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

Out-patient, auto-translation ECG home monitoring in cardiac arrhythmias diagnostics among myocardial infarction patients

Aim. To analyze efficacy of out-patient, auto-translation (AT) ECG home monitoring for early, differential diagnostics of cardiac arrhythmias (CA) and antiarrhythmic treatment control in myocardial infarction (MI) patients. Material and methods. The follow-up results for 136 Q-MI patients are presented. In 70 individuals, AT ECG was performed for 6 months, in “state-adjusted” and “ set discrete time” regimens. Sixty-eight patients underwent standard rehabilitation, controlled by out-patient cardiologists. Both groups were comparable by clinical severity and administered treatment (aspirin, beta blockers, ACE inhibitors, nitrates, etc.). Results. In AT ECG group, CA (including potentially dangerous CA) were registered more often, that gave a chance to correct antiarrhythmic therapy. Sudden death (SD) incidence reached 27.2% in AT ECG group, and 40% in control group (percentage from all-cause mortality group rates). Conclusion. AT ECG, as a variant of ECG home monitoring, substantially widens perspectives for out-patient CA diagnostics and management in MI patients, and possibly decreases SD incidence in early post-MI period

QT DURATION AND DISPERSION IN ANGINA AND MYOCARDIAL INFARCTION

We have studied 176 men, including 84 with acute myocardial infarction (mean age 59,2±2,2), 92 (mean age 49,2±3,5) with angina of various functional classes. We have registered 12-lead ECG at rest (50 mm/sec) to all simultaneously. QT and QTc dispersion were calculated as the difference between their maximal and minimal durations in all the 12 leads. The prognostic role of QT dispersion as a marker of potentially life-threatening arrhythmias, is insufficient in the angina group. Unlike those, patient with acute myocardial infarction demonstrate a far greater role QT time parameters in predicting potentially life-threatening arrhythmias; with QT dispersion sensitivity and specificity (threshold > 50 msec) proved 82,2% and 85,8% respectively, and for QTc (threshold ≥ 70 msec) – 88,1% and 94,5%