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

High normal blood pressure in young patients – a disease or a risk factor?

Aim. To study correlations between blood pressure (BP) level and autonomous dysfunction symptoms. Material and methods. The study included 84 males aged 18-45, with mean systolic BP (SBP) level of 110-139 mm Hg, and diastolic BP (DBP) level of 70-89 mm Hg. The standard physical and instrumental examination, 24-hour BP monitoring, and modified orthostatic test were performed. Results. In 80% of the patients with high normal (HN) BP, there were some clinical symptoms observed, e.g. headache and vertigo. Circadian BP profile was characterized by increased load index and elevated mean BP during all day, comparing to normotensive subjects. HN BP group was heterogeneous: in 42.3% of cases, BP variability was increased, nighttime BP was abnormally decreased, and hemodynamics reaction in orthostatic test was exaggerated. Conclusion. In young males with HN BP, autonomous dysfunction symptoms, associated with increased BP variability and abnormally increased nighttime BP drop, can be regarded as a complex of early cardiovascular disease predictors

Intrahospital switch of the P2Y12 inhibitors in patients with ST segment elevation myocardial infarction in ‘real-life’ clinical practice: the effect on the functional activity of thrombocytes and thrombocytopoiesis, prognostic value

Aim. To assess the P2Y12 inhibitors switch in patients ST segment elevation myocardial infarction (STEMI) in real-life’ clinical practice, evaluate the functional activity of thrombocytes and thrombocytopoiesis and determine the clinical and prognostic value of P2Y12 inhibitors switch in the framework of dual antiplatelet therapy in patients with STEMI.Material and methods. We conducted local, stratified, prospective study in which were involved 101 patients, hospitalized no later than 12hours after the STEMI manifestation. The antiplatelet therapy (APT), prescribed by the physicians at the pre-hospital and inpatient phases of treatment, was analyzed. Functional activity of thrombocytes, levels of thrombopoietin (THPO), stromal cell-derived factor 1 (SDF1) and thrombopoietic receptor (MPL) were investigated. The minimum observation period was 2 years. Death and repeated hospitalizations due to cardiovascular causes were monitored.Results. P2Y12 inhibitors were switched in 32,7% of patients with STEMI. In the hospital, clopidogrel, which was prescribed at the prehospital phase, was replaced with ticagrelor (early APT escalation) — 22,8%. Patients with early APT escalation by the seventh day had significantly greater inhibition of platelet aggregation activity parameters (slope of the aggregation curve, latent aggregation time and area under the aggregation curve). Activation of the collagen-induced platelet aggregation was detected. With the early escalation of APT, the THPO level was statistically significantly higher, both on the second and on the 7th day measurements: 256,2 (209,0; 396,8) pg/ml vs 137,5 (105,7; 179,1) pg/ml (p=0,000) and 283,4 (228,9; 334,3) pg/ml vs 226,5 (163,2; 287,3) pg/ml (p=0,045), respectively. The frequency of reaching the combined endpoint (death + re-hospitalization) was 7,9% in patients who had a P2Y12 switch, and 28,1% in patients who did not change the P2Y12 blocker.Conclusion. In actual clinical practice, patients with STEMI had the most frequent early APT escalation, which was characterized by a more significant suppression of adenosine diphosphate-induced platelet aggregation and secretion than in patients without P2Y12 inhibitors switch, but with activation of collagen-induced aggregation. An increase in thrombocytogenesis was revealed in early replacement of clopidogrel by ticagrelor. Intrahospital replacement of the P2Y12 inhibitor in patients with STEMI was accompanied by a decrease in the two-year death risk and repeated hospitalizations

PHARMACOTHERAPY AND OUTCOMES OF ACUTE ST-ELEVATION MYOCARDIAL INFARCTION – GENDER DIFFERENCES IN REAL CLINICAL PRACTICE

Aim. To analyze gender differences in pharmacotherapy and outcomes of ST-elevation myocardial infarction (STEMI) in patients of cardiology hospital in real clinical practice. Material and methods. A continuous pharmacoepidemiological analysis was performed on the base of 153 records of patients with STEMI (men 102, women 51), consecutively admitted to the emergency department of cardiology hospital in the period from October 2010 to April 2011.Results. Women were on average 10.6 years older than men, had significantly higher incidence of severe comorbid conditions and significantly fewer prescribed medications improving STEMI prognosis - thrombolytics (21% vs 50%; p<0.05), statins (20% vs 53%; p<0.05), beta-blockers (84% vs 91%; p<0.05) and dual antiplatelet therapy (21% vs 59%; p<0.05). Hospital mortality was significantly higher in women than this in men, at that mortality differences persisted for 12 months after discharge.Conclusion. Older age, higher comorbidity rate, and lower treatment compliance with the current clinical recommendations in female STEMI patients in comparison with these in male STEMI patients contribute to higher hospital mortality and 12-month mortality after discharge in women with STEMI

