[Optimization of lipid-lowering therapy in patients after ischemic stroke. Resolution of the Council of Experts]. / Optimizatsiya gipolipidemicheskoi terapii u patsientov, perenesshikh ishemicheskii insul't. Rezolyutsiya Soveta ekspertov.

Hyperlipidemia is the main risk factor for diseases caused by atherosclerosis including ischemic stroke. This publication provides practical recommendations and an algorithm for prescribing lipid-lowering therapy to post-ischemic stroke patients. The algorithm presents the steps for sequential administration of statins, ezetimibe, and PCSK9 inhibitors to achieve target levels of low-density lipoprotein cholesterol.

[Improvement of outcomes in patients with recent acute coronary syndrome: the place of PCSK9 inhibitors. The Resolution of National Advisory Board].

On April 9, 2018, the national advisory board "Improvement of outcomes in patients with recent ACS: the place of PCSK9 inhibitors" was held in Moscow. Leading Russian experts in the field of atherosclerosis and lipid-lowering treatment attended the board. The purpose of the Board was to determine the place of PCSK9 inhibitors in the improvement of outcomes in patients with recent (less than 1 year) acute coronary syndrome (ACS). During the Board, three major aspects of lipid-lowering treatment were discussed: 1) issues in reaching the target levels of LDL cholesterol in real clinical practice among patients with recent ACS; 2) the results of ODYSSEY OUTCOMES study and their role in the improvement of outcomes in patients with recent ACS; 3) treatment with PCSK9 inhibitors in the management of patients with recent (less than 1 year) ACS in everyday clinical practice, the role of lipid centers.

Specific Lp(a) apheresis: A tool to prove lipoprotein(a) atherogenicity.

BACKGROUND: An elevated lipoprotein(a) (Lp(a)) level is observed in more than 30% of patients with stable ischemic heart disease (SIHD). We conducted an investigation of the effects of specific Lp(a) apheresis on the progression of atherosclerosis in SIHD patients with Lp(a) levels greater than 50 mg/dL. METHODS: We prospectively enrolled 15 patients diagnosed with SIHD based on symptom-driven coronary angiography findings, with Lp(a) ≥50 mg/dL and a low density lipoprotein cholesterol (LDL-C) ≤2.5 mmol/L, who were on long-term statin therapy. They underwent weekly Lp(a) apheresis using Lp(a) Lipopak® adsorption columns which contain monospecific sheep polyclonal antibodies against human Lp(a). Fifteen age and gender matched SIHD patients receiving atorvastatin monotherapy served as controls. At baseline and 18 months post-treatment, quantitative coronary angiography, intracoronary ultrasound with virtual histology and carotid ultrasound were performed. Lipid profile, including Lp(a), was measured at the scheduled visits, and before and after each apheresis procedure. Levels of high-sensitivity C-reactive protein (hsCRP), matrix metalloproteinases (MMP)-7 and 9, and tissue inhibitor of matrix metalloproteinases (TIMP)-1 and 2 were determined at baseline and at the end of the study period. RESULTS: Each specific Lp(a) apheresis procedure was carried out with two adsorption columns resulting in an average acute decrease in Lp(a) levels of 75% (from 110 ± 22 to 29 ± 16 mg/dL) without significant changes in other plasma components. Lp(a) reduction over the course of 18 months was associated with a decrease in the mean percent diameter stenosis of 5.05% and an increase in minimal lumen diameter of 14%; the mean total atheroma volume was reduced by 4.60 mm3 (p < 0.05 for all). There was a decrease in absolute common carotid intima-media thickness in the Lp(a) apheresis group of 0.07 ± 0.15 mm both from baseline and compared with the control group (p = 0.01). Levels of hsCRP were reduced by 40% in patients on Lp(a) apheresis without significant changes in the levels of other biomarkers at the end of the study. CONCLUSION: Reduction of the atherosclerotic burden in coronary and carotid arteries was observed in patients treated with specific Lp(a) apheresis and statin over 18 months compared with statin therapy alone. These findings support the atherogenic role of Lp(a) and reinforce the need to assess the effects of Lp(a)-lowering on cardiovascular events and mortality. Trial Registration Clinicaltrials.gov (NCT02133807).

