[Duration of Dual Antiplatelet Therapy in Patients With Ischemic Heart Disease After Implantation of Endovascular Stents].

Optimal duration of dual antiplatelet therapy (DAPT) after stent implantation is uncertain. Some patients have an extended risk of thrombotic complications including that of very late stent thrombosis after cessation of recommended course of DAPT (6-12 months). On the other hand, there is a real risk of bleeding on DAPT. In this review, we present and discuss results of clinical trials of long-term DAPT and data of their meta-analyses. The review also contains consideration of some aspects of new AHA/ACC recommendations (2016) on duration of DAPT.

[Antioxidant and antiaggregant effects of covalent bienzyme superoxide dismutase-chondroitin sulfate-catalase conjugate in platelet interactions].

A covalent bienzyme superoxide dismutase-chondroitin sulfate-catalase conjugate (SOD-CHS-CAT) demonstrated the dose-dependent inhibitory action on induced aggregation of platelets in the presence of hydrogen peroxide. Antioxidant activity of SOD-CHS-CAT appeared at much lower doses than for other CAT derivatives. We detected the antiaggregation effect of SOD-CHS-CAT for platelet aggregation induced by ADP, serotonin, TRAP (with their different mechanism of action). Novel properties of SOD-CHS-CAT confirmed with its action agains spread-eagle platelets on glass surface. The new characteristics of SOD-CHS-CAT conjugate underline the prospects of its biopharmaceutical development for antioxidant therapy.

Effect of hydrogen peroxide and catalase derivatives on functional activity of platelets.

Effects of H(2)O(2) on platelet aggregation were estimated in vitro in the presence and absence of inductors (ADP, serotonin, TRAP) and native and modified catalase. Dose-dependent effect of H(2)O(2) (50 µM or more) was investigated in a pathophysiological concentration of 300 µM inducing platelet aggregation. H(2)O(2) modulated aggregation induced by ADP, serotonin, and TRAP significantly increasing the initial platelet aggregation followed by disaggregation, which was always more pronounced than in control. Catalase derivatives (native and modified forms) dose-dependently reduced the effect of H(2)O(2) and completely abolished it in a dose of 9000 U catalase activity per 1 ml of solution for native catalase and 1200 U/ml for modified one. Modified catalase, in contrast to native one, produced an independent inhibitory effect on induced platelet aggregation. Components of modified catalase (individual substance and simple mixture) had no antiaggregant effect.

Biopharmacology of enzyme conjugates: vasoprotective activity of supramolecular superoxide dismutase-chondroitin sulfate-catalase derivative.

Bienzyme conjugate was obtained by the covalent connection of superoxide dismutase with catalase through endothelial glycocalyx glycosaminoglycan - chondroitin sulfate (SOD-CHS-CAT). This SOD-CHS-CAT conjugate has vasoprotective activity in respect to platelet interactions, tonus of the ring arterial fragment of a rat blood vessel, as well as normalization of hemodynamic parameters in rats and rabbits in conditions of oxidative stress caused by the administration of hydrogen peroxide. The SOD-CHS-CAT conjugate had antiplatelet potential due to its antiaggregation action manifested through the combination of enzyme activities and an acquired supramolecular structure. The influence on arterial fragment tonus was equivalent for SOD and CAT in native and conjugated form. Blood pressure and heart rate were significant and effectively normalized with SOD-CHS-CAT conjugate in rats and rabbits (after hydrogen peroxide administration as a perturbance stimulus). We have discovered the possibility of using the antioxidant bienzyme conjugate in chronic prophylaxis. It is important for a real development of the oral form of the SOD-CHS-CAT conjugate. These results indicate that the development of enzyme conjugates can be medically significant, as a promising approach for the creation of new drugs.

[Disturbances of primary hemostasis in patients with dilation cardiomyopathy].

We studied morphological characteristics of platelets and parameters of platelet aggregation in patients with dilation cardiomyopathy. Augmented aggregatory activity of platelets was found in 76% of patients. In blood of majority of patients we found circulating leukocyte-platelet aggregates. This evidenced for development of inflammatory process and could be related to disturbances of blood rheology. In 2 patients examined by virusological method we revealed presence of a virus inside platelets. This phenomenon might serve as one of possible pathological pathways of disease progression at the account of spread of viral infection along vascular bed during thrombus formation.

