Age-Related Features of the Early Period of Liver Regeneration after Partial Hepatectomy in Rats.

Regenerative processes in the liver were studied in 3-month-old (young) and 9-month-old (aged) male Wistar rats on day 1 after 30 and 70% hepatectomy. Regardless of the resected liver volume, shifts in the biochemical parameters of the serum in aged rats were more pronounced than in young animals. After 30% hepatectomy, no age differences in the rate of hepatic regeneration were found, while after 70% liver resection this parameter was higher in young rats. Hepatectomy in young rats led to recruitment of MSC, hepatocyte precursors, endothelial and epithelial progenitor cells into the liver parenchyma and increased fluidity of the plasma and mitochondrial membranes of hepatocytes. In aged rats, the recruitment of MSC, hepatocyte precursors, and endothelial progenitor cells into the injured liver was impaired and the rigidity of the mitochondrial membranes of hepatocytes increased.

Age-Related Features of the Viscosity of Plasma and Mitochondrial Membranes of Hepatocytes in Liver Cirrhosis.

The viscosity of plasma and mitochondrial membranes of hepatocytes was studied in young (3-month-old) and old (9-month-old) male Wistar rats. It was shown that viscosity of hepatocyte plasma and mitochondrial membranes in young rats under optimal vital functions in the area of protein-lipid membrane contacts was significantly lower than in old rats. No age-related differences in the viscosity of lipid-lipid membrane contacts and in the polarity of protein-lipid contacts and lipid layers were found. Liver cirrhosis induced by carbon tetrachloride and ethanol administration was associated with increased fluidity of the plasma and mitochondrial membranes of hepatocytes in rats of both age groups. The decrease in membrane viscosity in young rats occurred due to a decrease of the viscosity in the area of protein-lipid and lipid-lipid contacts, while in old rats in the area of protein-lipid contacts. Carbon tetrachloride and ethanol did not affect the polarity of lipid contacts and lipid layers.

Erythrocyte membranes beta-adrenoreactivity changes after renal denervation in patients with resistant hypertension, relationship with antihypertensive and cardioprotective intervention efficacy.

Aim      To study the functional condition of sympathoadrenal system as evaluated by beta-adrenoreactivity of erythrocyte membranes (beta-ARM) during two years following renal denervation (RD) in patients with resistant arterial hypertension (RAH) and to determine the relationship of this index with long-term antihypertensive and cardioprotective effectivity of this invasive treatment.Material and methods  The study included 48 patients (mean age, 57.2±8.7 years, 18 men) with RAH on a stable antihypertensive therapy. Averaged daily systolic and diastolic blood pressure (SBP and DBP) and levels of beta-ARM were determined at baseline and in 7 days and 2 years following RD. Measurement of beta-ARM was based on beta-adrenoblocker inhibition of erythrocyte hemolysis induced by exposure to hypo-osmotic environment. The beta-adrenoblocker binds to erythrocyte membrane beta-adrenoceptors to prevent the erythrocyte destruction. Increased values of beta-ARM reflect a decrease in the number of functionally active erythrocyte membrane beta-adrenoceptors associated with long-term sympathetic hyperactivity.Results For two years of follow-up, values of average daily BP decreased from 160.4±16.0 / 88.1±14.6 to 145.3±19.3 / 79.4±13.6 mm Hg. At 7 days, the number of beta-ARM had decreased in the group of RD responders (р=0.028) who at two years had decreased their BP by 10 mm Hg or more, while in the group of non-responders, the number of beta-ARM remained unchanged. At one week, beta-ARM values correlated with changes in SBP and DBP (r= -0.54; р<0.05) and with left ventricular myocardial mass (LVMM) (r= -0.36; р<0.05) at two years of follow-up whereas beta-ARM delta at one week was interrelated with the renin concentration in the long-term (r= -0.44; р<0.05). At two years, the content of beta-ARM was increased in both groups.Conclusion      The decrease in beta-ARM content at 7 days after RD shows the procedure efficacy and allows an expectation of clinically significant decreases in BP and LVMM in the long-term after the surgical treatment. At two years after the intervention, the content of beta-ARM increased, and the BP decrease was apparently due to some other mechanisms.

