Methotrexate & rheumatoid arthritis associated atherosclerosis: A narrative review of multidisciplinary approach for risk modification by the international board of experts.

Rheumatoid arthritis (RA) is an idiopathic, autoimmune connective tissue disorder that primarily affects the synovial joints, causing symmetric, erosive-deforming polyarthritis. It is also associated with extra-articular manifestations, particularly cardiovascular (CV) diseases (CVD). CV risk modification in RA remains unsolved despite recent advances in the management of RA. RA is an independent risk factor for atherosclerosis. RA and atherosclerosis share similar pathophysiological features (such as the pro-inflammatory cascade activation including interleukin-6) and risk factors (such as microflora dysbacteriosis and smoking). Patients with RA experience an exacerbation of atherogenesis, with atheromas destabilization, endothelial dysfunction, vasculitis, and hypercytokinemia. Consequently, the inflammatory response associated with RA is the basis for CVD development. The treat-to-target strategy not only improved RA control but also had a favorable effect on the morpho-functional state of the CV system in patients living with RA. Thus, disease-modifying antirheumatic drugs (DMARDs) - in particular methotrexate - may have a beneficial effect on the prevention of CV events in RA. It must be mentioned that RA is a serious multi-system disease, not only because of a window period during which the course of RA can be reversed, but also due to early damage to the heart and blood vessels. For this reason, a thorough cardiological assessment must be performed for all patients with RA, regardless of sex, age, disease stage, and disease activity score.

HIV-Related Atherosclerosis: State-of-the-Art-Review.

The infection caused by the Human Immunodeficiency Virus (HIV) has spread rapidly across the globe, assuming the characteristics of an epidemic in some regions. Thanks to the introduction of antiretroviral therapy into routine clinical practice, there was a considerable breakthrough in the treatment of HIV, that is now HIV is potentially well-controlled even in low-income countries. To date, HIV infection has moved from the group of life-threatening conditions to the group of chronic and well controlled ones and the quality of life and life expectancy of HIV+ people, with an undetectable viral load is closer to that of an HIV- people. However, unsolved issues still persist. For example: people living with HIV are more prone to the age-related diseases, especially atherosclerosis. For this reason, a better understanding of the mechanisms of HIV-associated destabilization of vascular homeostasis seems to be an urgent duty, that may lead to the development of new protocols, bringing the possibilities of pathogenetic therapies to a new level. The purpose of the article was to evaluate the pathological aspects of HIV-induced atherosclerosis.

Chemotherapy, hypothyroidism and oral dysbiosis as a novel risk factor of cardiovascular pathology development.

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in the population, as well as the economic burden of the health care system. Currently, CVDs account for more than 17.6 million deaths a year and are projected to exceed 23.6 million by 2030. Unstable atheroma, and its rupture, underlies the pathology of most cardiovascular complications, particularly acute coronary syndrome, mortality from which, compared with other CV events, remains the leading one. Despite numerous efforts by WHO, national health systems, and medical authorities, the incidence and mortality from cardiovascular events remain critically high. Thus, the search for new risk factors for the development of CV pathology looks very relevant. Our working group decided to amalgamate our research data, which reflects the study of modern risk factors from the Armenian, Russian, Georgian, and Iranian medical schools. In particular, the aspects of cardiotoxic effects of chemotherapy, hypothyroidism, and oral dysbiosis are discussed.

The Keystones of Right Ventricular Arrhythmogenic Cardiomyopathy-Induced Morphological Disarrangement.

Arrhythmogenic right ventricular cardiomyopathy is an urgent problem of modern cardiology. This myocardial remodeling manifests various desmosomopathies, channelopathies, and other mutations resulting in a violation of the coordinated heart work, particularly the myocardium. The incidence of this cardiomyopathy is not significant. Still, it is worth noting that athletes are at an increased risk of developing this disease, emphasizing the importance of studying this topic and its relevance from cardiologists and sports physicians. Moreover, the clinical pattern of this disease is heterogeneous. This pathology requires strengthening control and attention of medical personnel and constant improvement and optimization of diagnostic methods and treatment protocols. In this article, the pathophysiological mechanisms, molecular genetic aspects, and the dynamics of morphofunctional changes are represented in detail. Understanding the mechanisms of etiopathogenesis and the features of morphological changes observed in this cardiomyopathy and its more detailed study is fundamental in developing modern treatment methods to improve patients' quality and life expectancy.

Anthracycline Associated Disturbances of Cardiovascular Homeostasis.

