Микрореологические свойства крови и капиллярный кровоток при артериальной гипертензии и сахарном диабете второго типа: исследование оптическими методами in vitro и in vivo

Aim. To study microrheological properties of RBCs and capillary blood flow parameters using optical methods in patients with arterial hypertension (AH) and type 2 diabetes mellitus (DM2).Methods. RBCs aggregation properties were evaluated in vitro using laser aggregometry and optical trapping. Сapillary nail refill was evaluated in vivo using nailfold digital capillaroscopy.Results. The aggregation of RBCs in patients suffering from AH was higher compared to healthy subjects who demonstrated a decrease in the aggregation time by 29±9%. A similar trend was observed in patients with AH and DM2. The comparison of the results obtained by different methods showed that patients with AH with a high capillary blood flow velocity measured in vivo reported a decrease in the aggregation index by 14±4% compared to patients with low velocity.Conclusion. The comparison of microrheological blood properties in patients with AH and AH+DM2 versus the control group showed statistically significant differences in the aggregation index that was higher in AH patients. These differences were more pronounced in patients with AH and DM2. The results obtained by in vitro and in vivo methods were consistent.Цель. Анализ агрегационных свойств эритроцитов и параметров капиллярного кровотока, измеренных различными оптическими методами, у пациентов с артериальной гипертензией (АГ) и сахарным диабетом второго типа (СД2).Материалы и методы. Измерения агрегационных свойств проводились invitro методами лазерной агре-гометрии и оптического захвата. Анализ кровотока в капиллярах ногтевого ложа испытуемых выполнен in vivo с использованием цифровой капилляроскопии.Результаты. Агрегация эритроцитов у пациентов с АГ повышена по сравнению со здоровыми испытуемыми: характерное время агрегации уменьшено на 29±9%. Эта же тенденция к усилению агрегации видна в группе пациентов с АГ и СД2. Сопоставление результатов, полученных с использованием различных методов измерения, показало, что в группе пациентов с АГ с повышенной скоростью кровотока, измеренной in vivo, индекс агрегации, измеренный invitro, снижен на 14±4% по сравнению с группой с пониженной скоростью.Заключение. Сравнение значений микрореологических параметров крови, характерных для групп пациентов с АГ, в том числе при наличии СД2, и здоровых доноров, показывает статистически значимые отличия: у пациентов с АГ агрегация эритроцитов повышена. Эти отличия выражены сильнее у пациентов с АГ и СД2. Кроме того, результаты, полученные различными оптическими методами in vitro и in vivo, согласуются между собой

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Improved risk stratification of patients with atrial fibrillation: an integrated GARFIELD-AF tool for the prediction of mortality, stroke and bleed in patients with and without anticoagulation.

OBJECTIVES: To provide an accurate, web-based tool for stratifying patients with atrial fibrillation to facilitate decisions on the potential benefits/risks of anticoagulation, based on mortality, stroke and bleeding risks. DESIGN: The new tool was developed, using stepwise regression, for all and then applied to lower risk patients. C-statistics were compared with CHA2DS2-VASc using 30-fold cross-validation to control for overfitting. External validation was undertaken in an independent dataset, Outcome Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). PARTICIPANTS: Data from 39 898 patients enrolled in the prospective GARFIELD-AF registry provided the basis for deriving and validating an integrated risk tool to predict stroke risk, mortality and bleeding risk. RESULTS: The discriminatory value of the GARFIELD-AF risk model was superior to CHA2DS2-VASc for patients with or without anticoagulation. C-statistics (95% CI) for all-cause mortality, ischaemic stroke/systemic embolism and haemorrhagic stroke/major bleeding (treated patients) were: 0.77 (0.76 to 0.78), 0.69 (0.67 to 0.71) and 0.66 (0.62 to 0.69), respectively, for the GARFIELD-AF risk models, and 0.66 (0.64-0.67), 0.64 (0.61-0.66) and 0.64 (0.61-0.68), respectively, for CHA2DS2-VASc (or HAS-BLED for bleeding). In very low to low risk patients (CHA2DS2-VASc 0 or 1 (men) and 1 or 2 (women)), the CHA2DS2-VASc and HAS-BLED (for bleeding) scores offered weak discriminatory value for mortality, stroke/systemic embolism and major bleeding. C-statistics for the GARFIELD-AF risk tool were 0.69 (0.64 to 0.75), 0.65 (0.56 to 0.73) and 0.60 (0.47 to 0.73) for each end point, respectively, versus 0.50 (0.45 to 0.55), 0.59 (0.50 to 0.67) and 0.55 (0.53 to 0.56) for CHA2DS2-VASc (or HAS-BLED for bleeding). Upon validation in the ORBIT-AF population, C-statistics showed that the GARFIELD-AF risk tool was effective for predicting 1-year all-cause mortality using the full and simplified model for all-cause mortality: C-statistics 0.75 (0.73 to 0.77) and 0.75 (0.73 to 0.77), respectively, and for predicting for any stroke or systemic embolism over 1 year, C-statistics 0.68 (0.62 to 0.74). CONCLUSIONS: Performance of the GARFIELD-AF risk tool was superior to CHA2DS2-VASc in predicting stroke and mortality and superior to HAS-BLED for bleeding, overall and in lower risk patients. The GARFIELD-AF tool has the potential for incorporation in routine electronic systems, and for the first time, permits simultaneous evaluation of ischaemic stroke, mortality and bleeding risks. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier for GARFIELD-AF (NCT01090362) and for ORBIT-AF (NCT01165710)

Two-year outcomes of patients with newly diagnosed atrial fibrillation: results from GARFIELD-AF.

