Ewa Szahidewicz-Krupska

Endothelial dysfunction in young healthy men is associated with aspirin resistance

The aim of this study was to investigate the relation between endothelial dysfunction and aspirin response in a young healthy population (102 men aged 18-40). Initial concentrations of the NO pathway metabolites (ADMA, l-arginine, SDMA), cardiovascular risk markers, oxidative stress markers (MDA, thiol index), sICAM1, sVCAM1, PAI-1, sE-selectin, sP-selectin, VEGF, thromboxane B2, 6-keto-PGF1α and arachidonate-induced platelet aggregation (to separate aspirin resistant from sensitive group) were measured. Flow-mediated-vasodilation (FMD) was measured before and after intravenous infusion of 16.0 g of l-arginine. Measurements were repeated following aspirin administration (75 mg/24 h) for 4 days. Both groups were homogenous regarding demographic and biochemical characteristics reflecting cardiovascular risk. Aspirin resistant subjects were characterized by lower baseline FMD and higher FMD following aspirin and l-arginine treatment, as compared to aspirin sensitive control. MDA and nitrotyrosine were greater, whereas thiol index was lower in aspirin resistant men. The sICAM1, sVCAM1, PAI-1, sE-selectin, sP-selectin and VEGF levels were similar in the analyzed groups. Thromboxane in aspirin resistant subjects was greater both at baseline and following aspirin therapy. However, a significant decrease following aspirin treatment was present in both groups. Aspirin resistance in young men is associated with endothelial dysfunction, which could be due to oxidative stress resulting from lipid peroxidation.

Effect of Regular Aerobic Activity in Young Healthy Athletes on Profile of Endothelial Function and Platelet Activity

The aim of the study was to assess the impact of regular professional sports activity on the endothelial and platelet function in young men. The studied group were 79 young men (18–40 y, 25 athletes and 54 without any regular physical activity). The nitric oxide (NO) metabolic pathway intermediates, oxidative stress markers, mediators of inflammation, and platelet aggregation were measured. Flow mediated dilation (FMD) was studied before and after intravenous 16,0 g L-arginine infusion, which was repeated after oral administration of acetylsalicylic acid (ASA-75 mg/day) for 4 days. Both groups had similar demographic characteristics. In the athletes, there was significantly higher hsCRP level, better serum lipid profile, and lower pulse pressure. Greater baseline FMD in athletes and in response to L-arginine disappeared following ASA treatment. There were no differences in the levels of the NO pathway metabolites. The control group was characterized by higher PAI-1 following ASA treatment and sICAM-1 both at baseline and after ASA, but no differences in MDA and 6-keto-PGF-1 alpha and platelet aggregation were noted. Regular professional physical activity modulates endothelial but not platelet function and may thus exert an effect on overall cardiovascular risk.

Elevated plasma ADMA contributes to development of endothelial dysfunction in children with acute lymphoblastic leukemia.

BACKGROUND Childhood acute lymphoblastic leukemia (ALL) survivors are at higher cardiovascular risk than the general population, which may result from anthracycline-related endothelial dysfunction (ED). However, a few studies indirectly show that ED may appear in ALL children before treatment begins. Hence, in this study we intended to verify the hypothesis that ED is part of the ALL phenotype. PATIENTS/METHODS Twenty-eight ALL children and 14 healthy age-matched control children were recruited. The study group was examined at baseline, then at the 33rd and 78th day of treatment. At each step of the protocol endothelial vasodilative function was assessed by a laser Doppler flowmeter, which was followed by blood collecting for subsequent analyses. RESULTS Compared to controls, the study group at baseline was characterized by significantly lower endothelial vasodilative responsiveness, accompanied by elevated asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) concentrations, which were correlated with lactate dehydrogenase (LDH) and aspartate transaminase (AST). Initial ALL treatment restored endothelial function, which followed changes in ADMA and LDH concentrations. DISCUSSION This is the first demonstration that functionally assessed ED is present in ALL children at the diagnosis and results from elevated ADMA and parallel inflammatory ED.

Interactions between the Cyclooxygenase Metabolic Pathway and the Renin-Angiotensin-Aldosterone Systems: Their Effect on Cardiovascular Risk, from Theory to the Clinical Practice

Coronary artery disease (CAD) and stroke are the most common and serious long-term complications of hypertension. Acetylsalicylic acid (ASA) significantly reduces their incidence and cardiovascular mortality. The RAAS activation plays an important role in pathogenesis of CVD, resulting in increased vascular resistance, proliferation of vascular-smooth-muscle-cells, and cardiac hypertrophy. Drugs acting on the renin-angiotensin-aldosterone system (RAAS) are demonstrated to reduce cardiovascular events in population with cardiovascular disease (CVD). The cyclooxygenase inhibitors limit the beneficial effect of RAAS-inhibitors, which in turn may be important in subjects with hypertension, CAD, and congestive heart failure. These observations apply to most of nonsteroidal anti-inflammatory drugs and ASA at high doses. Nevertheless, there is no strong evidence confirming presence of similar effects of cardioprotective ASA doses. The benefit of combined therapy with low-doses of ASA is—in some cases—significantly higher than that of monotherapy. So far, the significance of ASA in optimizing the pharmacotherapy remains not fully established. A better understanding of its influence on the particular CVD should contribute to more precise identification of patients in whom benefits of ASA outweigh the complication risk. This brief review summarizes the data regarding usefulness and safety of the ASA combination with drugs acting directly on the RAAS.