Age-Related Features of the Response of the Liver and Stem Cells during Modeling of Liver Cirrhosis.

We studied the age-related characteristics of the response of stem cells and liver in male Wistar rats to administration of carbon tetrachloride (CCl4) and ethanol. It was shown that modeling of liver cirrhosis caused inflammation, fibrosis, damage to sinusoidal capillaries, necrosis, and disturbances in the functional activity of hepatocytes in young rats. These processes were accompanied by mobilization of profibrotic mesenchymal stem cells (MSC), proinflammatory hematopoietic stem cells (HSC) and lymphocytes (CD45hiCD133+) from the bone marrow into the blood and migration to the liver. On the other hand, the number of hepatocyte precursors expressing Sox9 (cells of Hering's canal), immature cholangiocytes, Ito cells, oval cells, and endothelial cells of the liver sinusoids) sharply increased in the liver. In young rats, mobilization and migration of MSC, HSC, and hepatocyte precursors against the background of liver cirrhosis were more intensive than in old animals. The higher resistance of old rats to exposure is associated with age-related changes in the niches as well as in mobilization and migration of cells.

Age Peculiarities of Respiratory Activity and Membrane Microviscosity of Mitochondria from Rat Cardiomyocytes.

We studied respiratory activity and microviscosity of mitochondrial membranes from the left ventricular myocardium of 2-month-old (n=8) and 15-month-old (n=8) rats. The respiratory control (RC) during substrate phosphorylation was calculated as the ratio of oxygen absorption rates in the presence of ADP and after its utilization. In 2-month-old rats, RC was 4.66 (4.56; 4.71); in 15-month-old animals, it was significantly (р<0.05) lower: 3.57 (3.50; 3.62). Pyrene probe eximerization indices for regions of protein-lipid and lipid-lipid interactions in mitochondria of 2-month-old animals were significantly lower than in the group of 15-month-old rats, which indicated reduced microviscosity of the lipid environment of proteins. Thus, the decrease in RC of mitochondria from the left ventricle of 15-month-old animals and the increase in the microviscosity coefficients of their membranes indicate age-related changes in the structural and functional activity of mitochondria.

[Difficulties in diagnosis of heart failure with preserved ejection fraction in clinical practice: dissonance between echocardiography, NTproBNP and H2HFPEF score].

This pilot study was aimed to assess the percentage of patients admitted to a Russian hospital and diagnosed with heart failure with preserved ejection fraction (HFpEF) maintaining this diagnosis when evaluated against the ESC 2016 and Russian 2017 heart failure guidelines. In addition, we reviewed the probability of an HFpEF diagnosis when patients were assessed against the H2FPEF score. Forty-two patients (mean age 68 ±7,5) diagnosed with HFpEF on their discharge record, admitted between March 2018 and May 2018, were included. Twenty percent of patients did not meet Russian guideline criteria for HFpEF due to either the absence of symptoms and/or echocardiographic evidence of structural/functional abnormalities. Using the ESC 2016 guidelines (which required an elevation in NT Pro BNP) the diagnosis was confirmed in only 37% of patients, mostly due to the normal level of NTproBNP in 54.8% of those investigated. The probability of HFpEF by H2FPEF score in patients with dyspnea and HFpEF by ESC 2016 criteria was 93% and without HFpEF by ESC 2016 criteria 68% (p = 0.054). In contrast, the probability of HFpEF by H2FPEF score in patients with dyspnea and HFpEF by Russian criteria was 84.4%.