[Difficulties in evaluating the efficacy of antiplatelet therapy in clinical practice].

AIM: To evaluate platelet activity changes in patients with coronary artery disease (CAD) treated with aspirin, clopidogrel and combination of these drugs; to estimate the rate of resistance of CAD patients to antiplatelet treatment. MATERIAL AND METHODS: 199 patients with stable CAD were included in the study. Of them, 83 were given aspirin, 46 received clopidogrel, 34--double antiplatelet therapy (both aspirin and clopidogrel). The trial also studied an additional group of 18 CAD patients on double antiplatelet therapy who had hemorrhages. The control group consisted of 25 healthy volunteers. Platelet aggregation was measured both by a mean size of aggregates (MSA) and light transmission (LTM, Born method) using BIOLA platelet aggregation analyzer. A platelet shape, leukocyte-platelet aggregates (LPA) and erythrocyte-platelet aggregates (EPA) in the whole blood were studied using scanning electron microscopy. The levels of IL-6 and sVCAM were also measured. RESULTS: It was found that 59.8% patients with CAD had high platelet reactivity revealed in 94.9% of cases by measuring spontaneous and induced by 0.1 mcM ADP platelet aggregation. LTM revealed increased platelet reactivity only in 10.7% patients. Resistance to aspirin correlated with the presence of LTA (r = 0.629, p = 0.0001) and the number of large "reticulated" platelets (r = 0.334, p = 0.001). Low platelet reactivity was associated with the presence of circulating EPA (r = -0.362, p = 0.008). Administration of clopidogrel did not decrease platelet reactivity to normal levels in 34.7% patients which correlated with the presence of LPA and EPA. In 83.3% patients with hemorrhages platelet aggregation, induced by 5.0 mcM, ADP was dramatically decreased. CONCLUSION: Resistance to antiplatelet therapy is related to platelet heterogeneity, the presence of inflammation and state of erythrocytes. LT is capable to reveal only a part of patients resistant to antiplatelet drugs. To fully identify these patients, it is necessary to register spontaneous platelet aggregation and aggregation induced by low doses of ADP. Redundant inhibition of platelet reactivity could be the cause of hemorrhagic events.

Participation of IIb-IIIa glycoprotein in spontaneous platelet aggregation.

In some patients with stable and unstable angina pectoris and in some donors without clinical manifestations of cardiovascular diseases and other pathologies, spontaneous platelet aggregation was completely suppressed by glycoprotein IIb-IIIa antagonists blocking the interaction of this glycoprotein with fibrinogen. Antibodies inhibiting binding of glycoprotein Ib with von Willebrand factor had no effect on the level and rate of spontaneous platelet aggregation. In the donor group, the level of spontaneous aggregation was almost 1.5-fold higher in persons with a certain genetic polymorphism (Leu-->Pro substitution in position 33 of glycoprotein IIIa). The level of spontaneous aggregation correlated with the amount of glycoprotein IIb-IIIa on the platelet surface (r = 0.41).

[Platelet activation and inflammation markers in patients with coronary heart disease and depression].

AIM: To study morphological features and functional activity of platelets, their relations with the level of inflammation markers in coronary heart disease (CHD) patients with depression. MATERIAL AND METHODS: The study group consisted of 33 CHD patients with stable effort angina (NY-HA FC I-III), 14 had depression, 19 were free of depression. Sixteen healthy volunteers comprised the control group. Platelet aggregation was registered by a mean size of aggregates and turbidometrically. Platelets shape, leukocytic-thrombocytic and erythrocytic-thrombocytic aggregates (LTA, ETA) in the whole blood were studied electron-microscopically. The levels of IL-2, IL-6, TNF-alpha, sVCAM, hsCRP were measured in the blood, serotonin--in platelets. RESULTS: Spontaneous aggregation enhanced in 52.6% CHD patients (p < 0.05). The blood contained reticular platelets, high number of prothrombocytes (p < 0.05), mean volume of thrombocytes was greater (p < 0.05). This reflected changes in megakaryocytopoiesis. Some of the patients had LTA and ETA. Out of inflammation markers, only IL-6 and sVCAM were elevated (p < 0.01), hsCRP concentration rose, but not above normal range. Serotonin in platelets was the same in the patients and controls. Depression aggravated the disorders and elevated other indices. Spontaneous aggregation was high in 71.4% of depressive CHD patients. The count of reticular platelets, prothrombocytes, mean volume platelets were also elevated. LTA and ETA were high in all the depressive patients. Elevated were also concentrations of IL-6, sVCAM, IL-2, hsCRP. Serotonin in platelets was low (p < 0.05). CONCLUSION: Depression stimulates functional activity of platelets, is a factor of risk of intravascular inflammation and contributes to development of thrombotic complications in CHD patients.

