11-dehydro-thromboxane-b2 and Cardiovascular-Diseases

Topics: Adenosine Diphosphate; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Atherosclerosis; Biomarkers; Biotransformation; Blood Coagulation Tests; Blood Platelets; Cardiovascular Diseases; Clopidogrel; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Drug Interactions; Drug Resistance; Hemorrhage; Humans; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prospective Studies; Randomized Controlled Trials as Topic; Receptors, Purinergic P2; Receptors, Purinergic P2Y1; Receptors, Purinergic P2Y12; Thrombosis; Thromboxane A2; Thromboxane B2; Ticlopidine; Treatment Failure

Topics: Aspirin; Biomarkers; Cardiovascular Diseases; Case-Control Studies; Cyclooxygenase Inhibitors; Drug Interactions; Drug Resistance; Follow-Up Studies; Genetic Variation; Humans; Patient Compliance; Platelet Aggregation; Platelet Aggregation Inhibitors; Risk; Thromboxane A2; Thromboxane B2; Treatment Failure

Aspirin is widely used for cardioprotection with its antiplatelet effects due to the blocking of thromboxane A2 production. However, it has been suggested that platelet abnormalities in those with diabetes prevent adequate suppression with once daily aspirin.. In the ASCEND randomized double-blind trial of aspirin 100 mg once daily versus placebo in participants with diabetes but no history of cardiovascular disease, suppression was assessed by measuring 11-dehydro-thromboxane B2 excretion in urine (U-TXM) in a randomly selected sample of 152 participants (76 aspirin arm, 74 placebo arm), plus 198 (93 aspirin arm, 105 placebo arm) adherent to study drugs and selected to maximize the numbers ingesting their last tablet 12-24 h before urine sampling. U-TXM was assayed using a competitive ELISA assay in samples mailed a mean of 2 years after randomization, with time since taking last aspirin/placebo tablet recorded at the time of sample provision. Effective suppression (U-TXM < 1500 pg/mg creatinine) and percentage reductions in U-TXM by aspirin allocation were compared.. In the random sample, U-TXM was 71% (95% CI 64-76%) lower among aspirin vs placebo-allocated participants. Among adherent participants in the aspirin arm, U-TXM was 72% (95% CI 69-75%) lower than in the placebo arm and 77% achieved effective suppression overall. Suppression was similar among those who ingested their last tablet more than 12 h before urine sampling with levels in the aspirin arm 72% (95% CI 67-77%) lower than in the placebo arm and 70% achieving effective suppression.. Daily aspirin significantly reduces U-TXM in participants with diabetes, including at 12-24 h after ingestion.. ISRCTN ISRCTN60635500. Registered on 1 Sept 2005; ClinicalTrials.gov NCT00135226. Registered on 24 Aug 2005.

Topics: Aspirin; Cardiovascular Diseases; Diabetes Mellitus; Humans; Thromboxane B2

Diabetes mellitus type 2 (DM2) is associated with high platelet reactivity both in patients who do not receive antiplatelet drugs and in those treated with acetylsalicylic acid (ASA). The pathomechanism of this phenomenon has not been fully understood.. 1. To evaluate variability of platelet reactivity in patients with DM2 treated with oral antidiabetic drugs and receiving chronic ASA therapy. 2. To identify independent predictors of high platelet reactivity during ASA therapy in patients with DM2.. We studied 171 patients with DM2 treated with oral antidiabetic drugs and receiving long-term treatment with 75 mg of ASA daily, selected among the participants of the prospective AVOCADO study. Platelet function was simultaneously evaluated using 4 methods: 1. measurement of serum thromboxane B2 (TXB2) concentration; 2. measurement of urinary 11-dehydrothromboxane B2 (11-dhTXB2) concentration; 3. VerifyNow® automated analyser; 4. PFA-100® automated analyser.High platelet reactivity was defined as at least 3 of the following criteria: 1. serum TXB2 concentration in the upper quartile;2. urinary 11-dhTXB2 concentration in the upper quartile; 3. value ≥ 550 aspirin reaction units (ARU) by VerifyNow®;4. collagen-epinephrine closure time (CEPI-CT) below median of readings other than 300 s by PFA-100®. In all patients, DM2 control was evaluated, insulin resistance was measured using HOMA-IR, and routine laboratory tests were performed, including full blood count, renal function parameters, and inflammation markers.. Mean patient age was 67.8 years, and median duration of DM2 was 5 years. We found poor agreement between different tests of platelet function. ARU ≥ 550 (VerifyNow®) was found in 14.0% of patients, and CEPI-CT below median of readings other than 300 s (PFA-100®) was found in 32.8% of patients. Our criteria of high platelet reactivity were met by 9.9% of patients. In multivariate logistic regression analysis, independent predictors of high platelet reactivity despite ASA therapy included chronic heart failure, current smoking, and higher leukocyte count.. 1. Patients with DM2 are characterised by large variability of platelet reactivity, with little agreement between various methods. 2. Smoking, chronic heart failure, and subclinical inflammation may be associated with high platelet reactivity in patients with DM2 treated with ASA.

