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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.

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.

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.

The novel coronavirus infection COVID-19 in most cases manifests with respiratory symptoms and fever, however, some patients may have cardiovascular and gastroenterological manifestations. A feature of the clinical syndrome of COVID-19 is the development of pronounced immunopathological reactions and disorders of hemostasis, leading to the development of a wide range of cardiovascular complications. The course of COVID-19 may be complicated by the development of acute myocardial infarction, venous and arterial thrombosis and thromboembolism in various vascular pools, the development of acute myocardial damage and myocarditis. Among the gastroenterological manifestations, diarrhea, nausea or vomiting, as well as abdominal pain, are most often detected. These symptoms may precede the appearance of respiratory signs of the disease, and in some cases come to the fore in the clinical picture of the disease. In addition, in some patients there are laboratory signs of liver injury (increased serum transaminases). The exact pathogenesis of the above disorders continues to be studied.Новая коронавирусная инфекция COVID-19 в превалирующем большинстве случаев манифестирует респираторными симптомами и лихорадкой, однако у некоторых пациентов могут отмечаться сердечно-сосудистые и гастроэнтерологические проявления. Особенностью клинического синдрома COVID-19 является развитие выраженных иммунопатологических реакций и нарушений гемостаза, ведущее к широкому спектру сердечно-сосудистых осложнений. Течение COVID-19 может осложниться развитием острого инфаркта миокарда, венозных и артериальных тромбозов и тромбоэмболий в различных сосудистых бассейнах, острого повреждения миокарда и миокардита. Среди гастроэнтерологических проявлений наиболее часто выявляются диарея, тошнота или рвота, а также абдоминальная боль. Эти симптомы могут предшествовать появлению респираторных признаков заболевания, а в некоторых случаях выходить на первый план в клинической картине заболевания. Помимо этого, у части больных наблюдаются лабораторные признаки поражения печени (повышение сывороточных трансаминаз). Точный патогенез описанных нарушений продолжает изучаться.

