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Aim To study the relationship of the platelet function and plasma homeostasis with the blood flow in the infarct-related artery (IRA) and with the course of acute myocardial infarction (AMI).Material and methods This study included 93 patients with AMI (75 patients with ST-elevation AMI and 18 patients without ST segment elevation). 63 patients had TIMI 0-1 blood flow in the IRA and 30 patients had TIMI 2–3. Rotational thromboelastometry, impedance aggregometry, the endothelium-dependent vasodilation (EDVD) test, and the thrombodynamics test were performed for all patients. The primary clinical endpoint included the totality of in-hospital complications of AMI, and the secondary endpoint included the totality of out-of-hospital complications of AMI. Major bleedings (BARC 3-5) and minor bleedings (BARC 1-2) were evaluated separately.Results Patients with IRA TIMI 0–1 flow were characterized by a shorter blood clotting time (BCT), larger thrombus size and density, more intense platelet aggregation induced by arachidonic acid and ADP, and lower values of the EDVD test. It was found that the parameters of platelet aggregation induced by arachidonic acid (AUC Asa) in combination with BCT allowed assessment of the severity of IRA blood flow disorder (sensitivity 76 %, specificity 71 %) in patients with AMI, regardless of the presence of ST segment elevation on the ECG. In addition, the incidence of the primary endpoint was greater in patients with IRA TIMI 0–1 flow (41.3% and 16.7%, respectively; p=0.015). In patients with TIMI 2–3 flow in the long-term period of the disease, the incidence of minor bleedings was significantly higher (8.5% and 30.4 %, respectively; p=0.045).Conclusion Compared to patients with preserved blood flow, patients with AMI and IRA TIMI 0–1 flow are characterized by endothelial dysfunction and more intense processes of thrombogenesis and platelet aggregation. It has been shown for the first time that the combination of two simple criteria for assessing hemostasis (AUC Asa; BCT) allows assessment of the degree of IRA blood flow disorder in patients with AMI.

Thrombin is a key regulator of the homeostasis system. Also, it actively participates in progression of various systemic diseases, including atherosclerosis. There is a large amount of experimental and clinical data on the involvement of thrombin in the pathogenesis of ischemic heart disease (IHD). Thus, studying thrombin activity regulation is promising. Also, the question whether it is possible to use biomarkers of thrombin activity as predictors of cardiovascular complications in IHD patients is relevant. The present review focuses on major mechanisms of thrombin functioning, its role in development and progression of atherosclerosis, and available tests for evaluation of thrombin functional activity. Major clinical studies are discussed that evaluated the efficacy of thrombin inhibitors and protease-activated receptor antagonists.

A case of successful treatment for syncopal episodes caused by intermittent atrioventricular block in a patient with paroxysmal atrial fibrillation/atrial flutter using cardioneuroablation is presented.

Cardiogenic shock (CS) is one of the main causes of death in patients with acute myocardial infarction (AMI). Mortality from CS remains high, despite the introduction of myocardial revascularization and the use of modern medication. The use of mechanical circulatory support (MCS) is promising, it could reduce mortality in patients with AMI and CS.To define effectiveness and safety of MCS in patients with AMI and CS.Our study includes 47 patients with AMI and refractory CS, who were treated at the University Clinic of Cardiology of the Yevdokimov Moscow State University of Medicine and Dentistry from 2019 to 2022. Mortality and various complications were analyzed in patients with refractory CS, patients who received and did not receive mechanical circulatory support (intra-aortic balloon pump IABP, extracorporeal membrane oxygenation ECMO).Mortality among patients with refractory CS was significantly lower in the subgroup of patients who received mechanical circulatory support devices (59% vs 93%; p=0.02). Moreover, reliability is achieved mainly due to patients in whom were VA-ECMO implanted (p=0.02), not IABP (p=0.16).VA-ECMO associated with reduced mortality and should be considered in patients with AMI and refractory CS. Further research is needed to select the optimal method of mechanical circulatory support in patients with CS.Кардиогенный шок (КШ) основная причина летального исхода у пациентов с острым инфарктом миокарда (ОИМ). Смертность от КШ остается высокой, несмотря на широкое использование реваскуляризации миокарда и применение современных препаратов. Устройства механической поддержки гемодинамики являются наиболее перспективным вариантом снижения летальности пациентов с КШ. Цель. Изучить эффективность и безопасность методов механической поддержки кровообращения (МПК) у пациентов с ОИМ и рефрактерным КШ. Материалы и методы. В исследование включили 47 пациентов с ОИМ и рефрактерным КШ, проходивших лечение в ГБУЗ ГКБ им. И.В. Давыдовского с 2019 по 2022 г. Из всех участников 32 использовали МПК (10 внутриаортальную баллонную контрпульсацию ВАБК, 32 вено-артериальную экстракорпоральную мембранную оксигенацию ВА-ЭКМО). Проанализирована летальность и внутригоспитальные осложнения у пациентов с рефрактерным КШ в зависимости от использования МПК и ее вида. Результаты. Пациенты с рефрактерным КШ, которым проводили МПК, характеризовались достоверно меньшей летальностью (59,0% vs 93,3%; p=0,02). Данный эффект достигнут преимущественно за счет подгруппы, в которой применяли ВА-ЭКМО (59,0% vs 93,0%; p=0,02), а не ВАБК (70,0% vs 93,3%; p=0,16). Заключение. У пациентов с ОИМ и рефрактерным КШ имплантация системы ВА-ЭКМО уменьшает летальность. Необходимы дальнейшие исследования для оптимизации алгоритма МПК у пациентов с КШ.

