[Ð ossibility of using European (HFA-PEFF) and American (H2FPEF) algorithms for diagnosing heart failure with preserved ejection fraction in Russian clinical practice].

This article focuses on the significance of a unified approach to diagnosing heart failure with preserved left ventricular ejection fraction (HFpEF). The key hemodynamic index of HFpEF is increased left ventricular filling pressure (LVFP) and its noninvasive marker, the E / e' value obtained by tissue Doppler echocardiography (EchoCG). The modern verified algorithms for HFpEF diagnosis, HFA-PEFF and Н2FPEF, mandatorily take into account the E / e' value. However, the routing use of these algorithms in the Russian practice may be complicated since even among "advanced" specialists who are interested in heart failure, 38% of the interviewed do not use or do not know how to use tissue Doppler EchoCG or the algorithm for diagnosing HFpEF with E / e'. In addition to the obvious way of overcoming this problem by equipping respective medical facilities with ultrasonic apparatuses with tissue Doppler EchoCG software and educating physicians, a possibility of using simplified HFA algorithm without the E / e' value is being considered. However, such approach will inevitably lead to erroneous estimation of the probability of HFpEF and, at the best, to underestimation of this probability with ensuing mistakes in diagnosis and treatment. Simplifying the HFA-PEFF and H2FPEF algorithms by omitting one or more parameters is possible but this requires a special investigation to develop a new rating scale and actually a new algorithm, which, in turn, will require a new validation.

Visual Scale as a Non-Invasive Method for Evaluation of Risk and Severity of Coronary Atherosclerosis.

Aim      To evaluate quantitative and qualitative characteristics of atherosclerotic plaques (ASP) in carotid arteries (CA) and femoral arteries (FA) and to use these data for developing a visual scale (VS) for noninvasive diagnosis and determination of severity of coronary atherosclerosis.Material and methods  This study included 216 patients (115 men and 101 women) aged 24 to 87 years (mean age, 61.5±10.73 years). All patients underwent coronary angiography (CAG) for detecting and determining severity of CA atherosclerosis and duplex scanning (DS) for detecting atherosclerosis of CA and FA.Results Analysis of ultrasound parameters of ASP in CA and FA showed that the maximal ASP height, moderate stenosis and maximal stenosis of the arterial bed had higher predictive values than other ultrasound parameters. These parameters were used for forming diagnostic complexes, on the basis of which two individual VSs for CA and FA were developed. Based on the high prognostic value of both scales, they were combined into one that was named VSCOMB. A ROC analysis determined cut-off points of the VSCOMB for diagnosis of CA atherosclerosis of various severity. VSCOMB scores  >4 indicated pronounced CA atherosclerosis with sensitivity of 86.1 % and specificity of 87.5 % whereas VSCOMB scores  ≤4 excluded it. Thus, VSCOMB score 0-1 indicated the absence of CA atherosclerosis; score 2-4 indicated the presence of subclinical CA atherosclerosis; and score >4 indicated severe CA atherosclerosis.Conclusion      A VSCOMB was developed that includes a set of ultrasound parameters for CA and FA and is useful for noninvasive diagnosis of CA atherosclerosis of various severity. Simple and convenient use of VSCOMB allows it to be used at the screening stage to detect subclinical CA atherosclerosis and to prevent its progression.

[The Choice of Priorities in Contemporary Comparative Trials: Superiority vs non Inferiority. Causes and Effects].

The article compares two statistical approaches, which are commonly used in current comparative studies, a hypothesis that a drug is superior over another one (superiority) and a hypothesis that a drug is not inferior to another one in the efficacy and safety (non-inferiority). Using the example of specific studies, the difference between the methods and the tasks, for the solution of which one or another method should be applied, are shown. In order to prove the superiority in efficacy and safety of a new drug over an existing one, only a statistical approach that uses the "superiority" hypothesis is applicable. Studies using the "non-inferiority" hypothesis are generally used for comparing drugs, which are not considerably different in their efficacy, but the study drug has other advantages in the administration, storage, tolerability etc. The choice of statistical method is determined exclusively by the task of the study.

[Upper gastrointestinal bleeding in patients with stable coronary artery disease (registry of antithrombotic therapy "REGATТA" results)].