Topics: Adult; Aged; Aged, 80 and over; Aspirin; Biomarkers; Blood Platelet Disorders; Blood Platelets; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Logistic Models; Male; Middle Aged; Multivariate Analysis; Platelet Aggregation; Platelet Aggregation Inhibitors; Prospective Studies; Thromboxane B2

Low-dose aspirin seems to offer no benefit in the primary prevention of cardiovascular disease in type 2 diabetes mellitus (DM2). The anti-platelet effect may be diminished by poor glycemic control or inadequate dosing of aspirin.. To study the effects of both glycemic control and increasing aspirin dose on platelet response to aspirin in DM2 patients and matched controls.. Platelet effects of increasing doses of aspirin (30, 100 and 300 mg daily) were prospectively assessed in 94 DM2 patients and 25 matched controls by measuring thromboxane levels in urine (11-dhTxB2) and platelet aggregation using VerifyNow(®) and light transmission aggregometry (LTA). DM2 patients were stratified for glycemic control (hemoglobin-A1c [HbA1c] ≤ 53, 53-69, ≥ 69 mmol mol(-1)).. At baseline, median 11-dhTxB2 excretion was higher in the poorly controlled patients (77 ng mmol(-1)), and the moderately controlled (84 ng mmol(-1)) compared with the well-controlled patients (64 ng mmol(-1)) and controls (53 ng mmol(-1)), P < 0.01. Next, 30 mg of aspirin reduced 11-dhTxB2 excretion to 31, 29 and 24 ng mmol(-1) in the poorly, moderately and well-controlled patients, respectively, and to 19 ng mmol(-1) in controls, P < 0.001. VerifyNow(®) and LTA were also incompletely suppressed in DM2 patients using 30 mg of aspirin, but 100 mg resulted in similar platelet suppression in all groups, with no additional effect of 300 mg.. DM2 patients with inadequate glycemic control (HbA1c > 53 mmol mol(-1)) have higher baseline platelet activity and incomplete suppression of platelet activity with 30 mg of aspirin. However, 100 mg of aspirin leads to optimal inhibition irrespective of glycemic control, and 300 mg does not further improve platelet suppression.

Topics: Adult; Aged; Aspirin; Biomarkers; Blood Platelets; Cardiovascular Diseases; Chi-Square Distribution; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Multivariate Analysis; Netherlands; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prospective Studies; Regression Analysis; Thromboxane B2; Treatment Outcome

Results from prevention trials, including the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT), have fueled discussion about the cardiovascular (CV) risks associated with non-steroidal anti-inflammatory drugs (NSAIDs). We tested the hypotheses that (i) adverse CV events reported among ADAPT participants (aged 70 years and older) are associated with increased ratio of urine 11-dehydrothromboxane B(2) (Tx-M) to 2'3-donor-6-keto-PGF1 (PGI-M) attributable to NSAID treatments; (ii) coincident use of aspirin (ASA) would attenuate NSAID-induced changes in Tx-M/PGI-M ratio; and (iii) use of NSAIDs and/or ASA would not alter urine or plasma concentrations of F(2)-isoprostanes (IsoPs), in vivo biomarkers of free radical damage. We quantified urine Tx-M and PGI-M, and urine and plasma F(2)-IsoPs from 315 ADAPT participants using stable isotope dilution assays with gas chromatography/mass spectrometry, and analyzed these data by randomized drug assignment and self-report compliance as well as ASA use. Adverse CV events were significantly associated with higher urine Tx-M/PGI-M ratio, which seemed to derive mainly from lowered PGI-M. Participants taking ASA alone had reduced urine Tx-M/PGI-M compared to no ASA or NSAID; however, participants taking NSAIDs plus ASA did not have reduced urine Tx-M/PGI-M ratio compared to NSAIDs alone. Neither NSAID nor ASA use altered plasma or urine F(2)-IsoPs. These data suggest a possible mechanism for the increased risk of CV events reported in ADAPT participants assigned to NSAIDs, and suggest that the changes in the Tx-M/PGI-M ratio was not substantively mitigated by coincident use of ASA in individuals 70 years or older.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Aged, 80 and over; Alzheimer Disease; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cardiovascular Diseases; Celecoxib; Drug Therapy, Combination; F2-Isoprostanes; Female; Humans; Male; Naproxen; Pyrazoles; Sulfonamides; Thromboxane B2; Treatment Outcome