Analysis of the dynamics of different stages of clot formation and its lysis in patients with different COVID-19 severity.We prospectively included 58 patients with COVID-19 (39 patients with moderate disease severity and 18 patients with severe disease) and 47 healthy volunteers as a control group. All participants underwent the assessment of flow-mediated dilation (FMD) of brachial artery, impedance aggregometry, rotational thromboelastometry and thrombodynamics. Von Willebrand factor antigen (vWF:Ag) quantification was also performed in patients with COVID-19. Measurements were repeated on the 3rd and 9th day of hospitalization.Compared to the control group, patients with COVID-19 showed reduced values of platelet aggregation and greater values of the clot growth rate, as well as its size and density. On the first day of hospitalization, we found no differences in the activity of plasma hemostasis and endogenous fibrinolysis between subgroups of patients. With the progression of the disease, the growth rate and size of the clot were higher in the severe subgroup, even despite higher doses of anticoagulants in this subgroup. An increase in platelet aggregation was noted during the progression of the disease, especially in the severe subgroup. There were no differences in the results of the FMD test by subgroups of patients. The vWF:Ag level was significantly higher in the severe subgroup.Thus, plasma hemostasis followed by secondary platelet activation correlates with the severity of COVID-19. Patients with moderate to severe coronavirus infection have predominantly local rather than generalized endothelial dysfunction.Цель. Анализ динамики разных этапов образования тромба и его лизиса у пациентов с различной тяжестью течения COVID-19. Материалы и методы. Произведен анализ образцов 58 пациентов с COVID-19 (39 больных со средней тяжестью течения и 18 человек с тяжелым течением) и 47 здоровых добровольцев. Всем участникам проведены тест эндотелий-зависимой вазодилатации (ЭЗВД) плечевой артерии, импедансная агрегометрия, ротационная тромбоэластометрия и тест тромбодинамики. Пациентам с COVID-19 также выполнено измерение антигена фактора фон Виллебранда (ффВ:Аг). Измерения проводили в динамике на 3 и 9-й день госпитализации. Результаты. По сравнению с контрольной группой у пациентов c COVID-19 выявлены сниженные значения агрегации тромбоцитов и большие значения скорости роста сгустка, а также его размера и плотности. В 1-й день госпитализации не обнаружено различий в активности плазменного гемостаза и эндогенного фибринолиза между подгруппами пациентов. С течением заболевания скорость роста и размер тромба оказались выше в подгруппе тяжелого течения, даже несмотря на более высокие дозы антикоагулянтов у этой подгруппы больных. Зафиксирован рост агрегации тромбоцитов в ходе заболевания, особенно в подгруппе тяжелого течения. Различий в результатах теста ЭЗВД между подгруппами пациентов не зарегистрировано. Уровень ффВ:Аг был статистически значимо выше в подгруппе тяжелого течения. Заключение. Показано, что плазменный гемостаз с последующей вторичной активацией тромбоцитов коррелируют с тяжестью течения заболевания COVID-19. У пациентов со средним и тяжелым течением коронавирусной инфекции имеется преимущественно локальная, нежели генерализованная эндотелиальная дисфункция.

Coronavirus disease 2019 (COVID-19) is characterized by immune activation in response to viral spread, in severe cases leading to the development of cytokine storm syndrome (CSS) and increased mortality. Despite its importance in prognosis, the pathophysiological mechanisms of CSS in COVID-19 remain to be defined. Towards this goal, we analyzed cytokine profiles and their interrelation in regard to anti-cytokine treatment with tocilizumab in 98 hospitalized patients with COVID-19. We performed a multiplex measurement of 41 circulating cytokines in the plasma of patients on admission and 3–5 days after, during the follow-up. Then we analyzed the patient groups separated in two ways: according to the clusterization of their blood cytokines and based on the administration of tocilizumab therapy. Patients with and without CSS formed distinct clusters according to their cytokine concentration changes. However, the tocilizumab therapy, administered based on the standard clinical and laboratory criteria, did not fully correspond to those clusters of CSS. Furthermore, among all cytokines, IL-6, IL-1RA, IL-10, and G-CSF demonstrated the most prominent differences between patients with and without clinical endpoints, while only IL-1RA was prognostically significant in both groups of patients with and without tocilizumab therapy, decreasing in the former and increasing in the latter during the follow-up period. Thus, CSS in COVID-19, characterized by a correlated release of multiple cytokines, does not fully correspond to the standard parameters of disease severity. Analysis of the cytokine signature, including the IL-1RA level in addition to standard clinical and laboratory parameters may be useful to define the onset of a cytokine storm in COVID-19 as well as the indications for anti-cytokine therapy.

Objective: to assess results from the Stroke Network created on the basis of the Infarction Network in the metropolis Moscow for endovascular treatment in patients with occlusion of the large cerebral artery (the internal carotid artery, the M1 and M2 segments of the middle cerebral artery, and the main artery).Patients and methods. A total of 742 thromboextractions were performed in patients with ischemic stroke in Moscow Stroke Network hospitals in 2019. The final analysis included 729 patients aged 25 to 97 years (mean age, 71 years); of them there were 370 (50.8%) men and 359 (49.2%) women. The selection criteria for endovascular treatment for ischemic stroke were consistent with those set out in the 2015 American Heart Association/American Stroke Association (AHA/ASA) guidelines, which included a pre-stroke modified Rankin Scale (MRS) score of 0–1; ≥18 years of age; a National Institutes of Health Stroke Scale (NIHSS) score of ≥6; and an Alberta Stroke Programme Early CT score (ASPECTS) ≥6. The angiographic results were assessed using the Thrombolysis in Cerebral Infarction (TICI) scale. The clinical outcomes were measured with the NIHSS and the MRS.Results and discussion. Successful recanalization (TICI 2b/3) was achieved in 547 (75%) patients. The predominant technique for thromboextraction was thromboaspiration that was used in 376 (51.6%) patients. Combined procedures (the co-use of an aspiration catheter and a stent retriever) were the second most commonly used – in 231 (31.7%) patients. By the end of the 20th day, good functional recovery (MSR 0–2 scores) was observed in 213 (29.2%) patients. The 20-day mortality rate was 31.8%.Conclusion. The successfully functioning Infarction Network in Moscow was used to create the Stroke Network for treatment in patients with ischemic stroke and large cerebral artery occlusion, the clinical results of which are comparable to large European registry studies.