INTRODUCTION: Upper gastrointestinal (UGI) bleeding is a common complication of antiplatelet therapy. Data from real clinical practice that characterize the range of risk factors for UGI bleeding, prophylactic proton pump inhibitors (PPIs) therapy, bleeding frequency and their long-term effects in patients with stable coronary artery disease (CAD) are limited. AIM: To identify predictors of UGI bleeding in patients with stable CAD, to assess the role of PPI in the prevention of bleeding and the long-term prognosis of patients after bleeding. MATERIALS AND METHODS: 934 patients with stable CAD (median age 61 [5368] years, 78.6% men) were included in the single institution prospective REGistry of Long-term AnTithrombotic TherApy (REGATTA). Atherosclerosis of peripheral arteries (APA) and abdominal aortic aneurysm (AAA) screening was performed by doctor decision, as well as esophagogastroduodenoscopy. 76% of patients received dual antiplatelet therapy for 612 months after elective PCI. PPIs were prescribed in 28.3% of cases. RESULTS: The median follow-up was 2.5 [1.15.1] years. The frequency of overt UGI bleeding was 1.9 per 100 patients per year. Anamnesis of peptic ulcer disease (OR 4.7; 95% CI 1.911.8;p=0.001), erosion of the upper gastrointestinal tract (OR 6.7; 2.716.6;p=0.00004 ), as well as concomitant diseases associated with a decrease in blood supply to the mucosa, such as heart failure HF (OR 6.1; 2.316.0;p=0.0002), AAA (OR 9.3; 2.534.2;p=0.0008) and APA (OR 2.3; 0.985.5;p=0.05) turned out to be independent predictors of UGI bleeding. The frequency of AAA among those who underwent UGI bleeding was 19.6% (in patients without bleeding 1.4%;p0.001). 90.2% of patients with UGI bleeding received PPI; the frequency of UGI bleeding in patients receiving pantoprazole and omeprazole did not differ significantly. After UGI bleeding, rebleeding rate was 7.8%, thrombotic events (TE) rate 31.4%, mortality rate 17.7% for 30 days, 19.4% for 1 year and 35.3% for the entire observation period. The predictors of deaths were AAA (OR 92.5; 7.7107.9;p0.0001), APA (OR 4.2; 1.0317.2;p=0.045) and HF (OR 34.5; 8.5140.6;p0.0001). The worst prognosis was expected for patients who underwent UGI bleeding and thrombotic events: 2/3 of these patients died. CONCLUSION: In a prospective analysis of patients with stable CAD, we identified UGI bleeding was a significant risk factor for late thromboembolism and death, compared with patients without bleeding. Predictors of UGI bleeding and poor prognosis are factors that indicate atherothrombotic burden abdominal aortic aneurysm, peripheral atherosclerosis and HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04347200.

[Epicardial adipose tissue as a marker of visceral obesity and its association with metabolic parameters and remodeling of the left chambers of the heart in young people with abdominal obesity].

AIM: to study the correlation of epicardial adipose tissue (EAT) with metabolic parameters, 24-hours profile of blood pressure (BP) and left ventricular remodeling, with the volume of intraabdominal adipose tissue (IAAT), measured by multislice computed tomography (MSCT) in patients with abdominal obesity and metabolic syndrome. MATERIALS AND METHODS: the study included 80 participants with abdominal obesity (waist circumference > 80 cm in women and >94 cm in men) and without cardiovascular diseases and diabetes. Within this study the following examinations were performed: waist circumference and the body mass index measurement, blood sampling and measurements of lipid levels, uric acid, fasting glucose, insulin, HOMA index, 24-hour ambulatory blood pressure monitoring. Left ventricular (LV) mass index, relative wall thickness, LV mass/height index were estimated from echocardiographic data. EAT volume and IAAT was measured by MSCT. All patients was devided in two groups for analysis: 1 (n=28) - patients with isolated abdominal obesity, without metabolic syndrome, age was 37.5±6.43 years; 2 (n=52) - patients with metabolic syndrome, age - 38.8±5.88 years. The control group 0 included healthy individuals (n=13) without obesity, age was 30.5±5.97 years. RESULTS: A positive correlation was found between the volume of EAT with the level of insulin in the blood (r=0.2937, p.

[Neutrophil gelatinase-associated lipocalin for early diagnosis of acute kidney injury in patients with acute decompensated heart failure].