[Methodologic features of determining renin-like activity in human arteries]. / Metodicheskie osobennosti opredeleniia reninopodobnoi aktivnosti arterii cheloveka.

Human arterial tissue was shown to have renin-like activity. For its determination the authors propose methodological approaches. The optimum pH of renin activity in the vascular wall was found to be 5.8-6.0. The renin-like enzyme was ascertained to be present in the vascular wall as inactive and to be activated by trypsin. The renin activity was compared in the human vascular wall and human plasma. Their optimum pHs were nearly identical. The methodological features determined in this paper allowed one to differentiate the true renin-like activity from the activity of acid proteases.

[Various aspects of surgical treatment of vasorenal hypertension]. / Nekotorye aspekty khirurgicheskogo lecheniia vazorenal'noi gipertenzii.

The results of examination and treatment by surgery of 103 patients with vasorenal hypertension are analysed. Retromboses and restenoses of the reconstructed renal arteries and grafts and uncorrected hyperaldosteronism were the most frequent causes of the poor results. Adequate reconstruction of the renal arteries leads to correction of hyperaldosteronism in patients with normal or high activity of plasma renin. Low-renin secondary hyperaldosteronism in patients with vasorenal hypertension is an indication for simultaneous correction.

[Significance of single-dose captopril test in the differential diagnosis of primary aldosteronism]. / Znachenie testa s odnorazovym priemom kaptoprila v differentsial'noi diagnostike pervichnogo al'dosteronizma.

The captopril test was used to make a differential diagnosis of various types of primary aldosteronism. After captopril, there was no change in the activity of the renin-angiotensin-aldosterone system only in the group of patients with aldosterone-producing adenomas in a histological variant of "adenoma and atrophy". The findings suggest that aldosterone secretion regulation is autonomic in the adenoma unassociated with the function of the renin-angiotensin-aldosterone system only in the case of isolated adenoma with a histological variant of adenoma and atrophy. In patients with aldosterone-producing adenomas in the presence of the variant "adenoma and hyperplasia", aldosterone secretion retains sensitivity to the renin-angiotensin-aldosterone system as in patients with idiopathic hyperplasia and hypertensive disease, which indicates that it is possible to differentiate isolated "adenoma and atrophy" from hypertensive disease and idiopathic hyperplasia, despite its combination with tumor by using the captopril test.

[Correlation of the total activity of blood plasma renin with levels of active and inactive renin, angiotensinogen and angiotensin II under different functional loads in patients with hypertension]. / Sootnoshenie obshchei aktivnosti renina plazmy krovi, soderzhaniia aktivnogo i neaktivnogo renina, angiotenzinogena i angiotenzina II pri razlichnykh funktsional'nykh nagruzkakh u bol'nykh gipertonicheskoi bolezn'iu.

Components of the renin-angiotensin system (plasma renin activity, total and inactive renin, angiotensinogen and angiotensin II) were examined in 90 patients with labile and stable essential hypertension before and after functional and pharmacologic tests. New data have been obtained on intrasystemic regulatory mechanisms of the pressor renin-angiotensin systems. Different patterns of plasma active and inactive renin variations in response to salt loading are demonstrated in patients with different "renin" variants of essential hypertension. Angiotensin II is shown to have a stimulating effect on angiotensinogen synthesis.

[Mechanisms of the hypotensive action of captopril in essential hypertension]. / Mekhanizmy gipotenzivnogo deistviia kaptoprila pri gipertonicheskoi bolezni.