Background: HER2-targeted therapies have substantially improved outcomes for patients with HER2-positive breast and gastric cancers. Several other cancers exhibit HER2 expression and/or amplification of its gene (ERBB2), suggesting that HER2-targeted agents may have broader therapeutic utility. Zanidatamab is a humanized, novel bispecific antibody directed against two non-overlapping domains of HER2. The aim of this Phase 1 dose-escalation and expansion study (NCT02892123) was to evaluate the safety and efficacy of zanidatamab across a range of solid tumors. Parallel to drug development, there has been rapid advancements in NGS technologies including the Guardant360 assay that can specifically sequence ctDNA and detect amplifications of the ERBB2 gene, which can lead to overexpression of HER2. FISH, the current gold standard for HER2 amplification detection, is a tissue-based assay that assesses the raw ERBB2 copy number as well as ratio of ERBB2 to a centromeric protein of chromosome 17 where the ERBB2 gene resides. We evaluated concordance of the FISH and Guardant360 assays to detect ERBB2 amplification in plasma samples. Unlike gene copy number in tissue analysis, the observed plasma copy number (pCN) is also a function of the tumor burden and rate of tumor shedding of ctDNA into the bloodstream. Methods: HER2 status was determined from a fresh tumor biopsy or in archival FFPE tissue samples by IHC and FISH according to ASCO-CAP guidelines from the Phase 1 study with zanidatamab in multiple cancer types (cholangiocarcinoma [21], colorectal carcinoma [27], all other [87]). Plasma samples were collected prior to the first cycle of zanidatamab and on-treatment for testing with Guardant360, 74 gene ctDNA NGS-based assays. Results: A concordance of 82% was observed in ERBB2/HER2 amplifications between the Guardant360 and FISH assays. An exploratory adjustment method based on tumor DNA shedding was developed by Guardant using the maximum mutant allele fraction (maxVAF) as a surrogate for tumor content. Majority of patients experienced a decrease in HER2 pCN post treatment, with 9 PD patients having the least and 21 PR patients the largest changes in ctDNA fraction (maxVAF). Conclusion: These results indicate that ERBB2 amplification detected by the Guardant360 assay could be used as a surrogate for FISH analysis in lieu of invasive surgical procedures. Citation Format: Diana Shpektor, Daryanaz Dargahi, Antonios Samiotakis, Sara Wienke, Ali Livernois, Arielle Yablonovitch, Geethika Yalamanchili, Elaina Gartner, Funda Meric-Bernstam. ERBB2 amplification detected in ctDNA as a surrogate for tumor tissue FISH analysis of HER2 status in a phase 1 study with zanidatamab for the treatment of locally advanced or metastatic HER2 expressing cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT278.

Novel drug targets for sustained reduction in body mass index (BMI) are needed to curb the epidemic of obesity, which affects 650 million individuals worldwide and is a causal driver of cardiovascular and metabolic disease and mortality. Previous studies reported that the Arg95Ter nonsense variant of GPR151, an orphan G protein-coupled receptor, is associated with reduced BMI and reduced risk of Type 2 Diabetes (T2D). Here, we follow up on GPR151 with the Pakistan Genome Resource (PGR), which is one of the largest exome biobanks of human homozygous loss-of-function carriers (knockouts) in the world. Among PGR participants, we identify 3 GPR151 putative loss-of-function (plof) variants (Arg95Ter, Tyr99Ter, and Phe175LeufsTer7) with a cumulative allele frequency of 2.2% and present at homozygosity. We confirm these alleles in vitro as loss-of-function. We test if GPR151 plof is associated with BMI, T2D, or other metabolic traits. GPR151 deficiency in complete human knockouts is not associated with a clinically significant difference in BMI. Moreover, loss of GPR151 confers a nominally significant increase in risk of T2D (odds ratio = 1.2, p value = 0.03). Relative to wild-type mice, Gpr151-/- animals exhibit no difference in body weight on normal chow, and higher body weight on a high-fat diet, consistent with the findings in humans. Together, our findings indicate that GPR151 antagonism is not a compelling therapeutic approach for obesity.

Background During the ongoing coronavirus disease 2019 (COVID-19) pandemic, many individuals were infected with and have cleared the virus, developing virus-specific antibodies and effector/memory T cells. An important unanswered question is what levels of T-cell and antibody responses are sufficient to protect from the infection. Methods In 5340 Moscow residents, we evaluated anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin M (IgM)/immunoglobulin G (IgG) titers and frequencies of the T cells specific to the membrane, nucleocapsid, and spike proteins of SARS-CoV-2, using interferon gamma (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assay. Additionally, we evaluated the fractions of virus-specific CD4+ and CD8+ T cells using intracellular staining of IFN-γ and interleukin 2 followed by flow cytometry. We analyzed the COVID-19 rates as a function of the assessed antibody and T-cell responses, using the Kaplan–Meier estimator method, for up to 300 days postinclusion. Results We showed that T-cell and antibody responses are closely interconnected and are commonly induced concurrently. Magnitudes of both responses inversely correlated with infection probability. Individuals positive for both responses demonstrated the highest levels of protectivity against the SARS-CoV-2 infection. A comparable level of protection was found in individuals with antibody response only, whereas the T-cell response by itself granted only intermediate protection. Conclusions We found that the contribution of the virus-specific antibodies to protection against SARS-CoV-2 infection is more pronounced than that of the T cells. The data on the virus-specific IgG titers may be instructive for making decisions in personalized healthcare and public anti–COVID-19 policies. Clinical Trials Registration. NCT04898140.

The brain has a remarkable capacity to acquire and store memories that can later be selectively recalled. These processes are supported by the hippocampus which is thought to index memory recall by reinstating information stored across distributed neocortical circuits. However, the mechanism that supports this interaction remains unclear. Here, in humans, we show that recall of a visual cue from a paired associate is accompanied by a transient increase in the ratio between glutamate and GABA in visual cortex. Moreover, these excitatory-inhibitory fluctuations are predicted by activity in the hippocampus. These data suggest the hippocampus gates memory recall by indexing information stored across neocortical circuits using a disinhibitory mechanism., eLife digest Memories are stored by distributed groups of neurons in the brain, with individual neurons contributing to multiple memories. In a part of the brain called the neocortex, memories are held in a silent state through a balance between excitatory and inhibitory activity. This is to prevent them from being disrupted by incoming information. When a memory is recalled, an area of the brain called the hippocampus is thought to instruct the neocortex to activate the appropriate neuronal network. But how the hippocampus and neocortex coordinate their activity to switch memories ‘on’ and ‘off’ is unclear. The answer may lie in the fact that neurons in the neocortex consist of two broad types: excitatory and inhibitory. Excitatory neurons increase the activity of other neurons. They do this by releasing a chemical called glutamate. Inhibitory neurons reduce the activity of other neurons, by releasing a chemical called GABA. Koolschijn, Shpektor et al. hypothesized that the hippocampus activates memories by changing the balance of excitatory and inhibitory activity in neocortex. To test this idea, Koolschijn, Shpektor et al. invited healthy volunteers to explore a virtual reality environment. The volunteers learned that specific sounds in the environment predicted the appearance of particular visual patterns. The next day, the volunteers returned to the environment and viewed these patterns again. After each pattern, they were invited to open a virtual box. Volunteers learned that some patterns led to money in the virtual box, while other patterns did not. Finally, on day three, the volunteers listened to the sounds from day one again, this time while lying in a brain scanner. The volunteers’ task was to infer whether each of the sounds would lead to money. Given that the sounds were never directly paired with the content of the virtual box, the volunteers had to solve the task by recalling the associated visual patterns. As they did so, the brain scanner measured their overall brain activity. It also assessed the relative levels of excitatory and inhibitory activity in visual areas of the neocortex, by measuring glutamate and GABA. The results revealed that as the volunteers recalled the visual cues, activity in both the hippocampus and the visual neocortex increased. Moreover, the ratio of glutamate to GABA in visual neocortex also increased which was predicted by activity in the hippocampus. This suggests that the hippocampus reactivates memories stored in neocortex by temporarily increasing excitatory activity to release memories from inhibitory control. Disturbances in the balance of excitation and inhibition occur in various neuropsychiatric disorders, including schizophrenia, autism, epilepsy and Tourette’s syndrome. Damage to the hippocampus is known to cause amnesia. The current findings suggest that memories may become inaccessible – or may be activated inappropriately – when the interaction between the hippocampus and neocortex goes awry. Future studies could test this possibility in clinical populations.