BACKGROUND: the incidence of acute kidney injury (AKI) is high in patients with acute decompensated heart failure (ADHF) and is linked with increased morbidity and mortality rates. Predictive biomarkers of AKI could allow improve outcomes in AKI. PURPOSE: to evaluate the value of serum neutrophil gelatinase-associated lipocalin (NGAL) concentrations for early diagnosis of AKI in patients with ADHF with left ventricular (LV) systolic function. METHODS: we enrolled 60 men (average age was 62.0±11.1 years) hospitalized with ADHF with reduced LV systolic function (LV ejection fraction (LVEF).

[Clinical, Virusological and Immunological characteristics of hospitalised HIV-infected patients].

AIM: The primary objective of this study was to describe clinical, virusological and immunological characteristics of hospitalised HIV-infected patients, who had different stages of the disease. MATERIALS AND METHODS: This study was conducted at Moscow Infectious Diseases Hospital №2 in 2012-2015. We have clinically observed 5485 HIV-infected patientsand studied their clinical histories [age: 25-45 (87%), men - 3998 (72.9%), women - 1487 (27.1%)]. 593 (10.8%) have died. We have tested plasma and liquor HIV RNA viral load, immune status, number of viral DNA copies in blood, liquor, lavage, pleural fluid, large intestinal and esophagus biopsies and other materials. Statistica v. 10.0 and SPSS v. 20 were used for statistical analysis. RESULTS AND CONCLUSION: Clinical state of HIV-infected hospitalised patients has been described and the results of quantitive determination of HIV RNA in blood and liquor, absolute and relative CD4+ and CD8+ T-lymphocytes concentrations and immunoregulatory index in patients in various disease stages, including patients on antiretroviral therapy (ART) have been presented. Statistically significant correlation between blood and liquor HIV RNA load as well as between viral load and cellular immune markers in hospitalised HIV-infected patients has been found.

The prevalence of abdominal obesity and the association with socioeconomic status in Regions of the Russian Federation, the results of the epidemiological study - ESSE-RF.

AIM: The aim of the study is to determine the prevalence of AO in the population and to assess the association with socioeconomic factors according to the data of the ESSE-RF study (Epidemiology of Cardiovascular diseases in the Regions of the Russian Federation). MATERIALS AND METHODS: The object of the study is a random population sample of men and women aged 25-64 years from 13 regions of the Russian Federation (n=21 817). Abdominal obesity in men was defined as waist circumference (WC) >94 cm, and in women - WC >80 cm. Body mass index (BMI) >30.0 kg/m2 was adopted as the criterion of common obesity. RESULTS: The prevalence of AO in Russia was 55% (61.8% in women and 44% in men), while the percent of people with obesity, defined by BMI was significantly lower (33.4%). The number of examined patients with AO increased with age among both men and women (p<0.0001). A person with AO more often were people with low and very low income and low education levels (p<0.0001). Direct association between employment status and family status and AO in present study did not find, but WC was statistically significantly important criterion among male workers in comparison with those who never worked (p<0.0001), young men and women married, as well as married men of older age groups (p<0.0001).

[The individual fatty acids of blood plasma: biological role of substrates, parameters of quantity and quality, diagnostic of atherosclerosis and atheromotosis.]

The atherosclerosis and atheromotosis are supposed to be, according to phylogenetic theory of general pathology, two etiologically different aphysiological processes, unified by community of pathogenesis. The atherosclerosis is a derangement of biological function of trophology (feeding), biological reaction of exotrophy (external feeding) and biological function of adaptation, biological reaction of compensation in response to deficiency of ῳ-3 and ῳ-6 polyenoic fatty acids. In case of deficiency of polyenoic fatty acids in cells and during synthesis of eicosanoids of group I from unsaturated endogenous ῳ-6 С20: 3 digomo-γ-linoleic unsaturated fatty acid, atherosclerosis is developed, a complex metabolism disorder in vivo. The atheromotosis is a derangement of biological function of endoecology, biological reactions of inflammation and inherent immunity. This incomplete utilization in intima of arteries of non-ligand palmitic lipoproteins of very low → low density under effect not of polyfunctional resident macrophage but monocytes of hematogenic origin without expression of acid hydrolase of polyenoic ethers of cholesterol. In intima, in area of cumulation of endogenous phlogogens (initiator of inflammation) from the pool of intra-vascular medium, polyenoic unsaturated fatty acids are cumulated that were not absorbed by cells in structure of ligand low density palmitic lipoproteins using apoB-100- endocytosis. The pathogenic factor of atherosclerosis - derangement of biological function of trophology. biological function of exotrophy under alimentary deficiency of in vivo of ῳ-3 and ῳ-6 polyenoic fatty acids with physiological parameters of feeding. The pathogenic factor of atheromotosis - phylogenetically herbivorous (carnivorous) human misusing of animal (meat) food, palmitic unsaturated fatty acids, development by hepatocytes of a large number of palmitic triglycerides and lipoproteins of very low density of the same name. The late in phylogenesis insulin-dependent lipoproteins of very low density transfer palmitic lipoproteins of very low density to cells slowly. The cells absorb them also slowly. The cumulation of non-ligand palmitic lipoproteins of very low density → low density in blood competitively blocks physiological absorption of polyenoic unsaturated fatty acids by cells in structure of physiological palmitic lipoproteins of low density. The atherosclerosis occurs blood flow and atheromotosis in intima of arteries of elastic type.

