Predicting the risk of left ventricular diastolic dysfunction in obesity

Obesity may develop heart failure with preserved ejection fraction, which is based on left ventricular diastolic dysfunction (LV DD). Currently, the search for effective predictors of LV DD is extremely relevant.Aim. To assess the prognostic value of key and additional metabolic risk factors (RFs), neurohumoral and profibrotic factors in the development of LV DD in obese patients.Material and methods. The study included 149 men with general obesity. The mean age was 49,7±7,9 years. The inclusion criteria was the presence of class I-III general obesity. The average body mass index was 32,9±3,6 kg/m2. The exclusion criteria were hypertension, coronary atherosclerosis, type 2 diabetes, as well as LV DD according to transthoracic echocardiography. Depending on the presence of epicardial adiposity, patients were divided into two groups: group 1 — epicardial adipose tissue (EAT) thickness ≥7 mm (n=70), group 2 — EAT <7 mm (n=31). In all patients, the following laboratory parameters were determined in blood serum using enzyme immunoassay: type I and III collagen, Procollagen I C-Terminal Propeptide (PICP), matrix metalloproteinase-3 (MMP-3), transforming growth factor β1, vascular endothelial growth factor, tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-10, C-reactive protein (CRP), adiponectin, soluble leptin receptor, leptin, lipid parameters and free fatty acids (FFA). After 4,7±0,3 years, echocardiography was repeated in order to assess LV diastolic function.Results.  Comparative analysis of metabolic risk factors revealed a significant increase in the level of total cholesterol (p=0,001), low-density lipoprotein cholesterol (LDL-C) (p<0,0001), triglycerides (TGs) (p<0,0001). These groups had no differences in such parameters as high-density lipoprotein cholesterol (p=0,09) and glucose (p=0,12). An increase in the level of such pro-inflammatory cytokines as TNF-α (p<0,0001), CRP (p<0,0001), IL-6 (p<0,0001) in group 1 was revealed, while differences in IL-10 (p=0,34) levels were not significant. In group 1, there was a significant increase in leptin levels (p<0,0001), a decrease in levels of adiponectin (p<0,0001) and leptin receptor (p=0,001). In group 1, an increase in the level of all studied profibrotic factors was revealed. After 4,7±0,3 years, repeated echocardiography revealed that selected groups were comparable in such parameters as A, E, E/A, E/e’, e’, and the peak tricuspid regurgitation velocity. There was a significant difference in left atrial volume index (p=0,0003). LV DD was detected in 20 patients. Binary logistic regression revealed the following most significant predictors of LV DD in obese patients: glucose, LDL-C, triglycerides, leptin receptor, leptin, MMP-3, FFA, PICP, and EAT thickness.Conclusion. Thus, the following most significant predictors of LV DD in obese patients were identified glucose, LDL-C, triglycerides, leptin receptor, leptin, MMP-3, FFA, PICP, and EAT thickness

Profibrotic genetic polymorphisms as possible risk factors for the development of diastolic dysfunction in patients with epicardial adiposity

Aim. To determine the associations of variable sites of fibrogenesis genes with the risk of left ventricular (LV) diastolic dysfunction (DD) in patients with epicardial adiposity (EA).Material and methods. The study included 101 men with general obesity (Altai Territory) without cardiovascular diseases, diabetes and documented LVDD, of which, after determining the epicardial fat thickness (EFT), 2 groups were formed: group 1 — with EA (EA+), EFT ≥7 mm or more (n=70); group 2 — without EA (EA-), EFT <7 mm (n=31). The control group was formed from Kemerovo region residents of the corresponding sex and age and without a history of cardiovascular diseases and general obesity. Polymorphisms of the MMP9 rs17576, TGFB1 rs1800469, MMP3 rs6796620, MMP3 rs626750, MMP1 rs514921, LOC101927143 rs4290029, TIMP2 rs2277698 genes were determined in all patients using the polymerase chain reaction. After 4,7±0,3 years, all patients with general obesity underwent repeated echocardiography to assess LVDD.Results. We found that in the group with EA for rs626750 MMP3, the carriage of the homozygous T allele is 2 times more common (recessive inheritance, p=0,0022). After 4,7±0,3 years, LVDD was registered in 18 patients in the EA+ group and in 2 patients in the EA- group. When analyzing inheritance patterns, as well as comparing genotypes in groups of patients with EA with developed LVDD (n=20) and without LVDD (n=78), we found that patients with EA and LVDD are 3,4 times more likely to be a carrier of the homozygous T allele (recessive inheritance, p=0,02) for rs1800469 TGFB1.Conclusion. In patients with EA and LVDD, the carriage of the T rs1800469 TGFB1 allele is more common, which probably contributes to cardiac fibrosis and LVDD according to a recessive inheritance

