Assessment of the Level of Matrix Metalloproteinases, VEGF and MicroRNA-34a in Patients With Non-obstructive and Obstructive Lesions of the Coronary Arteries.

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.

[Assessment of systemic inflammation activity, myocardial structure and functional features, their relationship in patients with multiple myeloma, receiving bortezomib therapy].

AIM: To study the dynamics of calculated indices [neutrophil-lymphocyte ratio (NLR); systemic inflammation index (SIV)] and biomarkers of systemic inflammation [interleukin-1ß (IL-1ß); high-sensitivity C-reactive protein (hsCRP)], parameters of the structure-and-function state of the myocardium and intracardiac hemodynamics, and their relationship in patients newly diagnosed with multiple myeloma (MM) at the onset of the disease and after 6 courses of chemotherapy (CT) containing the proteasome inhibitor bortezomib. MATERIAL AND METHODS: This prospective study included 30 patients aged 63.8±10.0 years diagnosed with MM; 17 (56.7 %) of them were men. The following tests were performed for all patients: measurement of IL-1ß and hsCRP, calculation of the inflammation indexes NLR and SIV, transthoracic echocardiography before and after 6 courses of bortezomib-containing CT. At the time of study completion, 9 patients dropped out due to reasons not related to cardiovascular complications of CT. RESULTS: The antitumor therapy was associated with increases of immune-inflammation indexes: NLR increased from 1.54 [1.02; 1.83] to 2.9 [1.9; 4.35] (p=0.009) and SIV increased from 402.95 [230.5; 534.0] to 1102.2 [453.1; 1307.9] (р=0.014). IL-1ß increased from 5.15 [4.05; 5.77] to 6.22 [5.66; 6.52] pg/ml remaining within the reference range (p=0.142) whereas hsCRP decreased from 1.02 [0.02; 2.71] to 0.02 [0.02; 0.82] IU/l (p=0.138). Statistically significant changes in parameters of heart remodeling and clinical picture of cardiovascular complications were not observed. A correlation analysis showed significant inverse correlations of hsCRP with left ventricular ejection fraction (LV EF) (r= -0.557; p=0.003), the number of plasma cells (PC) with LV EF (r= -0.443; p=0.023), and a direct correlation of the number of PC with hsCRP (r=0.433; p=0.022). CONCLUSION: During the study, the accepted criteria for cardiotoxicity of bortezomib-containing chemotherapy in patients with MM, were not met. The identified correlations between the level of markers for acute inflammation, indexes of intracardiac hemodynamics, and the immediate MM substrate may indicate the role of chronic low-intensity inflammation in the pathogenesis of myocardial remodeling in patients with MM. This necessitates further studies on larger samples of patients to assess the prognostic significance.

[Assessment of the Dynamics of Oxidative Stress Indicators and Early Markers of Myocardial Damage and Dysfunction in Patients with Aggressive Lymphoproliferative Diseases During of Anticancer Therapy].

Aim      To evaluate the dynamics of indexes of oxidative stress and markers of myocardial injury and dysfunction in patients with aggressive type lymphomas during the antitumor therapy.Material and methods  This study included 75 patients with lymphoproliferative diseases of aggressive type. The main group consisted of 53 patients who received one course of antitumor therapy during the study. The comparison group consisted of 22 patients who have not received any specific treatment so far. Troponin I (TnI), high-sensitivity troponin (hsTnI), heart-type fatty acid binding protein (Н-FAВР), N-terminal pro-brain natriuretic peptide (NT-prоBNP), superoxide dismutase (SOD), and myeloperoxidase (MPO) were measured in patients of both groups at baseline, and in the main group, they were measured at 4 hours after administration of antitumor agents and on completion of the course. Functional status of the cardiovascular system was evaluated by electrocardiography in all patients at baseline and after the course of antitumor treatment and by echocardiography.Results The chemotherapy was associated with increased levels of NT-prоBNP, SOD, and MPO (30.670±15.367 vs. 52.309±25.718 pmo l/l; 1.61±0.135 vs. 1.74±0.193 U/ml; and 507.54±91.51 vs. 742.3±49.01 ng/ml, respectively). The study results indicated activation of oxidative stress on the background of the administered antitumor therapy, progressive myocardial dysfunction, and increased frequency of arrhythmic episodes.Conclusion      The study results allowed identifying NT-prоBNP, MPO, and SOD as important indexes for determining a patient group at high risk of cardiotoxicity during the antitumor treatment.