Background/Introduction There are numerous reports regarding the direct endothelial damage by the SARS-CoV-2 that can lead to activation of both plasma hemostasis and platelet aggregation. However, the mechanism of interaction between endothelium and haemostasis in COVID-19 remains unclear. Purpose The aim of our study was to assess the relationship between each link of clot formation process (endothelial function, plasma coagulation, platelet aggregation) with the severity of the disease. Methods 58 COVID-19 patients were included in our study. Patients were divided into moderate (n=39) and severe (n=18) subgroups. All patients underwent a flow-mediated dilation (FMD) test, impedance aggregation, rotational thromboelastometry, thrombodynamics and von Willebrand factor antigen (vWF: Ag) quantification. All measurements were repeated on days 3 (point 2) and 9 (point 3) of hospitalization. Results COVID-19 patients demonstrated the enhanced plasma coagulation (clotting time, s 613,0 [480; 820], clot growth rate, μm/min 32,75 [29,3; 38,7]). At point 1 no significant difference in parameters of plasma coagulation between patients' subgroups was noted. At point 2 a significant decrease in the size (CS, μm 1278.0 [1216.5; 1356.5] vs 965.0 [659.8; 1098.0], p There was no significant difference in platelet aggregation between subgroups at point 1. During the course of the disease the patients in the moderate and severe subgroups demonstrated a significant increase in platelet aggregation induced by arachidonic acid and ADP (severe: AUC ARA 48,0 [25,0; 59,0] vs 77,5 [55,8; 92,7], p=0,04; AUC ADP 44,0 [41,0; 56,0] vs 58,0 [45,5; 69,0], p=0,04; moderate: AUC ARA 31,5 [19,8; 50,7] vs 56,0 [39,0; 76,0], p=0,01; AUC ADP 43,0 [20,0; 59,0] vs 56,6 [50,3; 70,5], p=0,04;), in moderate subgroup the significant increase in TRAP-induced aggregation was also noted (AUC TRAP 58,0 [41,0; 69,5] vs 76,0 [58,3; 81,5], p=0,048). There were no significant differences in the FMD-test results between the patient subgroups. FMD-test results were predominantly within the reference ranges (7,1 [4,0; 8,8]). Patients in the severe subgroup had significantly higher levels of vWF: Ag (228,0 [205,3; 240,7] vs 232,0 [226,0; 423,0], p=0,03). Conclusion SARS-CoV-2 infection was characterized by increased levels of vWF:Ag, that could represent the local endothelial damage, meanwhile there was no generalized endothelial dysfunction assessed via FMD-test in moderate to severe patients. At the same time the enhanced plasma coagulation in COVID-19 patients was observed. Funding Acknowledgement Type of funding sources: None.

Background Coronavirus disease COVID-19 has spread worldwide extremely rapidly. Although many individuals have been infected and have cleared the virus, developing virus-specific antibodies and effector/memory T cells, an important question still to be answered is what levels of T cell and antibody responses are sufficient to protect from the infection. Methods In 5,340 Moscow residents, we evaluated the anti-SARS-CoV-2 IgM/IgG titers and the frequencies of the T cells specific to the nucleocapsid, membrane, and spike proteins of SARS-CoV-2, using IFNγ ELISpot, and we also evaluated the fractions of virus-specific CD4+ and CD8+ T cells using intracellular staining of IFNγ and IL2 followed by flow cytometry. Furthermore, we analyzed the post-inclusion COVID-19 rates as a function of the assessed antibody and T cell responses using the Kaplan-Meyer estimator method. Results We showed that T cell and antibody responses are closely interconnected and commonly are induced concurrently. Individuals positive for both antibody and T cell immunities demonstrated the highest levels of protectivity against the SARS-CoV-2 infection, indistinguishably from individuals with antibody response only. Meanwhile, individuals with T cell response only demonstrated slightly higher protectivity than individuals without both types of immunity, as measured from N-protein–specific or CD4+IL2+ T cells. However, these individuals were characterized by higher IgG titers than individuals without any immunity, although the titers were below the seropositivity cut-off. Conclusions The results of the study indicated the advantage of serology testing over the analysis of T cell responses for the prediction of SARS-CoV-2 infection rates on a populational level.

Background. Spontaneous coronary artery dissection (SCAD) is an underdiagnosed and rare cause of myocardial infarction (MI). SCAD is defined as the separation of the coronary artery wall by hemorrhage with or without intimal tear. It causes acute coronary syndrome in 1.7% to 4% of cases. Case Summary. We report a case of a patient with acute MI caused by SCAD with marked progression of dissection within 4 days and spontaneous healing in 2 months. Fibromuscular dysplasia (FMD) of the arteries is an associated condition of SCAD that was found in our patient. Conclusion. In young women admitted to the clinic with signs of acute myocardial infarction, SCAD should be suspected. FMD as an associated condition that should be ruled out in every SCAD patient. Conservative treatment of SCAD is the most preferable strategy.

The brain has a remarkable capacity to acquire and store memories that can later be selectively recalled. These processes are supported by the hippocampus which is thought to index memory recall by reinstating information stored across distributed neocortical circuits. However, the mechanism that supports this interaction remains unclear. Here, in humans, we show that recall of a visual cue from a paired associate is accompanied by a transient increase in the ratio between glutamate and GABA in visual cortex. Moreover, these excitatory-inhibitory fluctuations are predicted by activity in the hippocampus. These data suggest the hippocampus gates memory recall by indexing information stored across neocortical circuits using a disinhibitory mechanism.