[Association of ITGB3, P2RY12, and CYP2C19 gene polymorphisms with platelet functional activity in patients with coronary heart disease during dual antiplatelet therapy]. / Assotsiatsiia polimorfizmov genov ITGB3, P2RY12, CYP2C19 s funktsional'noi aktivnost'iu trombotsitov u patsientov s ishemicheskoi bolezn'iu serdtsa na fone dvukhkomponentnoi antiagregantnoi terapii.

AIM: To assess the association of CYP2C19 G681A, P2RY12 H1/H2, and ITGB3 T1565C polymorphisms with the extent of platelet aggregation in patients with coronary heart disease (CHD) during antiplatelet therapy. SUBJECTS AND METHODS: 166 male patients with CHD, living in the Western Siberian Region, were examined. All the patients underwent a test for platelet aggregation induced by ADP (2.5 and 5.0 µm) and epinephrine (0.2 µm). Genotyping was performed using an allele-specific polymerase chain reaction technique. RESULTS: The polymorphic variants of the P2RY12 and ITGB3 genes were ascertained to have no impact on the extent of platelet aggregation in patients receiving clopidogrel and acetylsalicylic acid. An association was found between CYP2C19 681A allele carriage and the increased extent of platelet aggregation induced by ADP. CONCLUSION: The carriage of the cytochrome P450 CYP2C19 681A allele rather than platelet receptor gene polymorphisms determines a risk for clopidogrel resistance in patients with CHD.

[Age features peripheral link erythron rats and its status with experimental cardiosclerosis].

Studied the performance of the peripheral unit erythrone rats aged 4 months (1st group) 12 months (2nd group) and 24 months (3rd group). Each age group (n=20) consisted of 10 intact animals and 10 animals c postinfarction cardiosclerosis (PICS). In the group of animals 24 months of age was showed an increase in the number of erythrocytes in the absence of difference in the amount of reticulocytes. Expressed anisocytosis and decrease in hemoglobin synthesis in animals of this age group suggests that the age-related disorders maturation of erythroid cells. The development of post-infarction myocardial remodeling has not affected polycythemia typical for animals of older age group. At the same time a significant increase in the reticulocyte count of peripheral blood smears was observed for this group of animals. Development of PICS for animals extreme age groups leads to a smoothing interage differences, noted in the animals in the intact condition.

[Criteria for selecting patients with resistant hypertension for a renal sympathetic denervation]. / Kriterii otbora bol'nykh s rezistentnoi arterial'noi gipertoniei dlya simpaticheskoi denervatsiya pochek.

AIM: to define and develop a procedure that can select patients with resistant hypertension (RH) for a renal sympathetic denervation (RSD) procedure, by being orienting to the specific initial values of ß-adrenoreactivity (ß-AR) and systolic blood pressure (SBP). SUBJECTS AND METHODS: The analysis included 23 RH patients receiving the maximally tolerable doses of 4 antihypertensive drugs. The investigations involving BP control and a Russian spectrophotometric procedure for determining ß-AR in terms of the change in the osmoresistance of erythrocyte membranes (EM) were performed at baseline and 4 and 24 weeks. RSD was carried out using endovascular radiofrequency ablation of the renal arteries. The therapy was not changed during the observation. RESULTS: If SBP was >170 mm Hg and ß-AR of EM >40 conditional units (CUs) at baseline, ΔSBP was 17.68±3.24 mm Hg and the efficiency of RSD was 100%. When SBP was <170 mm Hg and ß-AR of EM <40 CUs at baseline, ΔSBP was 0.97±4.21 mm Hg (p>0.05) and the efficiency of RSD was low. CONCLUSION: The overall estimate of baseline SBP and ß-AR of EM in patients with RH could determine the expediency of the RSD procedure in order to lower BP. The proposed procedure can optimize the selection of patients and enhance the efficiency of RSD in the treatment of RH.

[Possibility of evaluating the effectiveness of renal artery sympathetic denervation in resistant hypertension early after radiofrequency ablation]. / Vozmozhnost' otsenki effektivnosti simpaticheskoi denervatsii pochechnykh arterii pri rezistentnoi arterial'noi gipertonii v rannie sroki posle provedeniya radiochastotnoi ablyatsii.

