. The prognosis of patients was unfavorable: in I-II FC CHF, the median survival was 8.4 (95 % CI: 7.8-9.1) years and in III-IV FC CHF, the median survival was 3.8 (95 % CI: 3.4-4.2) years.

Aim To determine levels of markers for endothelial dysfunction and inflammation, endothelin-1, E-selectin, and tumor necrosis factor α (TNF-α) in patients with ischemic heart disease (IHD) and non-obstructive and obstructive coronary artery (CA) disease.Material and methods This study included 32 patients with verified IHD and non-obstructive (main group, n=19) and obstructive (comparison group, n=13) CA disease. Endothelial dysfunction was diagnosed by photoplethysmography and videocapillaroscopy. Serum concentrations of endothelin-1, E-selectin, and TNF- α were measured in all patients.Results Patients with non-obstructive CA disease showed a tendency towards more pronounced endothelial dysfunction (alternative stiffness index, 7.8 m /s [6.35; 9.08]; reflection index, 36.95 % [23.4; 52.65]; capillary density following reactive hyperemia, 54.33 cap /mm2 [48.92; 75.83]; capillary density following venous occlusion, 74.33 cap /mm2 [67.83; 93.00]) compared to the comparison group (alternative stiffness index, 9.05 m/s [7.08; 10.58]; reflection index, 28.25 % [23.35; 53.75]; capillary density following reactive hyperemia, 66.83 cap /mm2 [50.83; 78.67]; capillary density following venous occlusion, 87.0 cap /mm2 [77.58; 78.67]), although statistically significant differences were not found. Concentration of endothelin-1 was significantly higher in the IHD group with non-obstructive CA disease (0.45 ng/ml [0.28;0.65]) compared to patients with CA atherosclerotic stenosis (0.35 ng/ml [0.25; 0.38], p=0.035). Concentrations of E-selectin did not significantly differ between the groups (main group, 21.1 ng/ml [18.45; 35.03]; comparison group, 28.55 ng/ml [19.08; 35.01], p=0.29). In both groups, concentrations of TNF-α did not exceed the lower threshold of sensitivity (&lt;2.3 pg/ml).Conclusion Endothelial dysfunction and increased endothelin-1 in patients with non-obstructive CA disease along with inflammation may additionally contribute to the pathogenesis of IHD in the absence of hemodynamically significant CA stenoses. Too low level of TNFα in both groups prevented us from using it as a diagnostic marker. Further study is needed that would include a greater number of patients and a search for alternative markers.

The development of cardiovascular diseases (CVDs) is often asymptomatic. Identification of initial indicators of cardiometabolic disruption may assist in its early detection. The objective was to determine the relationships between plasma acylcarnitines (ACs) and cardiometabolic risk factors in adults with and without CVDs. The AC profile in human plasma of healthy controls [non-CVD group, n = 13)] and individuals diagnosed with CVDs (CVD group, n = 34) were compared. A targeted analysis of 29 ACs was performed using flow injection analysis-tandem mass spectrometry. There were significant direct correlations (p < 0.05) between ACs and cardiometabolic risk factors. Comparing the groups after adjustment for covariates, showed that the ACs that were best differentiated (p < 0.05) between the two groups and that presented "good" diagnostic accuracy were carnitine [30.7 (25.5-37.7) vs. 37.7 (32.3-45.0) µM], the short-chain ACs: acetylcarnitine [8.9 (7.4-10.2) vs. 11.9 (9.2-14.4) µM] and isovalerylcarnitine [0.10 (0.06-0.13) vs. 0.13 (0.10-0.16) µM], and the medium-chain ACs: hexanoylcarnitine [0.04 (0.03-0.05) vs. 0.06 (0.05-0.07) µM] and decenoylcarnitine [0.18 (0.12-0.22) vs. 0.22 (0.17-0.32) µM]. This assessment contributes to the identification of the unique metabolic features exhibited in association with cardiometabolic risk in adults diagnosed with CVD. The altered metabolites have the potential to be used as biomarkers for early detection of CVD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Heart failure is a complex syndrome whose phenotypic presentation and disease progression depends on a complex network of adaptive and maladaptive responses. One of these responses is the endothelial release of NRG (neuregulin)-1-a paracrine growth factor activating ErbB2 (erythroblastic leukemia viral oncogene homolog B2), ErbB3, and ErbB4 receptor tyrosine kinases on various targets cells. NRG-1 features a multitasking profile tuning regenerative, inflammatory, fibrotic, and metabolic processes. Here, we review the activities of NRG-1 on different cell types and organs and their implication for heart failure progression and its comorbidities. Although, in general, effects of NRG-1 in heart failure are compensatory and beneficial, translation into therapies remains unaccomplished both because of the complexity of the underlying pathways and because of the challenges in the development of therapeutics (proteins, peptides, small molecules, and RNA-based therapies) for tyrosine kinase receptors. Here, we give an overview of the complexity to be faced and how it may be tackled.