INTERLEUKIN 33 AND FIBROSIS: PATHOGENESIS UPDATED

Interleukin 33 (IL-33) is a member of the IL-1 family, which is widely expressed on all types of cells. IL-33 was identified as a functional ligand for the plasma membrane receptor complex, which is a heterodimer consisting of a membrane bound ST2 receptor (growth stimulating factor). IL-33 is involved in the development of immune response with predominant release of pro-inflammatory T helper type 2 cytokines. IL-33 is widely expressed on various structure-forming cells, such as epithelial, endothelial and smooth muscle cells. Increased expression of IL-33 is observed during necrosis of these cells (after tissue or cell damage), and it is released into extracellular space, and acts as an endogenous danger signal, sending a sort of warnings to neighboring cells and tissues. Recently, many studies have shown that IL-33 can participate in development and progression of fibrosis in various organs. However, it exerts anti-inflammatory effects upon development of other diseases. This review will discuss biological characteristics of IL-33 and a role of the IL-33/ST2 signaling pathway in the development of fibrosis

ROLE OF PERIVASCULAR ADIPOSE TISSUE IN THE DEVELOPMENT OF ATHEROSCLEROTIC AND NONATHEROSCLEROTIC DISEASES

Perivascular adipose tissue surrounds most large blood vessels and plays an important role in vascular homeostasis. Recent studies have shown that perivascular adipose tissue effects vasodilation and vasoconstriction, which indicates that the perivascular adipose tissue regulates tone and diameter of the vessels. Adipocytokines and chemokines, secreted from the perivascular adipose tissue, apparently have direct access to the adjacent arterial wall by diffusion, or through vasa vasorum. The present data indicate that perivascular adipose tissue plays an important role in atherosclerosis, hypertension. Recently, some studies were performed that examined the role of perivascular adipose tissue in non-atherosclerotic vascular diseases, such as neointimal formation, aortic aneurysm, arterial stiffness and vasculitis. The present review will discuss a role of perivascular adipose tissue in pathogenesis of atherosclerosis, hypertension and non-atherosclerotic vascular diseases

Dynamics of the Level of Myeloperoxidase and Serum Calprotectin in Local Cold Injury

Relevance. Cold injury is defined as a complex of pathophysiological and pathomorphological changes arising as a result of local or general cooling of the human body. Endothelial dysfunction provokes a powerful cascade of cellular interactions with expressed excretory activity, which ultimately leads to a pronounced remodeling of microcirculation and a protracted process of inflammation in the focus of alterations. Aim of the study. To establish the dynamics of the level of myeloperoxidase and calprotectin in the serum of patients with local cold injury. Materials and methods. The study included 80 patients with III–IV degree lesions in the late reactive period and the period of granulation and epithelialization. The average age of patients was 38 ± 8 years. The myeloperoxidase level was measured on the 5th and 30th days from the moment of cryopreservation using multiplex analysis of blood serum. Results. The level of myeloperoxidase and serum calprotectin increases. In late reactive period (day 5), MPO level in patients with frostbite is 7.25 times higher in comparison with control values, in the period of granulation and epithelialization (day 30), it remains elevated, but only 3.63 times higher than in the control group. In the late reactive period, the level of calprotectin in the blood serum of patients with local cold injury was 4.6 times higher in comparison with control values, and on the 30th day of cryopreservation, the value of calprotectin was 4.5 times higher than in the control group. Changes in the level of myeloperoxidase and serum calprotectin reflect the flow of destructive and reparative mechanisms in tissues during local cold trauma and can be used in predicting an unfavorable prolonged course of the wound process

Automated morphometric studies of collagen fibers as an auxiliary method for diagnosing cold injury