AIMS: The relationship between outcomes and time after diagnosis for patients with non-valvular atrial fibrillation (NVAF) is poorly defined, especially beyond the first year. METHODS AND RESULTS: GARFIELD-AF is an ongoing, global observational study of adults with newly diagnosed NVAF. Two-year outcomes of 17 162 patients prospectively enrolled in GARFIELD-AF were analysed in light of baseline characteristics, risk profiles for stroke/systemic embolism (SE), and antithrombotic therapy. The mean (standard deviation) age was 69.8 (11.4) years, 43.8% were women, and the mean CHA2DS2-VASc score was 3.3 (1.6); 60.8% of patients were prescribed anticoagulant therapy with/without antiplatelet (AP) therapy, 27.4% AP monotherapy, and 11.8% no antithrombotic therapy. At 2-year follow-up, all-cause mortality, stroke/SE, and major bleeding had occurred at a rate (95% confidence interval) of 3.83 (3.62; 4.05), 1.25 (1.13; 1.38), and 0.70 (0.62; 0.81) per 100 person-years, respectively. Rates for all three major events were highest during the first 4 months. Congestive heart failure, acute coronary syndromes, sudden/unwitnessed death, malignancy, respiratory failure, and infection/sepsis accounted for 65% of all known causes of death and strokes for <10%. Anticoagulant treatment was associated with a 35% lower risk of death. CONCLUSION: The most frequent of the three major outcome measures was death, whose most common causes are not known to be significantly influenced by anticoagulation. This suggests that a more comprehensive approach to the management of NVAF may be needed to improve outcome. This could include, in addition to anticoagulation, interventions targeting modifiable, cause-specific risk factors for death. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

PULSE WAVE VELOCITY AND ENDOTHELIAL FUNCTION COMPARISON IN HEALTHY PEOPLE AND CARDIOVASCULAR PATIENTS

The study aimed to identify the interrelations between pulse wave velocity (PWV) and endothelial function (EF), measured by a new non-invasive method vs. brachial artery Doppler ultrasound, as well as to investigate intima-media thickness (IMT) in carotid artery bifurcation area, in healthy people, patients with arterial hypertension (AH), and individuals with coronary heart disease (CHD). Comparing brachial-forearm PWV levels measured with the Tonocard device, and brachial artery linear blood flow velocity demonstrated statistically significant differences between velocity figures in healthy people, CHD patients, and AH participants. IMT values were significantly greater in CHD patients, but not in AH individuals, than in healthy people from the same age group. The new method for PWV and EF assessment provides an opportunity to evaluate CHD risk and risk-reducing therapy effectiveness in minimal time

MICROCIRCULATION IN CHRONIC HEART FAILURE PATIENTS TREATED WITH ACE INHIBITORS AND DIURETICS

Chronic heart failure (CHF) is a complex clinical syndrome, which can result in structural and/or functional cardiac disturbances, decreased ventricular pump function, and inadequate cardiac ejection. This study was aimed at investigating microcirculation features in CHF patients, as well as evaluating the effects of treatment with ACE inhibitors, diuretics, and anti-aggregants on microcirculation parameters (assessed by computerized nailfold capillaroscopy) among patients with normal and low ejection fraction (EF). The study included 58 participants: 20 healthy volunteers without cardiovascular disease (mean age 52,6±6,6 years; mean EF 63,1±4,5%); 36 patients with coronary heart disease (CHD) and myocardial infarction, arterial hypertension, and CHF in anamnesis; and 2 patients with dilated cardiomyopathy. All patients were divided into two groups, by EF values. Group I included 22 individuals (12 men, 10 women; mean age 63,2±9,4 years) with EF &gt;52%. Group II included 16 people (11 men, 5 women; mean age 62,9±8,5 years) with EF &lt;52%. The patients received enalapril (20 mg/d), acetylsalicylic acid (125 mg/d), and furosemide (40 mg twice a week). Microcirculation parameters (perivascular zone area, capillary blood flow velocity, arterial, intermediate, and venous diameters, and “sludge” phenomenon) were assessed at baseline and after 2 weeks of the treatment. The study results demonstrated the potential of non-invasive computerized nailfold capillaroscopy for microcirculation assessment in CHF patients. This method allowed the authors to identify the microcirculation features typical for CHF: 1) increased perivascular zone area, compared to healthy controls; 2) increased ratio “venous diameter / arterial diameter”; 3) reduced capillary blood flow velocity; 4) and “sludge” phenomenon