3. Discussion
NAFLD, liver steatosis, hypoxia, atherosclerosis, fibrosis, cardiometabolic, hepatic dysfunction, hepatic steatosis, cardiometabolic disorders, pneumoniae, steatosis
CARDIOVASCULAR DISEASE, FIBROSIS, DYSFUNCTION, ADVERSE EFFECTS, REGRESSION, OXIDATIVE STRESS, VASCULARIZATION, LIVER STEATOSIS, HYPOXIA, PATHOGENESIS, PATHOLOGICAL PROCESS, LIVER FIBROSIS, METABOLIC SYNDROME, HEPATIC STEATOSIS, ISCHEMIC NECROSIS, HEART FAILURE, MYOCARDIAL INFARCTION, HYPOXIC, ADHESION, VASODILATATION, DYSBIOSIS, ATHEROSCLEROSIS, STEATOSIS
The results of the study show that a three-week course of hypoxic conditioning in the IHHE mode against the background of a balanced medical treatment leads to a more pronounced regression in the values of known components of MS, such as TCh, LDL, BP, and an improvement of the liver fibrotic index than in the placebo group, and can also potentially have beneficial effects on a new marker of cardiovascular health—TMAO in patients with metabolic syndrome.TMAO, which belongs to the class of aminoxides, is known as a product of the metabolism of the intestinal microbiome. Many studies have established a link between the metabolism of certain microbes and the development of cardiovascular disease. As early as 1988, Saikku et al. noted higher antibody titers to C. pneumoniae in patients who suffered from myocardial infarction [The adverse effects of TMAO are due to several metabolic pathways. TMAO contributes to the early pathological process of atherosclerosis through accelerating endothelial activation and dysfunction, including reduced endothelial self-renewal and increased monocyte adhesion through activation of PKC/NF-κB/vascular cell adhesion molecule-1 (VCAM-1) [Dysbiosis, particularly through an unbalanced diet with a high-content carbohydrate intake, contributes to oxidative stress through increased expression of proinflammatory cytokines. This leads to the oxidation of low-density lipoproteins (LDLs), affecting the production of NO and endothelin-1 [One of the mechanisms through which an unbalanced gut microbiota is involved in the pathogenesis and progression of NAFLD is an increase in the permeability of the intestinal wall, development of ischemic necrosis of mesenteric epithelial cells and induction of liver fibrosis development [Given the role of TMAO in the progression of cardiometabolic disorders, various ways to suppress the production of TMAO are being developed, including antibiotic therapy, but the evidence base for them has not been formed [The fact of different qualitative and structural ratios of the intestinal microbiota under different oxygen regimes seems to be interesting [On the other hand, moderate hypoxic stimuli can activate various transcriptional pathways via hypoxia response element (HRE) through activation of HIF-1 providing the production of protective proteins with antioxidant activity, inducible NOs, glucose transporters, glycolytic enzymes, selected growth factors, etc. [Based on the results obtained in this work and the described known effects of hypoxic conditioning, it is shown that the use of an IHHE course has a systemic optimizing effect on various metabolic and molecular mechanisms involved in the pathogenesis of MS. Despite the absence of a significant decrease in TMAO values, it can be reasoned that the normalization of lipid metabolism with a decrease in TCh and LDL, a reduction in CRP values, and a reduction in steatosis and liver fibrosis indicators are also partially associated with the improvement of the intestinal barrier and hepato-biliary functioning. This position corresponds to the work of Serebrovskaya et al. [The possible involvement of TMAO in the pathogenesis of MS and NAFLD is indirectly confirmed by our data regarding the dynamics of TMAO and cardiometabolic indicators in a 3-week course of IHHE in patients with baseline elevated values of this metabolite (>5 μM/L). In the course of IHHE, their TMAO values decreased significantly, but the degree of reduction in TCh, LDL, and liver steatosis indicators was significantly less pronounced than in the group of patients with baseline normal TMAO values, which may indicate more significant changes in lipid metabolism and hepatic dysfunction and the need for longer IHHE courses to achieve the necessary effects in this group of patients.It is also important to note the detected effects of IHHE in cardiohemodynamic indicators—a significant decrease in SBP and DBP, resting heart rate, and a significant decrease in the predictor of heart failure, i.e., NT-proBNP, which confirms our previous results, as well as the well-founded conclusion in the systematic review of Behrend T. et al. (2022), that IHHE or continuous sessions of hypoxia at rest or in combination with exercise are generally effective to reduce blood pressure and positively influence vascular health due to the stimulation of vascular adaptions (e.g., increased vascularization and endothelium-dependent vasodilatation) as well as adaptations in the autonomic nervous system disturbed by TMAO’s pro-atherogenic and pro-inflammatory activities in patients with MS [To understand the positive dynamics of indicators of hepatic steatosis and fibrosis, the fact that hypoxia conditioning is thought to benefit smooth muscles in blood vessels but also elsewhere, including the bladder and gastrointestinal tract, mediated by diverse pathways involving heme oxygenase-1, NO, HIFs, VEGF, ATP-sensitive K+ channels, prostaglandins, bradykinin, different protein kinases, and ROS [In addition, changes in TMAO levels may be associated not only with changes in microbiome status, but also with changes in hepatic activity, as demonstrated by our results showing decreased TMAO levels and improved hepatic indicators, which were published earlier in our article [