Background. Cold injury is one of the most significant problems for the northern regions of the Russian Federation. Frostbite is defined as a complex of changes caused by the action of low temperatures, which lead to morphological changes in damaged tissue structures. As a result, the skin with underlying tissues and the intercellular matrix, the components of which are collagen fibers, are damaged, which eventually leads to remodeling and a protracted course of the wound process. Morphometric studies in combination with quantitative analysis of microphotographs (histological specimens) using GIS technologies make it possible to distinguish altered collagen fibers under the influence of low temperatures from relatively healthy tissues. The aim of the study. To assess the possibility of using computer analysis of microphotographs in  a  complex of morphometric studies of collagen fibers in local cold injury. Materials and methods. The study included 84 patients with III and IV degree frostbite of the lower extremities. Morphological study of tissues and microphotography were performed using Leica DM2500 microscope (Leica, Germany). The thickness of  collagen fibers was measured based on  visual measurements of characteristic areas of the microphotograph. Computer analysis of tissue microphotographs of  the  zone of cryoinjury was performed using the ArcINFO software (Esri, USA). Statistical processing of the study results was carried out using the SPSS Statistics software package (IBM Corp., USA). Graphs and diagrams were constructed using MS Office Excel (Microsoft Corp., USA). Results. With frostbite, severe tissue damage occurs, accompanied by the destructive processes of the extracellular matrix components. Low temperatures contribute to  changes in the width and orientation of collagen fibers in the damaged area. In  this  regard, a change in the texture of the histological specimen image leads to achange in the numerical characteristics of the standard deviation of the curvature coefficient in the studied area of the microphotograph. Thus, in the late reactive period, the described complex of morphometric studies makes it possible to classify particular microphotograph as having pathological signs or as a sample of healthy tissue

Dynamics of Matrix Metalloproteinases in Local Cold Injury

The relevance of cold injury is due to its high specific weight in the structure of injuries, complexities of complex therapy, and unsatisfactory results of treatment. It is known that in the pathogenesis of local cold injury, the leading role belongs to endothelial dysfunction, which secretes a huge amount of biologically active substances, including matrix metalloproteinases.Aim: to determine the dynamics of the content of matrix metalloproteinases of the second subfamily (MMP-2, MMP-9) in the serum of patients with local cold injury.Materials and methods. The study included 80 patients (60 men, 20 women) with frostbite of the III–IV degree of the foot to the level of the lower third of the leg in the late reactive period and the period of granulation and epithelization.Results. In the late reactive period in patients with cryopreservation, the level of MMP-2 was 3.4 times higher relative to the control (p = 0.011), on day 30 MMP-2 values did not differ from the control parameters (p = 0.103). The level of collagenase B (MMP-9) in patients with local cold injury on day 5 was 14.5 times higher than the control parameters (p = 0.002), on day 30 – 12.5 times higher compared to the control group (p = 0.000094).Conclusion. During the analysis of the data obtained, we can think about the dual nature of collagenases during the processes of inflammation. In a situation of distress, collagenases prevent endothelial dysfunction by eliminating the cellular structures of the endothelium to ensure adequate metabolism in tissues. Their importance as markers of failure of adequate flow of reparative processes is not excluded

Адипонектин и инсулин: молекулярные механизмы реализации метаболических нарушений

Adiponectin, the most common plasma adipocytokine, plays a crucial metabolic and anti-inflammatory role. With insulin resistance associated with obesity, an increase of adiponectin concentration, which leads to the activation of signaling pathways involved in the regulation of metabolism, occurs. Currently, adiponectin is being investigated as a potential therapeutic target for metabolic syndrome, although more research is required to understand the underlying mechanisms controlling its levels. In this review, we will examine the main mechanisms that control adiponectin levels in blood serum and its role in insulin-sensitizing effect, as well as evaluate the potential use of adiponectin and its receptors as a potential therapeutic target.Адипонектин – самый распространенный адипоцитокин в плазме крови, который играет критическую метаболическую и противовоспалительную роль. При инсулинорезистентности, связанной с ожирением, происходит увеличение концентрации адипонектина, что приводит к активации сигнальных путей, участвующих в регуляции метаболизма. В настоящее время  адипонектин исследуется в качестве потенциальной терапевтической мишени для метаболического синдрома, хотя необходимы дополнительные исследования, чтобы понять основные механизмы, контролирующие уровень адипонектина в крови. В этом обзоре мы представим основные механизмы, контролирующие уровень адипонектина в сыворотке крови, и его роль в инсулин-сенсибилизирующем действии, а также оценим потенциальное использование адипонектина и его рецепторов в качестве потенциальной терапевтической мишени