Specific Lipoprotein(a) apheresis attenuates progression of carotid intima-media thickness in coronary heart disease patients with high lipoprotein(a) levels.

BACKGROUND: To date, there have been no studies evaluating the effect of isolated lipoprotein(a) (Lp(a)) lowering therapy on carotid atherosclerosis progression. METHODS: We enrolled 30 patients who had coronary heart disease (CHD) verified by angiography, Lp(a) level ≥50 mg/dL, and low density lipoprotein cholesterol (LDL-C) level ≤2.6 mmol/L (100 mg/dL) on chronic statin therapy. Subjects were allocated in a 1:1 ratio to receive apheresis treatment on a weekly basis with immunoadsorption columns ("Lp(a) Lipopak"(®), POCARD Ltd., Russia) added to atorvastatin, or atorvastatin monotherapy. The primary efficacy end-point was the change from baseline in the mean intima-media thickness (IMT) of the common carotid arteries. RESULTS: After one month run-in period with stable atorvastatin dose, LDL-C level was 2.3 ± 0.3 mmol/L and Lp(a) - 105 ± 37 mg/dL. As a result of acute effect of specific Lp(a) apheresis procedures, Lp(a) level decreased by an average of 73 ± 12% to a mean of 29 ± 16 mg/dL, and mean LDL-C decreased by 17 ± 3% to a mean of 1.8 ± 0.2 mmol/L. In the apheresis group, changes in carotid IMT at 9 and 18 months from baseline were -0.03 ± 0.09 mm (p = 0.05) and -0.07 ± 0.15 mm (p = 0.01), respectively. In the atorvastatin group no significant changes in lipid and lipoprotein parameters as well as in carotid IMT were received over 18-month period. Two years after study termination carotid IMT increased by an average of 0.02 ± 0.08 mm in apheresis group and by 0.06 ± 0.10 mm in the control group (p = 0.033). CONCLUSION: Isolated extracorporeal Lp(a) elimination over an 18 months period produced regression of carotid intima-media thickness in stable CHD patients with high Lp(a) levels. This effect was maintained for two years after the end of study. TRIAL REGISTRATION: Clinicaltrials.gov (NCT02133807).

[Dynamics of ECG voltage in changing gravity].

Comparative analysis of the QRS voltage response to gravity variations was made using the data about 26 normal human subjects collected in parabolic flights (CNERS-AIRBUS A300 Zero-G, n=23; IL-76MD, n=3) and during the tilt test (head-up tilt at 70 degrees for a min and head-down tilt at-15 degrees for 5 min, n=14). Both the parabolic flights and provocative tilt tests affected R-amplitude in the Z lead. During the hypergravity episodes it was observed in 95% of cases with the mean gain of 16% and maximal--56%. On transition to the horizontal position, the Rz-amplitude showed a rise in each subject (16% on the average). In microgravity, the Rz-amplitude reduced in 95% of the observations. The voltage decline averaged 18% and reached 49% at the maximum. The head-down tilt was conducive to Rz reduction in 78% of observations averaging 2%. Analysis of the ECG records under changing gravity when blood redistribution developed within few seconds not enough for serious metabolic shifts still revealed QRS deviations associated exclusively with the physical factors, i.e., alteration in tissue conduction and distance to electrodes. Our findings can stand in good stead in evaluation of the dynamics of predictive ECG parameters during long-term experiments leading to changes as in tissue conduction, so metabolism.

ECG voltage modifications as response to gravity changes.

The aim of the study was to analyze ECG (QRS) voltage responses to body fluid shift due to gravity chances. Acute changes in gravity were created by two ways: 1) changes in gravity value during parabolic flights (within 27 subjects 45 ECG have been analyzed); 2) changes in gravity direction due to rotation of the body during postural tests (within 11 subjects 14 ECG have been analyzed). Results and conclusions. Gravity change leads to body fluid shift and changes of intrathoracic organs and tissues electroconduction. It influences on ECG voltage. During parabolic flights in up-right position: R amplitude in Z axis increases in hypergravity (+0.19 mV) and decreases in microgravity (-0.24 mV). During postural tests, R amplitude in Z axis increases in orthostatic position (+0.09 mV) and decreases in antiorthostatic position (-0.025 mV). Changes in QRS voltage during parabolic flights are more important than during postural tests. This could be due to more effective blood redistribution during parabolic flights.