Objective: To assess the impact of type 2 diabetes mellitus (T2DM) on prognosis of patients hospitalized because of acute decompensated heart failure (ADHF)., Materials and Methods: We analyzed data of the hospital register of ADHF which comprised information on 735 patients (254 [35%] with T2DM) consecutively admitted in 2010-2011. Median follow-up was 1790 days., Results: The presence of T2DM was associated with increased risk of death: during the index hospitalization due to ADHF (hazard ratio [HR] 1.7, 95% confidence interval [CI] 1.0-2.8), within 18 months (HR 1.4, 95% CI 1.0-1.8), and within 5 years (HR 1.3, 95% CI 1.0-1.5)., Conclusions: T2DM is common among acute decompensated heart failure patients (up to 35% of cases). T2DM is an independent risk factor of death during the index hospitalization and over the next 18 months and 5 years.

Introduction: The objective of this study was to assess the impact of a single-pill combination (SPC) of perindopril/indapamide (PER/IND) at full doses (10/2.5 mg) on endothelial and cognitive function as a clinical intermediate marker of vascular improvement., Methods: This open-label, uncontrolled, observational study enrolled 30 patients (20 females and 10 males) with grade II-III uncontrolled arterial hypertension (SBP/DBP ≥ 160/100 mmHg) and no evidence of cerebrovascular disease. All patients underwent assessment of macro- and microvascular endothelial function parameters at baseline and after 12 months of treatment with SPC PER/IND using photoplethysmography and video capillaroscopy. Cognitive function was assessed using the Montreal Cognitive Assessment scale (MoCA)., Results: All patients (mean age 60.06 ± 10.19 years) were at high risk for cardiovascular events: mean body mass index (BMI) 31.2 ± 3.9 kg/m 2 , 33% diagnosed with coronary artery disease angina class I, 30% with impaired glucose tolerance, and 7% with type 2 diabetes. Impaired endothelial function was observed at the both micro- and macrovascular levels. Endothelial function parameters improved after 12-month treatment with SPC PER/IND with an increase in occlusion index from 1.4 to 1.8 (P < 0.00005) and phase shift from 5.0 to 10.8 (P < 0.00001); all values achieved levels in the normal range. Resting capillary network density (CND) increased from 44.8 to 52 cap/mm 2 (P < 0.00007), and CND after a venous occlusion test increased from 55 to 61 cap/mm 2 (P < 0.006). Signs of cognitive impairment were present at baseline with a mean MoCA score of 23 (normal cognitive function score ≥ 26), but improved after 12-month treatment with a mean MoCA score of 27 (P< 0.0001). Treatment was well tolerated., Conclusion: SPC PER/IND at full doses for 12 months improves endothelial function, structural and functional parameters of the microcirculation, as well as cognitive function in patients with arterial hypertension at high cardiovascular risk., Funding: Les Laboratoires Servier.

Background: The frequency of sudden unexpected death is highest in the early post-myocardial infarction (MI) period; nevertheless, 2 recent trials showed no improvement in mortality with early placement of an implantable cardioverter-defibrillator after MI., Methods and Results: To better understand the pathophysiological events that lead to sudden death after MI, we assessed autopsy records in a series of cases classified as sudden death events in patients from the VALsartan In Acute myocardial infarctioN Trial (VALIANT). Autopsy records were available in 398 cases (14% of deaths). We determined that 105 patients had clinical circumstances consistent with sudden death. On the basis of the autopsy findings, we assessed the probable cause of sudden death and evaluated how these causes varied with time after MI. Of 105 deaths considered sudden on clinical grounds, autopsy suggested the following causes: 3 index MIs in the first 7 days (2.9%); 28 recurrent MIs (26.6%); 13 cardiac ruptures (12.4%); 4 pump failures (3.8%); 2 other cardiovascular causes (stroke or pulmonary embolism; 1.9%); and 1 noncardiovascular cause (1%). Fifty-four cases (51.4%) had no acute specific autopsy evidence other than the index MI and were thus presumed arrhythmic. The percentage of sudden death due to recurrent MI or rupture was highest in the first month after the index MI. By contrast, after 3 months, the percentage of presumed arrhythmic death was higher than recurrent MI or rupture (chi(2)=23.3, P<0.0001)., Conclusions: Recurrent MI or cardiac rupture accounts for a high proportion of sudden death in the early period after acute MI, whereas arrhythmic death may be more likely subsequently. These findings may help explain the lack of benefit of early implantable cardioverter-defibrillator therapy.

