[Anthracycline-induced Heart Failure: Treatment and Recovery Prospects].

The article presents a clinical case of heart failure associated with the anthracycline-containing antitumor therapy in a breast cancer patient with an initially low risk of developing cardiovascular complications.

Inhibitors of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase (Statins) Suppress Proliferation and Motility of Human CD4+ T Lymphocytes in Culture.

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) along with their blood lipid-lowering effect exhibit anti-inflammatory and immunomodulatory activity. We studied the effects of long-term (72-h or longer) exposure of human T lymphocytes in culture to atorvastatin and rosuvastatin (5-80 nM) on their functional activity. Treatment with statins inhibited PHA/IL-2-induced proliferation of CD4+ T lymphocytes isolated from the peripheral blood of healthy donors. This was accompanied by a decrease in the relative content of cells expressing active caspase-3. Addition of mevalonate or fetal bovine serum simultaneously with statins restored proliferative activity of cells. Culturing of CD4+ T lymphocytes with statins in the presence of IL-2 did not significantly affect the expression of chemokine receptors CCR4, CCR5, CXCR3, and CXCR4. Pretreatment with statins suppressed spontaneous and SDF-1-stimulated migration of CD4+ T lymphocytes, but little changed the content of intracellular phosphorylated protein kinases Akt, p38 and p42/44 (ERK1/2). The cellular effects of "lipophilic" atorvastatin were observed at lower concentrations compared to "hydrophilic" rosuvastatin.

Inhibitors of 3-Hydroxy-3-Methylglutaryl Coenzyme a Reductase (Statins) Suppress Differentiation and Reduce LPS/IFNγ-Induced Cytokine Production in Human Monocyte/Macrophage Culture.

We examined the effects of 72-h exposure to atorvastatin and rosuvastatin in concentrations of 2-10 nM on the cytokine expression in LPS/IFNγ-activated monocyte/macrophages derived from peripheral blood monocytes of healthy donors by culturing in the presence of GM-CSF. Pretreatment with statins was found to inhibit cytokine production in monocytes/macrophages after activation, while the level of cytokine mRNA in cells did not decrease. The number of cells containing active caspase-3 decreased in the culture. Culturing of monocytes/macrophages with statins was accompanied by changes in cell morphology and deceleration of cell growth. Cellular effects of "lipophilic" atorvastastin were observed at lower concentration compared to "hydrophilic" rosuvastatin.

[The prognostic value of high-sensitivity C-reactive protein blood level after coronary stenting for the development of stent restenosis].

Aim      To analyze the relationship between serum concentrations of high-sensitivity C-reactive protein (hsCRP) in dynamics and development of restenosis at 12 months following elective coronary stent placement (CSP).Material and methods  The key role in atherogenesis, neointimal proliferation and restenosis belongs to inflammation. This study included 91 patients (median age, 60 [56; 66] years) with stable exertional angina after an elective CSP using second-generation stents. Follow-up coronarography was performed for 60 patients at 12 months. Concentration of hsCRP was measured immediately prior to CSP and at 1, 3, 6, and 12 months after CSP. Restenosis of the stented segment (50% or more narrowing of the stented segment or a 5-mm vessel segment proximally or distally adjacent to the stented segment) was observed in 8 patients.Results According to results of the ROC analysis, the increase in hsCRP concentration >0.9 mg/l (>25%) at one month after CSP had the highest predictive significance with respect of restenosis (area under the ROC curve, 0.89 at 95 % confidence interval (CI) from 0.79 to 0.99; sensitivity, 87.5 %; specificity, 82.8 %; р=0.0005), which was superior to the absolute value of hsCRP concentration >3.0 mg/l (area under the ROC curve, 0.82 at 95 % CI from 0.68 to 0.96; р=0.0007).Conclusion      Increased concentration of hsCRP ≥0.9 mg /l (≥25 %) at a month after CSP was associated with restenosis of the coronary artery stented segment.