Introduction Enhanced activation of endogenous fibrinolysis in ST-elevation myocardial infarction (STEMI) patients is the main cause of spontaneous reperfusion of the infarct-related artery (IRA) in the acute period. Whether this enhanced activation remains in the deferred period of myocardial infarction remains unclear. Purpose The main purpose of our work was to analyze the process of clot formation and endogenous fibrinolysis in patients with a history of myocardial infarction. Methods We included 51 patients with a history of myocardial infarction (median, 35 months). Of these patients, 19 had a spontaneous reperfusion of the IRA (SR group) during the index event, and 32 had a total occlusion of the IRA (occlusion group). We assessed parameters of clot formation and endogenous fibrinolysis using thromboelastometry and a thrombodynamics assay. We analyzed endothelial function using the flow-mediated dilation test (FMD). Results The process of clot formation was more active in the occlusion group than in the SR group. Thus, the initial, mean, and total clot velocity times were significantly higher in the occlusion group than in the SR group: 57.2 mcm/min vs. 60.25 mcm/min; 28,1 mcm/min vs. 31.9 mcm/min; and 28.7 mcm/min vs. 31.9 mcm/min, respectively; p Conclusion STEMI patients with occlusion of the IRA and those with spontaneous reperfusion remain different in clot formation and endothelial function even after many years. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This study was supported by the Russian Science Foundation grant

Background Inflammation plays a major role in atherosclerotic plaques' progression and was shown to be associated with the formation of hypoxic areas within the plaques. However, the data about the impact of hypoxia on atherosclerosis are contradictory, in part due to inadequacy of in vitro and animal models to reproduce faithfully the complexity of human atherosclerotic plaques. Purpose The aim of this study was to investigate the effect of hypoxia on immune status in the ex vivo system of human atherosclerotic plaques. Methods We collected 25 atherosclerotic plaques from patients undergoing carotid endarterectomy, cut plaques into ring-shaped slices and cultured them for 24 hours at the liquid/air interface on collagen sponges under hypoxic (2% O2) and normoxic (12% O2) conditions. After 24 hours we evaluated T-cell activation status within plaques according to the presence of membrane activation markers by means of multiparametric flow cytometry and the activity of cytokine production using xMAP technology. Results We found that CD8 T cells from human atherosclerotic plaques cultured under hypoxic conditions compared to normoxic conditions have a decreased expression of CD69 activation marker (42.7 [34.3; 50.9]% vs 53.8 [33.3; 63.3]%, n=10, p=0.047) and lower level of CD69 and HLA-DR coexpression (16.0 [10.5; 22.3] vs 22.6 [11.3; 28.2], n=10, p=0.02). CD4 T cells did not show any significant changes in expression of activation markers under hypoxia. Hypoxic conditions also resulted in a reduced IL-10 production (104.2 [53.8; 170.9] vs 235.2 [158.5; 335.3] pg/100 mg of tissue, n=20, p=0.0001) and increased VEGF production (116.1 [79.8; 253.5] vs 89.9 [71.1; 148.8] pg/100 mg of tissue, n=20, p=0.033). Conclusions Our results indicate that hypoxia causes a decrease in the activity of cytotoxic T cells and increases stimuli for angiogenesis within the human atherosclerotic plaques. The established ex vivo model of human atherosclerotic plaques culture under hypoxia enables further studies of the hypoxia impact on atherosclerosis. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Russian Science Foundation grant

Background/Introduction Electrical storm (ES) is a potentially lethal state developing in 4–28% of ICD patients. Neuroaxial modulation (beta-blockers, deep sedation, epidural anesthesia, stellate ganglion blockade etc) is used to decrease arrhythmogenic predisposition of ventricular myocardium to trigger and maintain ventricular arrhythmias. Catheter renal arterial denervation (RDN) is recently described to prevent atrial fibrillation recurrence after pulmonary vein isolation. We used this procedure in addition to standard care to improve the results of ES treatment. Purpose This retrospective single-center case-series is aimed to analyze ES patient population and describe the effect of RDN on the in-hospital number of ventricular tachycardia (VT) episodes and ICD shocks and on the mid-term survival. Methods Pts admitted to the CCU for more than 3 sustained VT episodes or more than 3 appropriate ICD shocks during the 24h period in 2017–18 were enrolled into study. Demographic, echocardiographic, ICD check up, renal arteries anatomy and mid-term mortality/transplant data were retrospectively analyzed. Results Twelve pts (10 male, age 69,3±9,8 years; 2 female, age 72,0±8,5) were included. Nine pts (75%) had CAD, 3 pts (25%) – DCM. Echocardiography revealed LVEF 30±9%, and LV EDV – 216±38 ml. Time from ICD implantation to ES onset was from 4 mos to 13 yrs. In 2 pts RDN was performed after VT ablation, in 1 pt – both RDN and VT ablation were performed during the same procedure, in 4 pts – RDN was done prior to VT ablation and in 5 pts - without VT ablation. Mean number of ablations was 4,8 per artery. The power was 2 to 11 Wt and lesion duration was 90 sec. In 1 pt RF-balloon-based technology was used to achieve RDN. Dramatic decrease in the number of VT episodes (49c52 vs. 6±2) was found in 6/12 pts directly after RDN procedure. In-hospital rhythm control was accessed in 10/12 pts, 1 pt with DCM was transferred for heart transplant despite VT ablation and RDN. There were no RDN procedure related complications in this group of pts. During mean 22 mos of follow-up 2/11 pts needed repeat hospitalization due to ES recurrence (VT ablation and 2-chamber ICD to CRT-D upgrade, respectively, were performed), 2/11 died (1-probably arrhythmic death, 1-other cause), 1/11 was lost for follow up. Total efficacy of RDN after almost 2 years in this study was 50%. Mean LVEF increased to 38±7%. Conclusion(s) Catheter renal artery denervation is effective and safe additional procedure to treat ES patients. It allows decreasing the number of ICD shocks and decreases arrhythmogenic potential of ventricular myocardium. Prospective registry is warranted. Funding Acknowledgement Type of funding source: None