[Apheresis of immunoglobulins - new approach to the treatment of severe dilated cardiomyopathy]. / Aferez immunoglobulinov - novyi podkhod k lecheniiu tiazhelykh form dilatatsionnoi kardiomiopatii.

Two courses of immunoadsorption with 'Ig Adsopak' were used in the treatment of a patient with dilated cardiomyopathy (DCM) during which all class G and partially class M and A immunoglobulins were removed. Every course consisted of 5 daily procedures and resulted in removal of 98% of immunoglobulins. This was associated with complete removal of autoantibodies to beta1-adrenoreceptor. After the end of a course loss of immunoglobulins was replenished by intravenous infusion of Pentaglobin and Oktagam. Echocardiographic study carried out before, during and after second course of apheresis revealed reduction of left and right ventricular and atrial volumes and dimensions, improvement of contractility of anterior part of interventricular septum and of anterolateral left ventricular wall. As efficacy of drug therapy of dilated cardiomyopathy is low and facilities of cardiac transplantation are limited the method of therapeutic apheresis reveals novel perspectives of the treatment of dilated cardiomyopathies.

Development of immunosorbents for apoB-containing lipoproteins apheresis.

Three types of sorbents were developed for the specific removal of atherogenic apoB-containing low-density lipoprotein (LDL) and lipoprotein LDL (a) (Lp[a]) from human plasma. Two sorbents contained monospecific sheep polyclonal or mouse monoclonal antibodies against human apoprotein B-100. The third one was intended for specific removal of Lp(a) and contains sheep antibodies against human Lp(a). Thirty patients were treated for up to 9 years by LDL apheresis with anti-LDL immunosorbents. A pilot study of Lp(a) apheresis with 3 patients was conducted during 3 years. The results showed that extracorporeal immunosorption is safe and effective for lowering LDL and Lp(a). These procedures may be used both for metabolic investigations and for studies on possible regression of atherosclerosis.

[Characteristics of neurovirulence, stability, and immunogenicity of attenuated variants of TP-21 Langat virus]. / Kharakteristiki neirovirulentnosti, stabil'nosti i immunogennosti oslablennykh variantov virusa Langat TP-21.

Clones of Langat TP-21 virus with neurovirulence for primates much lower than that of Elantsev 15-20/3 strain may be obtained by threshold dilutions method on mice. Neurovirulence for monkeys of L1-L5 clones of Langat TP-21 virus obtained at our laboratory was similar to neurovirulence of A.Sabin's type III vaccinal poliomyelitis virus. Attenuated clones of Langat virus are stable and retain protective properties in experiments with mouse protection from pathogenic viruses of tick-borne encephalitis complex.

[The neurovirulence of variants of the Langat TP-21 virus in experiments on different species of lower monkeys]. / Neirovirulentnost' variantov virusa Langat TP-21 v opytakh na nizshikh obez'ianakh raznykh vidov.

Neurovirulence of the attenuated strains of Langat TP-21 virus was tested in monkeys of 5 species: M. mulatta, M. fascicularis, M. nemestrina, C. aethiops, and P. hamadryas. The individual susceptibility of the animals to the infection varied but there was no difference in species susceptibility. The monkeys were more susceptible to intraspinal than to intrathalamic inoculations. The animals not adapted to the laboratory conditions were more susceptible to infection than the adapted ones. The lesions in the spinal cord were the most informative pathomorphological data for differentiation of attenuated strains of Langat TP-21 virus.

[Study of the effect of the cDNA for the human apolipoprotein A-I gene in transgenic rabbits: modeling the neurological syndrome of human Tangier disease]. / Issledovanie na transgennykh krolikakh deistviia kDNK gena apolipoproteid A-I cheloveka: modelirovanie neirologicheskogo sindroma tenzhirskoi bolezni cheloveka.