The Molecular and Cellular Mechanisms Associated with a Microvascular Inflammation in the Pathogenesis of Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a severe disease with an often unfavorable outcome. The prevalence of HFpEF continues to increase, while effective treatment options remain elusive. All the medical strategies used to improve the outcome in a heart failure with reduced ejection fraction proved ineffective in HFpEF, which was probably due to the different mechanisms of development of these two types of heart failure and the diversity of the HFpEF phenotypes. According to the current paradigm of HFpEF development, a chronic mild pro-inflammatory state causes a coronary microvascular endothelial inflammation, with further myocardial fibrosis and diastolic dysfunction progression. This inflammatory paradigm of HFpEF has been confirmed with some evidence, and suppressing the inflammation may become a novel strategy for treating and managing HFpEF. This review summarizes current concepts about a microvascular inflammation in hypertrophied myocardium and provides a translational perspective of the anti-inflammatory and immunomodulatory approaches in HFpEF.

The severity of internal carotid artery stenosis is associated with the circulating Th17 level.

AIM: Immune and inflammatory reactions contribute to the progression of atherosclerosis. The walls of the different arteries and segments of the arteries have heterogeneous haemodynamic and histological features. We aimed to explore the relationship between the circulating T-cell subsets and the abundance of carotid atherosclerosis in different segments of carotid arteries. METHODS: 70 patients underwent ultrasound duplex scanning to determine the degree of stenosis of the common carotid artery (CCA), the CCA bifurcation or the internal carotid artery (ICA). The blood frequencies of T-, B-, NK-cells, regulatory T cells (Treg), activated T-helpers (Th), IL10-producing Th, Th1 and Th17, as well as blood levels of hsCRP, sCD25, IL10 and IL17a were assessed. RESULTS: The frequencies of Th17 were increased in patients with ICA stenosis >35% and >50% vs. patients with ICA stenosis <35%. Th17 blood level ≥0.55 % of lymphocytes was associated with more severe stenosis of ICA (OR 4.3 (1.0-17.6), p < 0.05 for ICA stenosis of 35-50% and 6.8 (1.3-35.0), p < 0.05 for ICA stenosis >50%). BMI positively correlated with the CCA bifurcation stenosis degree (r = 0.33, p < 0.05). CONCLUSION: The severity of ICA stenosis can be associated with the circulating Th17 level.

[The Incidence and Possible Predictors of Coronary Restenosis].

OBJECTIVE: Assess time and possible predictors of restenosis after the implantation of first- and second-generation coronary stents and bare metal stents (BMSs) in patients with stable coronary artery disease after elective coronary stenting. MATERIALS AND METHODS: From 2010 to 2014, 3,732 (2,897 males, 60 [53; 68] years old) patients with stable exertional angina of functional class I-III underwent coronary stenting. From 2014 to 2017, 1,487 (1,173 males and 314 females) patients returned. Repeat coronary angiography was performed in 699 patients. RESULTS: A total of 644 first-generation stents, 5,321 second-generation stents, and 473 BMSs were implanted. During the control coronary angiography, contrasting was repeated for 193 first-generation stents, 899 second-generation stents, and 77 BMSs. Restenosis (stenosis of 50 % or more in the previously stented segment) was detected in 28 (14 % of angiographic control) first-generation drug-eluting stents, 94 (10 %) second-generation drug-eluting stents, and 21 (27 %) BMSs. Patients with BMS restenosis returned significantly earlier than patients with restenosis of the first- and second-generation drug-eluting stents (11 [6, 27] months vs. 32 [11; 48]) months and 24 [12; 42] months, respectively; p<0.05). The initial and repeat levels of high-sensitivity C-reactive protein (hs-CRP) were higher in patients with restenosis (2.2 [1.2, 5.0] mg / L vs. 2.1 [1.0, 4.6] mg / L, respectively; p> 0.05) than in patients without restenosis (2.0 [0.9, 4.2] mg / L vs. 1.9 [0.7, 3.5] mg / L respectively, p>0.05). Blood levels of hs-CRP ≥2 mg / L according to receiver operating characteristic curve (ROC) analysis at return visit were used as a predictor to identify restenosis of stents with a diameter <3 mm and a length >25 mm - area under the curve (AUC) 0.67 (95 % confidence interval (CI) 0.51-0.84), p <0.05, odds ratio 3.7 (95 % CI 1.1-12.1), p<0.05. Stent type had a significant effect on the time to restenosis in the survival analysis (p<0.0005). CONCLUSION: The time from coronary stenting to the return visit of patients presenting with restenosis after the implantation of first- and second-generation drug-eluting stents is consistent; median time of the return visit of patients with restenosis of the first-generation stents was 2-3 years after coronary stenting. Blood levels of hs-CRP ≥2 mg / L at the return visit is a predictor of restenosis of stents with a diameter <3 mm and a length >25 mm.