Effect of Fibrinogen on Platelet Reactivity Measured by the VerifyNow P2Y12 Assay.

The VerifyNow assay is based upon the ability of activated platelets to cross-link beads coated with fibrinogen. However, fibrinogen is an abundant protein of blood, and therefore it may affect test results by competing with fibrinogen of beads for binding to platelets. To test this assumption, we assessed the influence of artificial alteration of fibrinogen level in blood samples obtained from donors (n = 9) and patients on clopidogrel therapy (n = 8) on the results of the VerifyNow P2Y12 assay. Fibrinogen level was altered by adding to blood samples 1/10 volume of fibrinogen solution (10.56 g/liter) or corresponding buffer. Relative to baseline, addition of buffer significantly increased platelet reactivity, whereas addition of fibrinogen decreased it. Analysis of the relationship between change in platelet reactivity values (dBase and dPRU) and change in fibrinogen concentration (dFg) revealed strong negative correlations: dBase = -63.3 × dFg - 27.1 (r = -0.924, p < 0.0005) and dPRU = -54.4 × dFg - 21.8 (r = -0.764, p < 0.0005). Thus, the results of our experiments suggest that: (i) blood fibrinogen strongly influences results of the VerifyNow P2Y12 assay, and (ii) correcting for fibrinogen effect may be needed to improve the accuracy of the test in the measuring of antiplatelet effect of clopidogrel therapy.

[Combination of Visual and Metabolic Markers in Assessment of Probability of Presence and Severity of Atherosclerosis of Coronary Arteries].

AIM: to assess possibilities of the use of biochemical markers combined with data of methods of imaging of arterial atherosclerotic lesions for evaluation of risk of presence and severity of coronary atherosclerosis. MATERIALS AND METHODS: We enrolled into this study patients (n=205, 136 men, 69 women, age 33-85 years, 94% on statin therapy) who underwent coronary angiography and carotid artery ultrasound dopplerography. Examination included determination of parameters of lipid profile and carbohydrate metabolism, markers of inflammation and metabolism of visceral adipose tissue. The severity of carotid artery atherosclerosis was estimated using mean common carotid artery intima-media thickness and atherosclerotic plaques presence. Severity of coronary atherosclerosis was evaluated using Gensini score. RESULTS: We found association between a number of biomarkers and severity of coronary artery involvement. Presence of coronary atherosclerosis (Gensini score >0) was associated with male sex, carotid artery stenosis >45%, and adiponectin level <8.0 pg/ml. Overt coronary atherosclerosis (Gensini score more or equal 35) significantly correlated with intima-media thickness more or equal 0.9 mm, C-reactive protein level >3.0 mg/l and adiponectin level <8.0 pg/ml.

[Role of polymorphic markers for the genes of hemostasis and platelet receptors in liver fibrosis progression in patients with chronic hepatitis C]. / Rol' polimorfnykh markerov genov gemostaza i trombotsitarnykh retseptorov v progressirovanii fibroza pecheni u bol'nykh khronicheskim gepatitom S.