Corrigendum to “Low-Level Laser Irradiation Exerts Antiaggregative Effect on Human Platelets Independently on the Nitric Oxide Metabolism and Release of Platelet Activation Markers”

[This corrects the article DOI: 10.1155/2017/6201797.].

Platelet Carbonic Anhydrase II, a Forgotten Enzyme, May Be Responsible for Aspirin Resistance

Background Thromboembolic events constitute a major health problem, despite the steadily expanding arsenal of antiplatelet drugs. Hence, there is still a need to optimize the antiplatelet therapy. Objectives The aim of our study was to verify a hypothesis that there are no differences in platelet proteome between two groups of healthy people representing different acetylsalicylic acid (aspirin) responses as assessed by the liquid chromatography/mass spectrometry (LC/MS) technique. Patients/Methods A total of 61 healthy volunteers were recruited for the study. Physical examination and blood collection were followed by platelet-rich plasma aggregation assays and platelet separation for proteomic LC/MS analysis. Arachidonic acid- (AA-) induced aggregation (in the presence of aspirin) allowed to divide study participants into two groups aspirin-resistant (AR) and aspirin-sensitive (AS) ones. Subsequently, platelet proteome was compared in groups using the LC/MS analysis. Results The LC/MS analysis of platelet proteome between groups revealed that out of all identified proteins, the only discriminatory protein, affecting aspirin responsiveness, is platelet carbonic anhydrase II (CA II). Conclusions CA II is a platelet function modulator and should be taken into consideration as a cardiovascular event risk factor or therapeutic target.

[PP.30.28] PLATELET CARBONIC ANHYDRASE II MAY BE RESPONSIBLE FOR ASPIRIN RESISTANCE - A LC/MS PROTEOMIC STUDY

Objective: Thrombo-embolic events are major health problem, despite the steadily-expanding arsenal of drugs inhibiting platelet function. Therefore, there is still a need to analyze platelet function to optimize anti-platelet therapy. The aim of our study was to verify a hypothesis that there are no differences in platelet proteome between two groups of healthy people representing different acetylsalicylic acid (Aspirin, ASA) response using a Liquid Chromatography/Mass Spectrometry - LC/MS technique. Design and method: A total of 61 healthy volunteers were recruited to the study. Physical examination and blood drawning for basic blood tests was followed by platelet rich plasma aggregation and platelet separation for LC/MS analysis. Arachidonic acid (AA) induced aggregation (in presence of Aspirin) allowed to divide study participants into two groups Aspirin resistant (AR) and Aspirin sensitive (AS). Then the platelet proteome was compared using the LC/MS analysis. Results: Aspirin failed to block AA induced aggregation in 36 cases (AR). 25 remaining individuals formed age and gender matched control group (AS). AS presented no platelet aggregation in response to AA in presence of fixed dose of Aspirin, whereas in the AR group aggregation was only partially (but significantly) blocked. Interestingly, also at baseline AA induced more potent aggregation in AR group comparing to controls. The LC/MS analysis of platelet proteomes between groups showed that out of all identified proteins, the only discriminatory protein, affecting Aspirin responsiveness, is carbonic anhydrase II (CAII). Conclusions: CAII is a platelet function modulator and should be taken into consideration as a cardiovascular event risk factor or therapeutic target.

[PP.29.28] SERUM PROTEINS INTERPLAYING WITH ISCHEMIC STROKE - A LC/MS HUMAN PROTEOMIC STUDY FOR BIOMARKERS AND POTENTIAL DRUG TARGETS

Objective: The aim of this study was to identify potential proteins-candidates for biomarkers and drug targets of acute ischemic stroke. Design and method: There were 32 patients at age of 29–80 years with diagnosed ischemic stroke were included into the study group. The control group was constituted of 30 volunteers demographically matched with study group. Patients enrolled on the study group presented clinical symptoms of stroke lasting no longer than 24 hours, confirmed by trained neurologists examination or new brain ischemia visible in MR/CT (magnetic resonance imaging / computed tomography). The analysis of plasma proteome was performed using liquid chromatography–mass spectrometry. Results: We managed to identify 10 proteins which serum concentrations significantly differ from observed in healthy controls – complement factor B, apolipoprotein A-I, fibronectin, alpha-2-HS-glycoprotein, alpha-1B-glycoprotein, heat shock cognate 71 kDa protein/heat shock-related 70 kDa protein 2, thymidine phosphorylase, cytoplasmic tryptophan--tRNA ligase, ficolin-2, beta-Ala-His dipeptidase. Conclusions: Listed proteins should be considered as risk factors or markers of ischemic stroke. Further clinical validation of these proteins should define their role in differential diagnostics and monitoring course of the ischemic stroke as well as in designing novel therapies.