Incomplete inhibition of platelet thromboxane generation, as measured by elevated urinary 11-dehydro thromboxane B(2) concentrations, has been associated with an increased risk of cardiovascular events. We aimed to determine the external validity of this association in aspirin-treated patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial and to determine whether there are any modifiable factors or interventions that lower urinary 11-dehydro thromboxane B(2) concentrations that could thereby reduce cardiovascular risk.. Urinary 11-dehydro thromboxane B(2) concentrations were measured in 3261 aspirin-treated patients at least 1 month after they had been randomly assigned to placebo or clopidogrel. Baseline urinary 11-dehydro thromboxane B(2) concentrations in the highest quartile were associated with an increased risk of stroke, myocardial infarction, or cardiovascular death compared with the lowest quartile (adjusted hazard ratio 1.66, 95% CI 1.06 to 2.61, P=0.03). Increasing age, female sex, history of peripheral artery disease, current smoking, and oral hypoglycemic or angiotensin-converting enzyme inhibitor therapy were independently associated with higher urinary concentrations of 11-dehydro thromboxane B(2), whereas aspirin dose > or =150 mg/d, history of treatment with nonsteroidal antiinflammatory drugs, history of hypercholesterolemia, and statin treatment were associated with lower concentrations. Randomization to clopidogrel (versus placebo) did not reduce the hazard of cardiovascular events in patients in the highest quartile of urinary 11-dehydro thromboxane B(2) levels.. In aspirin-treated patients, urinary concentrations of 11-dehydro thromboxane B(2) are an externally valid and potentially modifiable determinant of stroke, myocardial infarction, or cardiovascular death in patients at risk for atherothrombotic events.

Topics: Aged; Aspirin; Cardiovascular Diseases; Cyclooxygenase Inhibitors; Double-Blind Method; Female; Follow-Up Studies; Humans; Internationality; Male; Middle Aged; Risk Factors; Survival Rate; Thromboxane B2; Thromboxanes

This randomized, controlled, forced-switching, open-label, parallel-group study in 97 adult male and female smokers of conventional cigarettes evaluated biomarkers of tobacco smoke exposure and cardiovascular risk factors. After baseline measurements, smokers were either switched to a second-generation electrically heated cigarette smoking system (EHCSS) or continued smoking conventional cigarettes for 12 months. Biomarkers of exposure and cardiovascular risk factors were measured at 0.5, 1, 2, 3, 4, 5, 6, 9, and 12 months. There was a rapid and sustained reduction in all biomarkers of exposure after switching to the EHCSS, with statistically significant reductions from baseline in nicotine equivalents (-18%), plasma cotinine (-16%), total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (-73%), total 1-hydroxypyrene (-53%), urine mutagenicity (-52%), 4-aminobiphenyl hemoglobin adducts (-43%), carboxyhemoglobin AUC7-23 h (-80%), and 3-hydroxypropylmercapturic acid (-35%). These reductions in exposure in the EHCSS group were associated with statistically significant and pathophysiologically favorable changes in several cardiovascular risk factors, including white blood cell count (-0.78 x 10(3)/microL), hemoglobin (-0.16 g/dL), hematocrit (-0.44%), urine 11-dehydrothromboxane B2 (-374 ng/24 h), and high-density lipoprotein cholesterol (+5 mg/dL).