Aim To evaluate the effect of cryo-exposure duration and the use of the Achieve circular mapping catheter on efficacy of cryoballoon ablation (CBA).Material and methods CBA of pulmonary vein ostia (PVO) is a major method for heart rhythm control in patients with atrial fibrillation (AF). Since the inception, the PVO CBA method has evolved; the recommended application time was changed, and the Achieve circular catheter appeared. We performed a retrospective analysis of PVO CBA administered to patients with AF in the I.V. Davydovsky Municipal Clinical Hospital from 2017 through 2019. The study included 100 patients with available clinical and demographic characteristics and remote results of the intervention. Three patient groups were analyzed based on differences in surgical techniques: group 1, Guidewire / 240 (n=31) with the cryoballoon placing on a guidewire and PVO exposure duration of 240 s; group 2, Guidewire / 180 (n=26) with the cryoballoon placing on a guidewire and PVO exposure duration of 180 s; and group 3, Achieve / 180 (n=43) with the cryoballoon placing on the mapping catheter Achieve and PVO exposure duration of 180 с. The follow-up period was 33.2±4.5, 15.2±6.1, and 12.2±4.1 months in the Guidewire / 240, Guidewire / 180, and Achieve / 180 groups, respectively. The intervention was considered effective when there was no relapse at the time of interview. A relapse of AF was determined as one or more paroxysms recorded on electrocardiogram (ECG) or during 24-h ECG monitoring; the “blind period” (first 3 months after the procedure) was excluded from the follow-up. Safety evaluation included clinically significant complications, such as phrenic nerve damage, hemopericardium, gastroparesis, hemoptysis, acute cerebrovascular disease, and formation of atrio-esophageal fistula. Effects of independent factors were determined with binary logistic regression.Results In the Guidewire / 240 group, efficacy of PVO CBA for the maximum follow-up period was 74.4%, which was significantly different from the value for the Guidewire / 180 group (57.7 %, р=0.015). At the same time, the difference between the Guidewire / 240 and Achieve / 180 groups was statistically non-significant for a comparable follow-up period (р=0.144). Clinically significant complications were absent in all 3 groups. The independent factors that significantly increased the PVO CBA efficacy were the cryo-exposure duration of 240 s compared to 180 s (р= 0.018) and the use of the Achieve catheter (р=0.014).Conclusion Decreasing the cryo-exposure duration to less than 240 s is impractical (in absence of Achieve mapping catheter) since it impairs the long-term efficacy of PVO CBA and does not influence the risk of complications.

With the progress of COVID-19 studies, it became evident that SARS-CoV-2 infection is often associated with thrombotic complications. The goal of our present study was to evaluate which component of clot formation process including endothelial function, platelets aggregation and plasma coagulation, as well as endogenous fibrinolysis in patients with COVID-19 correlates with the severity of the disease. We prospectively included 58 patients with COVID-19 and 47 healthy volunteers as a control group that we recruited before the pandemic started. It turns out that plasma coagulation with subsequent platelet aggregation, but not endothelial function, correlates with the severity of the COVID-19. IL-6 blockade may play a beneficial role in COVID-19 induced coagulopathy.

A proinflammatory dysregulation of cytokine release is associated with various diseases, in particular with those of infectious etiology, as well as with cardiovascular diseases (CVD). We showed earlier that cytokines are released in two forms, soluble and in association with extracellular vesicles (EVs). Here, we investigated the patterns of expression and clustering of soluble and EV-associated cytokines in patients with ST-elevation myocardial infarction (STEMI). We collected plasma samples from 48 volunteers without CVD and 62 patients with STEMI, separated soluble and EV fractions, and analyzed them for 33 cytokines using a multiplexed bead-based assay. We identified soluble and EV-associated cytokines that are upregulated in STEMI and form correlative clusters. Several clustered soluble cytokines were expressed almost exclusively in patients with STEMI. EV-associated cytokines were largely not affected by STEMI, except for pro-inflammatory cytokines IL-6, IL-18, and MIG, as well as anti-inflammatory IL-2 that were upregulated in a correlated fashion. Our results demonstrated that soluble cytokines in patients with STEMI are upregulated in a coordinated fashion in contrast to the mainly unaffected system of EV-associated cytokines. Identification of cytokine clusters affected differently by STEMI now permits investigation of their differential contributions to this pathology.

Acute myocardial infarction (AMI) is associated with activation of various cells, including platelets that form monocyte–platelet complexes (MPCs). Here, we analysed MPC in vivo and in vitro and investigated the abilities of different monocyte subclasses to form MPC, the characteristics of the cells involved in MPC formation and MPC changes in AMI. We identified MPC by co-staining for platelet antigen CD41a and monocyte antigens CD14 and CD16. Platelet activation was evaluated from expression of phosphatidylserine as revealed by annexin V. Our results confirm published data and provide new information regarding the patterns of MPC in AMI patients. We found that the patterns of platelet aggregation with monocytes were different in AMI patients and controls: (1) in AMI patients, MPC formed by intermediate monocytes carry more platelets whereas in healthy controls more platelets aggregated with classical monocytes; (2) the numbers of MPC in AMI patients, being already higher than in controls, were further increased if these patients suffered various in-hospital complications; (3) on the basis of the CD41a fluorescence of the antibody-stained MPC, some of the aggregates seem to consist of monocytes and platelet-derived extracellular vesicles (EVs); (4) aggregation of monocytes with platelet EV occurred in in vitro experiments; and (5) these experiments demonstrated that monocytes from AMI patients aggregate with both platelets and platelet EVs more efficiently than do monocytes from controls. MPC in AMI patients may play an important role in this pathology.

Aim. To assess the processes of clot formation in relation to endogenic fibrinolysis in patients with various types of acute coronary syndrome (ACS).Material and methods. To the study, 89 persons (40 males) included: 59 with ACS, 30 — control group. Among the ACS patients, 28 were ST-elevation (STEMI), 31 with non-ST-elevation ACS (NSTEACS). All participants were assessed for clotting formation parameters and thrombus lysis with rotational elastometry on ROTEM equipment (Germany) and “Hemacore” Thrombodynamics (Russia), before coronary arteriography.Results. Clot density and its size in 10 minutes were significantly higher in ACS comparing to control patients (2867 units vs 25084 units, pConclusion. With the measurement in vitro, the process of clotting and thrombus lysis is more active in ACS patients comparing to controls, that point on a baseline activated hemostasis. Within the ACS group, higher the existing clot in vessel lumen, more active the shift of the balance to anticoagulation and fibrinolysis.