Aim of the study - to assess the effect of remote ischemic preconditioning (RIPC) on the incidence of endothelial dysfunction (ED) and its impact on hospital prognosis in patients with ST segment elevation acute myocardial infarction (STEMI).We conducted a single - centre, open - label prospective study that included 173 patients with STEMI who underwent primary percutaneous coronary intervention within the first 24 hours of the symptoms onset. Before the PCI, patients were randomized into two groups. In the first group (n=86) during the preparation for PCI, we performed RIPC procedure by inflation of the cuff of the tonometer to 200 mm Hg and its further deflation on patient's shoulder, thus creating short cycles of controlled ischemia/reperfusion in hand (4 cycles of ischemia/reperfusion for 5/5 minutes respectively). In the second, control group (n=87), the standard primary PCI was performed without the previous RIPC. Evaluation of the endothelial function was performed on the 2-7th day after admission using the endothelium - dependent flow - mediated dilatation test (FMD) of the brachial artery. Primary endpoints in this study included the presence of ED, in - hospital mortality, life - threatening arrhythmias (ventricular fibrillation/ventricular tachycardia after first 24 hours upon admission), stent thrombosis, clinical signs of heart failure, and a combined endpoint consisting of all the listed above.The median values for FMD-test did not differ significantly between the study groups upon admission. Assessment of the FMD of the brachial artery on the 2-7th day after PCI showed that among the patients who underwent RIPC there was a significantly lower percentage of patients with ED than in the patients with STEMI who did not undergo RIPC before PCI (43.1% vs. 75.8% respectively, p=0.0001). We found a significant reduction in the incidence of heart failure and of combined endpoint in the group of patients without ED compared with patients with ED: 0% vs. 9.3% (n=7; p=0.023) and 3.8% (n=2) vs. 16% (n=12; p=0.032) respectively. When assessing the effect of RIPC on hospital prognosis, we also found a significant decrease in the incidence of heart failure and a trend towards a decrease in the combined endpoint in the group of patients who underwent RIPC compared to the control group: 1.5% (n=1) vs. 9.7% (n=6; p=0.045) and 6.2% (n=4) vs. 16.1% (n=10; p=0.073) respectively.Performance of RIPC before the primary PCI significantly reduces the incidence of ED in patients with STEMI on the 2-7th day of the disease onset. The presence of ED in patients with STEMI is associated with a significant increase in the incidence of heart failure and of the combined endpoint during in - hospital period. RIPC significantly reduces the incidence of heart failure in patients with STEMI during in - hospital period.Цель исследования - оценить влияние отдаленного ишемического прекондиционирования (ОИПК) на частоту развития эндотелиальной дисфункции (ЭД) и ее влияние на госпитальный прогноз у больных острым инфарктом миокарда с подъемом сегмента ST (ОИМпST). Материалы и методы. Авторы провели одноцентровое открытое проспективное исследование, в которое включено 173 пациента с ОИМпST, которым проводилось первичное чрескожное коронарное вмешательство (ЧКВ) в первые 24 ч от появления симптомов. Перед проведением ЧКВ пациентов рандомизировали в две группы. В I группе (n=86) во время подготовки к ЧКВ пациентам проводили процедуру ОИПК путем циклического раздувания манжеты тонометра до 200 мм рт. ст. и сдувания на плече пациента, создавая, таким образом, кратковременные эпизоды контролируемой ишемии/реперфузии тканей руки (4 цикла ишемии/реперфузии по 5/5 мин соответственно). Во II группе (n=87), которая являлась контрольной, стандартное первичное ЧКВ проводилось без предшествующего ОИПК. Оценка функциональной активности эндотелия проводилась на 2-7-е сутки от начала развития заболевания посредством теста эндотелийзависимой вазодилатации (ЭЗВД) плечевой артерии. Конечными точками в исследовании были наличие ЭД, госпитальная летальность, жизнеугрожающие аритмии (фибрилляция желудочков и желудочковая тахикардия спустя 24 ч от поступления), достоверный тромбоз стента, клинические признаки недостаточности кровообращения, а также комбинированная конечная точка, состоявшая из всех вышеперечисленных признаков. Результаты. Значение медианы показателя ЭЗВД плечевой артерии при поступлении достоверно не отличалось между исследуемыми группами. Оценка ЭЗВД плечевой артерии на 2-7-е сутки после ЧКВ показала, что среди пациентов, которым проводилось ОИПК, отмечался достоверно меньший процент пациентов с ЭД, чем у пациентов с ОИМпST, которым перед ЧКВ ОИПК не выполнялось (43,1% против 75,8% соответственно, р=0,0001). Выявлено достоверное снижение количества случаев сердечной недостаточности и комбинированной конечной точки в группе пациентов без ЭД в сравнении с пациентами с ЭД: 0% против 9,3% (n=7; p=0,023) и 3,8% (n=2) против 16% (n=12; p=0,032) соответственно. При оценке влияния ОИПК на госпитальный прогноз авторы также выявили достоверное снижение количества случаев сердечной недостаточности и тенденцию к снижению комбинированной конечной точки в группе пациентов, которым проводилось ОИПК, в сравнении с контрольной группой: 1,5% (n=1) против 9,7% (n=6; p=0,045) и 6,2% (n=4) против 16,1% (n=10; p=0,073) соответственно. Заключение. Проведение ОИПК перед первичным ЧКВ достоверно уменьшает частоту встречаемости ЭД у пациентов с ОИМпST на 2-7-е сутки заболевания. Наличие ЭД у пациентов с ОИМпST ассоциировано с достоверным увеличением частоты встречаемости сердечной недостаточности и комбинированной конечной точки в госпитальный период. ОИПК достоверно уменьшает частоту развития сердечной недостаточности у пациентов с ОИМпST в госпитальный период.

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.