[Assessment of the structural and functional state of blood vessels in patients with hypertrophic cardiomyopathy].

Aim      To evaluate the structural and functional condition of the vasculature using fingertip photoplethysmography and computerized videocapillaroscopy in patients with hypertrophic cardiomyopathy (HCMP).Material and methods  The study included patients with HCMP (n=48; 28 (57 %) men; age, 54.3±13.6 years) and healthy volunteers (control group, n=33, 15 (45 %) men; age, 58.2±8.8 years). Standard laboratory and instrumental examination (blood count and biochemistry, electrocardiography, echocardiography, Holter electrocardiogram monitoring) were performed for all HCMP patients. The condition of vascular wall at various levels of the vasculature was evaluated by fingertip photoplethysmography (apparatus Angioscan-01) and computerized nail-fold videocapillaroscopy (apparatus Capillaroscan-01). The photoplethysmography study analyzed structural parameters, including the arterial wall stiffness index (aSI) of large blood vessels and the resistance index (RI) of small muscular arteries. Endothelial dysfunction was evaluated by the occlusion index (OI) and phase shift (PS). The capillaroscopy study assessed structural parameters, including the resting capillary density (rCD) and the capillary density following venous occlusion (voCD), and functional parameters, including the percentage of perfused capillaries (PPC), the percentage of restored capillaries (PRC), and the capillary density after the reactive hyperemia test (rhCD).Results The study showed increases in aSI (8.8 [6.8; 12.2] and RI (32.5 [17.4; 47.9] in the HCMP group. The OI was significantly lower in the HCMP group (1.3 [1.1; 1.5]) than in the control group (1.8 [1.5; 2.7], р<0.001). Also, PS values were significantly decreased in the HCMP group (4.4 [2.3; 8.6]) compared to the control group (8.4 [5.1; 12.1]. p=0.018). Disorders of structural and functional capillary indexes were observed in HCMP patients compared to the control group; rCD and voCD were decreased in the HCMP group (60 [52.6; 68] and 88 [75; 90], respectively) compared to the control group (75.8 [60; 87] and 90 [73; 101]), however, no intergroup difference reached a statistical significance. The rhCD, PPC, and PRC values were decreased in the HCMP group (66.3 [55; 72], 86.7 [70.9; 104.2] and 1.7 [-6.95; 20.3], respectively) compared to the control group (86 [68.6; 100], 103 [96; 114] and 18.4 [8.1; 27.4], respectively); PPC and PRC values were significantly different (р<0.005 and p<0.004, respectively).Conclusion      In patients with HCMP, fingertip photoplethysmography and computerized videocapillaroscopy showed increased wall stiffness in both large blood vessels and microvasculature, pronounced endothelial dysfunction, and decreases in capillary density and percentage of restored capillaries following respective tests.

[Vasculotoxicity of Chemotherapy: Assessment оf Endothelial Dysfunction Biomarkers' Levels in Gastric Cancer Patients].