BackgroundCLL is an incurable hematologic malignancy characterized by progressive accumulation of clonally derived CD19+ B-cell lymphocytes. CAR T cell therapies are promising treatments but inherent T cell dysfunction has limited their development in CLL. Preclinical studies suggest ibrutinib may modulate CAR T cells directly to improve their function independently of antitumor effects. Liso-cel is an autologous, CD19-directed, defined composition, 4–1BB CAR T cell product administered at equal target doses of CD8+ and CD4+ CAR+ T cells. The ongoing TRANSCEND CLL 004 study evaluates the efficacy and safety of liso-cel alone (monotherapy) or with concurrent ibrutinib (combination) in relapsed/refractory (R/R) CLL.1 We investigated the effect of ibrutinib on post-infusion CAR+ and endogenous T cells relative to monotherapy using a novel cell-sorting, low-input RNA-seq method for analysis of patient cells beyond peak expansion, including 1 and 2 months after liso-cel infusion.MethodsCAR+ and endogenous T cells from patients in TRANSCEND CLL 004 (NCT03331198; monotherapy, n=16; combination, n=19) were isolated from peripheral blood mononuclear cells by fluorescence-activated cell sorting. RNA-seq was performed using cell lysate as input material. CAR+ T cell pharmacokinetics were assessed by flow cytometry. Serum interleukin-6 was measured by electrochemiluminescent multiplex immunoassay. Minimal residual disease (ResultsGene set enrichment analyses revealed positive enrichment of cell proliferation-associated gene sets and negative enrichment of inflammation-associated gene sets at peak expansion in CAR+ T cells from combination relative to monotherapy patients. Similar, but less marked, proliferation- and inflammation-associated gene expression changes were also observed in endogenous T cells. Accordingly, increased CAR+ T cell expansion and reduced serum interleukin-6 were observed in combination patients. In addition, an independently derived CLL ibrutinib gene expression score2 was increased and sustained in CAR+ and endogenous T cells from combination but not monotherapy patients over time. A higher ibrutinib score trended with a higher rate of undetectable minimal residual disease, longer progression-free survival (PFS), and longer duration of response. Lastly, a T cell exhaustion-related gene signature was significantly reduced in CAR+ but not endogenous T cells with combination treatment, and this reduction was associated with improved PFS.ConclusionsConcurrent ibrutinib treatment in patients with R/R CLL resulted in measurable effects in CAR+ and endogenous T cells, including changes in gene signatures related to proliferation, inflammation, and T cell exhaustion. These changes were associated with enhanced CAR T cell function and efficacy.AcknowledgementsWe would like to thank the patients, caregivers, investigators, and study personnel. This study was funded by Juno Therapeutics, a Bristol-Myers Squibb Company. All authors contributed to and approved the abstract; writing and editorial assistance were provided by Allison Green, PhD, of The Lockwood Group (Stamford, CT, USA), funded by Bristol Myers Squibb.Trial RegistrationNCT03331198ReferencesWierda WG, Dorritie KA, Munoz J, et al. TRANSCEND CLL 004: phase 1 cohort of lisocabtagene maraleucel (liso-cel) combined with ibrutinib (IBR) for patients (pts) with R/R CLL/SLL. Hematol Oncol 2021;39(S2):141–143.Rendeiro AF, Krausgruber T, Fortelny N, et al. Chromatin mapping and single-cell immune profiling define the temporal dynamics of ibrutinib response in CLL. Nat Commun 2020;11:577.Ethics ApprovalThis study used patient cells obtained from a clinical trial that was done in accordance with with the Declaration of Helsinki, International Conference on Harmonization Good Clinical Practice guidelines, institutional review boards at participating institutions approved the study protocol and amendments, and all patients provided written informed consent.

PURPOSE to study elucidate association of active cytomegalovirus (CMV) infection with endothelial dysfunction in patients with acute myocardial infarction (AMI). MATERIALS AND METHODS The study included 42 volunteers without ischemic heart disease (IHD) and 63 patients with AMI. Blood samples for analysis of the deoxyribonucleic acid (DNA) of CMV in plasma by real-time polymerase chain reaction were taken in patients - before coronary angiography, in volunteers - at admission. In addition, in patients with AMI and volunteers without IHD, endothelial function was analyzed using endothelium-dependent vasodilatation (EDVD) test of the brachial artery. RESULTS We showed that in patients with AMI, the concentration of CMV DNA in plasma was statistically significantly increased when compared with that in volunteers without IHD, which reflects active CMV infection - 1185.7 (0; 3003.0) vs. 0 (0; 910.8) copies of DNA / ml plasma (p=0.011). In comparison with volunteers without IHD, patients with AMI also more often had endothelial dysfunction - 11.5 (7.5, 15.2) % vs. 4.4 (0; 9.6) % of cases (p.

Background and aims The mechanisms that drive atherosclerotic plaque progression and destabilization in humans remain largely unknown. Laboratory models are needed to study these mechanisms under controlled conditions. The aim of this study was to establish a new ex vivo model of human atherosclerotic plaques that preserves the main cell types in plaques and the extracellular components in the context of native cytoarchitecture. Methods Atherosclerotic plaques from carotid arteries of 28 patients undergoing carotid endarterectomy were dissected and cultured. At various time-points, samples were collected and analysed histologically. After enzymatic digestion, single cells were analysed with flow cytometry. Moreover, tissue cytokine production was evaluated. Results We optimised the plaque dissection protocol by cutting plaques into circular segments that we cultured on collagen rafts at the medium–air interface, thus keeping them well oxygenated. With this technique, the relative presence of T and B lymphocytes did not change significantly during culture, and the sizes of lymphocyte subsets remained stable after day 4 of culture. Macrophages, smooth muscle cells, and fibroblasts with collagen fibres, as well as T and B lymphocyte subsets and CD16 natural killer cells, remained largely preserved for 19 days of culture, with a continuous production of inflammatory cytokines and chemokines. Conclusions Our new model of ex vivo human atherosclerotic plaques, which preserves the main subsets of immune cells in the context of tissue cytoarchitecture, may be used to investigate important aspects of atherogenesis, in particular, the functions of immune cells under controlled laboratory conditions.

Among various questions pertinent to grounding human cognitive functions in a neurobiological substrate, the association between language and motor brain structures is a particularly debated one in neuroscience and psychology. While many studies support a broadly distributed model of language and semantics grounded, among other things, in the general modality-specific systems, theories disagree as to whether motor and sensory cortex activity observed during language processing is functional or epiphenomenal. Here, we assessed the role of motor areas in linguistic processing by investigating the responses of 28 healthy volunteers to different word types in semantic and lexical decision tasks, following repetitive transcranial magnetic stimulation (rTMS) of primary motor cortex. We found that early rTMS (delivered within 200ms of word onset) produces a left-lateralised and meaning-specific change in reaction speed, slowing down behavioural responses to action-related words, and facilitating abstract words - an effect present only during semantic, but not lexical, decision. We interpret these data in light of action-perception theory of language, bolstering the claim that motor cortical areas play a functional role in language comprehension.