Objective: The aim of our investigation was to assess the influence of rosuvastatin therapy and myocardial revascularization on angiogenic growth factors in coronary artery disease patients., Methods and Results: Two main groups were examined: group one consisted of patients with successful percutaneous coronary intervention and group two consisted of patients 3 months on rosuvastatin therapy.Vascular endothelial growth factor (VEGF), VEGF receptor Flt-1 (sVEGF-R1) and transforming growth factor beta-1 (TGF-beta1) levels were measured in healthy volunteers and CAD patients before and 6 days after myocardial revascularization.VEGF and basic fibroblast growth factor (bFGF) levels were measured before and 3 months after rosuvastatin therapy, as well as total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDLC), high-density lipoprotein cholesterol (HDLC), C-reactive protein (CRP), interleukin 6 (IL-6) and endothelium-dependent vasodilation. VEGF levels did not differ, but beta-TGF levels were significantly lower in CAD patients in comparison with healthy subjects, P < 0.0001. Myocardial revascularization caused changes of VEGF levels from 192.4 +/- 166.1 pg/ml to 264.7 +/- 226.6 pg/ml (P = 0.0066). There were positive changes in lipid levels, lowering of CRP and IL-6 concentrations, improving of endothelial function and decreasing of VEGF levels from 382 +/- 249 pg/ml to 297 +/- 220 pg/ml (P = 0.006) 3 months after rosuvastatin treatment., Conclusions: There is an elevation of VEGF levels early after myocardial revascularization that may reflect a transient ischaemia and potentially may provoke atherosclerotic plaque neovascularization. Rosuvastatin leads to a decrease of VEGF levels that can be a reflection of the influence on endogenous angiogenesis. There was no correlation between inflammatory factors and VEGF that gives a suggestion about an absence of direct CRP and IL-6 impact on VEGF decreasing during statin treatment.

Low-dose (250 mg daily) oral probucol produces a significant antioxidant effect in coronary patients: increases activity of glutathione peroxidase (enzyme utilizing lipoperoxides) and reduces the content of free-radical oxidation products in the blood. Probucol therapy for 7 days before and for 6 months after coronary angioplasty significantly reduces the severity of coronary artery stenosis.

Low-molecular-weight aldehydes (glyoxal, methylglyoxal, 3-deoxyglucosone) generated on autooxidation of glucose under conditions of carbonyl stress react much more actively with amino groups of L-lysine and epsilon-amino groups of lysine residues of apoprotein B-100 in human blood plasma low density lipoproteins (LDL) than their structural analogs (malonic dialdehyde (MDA), 4-hydroxynonenal) resulting on free radical oxidation of lipids under conditions of oxidative stress. Glyoxal-modified LDL aggregate in the incubation medium with a significantly higher rate than LDL modified by MDA, and MDA-modified LDL are markedly more poorly absorbed by cultured human macrophages and significantly more slowly eliminated from the rat bloodstream upon intravenous injection. Studies on kinetics of free radical oxidation of rat liver membrane phospholipids have shown that ubiquinol Q(10) is the most active lipid-soluble natural antioxidant, and suppression of ubiquinol Q(10) biosynthesis by beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors (statins) is accompanied by intensification of lipid peroxidation in rat liver biomembranes and in LDL of human blood plasma. Injection of ubiquinone Q(10) protects the human blood plasma LDL against oxidation and prevents oxidative stress-induced damages to rat myocardium. A unified molecular mechanism of atherogenic action of carbonyl-modified LDL in disorders of lipid and carbohydrate metabolism is discussed.

Parameters of oxidative stress were studied in patients with chronic heart failure and/or type 2 diabetes mellitus. Chronic heart failure was accompanied by severe oxidative stress, while in patients with type 2 diabetes mellitus the signs of oxidative stress were less pronounced. The intensity of free radical oxidation in patients with chronic heart failure and type 2 diabetes mellitus was not higher compared to patients with chronic heart failure.