COMPARISON OF DIRECT COSTS OF DABIGATRAN AND WARFARIN THERAPY IN PATIENTS WITH NON-VALVULAR ATRIAL FIBRILLATION DURING PREPARATION FOR ELECTIVE CARDIOVERSION IN THE REAL CLINICAL PRACTICE

Aim. To compare direct medical costs of dabigatran and warfarin therapy in patients with non-valvular atrial fibrillation (NVAF) during preparation for elective cardioversion. Material and methods. An open non-randomized study was conducted to evaluate direct medical costs (cost of drug, cost of the international normalized ratio (INR) adjust- ment in outpatient clinic, cost of visits to cardiologist). Patients (n=62) with persistent NVAF (AF paroxysm duration &gt; 48 hours) were enrolled. All of them requested medical as- sistance and were decided to perform an elective cardioversion. The patients received warfarin (n=32) or dabigatran (n=30). The patients of the both groups were similar in the main clinical characteristics and thromboembolic risk levels according to CHA2DS2-VASc scale.Results. Treatment duration before elective cardioversion was 21±2 and 30.5±4.5 days for dabigatran and warfarin groups, respectively (p&lt;0.05). Average costs of visits to cardiologists were 3,720 and 744 RUB in warfarin and dabigatran groups, respectively (p&lt;0.05), and drug costs were 53.63 and 1,172.01 RUB, respectively (p&lt;0.05). The costs of laboratory INR monitoring were 3,058 RUB in warfarin group. Total costs per patient were 6,831.63 and 1,916.01 RUB in warfarin and dabigatran groups, respectively (p&lt;0.05). Conclusion. In the real clinical practice in patients with NVAF dabigatran antithromboembolic therapy substantially reduces direct medical costs in comparison with warfarin ther- apy during preparation for elective cardioversion. Dabigatran therapy reduces time from the decision of elective cardioversion and antithromboembolic therapy start to car- dioversion performance.</p

THE ADHERENCE TO RECOMMENDED THERAPY IN PATIENTS AFTER ACUTE CORONARY SYNDROME, AND RISK OF CARDIOVASCULAR COMPLICATIONS WITHIN A YEAR AFTER HOSPITAL ADMISSION

Aim. In patients after acute coronary syndrome (ACS) to study the effect of adherence to recommended therapy on the risk of cardiovascular events during a year after hospital admission, and to identify the main causes of low adherence to prescribed therapy. Material and methods. Patients with ACS (n=271), consistently admitting to the emergency cardiology department were included into the study. Complex therapy (acetylsalicylic acid (ASA), beta-blockers (BB), ACE inhibitors, statins) was prescribed to all patients. The drugs prescription rate was analyzed. The cardiovascular events (death, myocardial infarction, stroke, episodes of unstable angina, decompensated heart failure) were recorded for 12 months. The adherence of patients to recommended therapy was evaluated. Results. After hospital discharge ASA therapy was recommended to 98% of patients, BB — 95%, ACE inhibitors — 97%, statins — 63%. In 12 months only 73% of patients continued therapy with ASA, 66% — BB, 74% — ACE inhibitors, 44% — statins. The rate of hospital re-admission was significantly higher in patients with low adherence: 80% (n=32) vs 24% (n=55) among compliant patients. The main causes of hospital re-admission were decompensated heart failure (46%), recurrent episodes of angina (32%) or ACS (19%). Conclusion. A significant part of patients (about 1/3) terminates the recommended therapy within 12 months after ACS. Low adherence to therapy is often determined by subjective factors and associated with a 3-fold increased risk of cardiovascular events (RR 3.27; 95% CI 2.49-4.30; p=0.05)

High residual platelet reactivity during dual antiplatelet therapy, found by optical aggregometry and the rate of atherothrombotic complications after coronary artery stenting in patients with ischemic heart disease in clinical practice

Aim. To study the prevalence of high residual platelet reactivity (HRPR) during the dual antiplatelet therapy (DAT) with acetylsalicylic acid (ASA) and clopidogrel by optical aggregometry in patients with ischemic heart disease (IHD) after percutaneous transluminal coronary angioplasty (PTCA) in clinical practice, as well as to determine its value for the prediction of clinical course and outcome of disease.Material and methods. Patients after PTCA and during DAT were included into the study. Evaluation of the functional activity of platelets by optical aggregometry was performed in all patients at baseline. Resistance to ASA, clopidogrel and DAT were detected. Endpoints included cases of repeated atherothrombotic events (sudden cardiac death, myocardial infarction, unstable angina, ischemic stroke, stent thrombosis). Adherence to therapy was evaluated by Morisky-Green test.Results. 97 patients were included into the final analysis. The risk of myocardial infarction or unstable angina pectoris in the ASA-resistant patients was significantly higher than this in the DAT-sensitive patients [relative risk (RR)=7.68; 95% confidence interval (CI) 2.8-20.54; p=0.045]. Maximum RR for stent thrombosis was in clopidogrel-resistant (RR=7.1; 95% CI 1.41-35.82; p=0.0485) and DAT-resistant patients (RR=12.8; 95% CI 4.5-36.38; p=0.0491), compared with patients with a sensitivity to antiplatelet therapy. DAT-resistance was associated with a higher RR of the combined endpoint, compared with the sensitivity to antiplatelet therapy (RR=10.24; 95% CI 3.96-26.5; p=0.046]), and have a tendency to association with increased risk of combined endpoint compared with isolated ASA-resistance (RR=1.3; 95% CI 0.68-2.6; p=0.081).Conclusion. HRPR during DAT is common in clinical practice in patients with ischemic heart disease after PTCA. Routine use of optical aggregometry in DAT may help to identify patients with an increased risk of thrombotic events in the postoperative period and to assign them an alternative antiplatelet therapy