AIM: to investigate time course of changes in the adrenoreactivity (AR) of erythrocyte membranes (EM) after radiofrequency ablation of the synaptic nerves of the renal arteries (RA) in patients with resistant hypertension (RH) and to assess whether this indicator can be used for the early evaluation of the efficiency of an invasive intervention into the RA. SUBJECTS AND METHODS: 24 patients with RH, who received full-dose antihypertensive therapy with at least three drugs, including a diuretic, were examined. Renal sympathetic denervation (RSD) was carried out by endovascular radiofrequency ablation (RFA) of the RA. 24-hour blood pressure (BP) monitoring and determination of the ß-adrenoreactivity (ß-AR) of EM were performed, by taking into account the change in erythrocyte osmoresistence at baseline and 1 and 24 weeks after RFA. The therapy was not changed during the observation. RESULTS: The patients included in the study were divided into 2 groups. One week following RSD, 15 patients of Group 1 were noted to have a decrease in the ß-AR of EM by 10 conditional units or more; average daily systolic BP (SBP) and diastolic BP (DBP) reduced by 8.3 and 2.8 mm Hg, respectively. In 9 patients of Group 2, the ß-AR of EM was unchanged in this observation period or increased compared with baseline. In this group, the decrease in average daily SBP and DBP was noted to be less pronounced than that in Group 1 (by 1.4 and 1.5 mm Hg, respectively). At 24 weeks after RSD, Group 1 was seen to have an effective daily decrease in average daily SBP and DBP by 25.6 and 14.3 mm Hg, respectively (p=0.01 and 0.05). The average value of the ß-AR of EM significantly declined compared with baseline. In Group 2, no statistically significant changes were reported; SPB and DBP lowered by 7.0 and 3.0 mm Hg, respectively. There was a significant decrease in the ß-AR of EM compared with that at week 1. CONCLUSION: The decline in the ß-AR of EM within the first week after RFA is suggestive of the decreased activity of the sympathoadrenal system and may be used as an early efficiency index of RSD after the procedure.

Age-Dependent Changes in Na(+),K(+)-ATPase Activity and Lipid Peroxidation in Membranes of Erythrocytes during Cardiosclerosis Development in Rats.

Activity of Na(+),K(+)-ATPase was measured in erythrocyte ghosts of 4- and 12-month-old rats, intact and with postinfarction cardiosclerosis. Enhanced accumulation of secondary LPO products and reduced activity of Na(+),K(+)-ATPase were observed in erythrocyte ghosts of 12-month-old rats. The development of postinfarction cardiosclerosis in 4-month-old rats was accompanied by enhanced accumulation of LPO products and decreased activity of Na(+),K(+)-ATPase. In comparison with young rats with postinfarction cardiosclerosis, 12-month-old rats with this pathology were characterized by less pronounced decrease in Na(+),K(+)-ATPase activity and increase in accumulation of LPO products in comparison with intact control.

[A change in adrenal responsiveness in sotalol-treated patients with paroxysmal atrial fibrillation depending on autonomic nervous system tone].

AIM: To evaluate the efficacy of sotalol depending on the magnitude of changes in adrenal responsiveness and autonomic nervous system tone in patients with paroxysmal atrial fibrillation (AF). SUBJECTS AND METHODS: Twenty-six patients with paroxysmal AF in the presence of coronary heart disease (CHD) and hypertension were examined. Sinus rhythm variability and sympathicotonic and vagotonic disorders were studied in patients with paroxysmal AF before and during sotalol treatment. A commercial Beta-ARM-Agat kit was used to estimate the adrenal responsiveness of erythrocyte membranes (ß-APM), which can judge the body's individual sensitivity to ß-adrenoblockers. RESULTS: Sotalol used in the average therapeutic doses of 160-240 mg did not reduce ejection fraction or increase atrioventricular conduction up to abnormal values. In patients with borderline and mild hypertension, the drug lowered blood pressure statistically significantly (p=0.01) and was well tolerated. The drug increased the sensitivity of ß-adrenoblockers in patients with adrenergic AF. CONCLUSION: The effect of sotalol on the autonomic nervous system manifested in the higher power of a high-frequency spectral component of heart rate variability than in that of a low-frequency one. Long-term sotalol administration significantly reduced ß-APM, increasing the sensitivity of adrenoceptors.

