Microbial-Derived Uremic Toxins: Role in the Pathogenesis of Comorbidities in Patients with Chronic Kidney Disease

Аim: to analyze the significance of microbial-derived uremic toxins (MDUT) in the pathogenesis of comorbidities in patients with chronic kidney disease (CKD).Key findings. Increased excretion of nitrogen metabolism products into the intestines of patients with CKD is associated with uremic dysbiosis; changes in the metabolic activity of the gut microbiota and the leaky gut syndrome; which largely cause the accumulation of MDUT in the internal environment of the body: indoxyl sulfate; p-cresyl sulfate; trimethylamine-N-oxide; etc. The results of recent studies allow to consider these metabolites as an independent risk factor for adverse outcomes in people with CKD due to the progression of renal dysfunction to the terminal stage; as well as frequent cardiovascular; neurological; bone mineral; nutritional and other complications.Conclusion. MDUT are one of the key modulators of the pathogenetic relationship between the gut and kidneys. Therapeutic manipulations with intestinal microbiota can be considered a promising strategy for preventing complications associated with uremia

Gender particulars of morphological phenotypes of the right atrial appendage myocardium in patients with chronic heart failure who underwent an open heart surgery

Background: For many decades, women in all age groups have a high risk of mortality and perioperative complications of cardiac surgery (CS), with its cause being unclear until now. Preoperative prediction of cardiovascular complications (CVC), based only on the clinical and instrumental criteria without taking gender into account, also remains unsuccessful. There is an opinion that the structural and functional changes in the myocardium, which exist before the operation, could significantly affect the patient's condition after cardiac surgery.Aim: To identify morphological and molecular predictors of unfavorable prognosis in chronic heart failure (CHF) patients of both genders after CS.Materials and methods: The study included 87 CHF patients of both genders referred for an elective cardiac surgery. Before the operation, a standard examination and treatment of CHF and concomitant disorders were performed. A sample of the right atrial appendage (RAA) myocardium that had been resected during the CS, was studied by histological, immunohistochemical (IHC) (expression of caspase-3, bcl-2, MMP-2, TIMP-1, p38α, CD-34) and morphometric methods. At days 10 to 14 after CS, the presence of CVC was assessed in all the participants. We examined the relationship between the development of CVC and morphological changes in the RAA myocardium before surgery, taking into account the patients' gender.Results: Compared to the group with the favorable postoperative course in the myocardium, in the male/female group with unfavorable post-CS course there was a significant reduction in the cardiomyocyte (CMC) diameter (13.26 ± 3.14; p < 0.01 / 13.99 ± 3.64; p < 0.01), the bulk density (BD) of CMC (55.4 ± 9.45; p < 0.01 / 51.22 ± 10.12; p < 0.01) vol. %, a trophic index (0.24 ± 0.1; p < 0.01 / 0.21 ± 0.06; p < 0.01), as well as a significant increase in the stromal BD (44.91 ± 9.23; p < 0.01 / 47.78 ± 10.12; p <0.01) vol. % and the Kernogan index (1.78 ± 0.49; p < 0.01 / 1.43 ± 0.64; p = 0.143). IHC analysis of the RAA myocardium in the male/female group with an unfavorable postoperative course showed an increase in the amount of caspase-3 (+) CMC (3.9 ± 0.46; p < 0.01 / 3.34 ± 0.4; p < 0.01), an increase in the activity of +/++/+++ p38α (3/30/69; p < 0.01 / 2/39/60; p < 0.01) %, the expression of MMP-2 (2/56/43; p < 0.01 / 0/68/31; p < 0.01) %, with a decrease in the expression of TIMP-1 (19/29/52; p < 0.01 / 8/24/67; p < 0.01) % and BD of CD-34 stromal cells (18.46 ± 8.5; p < 0.01 / 27.54 ± 5.88; p < 0.01) %, compared with groups with a favorable current.Сonclusion: The study showed the role of caspase-3, MMP-2, and CD-34 in the RAA myocardium as prognostic markers of CVC in the early postoperative period, as well as gender differences in modulation of the apoptotic pathways and inefficiency of anti-apoptotic mechanisms in the RAA myocardium. Based on the assessment of the RAA myocardial reorganization, an integral prognostic picture of the structural and functional changes in the myocardium has been proposed, which makes it possible to identify a special patient cohort with an exceptionally high risk of unfavorable course of the post-CS period

ROLE OF GENDER SPECIFICS IN MYOCARDIAL REMODELLING, CARDIOVASCULAR COMPLICATIONS DEVELOPMENT AND EFFICACY OF PHARMACOTHERAPY IN HEART FAILURE PATIENTS AFTER CARDIAC SURGERY