MONITORING OF THE EFFECTIVENESS OF ANTIPLATELET THERAPY IN CARDIOLOGY PRACTICE

Monitoring of the effectiveness of drug therapy is one of the most debated issues in everyday clinical practice. The emergence of new drugs,  methods of analysis, standards, management protocols, and clinical guidelines increases the information load on practitioners and requires a significant investment of time and efforts for self-education. The purpose of the review is to help practitioners in summary form to obtain the necessary information on the issue of control of antiplatelet therapy. The review brings together data  from current  clinical recommendations on antiplatelet therapy in patients with ischemic heart disease, gives information of existing approaches to control of antiplatelet therapy specified in the guidelines and the consensuses of experts. It presents information on the most common modern methods of monitoring of the antiplatelet therapy effectiveness

RISK OF THROMBOEMBOLIC COMPLICATIONS AND ANTITHROMBOTIC THERAPY IN IN-PATIENTS WITH PERMANENT AND RECURRENT ATRIAL FIBRILLATION IN REAL CLINICAL PRACTICE

Aim. Тo evaluate compliance of ongoing antithrombotic therapy (ATT) in various forms of atrial fibrillation (AF) with the risk level of thromboembolic complications (TEC), calculated with the СHADS2 and CHA2DS2–VASc scales in real clinical practice. Material and methods. A retrospective study of hospital records of 308 in-patients admitted to the cardiology departments of two multidisciplinary hospitals during the year because of nonvalvular AF . Risk of thromboembolic complications was estimated with the CHADS2 and CHA2DS2–VASc scales and appointed ATT was analyzed. Results. Patients with high risk of TEC were predominated in the study population: 77.6% and 91.9% according to CHADS2 and CHA2DS2–VASc scales, respectively. Moderate risk was found in  17.6%  and  6.1%  of  patients  according  to  CHADS2 and  CHA2DS2–VASc  scales,  respectively.  Only  32.2%  and  28.6%  28.6%  of  patients  at  high  risk  according  to  CHADS2 and  CHA2DS2–VASc scales, respectively received warfarin in hospital. All patients with permanent AF in this sample had a high risk of TEC according to the both scales. In the group of paroxysmal/persistent AF the high, moderate and low risk of TEC was identified in 87%, 9.9%, and 3.1% of patients, respectively , according to CHA2DS2–VASc scale and in 64.25%, 28.5% and 7.5% of patients, respectively , according to CHADS2 scale. Difference in high-risk patient rate was not significant among patients with permanent AF . In high risk group contraindications for receiving indirect anticoagulants were more frequent in the group with permanent AF (OR 3.1; 95% CI 0.88–10.7; p&gt;0,05). The probability of warfarin prescription in patients with permanent AF was higher than in patients with paroxysmal or persistent AF (OR 1.98, 95% CI 1,18-3,31), and probability of aspirin prescription was lower (OR 0.82; 95% CI 0,51-1,32; p&gt;0,05).  Conclusion. In real clinical practice oral anticoagulants are prescribed insufficiently in patients at high risk. Usage of CHA2DS2–VASc scale compared with usage of CHADS2 scale, leads to significant increase in the proportion of patients at high risk due to reduction in the proportion of patients with moderate risk in persistent or permanent AF . Usage of CHADS2 scale can lead to an underestimation of the TEC risk in patients with persistent or permanent AF .</p

RISK OF RECURRENT THROMBOTIC EVENTS IN PATIENTS WITH ACUTE CORONARY SYNDROME AND HIGH PLASMA LEVELS OF D-DIMER

Aim. To study the association of plasma D-dimer levels and the risk of thrombotic events in patients hospitalised with acute coronary syndrome (ACS).Material and methods. The study included 70 patients, aged 34-88 years, who were admitted to the Acute Coronary Care Unit with the ACS diagnosis.Results. During the follow-up period, thrombotic events were registered in 12 patients (17%). Three patients with myocardial infarction (MI) suffered recurrent MI. Nine patients were rehospitalised with the unstable angina (UA) diagnosis. All participants were divided into quartiles by the levels of D-dimer (25% percentile 136 ng/ml; median 1250 ng/ml; and 75% percentile 2930 ng/ml). High plasma levels of D-dimer (third quartile) were associated with a 1,5-fold increase in the risk of recurrent thrombotic events among ACS patients.Conclusion. In ACS patients, plasma D-dimer levels could be regarded as one of the additional risk factors of thrombotic events