Two transgenic rabbits which carried human apolipoprotein A-1 (apo A-1) cDNA under mouse ribosomal protein L/32 promoter were obtained. The effectiveness of transgenosis was confirmed by DNA dot/blot and Southern blot hybridizations. Both transgenic animals had paralyses of fore or fore and high limbs. Electron microscopy demonstrated distinct degradative changes of those parts of spinal cord which were responsible for leg skeletal muscle innervation. RNA dot/blot hybridization showed transgene expression in liver and brain but not in kidney of adult transgenic animal. However, analysis of blood serum lipids and immunochemical determinations gave no indications of the presence of human apo A-1 in adult transgenic rabbit. The data obtained allow us to suggest that the observed pathology was due to interference of native and foreign protein products of apo A-1 gene expression in CNS in the course of embryo development. This suggestion was supported by results of in situ hybridization of 5- and 9-week human embryo sections with apo A-1 cDNA, showing effective expression of apo A-1 gene in neural cells of CNS. Results of transgenosis may be viewed as modeling of the neurological syndrome of human Tangier disease.

C3a and C5a anaphylatoxins bind to heparin-based sorbent in low density lipoprotein apheresis: in vitro and in vivo investigations.

Plasmasorption on a heparin-based sorbent was performed in vitro. It demonstrated affinity of the C3a and C5a anaphylatoxins for the sorbent: C3a was removed almost completely (97%), and the C5a concentration decreased on average by 55%. The plasma level of C3a and C5a complement components was also monitored during the procedure of clinical extracorporeal low density lipoprotein (LDL) apheresis on the sorbent in patients with familial hypercholesterolemia. A two- to threefold increase in C3a (up to 1,500 ng/ml) was observed after plasma separation by the IBM 2997 cell sorter. Subsequent processing of the plasma through the column led to the low level of C3a detected (less than 50 ng/ml), demonstrating significant uptake of C3a by the sorbent column. The removed C3a was found in the eluate obtained after regeneration of the sorbent with 2 M NaCl solution. No significant increase in C5a was found during the procedure. Nevertheless, some C5a was detected in the eluate from the sorbent. The content of C3a and C5a in patients blood after the treatment was approximately the same as it was initially, 200-500 ng/ml for C3a and less than 10 ng/ml for C5a. The removal of C3a and C5a anaphylatoxins by heparin-based sorbent should be regarded as an advantage of this type of plasmasorbent.

[Specific plasma sorption of proteinases--a new approach to the treatment of acute pancreatitis]. / Spetsificheskaia plazmosorptsiia proteinaz--novyi podkhod k lecheniiu ostrogo pankreatita.

The authors treated destructive forms of acute pancreatitis for the first time by means of specific plasma sorption of proteinases with the use of a proteinase plasma sorbent which is an acid-stable proteinase inhibitor immobilized on sepharose (ASI-Sepharose). Specific plasma sorption of proteinases on ASI-Sepharose was applied to the treatment of 29 patients with various forms of acute destructive pancreatitis. At the end of specific plasma sorption procedure the activity of blood plasma proteolytic enzymes in the patients reduced by 60-75%, which was attended by marked improvement of the condition in most cases; aggravation of the patients' condition was not encountered. The mortality in this group was 20.7% and was due to complications occurring during the development of the main disease. The mortality rate among patients treated by specific proteinase plasma sorption is much lower than that recorded in the USSR for destructive forms of acute pancreatitis which ranges from 30 to 75%.

[The dynamics of the concentrations of immunoglobulins and circulating immune complexes during low-density lipoprotein apheresis in patients with hereditary hypercholesterolemia]. / Dinamika kontsentratsii immunoglobulinov i tsirkuliruiushchikh immunnykh kompleksov v protsesse afereza lipoproteidov nizkoi plotnosti u bol'nykh nasledstvennoi giperkholesterinemiei.

Sessions of-low density lipoproteins (LDL) apheresis using sorbents with mono- and polyclonal antibodies possessing the most selective and specific effect with respect to LDL provoked a less marked decrease of the concentrations of immunoglobulins and circulating immune complexes. This attests to their high selectivity and specificity. Sorbents with dextran sulfate and heparin sepharose exerted a more evident influence on the concentrations of these serum components. However, that was not accompanied by any clinical manifestations of immune deficiency. The use of plasmapheresis brought about a more pronounced lowering of the concentrations of the serum components under study.