Aim. To assess gender influence on myocardial remodelling, pharmacotherapy efficacy and complications development in chronic heart failure patients (CHF) post cardiac surgery.Material and methods. In the study, 87 patients included, both genders, with CHF, who had been planned for cardiac surgery. All underwent standard investigations and CHF treatment, as other pathologies. Myocardium specimens from the right atrium appendage (RAA) were collected during surgery, investigated with general histology, immune histochemistry (expression of MMP-9, TIMP-1 and р38αMAPK) methods. For the evaluation of treatment influence on myocardium, intervention groups were selected: enalapril and metoprolol, perindopril and amlodipine (Prestance®, “Les Laboratoires Servier”, France). In all participants, at 10-14 day post surgery, the rate of complications was evaluated, by groups. At least one complication led to selection the participant as adverse in-hospital outcome. The relations were studied, of post-surgery complications with EchoCG data and morphological changes in LAA myocardium, taken the gender and left ventricle ejection fraction (LVEF).Results. In cardiac surgery group with heart failure and preserved LVEF (HFpEF) with the increase of CHF functional class, normal LVEF remained, and there was worsening of the LV diastolic function. In HFpEF males there was decrease of EF with transition to “grey zone” by III functional class, and eccentric remodeling predominated with unchanged diastolic function. In HF mid-range EF group, regardless of gender, there was eccentric LV remodelling. In RAA myocardium of women there was lower grade of myocardial fibrosis and mononuclear areas of infiltration, and there was higher rate of cardiovascular as extracardiac complications. High grade of MMP-9 in RAA revealed in the group of HF mid-range EF and adverse outcome, regardless gender, and increased expression of р38αMAPK in females of thisgroup. In perindopril and amlodipine group there was lower grade of MMP-9 and р38αMAPK expression.Conclusion. The study demonstrated gender differences in remodelling of myocardium in HFpEF patients. This makes to consider female gender, HF midrange EF, MMP-9 expression in RAA myocardium, as prognostic markers of surgery adverse outcome. Combination of perindopril and amlodipine demonstrated protective influence on myocardium, with more prominent effect in females

CARDIOPROTECTIVE PROPERTIES OF PROGESTINES: INFLUENCE OF DROSPIRENONE ON MYOCARD IN EXPERIMENTAL HEART FAILURE

Aim. To assess the influence of synthetic progesterone — drospirenone, on remodeling of the left ventricle myocardium (LV) in ovariectomized (OE) female rats under circumstances of experimental heart failure (EHF).Material and methods. The study was done on 25 female Wistar rats, mass 260-300 g. Twenty animals (in 2 months after bilateral ovariectomy) underwent modeling of EHF by subcutaneous load of 0,1% mesaton solution for 14 days with following swimming to profound exhaustion. Four rats were removed on 14th day of EHF. Sixteen experimental animals with EHF were selected to 3 groups: 10 underwent 14 days subcutaneous load of drospirenon (Sigma-Aldrich, USA), dose 2 mg/kg (n=5) and 0,5 mg/kg (n=5), 6 were being loaded saline 0,2 mL daily. On 28th day the animals were removed from the experiment. With light microscopy method, immune cytochemistry, morphometry the LV myocardium was investigated.Results. In OE rodents on the 14th day of EHF there was clear and significant heteromorphism of contractile cardiomyocytes (CMC) with the signs of hypertrophy and dystrophy; increase of the volume density (VD) of stroma, reorganized extracellular matrix (EM), expression of metalloproteases-2,9 (MMP-2,9) and tissue inhibitor of metalloproteases-1 (TIMP-1), CMC with apoptosis. After remodeling of EHF at 28th day in myocardium there was further increase of CMC number with significantly changed morphology and tinctorial properties, degradation of EM components. In rats receiving 14 days drospirenon, regardless of dosage, there was regression of pathological changes, decrease of CMC hypertrophy grade, as the nuclei, decrease of CMC with the signs of apoptosis, and stabilized EM components.Conclusion. The cardioprotective properties of drospirenon are discussed, that even in minimal therapeutic concentrations facilitates structural and functional rehabilitation of myocardium under conditions of gonade hormones deficiency and EHF

DYNAMICS OF THE POLYUNSATURATED FATTY ACIDS VALUES IN THE BLOOD OF CHRONIC HEART FAILURE PATIENTS

Aim. To assess the dynamics of levels of eicosapentaenoic (EPA), docosahexaenoic (DHA), arachidonic (AA) and linoleic (LA) fatty acids (FA), omega-3 index, relation of omega-3/omega-6 polyunsaturated FA (PUFA) in the blood of decompensated chronic heart failure (CHF) patients under the standard management.Material and methods. The values of 22 FA were assessed in stable CHF (SCHF, n=12) and decompensated CHF (DCHF, n=24) and after decompensation treatment. The omega-3 index was calculated (relation of the sum of EPA and DHA to the sum of all FA) and relation of the sum of EPA and DHA to the sum of AA and LA.Results. Values of EPA and DHA, omega-3 index in DCHF group were lower in SCHF (0,085 [0,06;0,17] vs 0,26 [0,15;0,4] mM/mL, p=0,0005; 0,37 [0,16;0,62] vs 0,84 [0,55;1,10] mM/mL, p=0,004; 1,11 [0,65;2,11] vs 2,44 [1,80;3,71]%, p=0,0008, respectively). After the treatment of DCHF, levels of EPA and DHA, omega-3 index raised, and reached 0,16 [0,11;0,21] mM/mL, p=0,0016; 0,46 [0,35;0,76] mM/mL, p=0,045; 1,74 [1,14;2,42]%, p=0,043, respectively. Statistically significant differences of AA and LA in the blood of SCHF and DCHF were not found. With the treatment, there was increase of AA value growth (3,40 [2,56;4,91] mM/mL, p=0,011) and tendency of LA increase (9,13 [5,08;11,28] mM/mL, p=0,09). Dynamics of omega-3/omega-6 relation witnessed the predominant part of omega-6 of PUFA in all participants, especially in DCHF. After treated fluid retention syndrome in patients this relation changed due to the raise of omega-3 PUFA.Conclusion. In the DCHF there is significant increase of omega-3 index in the blood, concentrations of EPA and DHA. Standard therapy of CHF decompensation supports the increase of EPA, DHA, AA, omega-3 index. Mechanisms of the revealed PUFA dynamics in CHF patients, including the treatment outcomes, are subject for further investigation