We measured the content of lipid peroxides in plasma LDL from patients with chronic CHD not accompanied by hypercholesterolemia; CHD and hypercholesterolemia; type 2 diabetes mellitus and decompensation of carbohydrate metabolism; and CHD, circulatory insufficiency, and type 2 diabetes mellitus (without hypercholesterolemia). The content of lipid peroxides in LDL isolated from blood plasma by differential ultracentrifugation in a density gradient was estimated by a highly specific method with modifications (reagent Fe(2+) xylene orange and triphenylphosphine as a reducing agent for organic peroxides). The content of lipid peroxides in LDL from patients was much higher than in controls (patients without coronary heart disease and diabetes). Hypercholesterolemia and diabetes can be considered as factors promoting LDL oxidation in vivo. Our results suggest that stimulation of lipid peroxidation in low-density lipoproteins during hypercholesterolemia and diabetes is associated with strong autooxidation of cholesterol and glucose during oxidative and carbonyl (aldehyde) stress, respectively. These data illustrate a possible mechanism of the progression of atherosclerosis in patients with diabetes mellitus.

Antioxidant probucol in both high (1000 mg) and low (250 mg) daily doses effectively reduced manifestations of oxidative stress in patients with atherosclerosis (assessed by in vivo accumulation of lipoperoxides in atherogenic LDL). When probucol was administered in a dose of 250 mg/day for 7-10 days before transluminal balloon coronary angioplasty and then for 6 months after surgery, the incidence of restenosis decreased to 25% compared to 45% in the control (without probucol therapy). In the group of operated patients receiving probucol (250 mg/day for 6 months) the minimal artery lumen was significantly higher, and the degree of artery occlusion significantly lower than in the control group not treated with probucol.

Glycosylation end-products formed during diabetes mellitus promoted atherogenic oxidative modification of low-density lipoproteins. We evaluated the effects of compensation of carbohydrate metabolism and therapy with antioxidant probucol on parameters of free radical oxidation in patients with type II diabetes mellitus. Compensation of carbohydrate metabolism reduced manifestations of oxidative stress, which was manifested in accelerated enzymatic utilization of reactive oxygen species and lipid peroxides and decreased content of free radical oxidation products in low-density lipoproteins. In patients with type II diabetes mellitus combination therapy with antioxidant probucol decreased the severity of oxidative stress and stabilized carbohydrate metabolism without increasing the dose of hypoglycemic preparations.

The oxidative modification of low density lipoprotein (LDL) is thought to play an important role in atherogenesis. Drugs of beta-hydroxy-beta-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) family are usually used as a very effective lipid-lowering preparations but they simultaneously block biosynthesis of both cholesterol and ubiquinone Q10 (coenzyme Q), which is an intermediate electron carrier in the mitochondrial respiratory chain. It is known that reduced form of ubiquinone Q10 acts in the human LDL as very effective natural antioxidant. Daily per os administration of HMG-CoA reductase inhibitor simvastatin to rats for 30 day had no effect on high-energy phosphates (adenosin triphosphate, creatine phosphate) content in liver but decreased a level of these substances in myocardium. We study the Cu2+-mediated susceptibility of human LDL to oxidation and the levels of free radical products of LDL lipoperoxidation in LDL particles from patients with atherosclerosis after 3 months treatment with natural antioxidants vitamin E as well as during 6 months administration of HMG-CoA reductase inhibitors such as pravastatin and cerivastatin in monotherapy and in combination with natural antioxidant ubiquinone Q10 or synthetic antioxidant probucol in a double-blind placebo-controlled trials. The 3 months of natural antioxidant vitamin E administration (400 mg daily) to patients did not increase the susceptibility of LDL to oxidation. On the other hand, synthetic antioxidant probucol during long-time period of treatment (3-6 months) in low-dose (250 mg daily) doesn't change the lipid metabolism parameters in the blood of patients but their high antioxidant activity was observed. Really, after oxidation of probucol-contained LDL by C-15 animal lipoxygenase in these particles we identified the electron spin resonance signal of probucol phenoxyl radical that suggests the interaction of LDL-associated probucol with lipid radicals in vivo. We observed that 6 months treatment of patients with pravastatine (40 mg daily) or cerivastatin (0.4 mg daily) was followed by sufficiently accumulation of LDL lipoperoxides in vivo. In contrast, the 6 months therapy with pravastatin in combination with ubiquinone Q10 (60 mg daily) sharply decreased the LDL initial lipoperoxides level whereas during treatment with cerivastatin in combination with probucol (250 mg daily) the LDL lipoperoxides concentration was maintained on an invariable level. Therefore, antioxidants may be very effective in the prevention of atherogenic oxidative modification of LDL during HMG-CoA reductase inhibitors therapy.