Topics: Adult; Biomarkers; Carboxyhemoglobin; Cardiovascular Diseases; Cholesterol, HDL; Cotinine; Female; Follow-Up Studies; Humans; Male; Middle Aged; Mutagens; Nicotine; Nicotinic Agonists; Risk Factors; Smoking; Thromboxane B2

Although the concept of aspirin resistance is extensively reported in medical literature, its precise mechanisms and clinical outcomes are largely unknown. In this study, we examined individual thromboxane biosynthesis and platelet aggregation in aspirin-treated patients, and whether the results of a platelet aggregation test influenced clinical outcomes.. Subjects taking 81 mg of aspirin (n = 50) and controls (n = 38) were evaluated for platelet aggregation and platelet cyclooxygenase-1 (COX-1) activity by measuring collagen-induced thromboxane B2 production. For aggregometry, both light transmission (LT) and laser-light scattering methods were employed to quantitatively evaluate aggregate sizes and numbers. Aspirin treatment resulted in the inhibition of collagen-induced platelet aggregation, particularly the transition from small to large platelet aggregates. Although platelet COX-1 activity seemed to be uniformly inhibited in all patients, platelet aggregation studies showed great inter-individual differences; variation in platelet COX-1 activity only accounted for 6-20% of the individual aggregations. Factor analysis revealed the existence of a common factor (other than platelet COX-1) that explained 48.4% of the variations in platelet aggregation induced by collagen, adenosine diphosphate (ADP), and collagen-related peptide. We then prospectively enrolled 136 aspirin-treated patients in our study, and we found that being in the upper quartile level of LT, or with large aggregate formation induced by collagen, was an independent risk factor for developing cardiovascular events within 12 months [hazard ratio (HR) = 7.98, P = 0.008 for LT; HR = 7.76, P = 0.007 for large aggregates]. On the other hand, the existence of diabetes mellitus was an independent risk factor for overall outcomes (HR 1.30-11.9, P = 0.015-0.033).. Aspirin resistance expressed as unsuppressed platelet COX-1 activity is a rare condition in an out-patient population. Other factor(s) affecting collagen-induced platelet aggregation may influence early outcomes in aspirin-treated patients.

Topics: Aged; Aspirin; Blood Platelets; Cardiovascular Diseases; Collagen; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Drug Resistance; Female; Humans; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prospective Studies; Risk Factors; Signal Transduction; Thromboxane B2; Treatment Outcome

Recent data suggest a decreased clinical efficacy of low-dose aspirin in patients weighing ≥70 kg. We therefore investigated the impact of body weight and class 1 obesity on thromboxane generation and platelet reactivity to arachidonic acid (AA) in 316 patients on dual antiplatelet therapy following angioplasty and stenting.. Platelet surface expression of P-selectin and activated glycoprotein (GP) IIb/IIIa in response to AA were determined by flow cytometry as sensitive markers of platelet activation. Urinary 11-dehydro-thromboxane B2 (11-dehydro-TXB2) and serum TXB2 were measured by commercially-available immunoassays. On-treatment residual AA-inducible platelet aggregation was assessed by light transmission aggregometry (LTA), the VerifyNow aspirin assay and multiple electrode aggregometry (MEA).. Class 1 obesity was independently associated with increased platelet surface expression of P-selectin and activated GPIIb/IIIa, but not with urinary 11-dehydro-TXB2, serum TXB2, and on-treatment platelet aggregation by all assays. Of all measured parameters, only MEA showed a positive albeit very weak correlation with body weight (r = 0.13, p = 0.02). Furthermore, the results of all tests did not differ significantly between patients without and with a body weight ≥ 70 kg. After adjustment for age and diabetes by multivariate logistic regression analysis, the frequency of high-on treatment residual TXB2 generation and high on-treatment residual AA-inducible platelet reactivity (HRTG/HRPR) did not differ significantly between obese and non-obese patients.. Class 1 obesity is associated with enhanced platelet activation in response to AA in patients on dual antiplatelet therapy. This seems to be independent of cyclooxygenase-1 inhibition and does not translate into HRTG/HRPR.