Background/Introduction Electrical storm (ES) is a potentially lethal state developing in 4–28% of ICD patients. Neuroaxial modulation (beta-blockers, deep sedation, epidural anesthesia, stellate ganglion blockade etc) is used to decrease arrhythmogenic predisposition of ventricular myocardium to trigger and maintain ventricular arrhythmias. Catheter renal arterial denervation (RDN) is recently described to prevent atrial fibrillation recurrence after pulmonary vein isolation. We used this procedure in addition to standard care to improve the results of ES treatment. Purpose This retrospective single-center case-series is aimed to analyze ES patient population and to describe the effect of RDN on the in-hospital number of ventricular tachycardia (VT) episodes and ICD shocks and on the mid-term survival. Methods Pts admitted to the CCU for more than 3 sustained VT episodes or more than 3 appropriate ICD shocks during the 24h period in 2017–18 were enrolled into study. Demographic, echocardiographic, ICD check up, renal arteries anatomy and mid-term mortality/transplant data were retrospectively analysed. Results Eleven pts (all male, age 69±9 years) were included. Seven pts (73%) had CAD, 3 pts (27%) – DCM. Echocardiography revealed LVEF 28±8%, and LV EDV - 226±91 ml. Time from ICD implantation to ES onset was from 4 mos to 13 yrs. In 5 pts RDN was performed without VT ablation, in 3 pts – prior to VT ablation, in 2 – after VT ablation and in 1 pt – both RDN and VT ablation were performed during the same procedure. Mean number of renal arteries was 2,5 per pt. Mean number of ablations was 4,8 per artery. The power was 2 to 11 Wt and lesion duration was 90 sec. Dramatic decrease in the number of VT episodes (49±52 vs. 6±2) was found in 6/11 pts directly after RDN procedure. In-hospital rhythm control was accessed in 10/11 pts, 1 pt with DCM was transferred for heart transplant due to recurrence of VT after VT ablation and RAD (excluded from survival analysis). There were no RDN procedure related complications in this group of pts. In mean 6 mos of follow-up 9/10 pts are free from ES recurrence, 1/10 was lost for the follow up. Conclusion(s) Catheter renal artery denervation is effective and safe additional procedure to treat ES patients. It allows to decrease the number of ICD shocks and stabilize arrhythmogenicity of ventricular myocardium. Larger multi-center randomized trials are warranted.

Atherosclerosis underlies the development of many cardiovascular diseases that continue to hold a leading place among the causes of death in developed countries. The role of activated immune cells in atherosclerosis progression has been convincingly demonstrated, but the mechanism of their action remains poorly investigated. Since atherosclerosis is associated with chronic inflammatory response, involvement of viral and bacterial infections in atherogenesis has been examined. A special place among the infectious agents is held by human herpesviruses as the most common persistent viruses in human population coupled to chronic inflammation during atherosclerosis. We found that activation of cytomegalovirus (CMV, human herpesvirus 5) infection is associated with the emergence of acute coronary syndrome, which is in a good agreement with the data on productive CMV infection published elsewhere. In this review, we discuss the data obtained by us and other researchers regarding the role of cytomegalovirus infection and related potential mechanisms resulting in the expansion of atherosclerotic plaques during ischemic heart disease and stroke, including virus transfer to immune and endothelial cells via extracellular vesicles. In particular, the data presented in the review demonstrate that virus spreading in the vascular wall triggers immune system activation in atherosclerotic plaques and causes endothelial dysfunction. Moreover, productive CMV infection in patients with acute myocardial infarction correlates with the extent of endothelial dysfunction. The mechanisms described by us and other researchers may explain the role of CMV infection in atherosclerosis and development of ischemic heart disease.

The relationship between acute coronary syndrome (ACS) and local and systemic inflammation, including accumulation of macrophages in atherosclerotic plaques and upregulation of blood cytokines (e.g., C-reactive protein (CRP)), has been known for more than 100 years. The atherosclerosis-associated inflammatory response has been traditionally considered as an immune system reaction to low-density lipoproteins. At the same time, some data have indicated a potential involvement of cytomegalovirus (CMV) in the activation and progression of atherosclerosis-associated inflammation, leading to ACS. However, these data have been tangential and mainly concerned the relationship between a coronary artery disease (CAD) prognosis and the anti-CMV antibody titer. We assumed that ACS might be associated with CMV reactivation and virus release into the bloodstream. The studys aim was to test this assumption through a comparison of the plasma CMV DNA level in patients with various CAD forms and in healthy subjects. To our knowledge, no similar research has been undertaken yet. A total of 150 subjects (97 CAD patients and 53 healthy subjects) were examined. Real-time polymerase chain reaction (RT-PCR) was used to determine the number of plasma CMV DNA copies. We demonstrated that the number of plasma CMV genome copies in ACS patients was significantly higher than that in healthy subjects (p = 0.01). The CMV genome copy number was correlated with the plasma CRP level (p = 0.002). These findings indicate a potential relationship between CMV activation and atherosclerosis exacerbation that, in turn, leads to the development of unstable angina and acute myocardial infarction. Monitoring of the CMV plasma level in CAD patients may be helpful in the development of new therapeutic approaches to coronary atherosclerosis treatment.

to study elucidate association of active cytomegalovirus (CMV) infection with endothelial dysfunction in patients with acute myocardial infarction (AMI).The study included 42 volunteers without ischemic heart disease (IHD) and 63 patients with AMI. Blood samples for analysis of the deoxyribonucleic acid (DNA) of CMV in plasma by real-time polymerase chain reaction were taken in patients - before coronary angiography, in volunteers - at admission. In addition, in patients with AMI and volunteers without IHD, endothelial function was analyzed using endothelium-dependent vasodilatation (EDVD) test of the brachial artery.We showed that in patients with AMI, the concentration of CMV DNA in plasma was statistically significantly increased when compared with that in volunteers without IHD, which reflects active CMV infection - 1185.7 (0; 3003.0) vs. 0 (0; 910.8) copies of DNA / ml plasma (p=0.011). In comparison with volunteers without IHD, patients with AMI also more often had endothelial dysfunction - 11.5 (7.5, 15.2) % vs. 4.4 (0; 9.6) % of cases (p.

AIM OF STUDY To assess influence of remote ischemic preconditioning (RIPC) and local ischemic postconditioning and their co-application.

Transcranial Alternating Current Stimulation (tACS) is a neuromodulatory technique able to act through sinusoidal electrical waveforms in a specific frequency and in turn modulate ongoing cortical oscillatory activity. This neurotool allows the establishment of a causal link between endogenous oscillatory activity and behavior. Most of the tACS studies have shown online effects of tACS. However, little is known about the underlying action mechanisms of this technique because of the AC-induced artifacts on Electroencephalography (EEG) signals. Here we show a unique approach to investigate online physiological frequency-specific effects of tACS of the primary motor cortex (M1) by using single pulse Transcranial Magnetic Stimulation (TMS) to probe cortical excitability changes. In our setup, the TMS coil is placed over the tACS electrode while Motor Evoked Potentials (MEPs) are collected to test the effects of the ongoing M1-tACS. So far, this approach has mainly been used to study the visual and motor systems. However, the current tACS-TMS setup can pave the way for future investigations of cognitive functions. Therefore, we provide a step-by-step manual and video guidelines for the procedure.