Aim To evaluate dynamics of biomarkers for endothelial dysfunction (ED), including endothelin-1 (ET-1) and von Willebrand factor (VWF) in patients with stomach cancer (adenocarcinoma) before and after polychemotherapy (PCT); to compare these results with respective values in healthy volunteers and patients with cardiovascular diseases (CVD); to study correlations of the ED biomarkers with indexes of instrumental evaluation of endothelial dysfunction.Material and methods The study included 75 participants, including 25 healthy volunteers (control group), 25 patients with documented CVDs (arterial hypertension + ischemic heart disease), and 25 patients of the main group with histologically documented stage II-IV stomach cancer (adenocarcinoma) who received different courses of PCT with platinum-based agents (oxaliplatin, cisplatin) and fluoropyrimidines (5 fluorouracil, capecitabin). Laboratory measurement of ED biomarkers, computerized nailfold video capillaroscopy (CNVC), and finger laser photoplethysmography (PPG) (methods for noninvasive evaluation of vascular wall and ED), electrocardiography, 24-h ECG Holter monitoring, and echocardiography (EchoCG) were performed for all patients of the main group prior to PCT and within one months after the last course completion. This evaluation was performed once for healthy volunteers and patients of the CVD group upon inclusion into the study.Results In the main group, ET-1 levels were non-significantly lower than normal and did not change during the courses of antitumor treatment (0.95 [0.6; 1.4] and 0.94 [0.7; 1.4] pg /ml (р<0.9) before and after PCT, respectively). Statistically significant differences were found between the control group and oncological patients after the treatment (р<0.04). Levels of VWF remained within the normal range in all examined participants and did not significantly differ between study groups, including oncological patients before and after the specific treatment (р>0.05 for all comparisons). The correlation analysis detected significant correlations of ET-1 levels with functional disorders of microcirculation, ET-1 with the occlusion index (rs=0.56; p=0.005), ЕТ-1 with percentage of capillary restoration (PCR, rs= -0.72; p=0.018) and with the incidence rate of supraventricular extrasystole (rs=0.48; p=0.032).Conclusion The dynamics of ED biomarkers was studied for the first time in patients with stomach cancer receiving a specific antitumor therapy. Although no significant changes in ЕТ-1 and VWF were observed during the PCT (probably due to exhaustion of the endothelial system and a small patient sample), these indexes can be considered as early vasculotoxicity markers due to the presence of significant correlations with indexes of impaired endothelial function according to the results of instrumental evaluation.

[Assessment of the Role of Oxidative Stress Indicators and Early Markers of Myocardial Injury and Disfunction in Patients with Lymphoproliferative Diseases].

PURPOSE: to study dynamics of indicators of oxidative stress and their role in development of cardiotoxicity in patients with lympho-proliferative diseases at the background of polychemotherapy. MATERIALS AND METHODS: We included into this study 30 patients with newly detected Non-Hodgkin lymphomas. The control group comprised 15 healthy volunteers. For registration of dynamics of formation of oxygen active forms (OAF), we used highly sensitive chemiluminescence assay. The state of initial stage of lipoperoxidation OAF and radicals of organic compounds) was assessed by dynamics of the leukocyte chemiluminescence. The state of final stage of lipoperoxidation (formation of nonmetabolizing lipid hydroperoxides and other compounds) was assessed by the level of malonic dialdehyde. We also determined indicator of leukocyte chemiluminescence intensity (both basal and zymosan-stimulated). For assessment of the cardiovascular system functional state before and after chemotherapy we used electrocardiography (ECG), echocardiography (EchoCG) and 24-hour ECG monitoring. RESULTS: The data obtained were indicative of increased generation of free radicals by leukocytes during polychemotherapy. After chemotherapy course we detected various types of cardiotoxicity. We noted substantial elevation of frequency of supraventricular and ventricular extrasystoles. There was direct correlation between rate of appearance of supraventricular extrasystoles and level of chemiluminescence of leukocytes (r=0.7; p=0.03). According to data of EchoCG although the left ventricular ejection fraction remained within the normal range during chemotherapy, there was a persistent tendency to its decrease (р<0.001). CONCLUSION: In this study we for the first time in patients with Non-Hodgkin lymphomas detected an elevation of level of free radical reactions and lipid peroxidation with simultaneous lowering of antiperoxidative activity of blood plasma and their relation to development of cardiotoxic effects. The results obtained indicate to necessity of search for novel early markers of oxidative stress activation, myocardial injury and disfunction able to help to substantially decrease risk of development of cardiovascular complications during and after chemotherapy.