Effect of metformin on transcriptome and adipokinome of adipocytes of local fat deposts of patients with ischemic heart disease

BACKGROUND: The information available to date on the effect of metformin on the transcriptome and secretory capacity of adipocytes in human adipose tissue (AT) is scarce and contradictory. The study analyzed whether metformin in vitro modulates gene expression and secretion of adiponectin and leptin in the AT of subcutaneous (SAT), epicardial (EAT) and perivascular (PVAT) localization of patients with ischemic artery disease (IHD).AIM: To assess the effect of metformin at various concentrations (1 and 10 mmol / L) on the level of expression of adiponectin and leptin genes and their content in adipocytes of subcutaneous, epicardial and perivascular AT of patients with IHD.MATERIALS AND METHODS: The study included 134 patients with IHD and indications for direct myocardial revascularization by coronary artery bypass grafting (CABG). During the operation, biopsies of SAT, EAT and PVAT were obtained for 3–5 gram, which served as a source of adipocytes. Isolated adipocytes were cultured for 24 hours with and without metformin (1 and 10 mmol / L). After a day of incubation, the expression of the ADIPOQ and LEP genes and the level of secretion of adiponectin and leptin in the culture medium of adipocytes were determined. Statistical processing was performed using the GraphPad Prism 6 software package (GraphPad Software, La Jolla, CA, USA) and Statistica software, 6.1 (Dell Software, Inc., Round Rock, TX, USA).RESULTS: The adipocytes of the EAT and PVAT of patients with IHD were characterized by an imbalance in the adipokine system, manifested by a low level of ADIPOQ expression and a high LEP expression in comparison with adipocytes of the SAT. Metformin increased the level of ADIPOQ expression and its secretion by adipocytes regardless of their location, while a low concentration (1 mmol / L) in adipocytes of EAT had a stronger effect compared to 10 mmol / L. Metformin had a multidirectional effect on the level of leptin in adipocytes, which depended on their localization: both in low (1 mmol / L) and high concentrations (10 mmol / L), the drug reduced the level of LEP expression and protein secretion in the culture medium of adipocytes of the SAT. EAT had no significant effect on adipocytes. In PVAT, metformin increased the expression and secretion of leptin regardless of concentration.CONCLUSION: Metformin has a direct effect on adipocytes in SAT, EAT, and PVAT and is able to modulate their activity, which is a promising strategy for maintaining the balance of adipokines in AT, especially epicardial and perivascular localization

Features of plasminogen activator inhibitor-1 synthesis by local fat depots of different localization in cardiovascular diseases

Aim. To determine the features of expression and secretion of plasminogen activator inhibitor-1 (PAI-1) by subcutaneous, epicardial and perivascular adipocytes depending on the complexity of coronary artery disease (CAD).Material and methods. The study included 86 patients with CAD, including 35 with moderate atherosclerotic lesions of the coronary arteries (CA) (SYNTAX Score ≤22), 22 with severe (SYNTAX Score of 23-31 pints), 29 with extremely severe (SYNTAX Score ≥32). As a comparison group, 52 patients with heart defects were examined. During an elective surgical intervention, adipose tissue (AT) samples were obtained for subsequent cultivation and determination of PAI-1 gene expression and PAI-1 secretion in AT supernatants of various localizations. Statistical analysis was performed using Statistica 10.0.Results. In CAD, PAI-1 production in all three types of AT and plasma PAI-1 concentration were increased compared with patients with heart defects. Epicardial AT (EAT) in CAD was characterized by the maximum levels of expression and secretion of PAI-1 relative to patients with heart defects and subcutaneous and perivascular (PVAT) fat depots. Moderate coronary involvement (adipose tissue <22) is characterized by the lowest expression and secretion of PAI-1 in all types of AT and plasma concentration of PAI-1. Direct correlations of PAI-1 expression and secretion in EAT and PVAT and plasma PAI-1 level with its secretion in EAT in patients with CAD and heart defects were revealed. A direct correlation between the plasma level of PAI-1 and its secretion in PVAT was found only in CAD.Conclusion. In CAD, there is not only an increase in the plasma PAI-1 level, but also an increase in the expression of PAI-1 gene and the secretion of PAI-1 in all three types of AT compared with patients with heart defects. PAI-1 expression and secretion in EAT, PAI-1 plasma level, and age are predictors of severe/extremely severe coronary involvement in CAD