AIM: to estimate the clinical and prognostic value of the carriage of different allele variants of the gene polymorphisms of the coagulation system and platelet receptors in the progression of liver fibrosis (LF) in patient with chronic hepatitis C (CHC). SUBJECTS AND METHODS: The investigation enrolled 177 patients with CHC and liver cirrhosis at its outcome who were divided into 2 groups according to the rate of LF progression: 1) 89 patients with rapid (rapid fibrosis) and 2) 88 patients with slow (slow fibrosis) progression. The polymorphism of the study genes was studied using a real-time polymerase chain reaction and a melting curve analysis. RESULTS: In CHC patients, the FV 1691G/A genotype was more often in the rapid progressors than that in the slow progressors (10.11% vs 1.14%; p=0.011). The A allele of the 1691 G/A FV gene was more common in the rapid fibrosis group than that in the slow fibrosis group (1.7% vs 5.56%, odd ratio 9.787; p=0.139). In our investigation, the polymorphic marker GA in the FII 20210 G/A gene, as well as the 4G allele (5G4G + 4G4G genotypes) and the 4G allele of PAI-I -675 5G/4G were more often seen in the rapid fibrosis group than that in the slow fibrosis group; the detection rate was only at the trend level (p=0.118, p=0.112, and p=0.117 respectively). There were no significant differences between the groups in the spread of variant genotypes and alleles of other study genes. Integral model construction by coding «profibrogenic¼ genotypes (FV 1691 G/A, FII 20210 G/A, PAI-I -675 5G/4G) showed that the fibrosis progression rate expressed as fibrosis units annually also increased with higher total scores (p=0.039), indicating the combined effect of these genes. CONCLUSION: The carriage of mutant genotypes of FV 1691 G/A, FII 20210 G/A, and PAI-I -675 5G/4G genes is a prognostic factor for rapid CHC progression.

[Mathematic Model for Prediction of Liver Fibrosis Progression Rate in Patients with Chronic Hepatitis C Based on Combination of Genomic Markers].

AIM OF STUDY: To evaluate clinical significance of different combinations of gene polymorphisms IL-1b, IL-6, IL-10, TNF, HFE, TGF-b, ATR1, N0S3894, CYBA, AGT, MTHFR, FII, FV, FVII, FXIII, ITGA2, ITGB3, FBG, PAI and their prognostic value for prediction of liver fibrosis progression rate in patients with chronic hepatitis C (CHC). SUBJECTS AND METHODS: 118 patients with CHC were divided into "fast" and "slow" (fibrosis rate progression ≥ 0.13 and < 0.13 fibrosis units/yr; n = 64 and n = 54) fibrosis groups. Gene polymorphisms were determined. Statistical analysis was performed using Statistica 10. RESULTS: A allele (p = 0.012) and genotype AA (p = 0.024) of AGT G-6T gene, as well as T allele (p = 0.013) and MT+TT genotypes (p = 0.005) of AGT 235 M/T gene were significantly more common in "fast fibrosers" than in "slow fibrosers". Patients with genotype TT of CYBA 242 C/T had a higher fibrosis progression rate than patients with CC+CT genotype (p = 0.02). Our analysis showed a protective effect of TTgenotype of ITGA2 807 C/T on fibrosis progression rate (p = 0.03). There was a trend (p < 0.15) to higher fibrosis progression rate in patients with mutant alleles and genotypes of TGFb +915 G/C, FXIII 103 G/T, PAI-675 5G/4G genes. Other gene polymorphisms were not associated with enhanced liver fibrosis. To build a mathematical modelfor prediction of liverfibrosis progression rate we performed coding with scores for genotypes and virus genotype. Total score correlated with the fibrosis progression rate (R = 0.39, p = 0.000). CONCLUSION: Determination of genetic profile of the patient and virus genotype allows to predict the course of CHC.

[Markers of visceral adipose tissue metabolic abnormalities in patients with coronary atherosclerosis in relation to the presence of type 2 diabetes mellitus]. / Markery narusheniya metabolizma vistseral'noi zhirovoi tkani u patsientov s koronarnym aterosklerozom v zavisimosti ot nalichiya sakharnogo diabeta 2-go tipa.