The novel synonymous variant in LIPA gene affects splicing and causes lysosomal acid lipase deficiency.

Lysosomal acid lipase deficiency (LALD; MIM#278000) is a continuum of autosomal recessive diseases caused by defects in the gene LIPA and historically divided into two phenotypes: severe infantile-onset form called Wolman disease (WD) and childhood/adult-onset form known as cholesteryl ester storage disease (CESD). We report a novel synonymous homozygous variant c.600G > A in LIPA of a patient with LALD. Functional analysis of the patient cDNA and minigene assay revealed this variant as the cause of exonic cryptic splice site activation and 63 b.p. deletion in exon 6. To investigate the impact of this in-frame deletion on protein function, we performed 3D modeling of the human lysosomal acid lipase and showed the alteration of highly conservative region in close proximity to protein active site, which may completely eliminate the enzymatic activity. Using transcript specific real-time quantitative PCR method, we evaluated the relative ratio of the patient's wild type transcript isoform which is significantly reduced and correlates with severe childhood-onset variant of LALD.

Atherosclerosis of brachiocephalic arteries and arterial stiffness in patients with breast cancer.

Cardiovascular toxicity is one of the important problems of clinical oncology. Atherosclerosis progression was demonstrated in patients with cancer and chemotherapy.Te aim - to evaluate the vascular wall characteristics and to determine the predictors of AS of brachiocephalic arteries progression during anticancer therapy in patients with breast cancer. METHODS: Te study involved 43 patients with newly diagnosed breast cancer (BC) (II-III stage) with overexpression of HER2; median age 50 (40;57) years. All patients underwent neoadjuvant drug therapy with antracyclines, taxanes and trastuzumab followed by surgery, radiation and hormone therapy according to the indications. Before anticancer therapy the general clinical examination was conducted and lipid profle, plasma lipoprotein (a) [Lp(a)] level, titres of autoantibodies IgM and IgG to lipoproteins and their oxidized derivatives were estimated. Te vascular wall stiffness (pulse wave velocity on the carotid-femoral (PWVcf) and shoulder-ankle (PWVsa) segments, the central pressure, carotid intima-media thickness (CIMT) and the degree of stenosis of the brachiocephalic arteries) were determined at baseline and at each stage of anticancer therapy. Te atherosclerosis progression was determined if the new stenosis (≥15%) or increase of preexisting stenosis (≥5%) were revealed; CIMT increase ≥ 0.1 mm. Te parameters of cellular immunity (peripheral blood lymphocyte phenotyping via direct immunofluorescence and flow cytometry), lipid spectrum parameters, serum concentration of Lp (a), autoantibodies IgM and IgG against lipoproteins and their oxidized derivatives, as well as PWVсf and PWVsa were assessed in 17 BC patients before the onset of neoadjuvant therapy and in 20 healthy women. RESULTS: BC patients and healthy women were comparable in traditional cardiovascular risk factors but differed in PWVsa and PWVcf levels (p<0.05). In BC patients the activation of T-cell immunity with the stimulation of both subpopulations with pro-inflammatory and regulatory properties was observed (p<0.05). Te direct correlations between the content of activated T-lymphocytes (T-act), T-helpers (T) 1 and PWVsa (p<0.05), as well as T-act, T1 and T2 and PWVcf (p<0.05) were revealed in the general group. Te decrease of systolic blood pressure (SBP), central SBP (SBPc), central diastolic blood pressure (DBPc), PWVcf and PWVsa levels accompanied with a temporary heart rate increase were observed during anticancer therapy; SBP, SBPc, PWVcf levels restored by the end of the follow-up period. Te CIMT increase was detected in 22 (51%), and the atherosclerosis progression in 26 (60%) BC patients during anticancer therapy. Lp (a) level above 12.8 mg/dl was associated with CIMT increase (p<0.05). Age > 48 years and radiation therapy were risk factors for CIMT increase and atherosclerosis progression (p<0.05), respectively. CONCLUSIONS: Te vascular stiffness is increased in BC patients, which is associated with the activation of effector subpopulations of T-lymphocytes and the elevation of circulating level of both pro-atherogenic and anti-atherogenic T-cells. Te level of Lp (a) above 12.8 mg/dl is associated with atherosclerosis progression, which requires further research. Age and radiation therapy are the risk factors for atherosclerosis progression during anticancer therapy.