Despite the dynamic progress of modern medicine, oncological and cardiovascular diseases (CVD) remain a severe economic burden worldwide. Therefore, the study of chemotherapeutic cardiotoxicity appears to be comprehensively demanded. Nowadays, pharmacological therapy in oncology has undoubtedly unprecedented development, but at the same time, the rates of cardiovascular complications of chemotherapy still remain unchanged. The well-established and highly effective, but at the same time, cardiotoxic anthracyclines have not lost their relevance. Furthermore, they remain indispensable components of an immense amount of chemotherapy regimens, such as AC, FAC, etc. Moreover, the anthracycline-containing chemotherapy regimens have become a standard of care in several cancer types. In the context of the above mentioned, the study of the pathophysiological mechanisms, biochemical aspects, and dynamics of the morphological remodeling of doxorubicin-induced cardiovascular homeostasis disturbances will enable finding new targets of pharmacological therapy, which either in the short or long perspectives, will have a beneficial effect, improving both the quality of life and prognosis of oncological patients. This article covers a versatile overview of the molecular mechanisms of doxorubicin-induced cardiotoxicity. The pathogenesis of cardiotoxicity assessment could help to explore specific molecular mechanisms that initiate cardiovascular alteration that may favorably affect the future development of targeted drugs that could prevent cardiovascular events in cancer patients.

Diabefit as a Modifier of Fructose-induced Impairment of Cardio-vascular System.

Today, cardiovascular diseases, due to their widespread prevalence, are among the most relevant biomedical problems in the modern world. The development of cardiovascular comorbidity among patients with diabetes mellitus is of high clinical urgency. Therefore, the study of cardiovascular risk modification among patients with diabetes mellitus is of paramount importance. In the context of the above, the data on the cardiotoxicity of fructose look very alarming since these patients usually use fructose as an affordable alternative to glucose. At the same time, it is an independent inducer of destabilization of cardiovascular homeostasis. Sixty rats were used in the experiment to study this problem. Modeling of fructose-induced overload was performed using a diabetic fructose supplement in an aqueous solution. The collection of herbs "Diabefit" was used as an infusion in addition to feeding highly enriched with fructose. The used markers which reflect the state of the heart and the blood vessels were: MDA, SOD, NO, and ET-1. MDA, ET-1, and NO concentrations demonstrated a significant increase in the fructose overload group and a significant decrease in the Diabefit group. At the same time, changes in SOD level as an indicator of the antioxidant reserve, on the contrary, implied a decrease in the group with a high fructose content and increased in the Diabefit group. All detected changes were associated with fructose-induced inhibition of SOD activity and its restoration using the Diabefit phyto-collection.

Age-related differences in hypoxia-associated genes and cytokine profile in male Wistar rats.

Hypoxia tolerance of the organism depends on many factors, including age. High newborn organisms tolerance and high level of oxidative stress throughout aging were demonstrated by many studies. However, there is lack of investigations reflecting the expression of key hypoxia-inducible factor HIF in different age organisms in correlation to levels of pro-inflammatory and anti-inflammatory cytokines. Liver is a sensitive to hypoxia organ, and is an important organ in providing an acute reaction to infections - it synthesizes acute inflammation phase proteins, in particular, C-reactive protein. The aim of study was to determine relationship between age-related tolerance to hypoxia and HIF-1 and PHD2 (prolyl hydroxylase domain protein) expression levels in the liver and the production of cytokines in the spleen in newborn, prepubertal and adult Wistar rats. Newborn rats are characterized by high mRNA Hif-1α expression level in the liver, accompanied by a low content of HIF-1 protein and high level of PHD2. The growth in HIF-1α protein level throughout age is accompanied by the growth of pro-inflammatory cytokines level. Prepubertal animals are the least hypoxia resistant and their HIF-1α mRNA expression level was higher than in adult animals. The PHD2 activity in prepubertal animals was significantly reduced in comparison to newborn rats, and the HIF-1α protein level did not change. Further studies require the identification of additional mechanisms, determining the regulation of the HIF-1α level in prepubertal animals.

Sex differences of inflammation in target organs, induced by intraperitoneal injection of lipopolysaccharide, depend on its dose.

PURPOSE: The aim of our research was to study sex differences and the severity of inflammatory changes in target organs and the peculiarities of immunological disorders when low and high doses of lipopolysaccharide (LPS) were administered to rats. METHODS: Male and female 2- to 3-month-old Wistar rats (200-250 g) were injected intraperitoneally with Escherichia coli LPS in one of two doses: 1.5 or 15 mg/kg. In a day after the LPS injection, we studied endotoxin, corticosterone, sex steroids, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activity levels in the serum; morphological disorders in the lung, liver, thymus, and spleen; ex vivo production of IL-2, IL-4, tumor necrosis factor (TNF), and interferon γ (IFNγ) by splenic cells activated by ConA; and relative amount of T- and B-lymphocytes in the peripheral blood. RESULTS: After the injection of low-dose LPS, the serum endotoxin level increased only in males and was combined with a more pronounced inflammatory response in the lungs and thymus and an increase in ALT and AST activity levels without any changes in corticosterone level. After the injection of high-dose LPS, the inflammatory and pathological changes in the target organs manifested as severe endotoxemia and sex differences of pathological changes in the lungs and liver were not revealed. The level of production of IL-2, IL-4, IFNγ, and TNF by splenic cells and the number of T-lymphocytes, including cytotoxic cells, in the peripheral blood, decreased in males, which is an evidence of a pronounced suppression of the immune response. CONCLUSION: We have shown that the morphofunctional changes in the organs of the immune system in females and males, as well as the intensity of the sex differences of inflammation, depend on the severity of systemic inflammatory response, induced by different doses of LPS.