[PP.28.11] INSULIN RESISTANCE AND HYPERINSULINEAMIA IN YOUNG NON-DIABETIC SUBJECTS - EFFECT ON THE PROFILE OF ENDOTHELIAL AND PLATELET FUNCTION

Objective: The aim of the study was to compare endothelial function in young male subjects with normal insulin metabolism to those ones with hyperinsulinemia and insulin resistance. Functional changes in platelets, including their response to acetylsalicylic acid (ASA) were investigated. The next aim was to evaluate the need for cardiovascular risk screening in young non-diabetic subjects with insulin metabolism disorders. Design and method: 79 healthy men aged 18–40 were divided twice into two groups: - hyperinsulinemic and normoinsulinemic. - insulin-resistant and insulin-sensitive. After phisical examination, biochemical parameters, selected platelet activity parameters, inflammatory, angiogenic and aggregatory endothelial parameters, RAAS (renin-angiotensin-aldosteron-system) parameters, metabolites of the nitric oxide pathway and oxidative stress markers were analyzed. Pulse wave velocity (PWV) and flow mediated vasodilation (FMD) at the baseline and after L-arginine intravenous infusion was measured. The protocol was repeated after 4 days of oral 75 mg ASA administration. Results: The analyzed groups were similar regarding demographic characteristics. In the hyperinsulinemic group a prevalence of higher systolic blood pressure was greater than in normoinsulinemic one. In insulin-resistant group both - systolic and the diastolic blood pressure was higher than in insulin-sensitive subjects. Hyperinsulinemic and insulin resistant men were characterized by more pro-atherogenic lipid profile. The insulin resistant group had higher levels of P-selectin. Insulin resistant and hyperinsulinemic subjects were characterized by greater TXB2 levels and aggregatory platelet response to arachidonic acid and ristocetin. The hyperinsulinemic group had lower VEGF concentrations. Insulin-resistant and hyperinsulinemic subjects were characterized by greater thiol index following ASA administration. Conclusions: In the group of potentially healthy, young male there is a tendency to initiate metabolic disturbances, involving insulin excretion, sensitivity and dyslipidemia, which predispose to development of hypertension, pointing thus at the need for cardiovascular screening in this population. There was increased platelet activity in insulin resistant group. In hyperinsulinemic group anti-aggregatory activity of ASA was attenuated. In both; insulin-resistant and hyperinsulinemic group, ASA exerted an antioxidative effect, independently on its anti-aggregatory action, which could point at beneficial effect in whole group of subjects with insulin metabolism disorders.

[PP.25.12] EFFECT OF REGULAR AEROBIC ACTIVITY IN YOUNG HEALTHY PROFESSIONAL ATHLETES ON PROFILE OF ENDOTHELIAL FUNCTION AND PLATELET ACTIVITY

Objective: Regular physical activity may modulate cardiovascular risk due to its effect on endothelial and platelet function. The aim of this observational study was to assess the interplay between professional physical activity, endothelial and platelet function in young athletes. Design and method: The studied group constituted of n = 79 young men at age of 18–40 years (n = 25 were professional athletes and n = 54 men without any regular physical activity constituted control group). The levels of the nitric oxide (NO) metabolic pathway, oxidative stress markers (malonyldialdehyde-MDA, thiol index–GSH/GSSG), levels of sICAM-1, sVCAM-1, Serpin E1(PAI-1), sE-Selectin, sP-Selectin, VEGF, prostanoids (thromboxane B2(TXB2), 6-keto-PGF1-alpha) and platelet aggregation were measured. Flow-mediated-vasodilation (FMD) was studied before and after intravenous L-arginine (16.0 g) infusion, which was repeated after oral administration of acetylsalicylic acid (ASA-75 mg/day) for 4 days. Results: Both groups had similar demographic characteristics. There was a significantly higher CRP level, lower serum lipid profile and pulse pressure in the athletes group. Significantly greater FMD in athletes group at baseline as well as both, in response to L-arginine and following ASA treatment was observed. There were no differences in the levels of the NO pathway metabolites. The control group was characterized by lower thiol index and TXB2 levels and higher PAI-1 following ASA treatment and sICAM-1 both at baseline and after ASA, but no differences in MDA and 6-keto-PGF1-alfa levels and platelet aggregation were noted. Conclusions: The regular professional physical activity lowers the cardio-vascular risk through modification of inflammation, endothelial vasodilation and lipid profile. Lack of physical activity in young healthy men is associated with endothelial dysfunction. Endothelial dysfunction in physically non-active men results not from decreased nitric oxide synthesis, but its increased degradation. Professional physical activity does not significantly affect platelet function.