Low Blood Content of IL-10-Producing CD4+ T Cells as a Risk Factor for Progression of Coronary Atherosclerosis.

In a 2-year prospective study, prognostic significance of the blood content of IL-10-producing CD4+ T lymphocytes for progression of coronary artery atherosclerosis was assessed. Patients with verified stable angina (n=36) admitted for scheduled coronary angiography and coronary stenting were enrolled. The blood levels of CD4+FoxpP3+ Treg, CD4+IFNγ+ Th1, CD4+IL17+ Th17, CD4+IL10+ cells, sCD25, IL-10, IL-17, C-reactive protein, and lipoprotein (a) were assayed before endovascular interventions. The blood content of CD4+IL10+ T cells below 3.3% was associated with progression of coronary artery atherosclerosis (OR 12.0 (2.3, 61.0), sensitivity 77%, specificity 78%, p=0.003). No differences in other immunological parameters and common atherosclerosis risk factors in the groups were revealed. We hypothesize that the content of CD4+IL10+ T cells can be an important predictive marker for the progression of coronary atherosclerosis.

Immunotropic Effects and Proposed Mechanism of Action for 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors (Statins).

Inhibitors of HMG-CoA reductase (statins) are the major group of lipid-lowering drugs. Along with hypocholesterolemic activity, statins exhibit anti-inflammatory and immunomodulatory properties that expand their clinical use, particularly, in the treatment of chronic inflammatory and autoimmune disorders. In this review, we critically analyze the data of statin effects on immune cells (e.g., monocytes and T cells) involved in the development of atherosclerosis and other chronic inflammatory diseases. We (i) discuss the properties of statins and routes of cell entry, as well as their major intracellular targets; (ii) evaluate the data on the effects of statins on the subset composition of circulatory monocytes, ability of monocytes to migrate to the site of inflammation (cell motility and expression of adhesion molecules and chemokine receptors), production of cytokines, matrix metalloproteinases, and reactive oxygen species by monocytes/macrophages, and antigen-presenting activity in peripheral blood monocyte-derived dendritic cells; and (iii) summarize the data on the regulation of proliferation and differentiation of various CD4+ T cell subsets (type 1/2/17 helper T cells and regulatory T cells) by statins.

[Subpopulation Composition of CD4+ T-lymphocytes as Factor Contributing to the Progression of Atherosclerosis of Carotid Arteries].

AIM: to assess prognostic significance of blood content of regulatory and effector T-lymphocytes for progression of atherosclerosis (AS) of carotid arteries. MATERIAL AND METHODS: We enrolled in this study 33 men with various severity of carotid AS. Carotid artery duplex scan was done at admission and in 1 year after enrollment. AS progression was defined as appearance of novel stenosis in common or internal carotid artery or more or equal 5% increase of preexisting stenosis. Peripheral blood lymphocyte phenotyping was performed by direct immunofluorescence and flow cytometry at the enrollment. T-helpers (Th) 1 were identified as CD4+IFNgamma+ cells, Th2 - CD4+IL4+, activated T-cells (T-act) - D4+CD25lowCD127high, regulatory T-cells (T-reg) - D4+CD25highCD127 low and CD4+FoxP3+, Th17 - CD4+IL17a+ cells. RESULTS: Progression of carotid AS was observed in 18 patients. Basal values of Th17 were higher while ratio T-reg/Th17 was lower in patients with compared with those without AS progression. ROC-analysis showed high sensitivity and specificity of blood levels of Th17, T-act and T-reg/Th17 ratio for carotid AS progression during one year in patients with low density lipoprotein cholesterol (LDLCH) level below 3.5 mmol/l. CONCLUSION: The imbalance between circulating levels of regulatory T-cells and T-helpers 17 with the prevalence of proinflammatory T-helpers 17 may reflect a predisposition for carotid AS progression, what also refers to patients with relatively low LDLCH.