Coupling of the Functional Stability of Rat Myocardium and Activity of Lipid Peroxidation in Combined Development of Postinfarction Remodeling and Diabetes Mellitus.

Coupling of the functional stability of rat myocardium and activity of lipid peroxidation processes in combined development of postinfarction remodeling and diabetes mellitus has been studied. The functional stability of myocardium was studied by means of the analysis of inotropic reaction on extrasystolic stimulus, the degree of left ventricular hypertrophy, and the size of scar zone. It was shown that in combined development of postinfarction cardiac remodeling of heart (PICR) with diabetes mellitus (DM) animal body weight decreased in less degree than in diabetic rats. Animals with combined pathology had no heart hypertrophy. The amplitude of extrasystolic contractions in rats with PICR combined with DM had no differences compared to the control group. In myocardium of rats with PICR combined with DM postextrasystolic potentiation was observed in contrast with the rats with PICR alone. The rats with combined pathology had the decreased value of TBA-active products. Thus, the results of study showed that induction of DM on the stage of the development of postinfarction remodeling increases adaptive ability of myocardium. It is manifested in inhibition of increase of LPO processes activity and maintaining of force-interval reactions of myocardium connected with calcium transport systems of sarcoplasmic reticulum of cardiomyocytes.

Lipid peroxidation during cardiac remodeling in 12-month-old rats with experimental infarction.

Blood serum was from 12-month-old Wistar rats with experimental myocardial infarction caused by occlusion of the upper third of the left coronary artery was analyzed. The content of conjugated dienes by the 45th day after primary experimental myocardial infarction returned to normal and did not differ from that in intact animals of the same age group. MDA concentration in rats of the treatment group was lower compared to normal. It was demonstrated that normalization of LPO was accompanied by significant exhaustion of the endogenous antioxidant system (SOD and catalase). Our results suggest that special therapy is required for correction of the endogenous antioxidant defense system.

Rhythmoinotropic myocardial reactions in rats with postinfarction cardiosclerosis against the background of streptozotocin-induced diabetes.

We studied rhythmoinotropic reactions of the myocardium in rats with postinfarction cardiosclerosis and in rats with postinfarction cardiosclerosis against the background of streptozotocin-induced diabetes. Inotropic myocardial response in rats with postinfarction cardiosclerosis was significantly inhibited after rest periods, while in streptozotocin diabetic rats the rhythmoinotropic myocardial reaction was comparable with the reaction of intact myocardium. The combination of postinfarction cardiosclerosis and diabetes paradoxically contributed to preservation of contractile function of the myocardium in rats.

Free radical lipid peroxidation during amiodarone therapy for postinfarction cardiosclerosis.

Postinfarction remodeling of the heart in animals with myocardial infarction was accompanied by activation of lipid peroxidation in myocardial tissue and blood serum and decrease in antioxidant enzyme activity. In animals with postinfarction cardiosclerosis treated with amiodarone, we observed decreased accumulation of lipid peroxidation products and normalization of superoxide dismutase activity.

Cardioprotective effect of trimetazidine during thrombolytic therapy in patients with acute myocardial infarction.

We studied the cardioprotective effect of anti-ischemic drug trimetazidine in the thrombolytic therapy of acute myocardial infarction. Trimetazidine (60 mg/day) effectively inhibits lipid peroxidation and moderates reperfusion damage to the myocardium assessed by ECG, QRS index of damaged heart, and release of creatine phosphokinase into circulation.