Captopril effects were studied in 27 patients with second-stage essential hypertension following administration of a single 25 mg oral dose of the drug. Blood pressure (BP), blood angiotensin-1-converting enzyme (ACE) activity, active (APR) and inactive (IPR) plasma renin levels were measured every 30 minutes for 3 hours. Before and near the end of the acute test, urinary kallikrein and catecholamine excretions were measured, and systemic and regional hemodynamic changes assessed. BP decreased in 21 patients: 11 of those had low basal APR (group 1), and 10 had normal or moderately elevated APR (group 2). The greatest hypotensive effect was observed within 1.5 hours after the administration, coinciding with the most marked ACE inhibition. There was no significant intergroup difference with respect to the extent of the hypotensive effect. No correlation was found between the hypotensive effect and the degree of ACE inhibition. All patients showed significantly decreased arteriolar tone, increased venous distensibility, decreased total peripheral resistance, and expanded end diastolic volume, while their cardiac output and heart rate remained unaffected. Hypertensive patients with low APR gave no evidence of renin-angiotensin inhibition or kallikrein-kinin activation that might have accounted for the hemodynamic effect of captopril.

[Comparative evaluation of the efficacy of methods of cryo- and trypsin activation of inactive renin in vitro]. / Sravnitel'naia otsenka éffektivnosti metodov krio- i tripsinovoi aktivatsii neaktivnogo renina in vitro.

The total renin activity (TRP) and inactive renin levels (IR) in the blood plasma were examined with the help of cryo- and trypsin activation in 9 normal subjects, in 40 patients with essential hypertension and in 18 patients with primary aldosteronism (PA). The cryoactivation method was shown to detect 40-80% of IR determined by the method of trypsin activation. Both methods revealed analogous ratios of the two renin forms in its total production in the presence of essential hypertension (in different "renin" subgroups) and arterial hypertension secondary to PA and may be used as the methods of choice when examining essential hypertension patients with the normal and subnormal plasma renin activity. The method of trypsin activation is more preferable for a more accurate quantification of small amounts of IR found in essential hypertension patients with a high plasma renin activity. With a high level of the TRP (over 8 ng/ml/h) activation should be performed in diluted plasma.

[Concentration of adrenocorticotrophic hormone and aldosterone secretion in essential hypertension and hyperaldosteronism]. / Soderzhanie adrenokortikotropnogo gormona i sekretsiia al'dosterona pri gipertonicheskoi bolezni i giperal'dosteronizme.

The authors studied the effect of adrenocorticotropic hormone (ACTH), potassium and plasma renin activity on blood aldosterone in normal subjects as well as in patients with essential hypertension (of a labile and stable course) and hyperaldosteronism (primary and idiopathic). It was demonstrated that in normal subjects and patients with labile essential hypertension, the secretion of aldosterone was simultaneously stimulated by the renin-angiotensin system (RAS) and the hypothalamus-adenopituitary. The RAS dominated in normal conditions whereas in labile hypertension the hypothalamus-adenopituitary system was predominant. In stable hypertension, the RAS and hypothalamus-pituitary influenced aldosterone secretion in an equal degree. Hyperaldosteronism was associated with the most pronounced deviations in the relationship between stimulants and aldosterone. In addition to decreased plasma levels of renin activity and potassium, the corticotropic activity of the hypothalamus-adenopituitary was increased during the first 10 years of the disease, while later on the function of this system became inhibited. The highest ACTH levels were recorded in idiopathic hyperaldosteronism.

[Endogenic activation of prorenin in hypertension]. / Ob endogennoi aktivatsii prorenina pri gipertonicheskoi bolezni.

Two forms of renin (active-APR and inactive-IPR) and its total production were studied in relation to the daily excretion of kallikrein in patients with essential hypertension of the labile and the stable stage at rest and following the stimulation by an hour's walk and the intravenous infusion of prostaglandin E (PGE). The results showed inverse correlations of APR and IPR in the total production of renin in hypertensive patients in different "renin" subgroups, and an inverse correlation between the level of IPR and the 24-hour excretion of kallikrein in the basal conditions and following an hour's walk. PGE infusion elevated APR and decreased IPR levels, leaving the total production of renin unchanged. The level of kidney kallikrein was inversely correlated with IPR and directly correlated with APR. The findings suggested the involvement of kidney kallikrein in the endogenic activation of prorenin.