Inhibitors of the key enzyme of cholesterol biosynthesis beta-hydroxy-beta-methylglutaryl-coenzyme A reductase (statins) decrease cholesterol content in atherogenic low-density lipoproteins in patients with coronary heart disease and hypercholesterolemia, but inhibited biosynthesis of ubiquinone Q10 protecting low-density lipoproteins from free radical oxidation. Cerivastatin in a daily dose of 0.4 mg markedly increased the content of lipid peroxides in low-density lipoproteins. However, complex therapy with cerivastatin and antioxidant probucol (250 mg/day) was accompanied by a sharp decrease in the content of lipid peroxides in low-density lipoproteins in patients with coronary heart disease in vivo. These data indicate that antioxidant agents should be used in combination with inhibitors of beta-hydroxy-beta-methylglutaryl-coenzyme A reductase (hypolipidemic preparations) for the therapy of patients with coronary heart disease.

Hypocholesterolemic preparations, inhibitors of the key enzyme of cholesterol biosynthesis beta-hydroxy-beta-methylglutaryl coenzyme A reductase (statins), block the synthesis of ubiquinone Q10, intermediate electron carrier in the mitochondrial respiratory chain. This should decrease energy supply to tissues. Daily peroral administration of beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitor simvastatin (24 mg/kg perorally) for 30 days had no effect on the contents of macroergic phosphates (ATP and creatine phosphate) in the liver, but decreased these parameters in the myocardium.

This study sought to determine the relationship between myocardial dysfunction and peripheral haemodynamic disorders to exercise intolerance in patients with chronic heart failure (CHF). Seventeen patients with mild to moderate CHF (peak oxygen consumption (VO2) >16 ml/min/kg) and 13 with severe CHF (peak VO2 <16 ml/min/kg) underwent invasive (Swan-Ganz) cardiopulmonary exercise testing and forearm venous occlusion plethysmography at rest and during maximal dilatation in reactive hyperaemia. There was a shift from central to peripheral haemodynamic factors limiting exercise, suggesting an increasing importance of peripheral factors in parallel to the progression of CHF. In mild to moderate CHF peak VO2 was closely related to central haemodynamics (r = 0.57 for cardiac index at rest; r = 0.76 for cardiac index at maximal workload; r = -0.54 for right arterial pressure at maximal workload; all p<0.05) and poorly correlated with peripheral haemodynamics (blood flow, vascular resistance and venous tone). In contrast, in severe CHF peak VO2 was closely related to peripheral haemodynamic factors (r = 0.79 for forearm blood flow; r = -0.82 for vascular resistance; r = -0.77 for venous tone; all p<0.05) and less to central ones. Thus, exercise tolerance of patients with mild to moderate CHF is predominantly determined by central haemodynamic factors, notably by the cardiac index. In severe CHF peripheral factors assume ever greater importance in the determining of exercise capacity.

Currently the problem of left ventricular remodelling in the early and late stages after myocardial infarction are under intense study. Studies of the role of remodelling of the left ventricle in patients with long-term arterial hypertension have been recently initiated. The purpose of this investigation was to study whether left ventricular remodelling is common for different primary myocardial disorders. The study population consisted of 212 patients with primary myocardial lesions (121 with dilated cardiomyopathy, 45 with chronic myocarditis and 46 with prolonged damage of the myocardium with alcohol; 196 male and 16 female, mean age 42.6+/-11.3 years) and 32 age matched normal subjects (24 male and eight female). Cardiac catheterization for ventriculography and coronary angiography was performed in all subjects for detection of left ventricular haemodynamics, including chamber volume and shape at end-systole and end-diastole. Worsening of heart failure was associated with a progressive enlargement of the left ventricle, with increases in end-systolic left ventricular wall stress, that lead to increases in left ventricular muscle mass, alteration of left ventricular geometry from a more ellipsoid to a more spherical shape and a progressive decrease of relative wall thickness index that reflects inadequate enlargement of the ventricular chamber in comparison with the increase in muscle mass. This process of left ventricular remodelling was common to all the primary myocardial disorders studied. Thus, regardless of the different etiological nature, most primary myocardial disorders show a similar left ventricular remodelling process suggesting common mechanisms for the development of chronic heart failure.