AIM: To assess the specific features of visceral adipose tissue metabolism in patients with coronary atherosclerosis, complicated or uncomplicated type 2 diabetes mellitus (T2DM). MATERIAL AND METHODS: A cohort of 429 patients (325 men and 104 women; mean age, 61.3±9.4 years) with coronary atherosclerosis who had been admitted to the National Research Centre for Preventive Medicine, Ministry of Health of Russia, to undergo coronarography (CG) and to receive high-tech treatments and met the criteria for being included in and excluded from this investigation, was examined. The Gensini scoring scale was used to estimate the magnitude of coronary atherosclerosis from CG RESULTS: Carotid artery duplex ultrasound scanning estimating the intima-media thickness was performed in 48% of the patients. DM was diagnosed from examination results (fasting plasma glucose ≥7.0 mmol/l and glycated hemoglobin >6.5%) and an endocrinologist's report. 94% of the patients took statins. RESULTS: Overall, 18% of the examinees had DM that was 2.5 times more common in the women than in the men (32.7 and 13.2%, respectively (p=0.000). The diabetic and non-diabetic patients showed no significant differences in age: 62.9±8.3 and 60.9±9.6 years, respectively (p=0.105). There were statistically significant differences in the magnitude of coronary artery atherosclerosis according to the Gensini scale in relation to the presence of T2DM; thus, the median Gensini score was 48 in the diabetic patients and 46 in the persons with no signs of the disease (Mann-Whitney test; p=0.03). Analysis of adipokine levels showed that the median leptin level was significantly higher than that in the male patients with T2DM than in the persons with no signs of the disease. In the patients with T2DM, the median adiponectin level turned out to be significantly lower in both men and women. CONCLUSION: The coronary atherosclerosis severity rated using the Gensini scale is shown to increase in the presence of T2DM. The probability of detecting obvious (>45%) carotid artery lesion is associated with the presence of DM in both men and women. The male patients with T2DM concurrent with coronary atherosclerosis are noted to have an elevated leptin level, but a lower adiponectin concentration was found in both the men and women.

[Nonimmunogenic staphylokinase in the treatment of acute ischemic stroke (FRIDA trial results)]. / Neimmunogennaya stafilokinaza ­ novyi tromboliticheskii preparat v lechenii ishemicheskogo insul'ta (rezul'taty issledovaniya FRIDA).

AIM OF THE STUDY: To investigate the efficacy and safety of non-immunogenic staphylokinase (NS) compared with alteplase (A) in patients with acute ischemic stroke (AIS) within 4.5 h after symptom onset. MATERIAL AND METHODS: 336 patients with IS within 4.5 h after symptom onset were included in a randomized, open-label, multicenter, parallel-group, non-inferiority comparative trial of NS vs A (168 patients in each group). NS was administered as an intravenous bolus in a dose of 10 mg, regardless of body weight, over 10 s, A was administered as a bolus infusion in a dose of 0.9 mg/kg, maximum 90 mg over 1 hour. The primary efficacy endpoint was a favorable outcome, defined as a modified Rankin scale (mRS) score of 0-1 on day 90. Safety endpoints included all-cause mortality on day 90, symptomatic intracranial haemorrhage, and other serious adverse events (SAEs). RESULTS: At day 90, 84 (50%) patients reached the primary endpoint (mRS 0-1) in the NS group, 68 (41%) patients - in the A group (p=0.10, OR=1.47, 95% CI=0.93-2.32). The difference between groups NS and A was 9.5% (95% CI= -1.7-20.7) and the lower limit of the 95% CI did not cross the margin of non-inferiority (pnon-inferiority<0.0001). There were no significant differences in the frequency of deaths between the groups: on day 90, 17 (10%) patients in the NS group and 24 (14%) in the A group had died (p=0.32). There was a trend towards significant differences in the frequency of symptomatic intracranial haemorrhage: NS group - 5 (3%) patients, A group - 13 (8%) patients (p=0.087, OR=0.37, 95% CI=0.1-1.13). There were significant differences in the number of patients with SAEs: in the NS group - 22 (13%) patients, in the A group - 37 (22%) patients (p=0.044, OR=0.53, 95% CI=0.28-0.98). CONCLUSION: The presented results of the FRIDA trial are the first in the world to use a drug based on NS in patients with IS. It has been shown that a single bolus (within 10 s) administration of NS at a standard dose of 10 mg, regardless of body weight, allows to conduct fast, effective and safe thrombolytic therapy in patients with IS within 4.5 h after symptom onset. In further clinical tials of NS, it is planned to expand the therapeutic window beyond 4.5 h after symptom onset in patients with IS.