Topics: Aged; Angioplasty; Aspirin; Biomarkers; Blood Platelets; Cardiovascular Diseases; Dual Anti-Platelet Therapy; Female; Flow Cytometry; Humans; Male; Middle Aged; Obesity; P-Selectin; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Platelet Glycoprotein GPIIb-IIIa Complex; Stents; Thromboxane B2; Time Factors; Treatment Outcome

Elevated urinary 11-dehydro thromboxane B. Genome-wide and targeted genetic association studies of urinary 11-dehydro TxB. The strongest associations were in PPARGC1B (rs4235745, rs32582, rs10515638) and CNTN4 (rs10510230, rs4684343), these 5 single nucleotide polymorphisms (SNPs) were independently associated with 11-dehydro TxB. PPARGC1B and CNTN4 genotypes are associated with elevated thromboxane A

Topics: Aged; Aspirin; Cardiovascular Agents; Cardiovascular Diseases; Carrier Proteins; Contactins; Europe; Female; Gene Frequency; Genetic Markers; Genetic Predisposition to Disease; Genome-Wide Association Study; Haplotypes; Humans; Incidence; Male; Middle Aged; Multicenter Studies as Topic; Phenotype; Polymorphism, Single Nucleotide; Primary Prevention; Progression-Free Survival; Randomized Controlled Trials as Topic; Risk Factors; RNA-Binding Proteins; Thromboxane A2; Thromboxane B2; Time Factors; White People

Soluble proprotein convertase subtilisin/kexin type 9 (PCSK9) has been shown to be predictive of cardiovascular events (CVEs) in patients who are at high cardiovascular risk. No data on the effect of PCSK9 levels in patients with atrial fibrillation (AF) are available.. This study investigated the association between PCSK9 and CVEs in AF as well as the relationship between PCSK9 and urinary 11-dehydro-thromboxane B. We conducted a prospective, single-center cohort study, including 907 patients with AF treated with vitamin K antagonists (3,865 patient-years), to assess CVEs, including fatal and nonfatal myocardial infarction, ischemic stroke, and cardiovascular death. At admission, plasma PCSK9 and urinary 11-dh-TxB. The mean age of patients was 73.5 ± 8.2 years, and 43.0% were women. At follow-up, 179 CVEs (4.6%/year) occurred: 43 (15.3%), 49 (15.5%), and 87 (28.0%) in the first, second, and third tertiles of PCSK9, respectively (log-rank test p = 0.009). Patients with CVEs had higher median PCSK9 compared with those without (1,500 pg/ml [IQR: 1,000 to 2,300 pg/ml] vs. 1,200 pg/ml [IQR: 827 to 1,807 pg/ml], respectively; p < 0.001). Multivariable Cox regression analysis showed that the third versus the first tertile of PCSK9 (hazard ratio: 1.640; 95% confidence interval: 1.117 to 2.407; p = 0.012), female sex, age, diabetes, smoking, heart failure, previous cerebrovascular and cardiac events, digoxin use, and total cholesterol to high-density lipoprotein cholesterol ratio were associated with CVEs. In 682 patients not treated with antiplatelet therapy, circulating PCSK9 and 11-dh-TxB. Plasma PCSK9 levels are associated with an increased risk of CVEs in patients with AF. The direct correlation between PCSK9 and 11-dh-TxB

Topics: Aged; Atrial Fibrillation; Cardiovascular Diseases; Female; Humans; Incidence; Male; Predictive Value of Tests; Proprotein Convertase 9; Prospective Studies; Risk Assessment; Thromboxane B2

Several studies have indicated that approximately 25 % of patients treated with aspirin exhibit high on-treatment platelet reactivity (HTPR), which is potentially associated with cardiovascular events (CVEs). However, this association is still controversial, since the mechanisms by which HTPR contributes to CVEs remain unclear and a no standardised definition of HTPR has been established. To determine whether HTPR is associated with CVE recurrence and what type of assay would best predict CVE recurrence, we conducted a multicentre prospective cohort study of 592 stable cardiovascular outpatients treated with aspirin monotherapy for secondary prevention. Their HTPR was determined by arachidonic acid- or collagen-induced aggregation assays using two different agonist concentrations. Residual cyclooxygenase (COX)-1 activity was assessed by measuring serum thromboxane (TX)B2 or urinary 11-dehydro TXB2. Shear-induced platelet thrombus formation was also examined. We followed all patients for two years to evaluate how these seven indexes were related to the recurrence of CVEs (cerebral infarction, transient ischaemic attack, myocardial infarction, unstable angina, revascularisation, other arterial thrombosis, or cardiovascular death). Of 583 patients eligible for the analysis, CVEs occurred in 69 (11.8 %). A Cox regression model identified several classical risk factors associated with CVEs. However, neither HTPR nor high residual COX-1 activity was significantly associated with CVEs, even by applying cut-off values suggested in previous reports or a receiver-operating characteristic analysis. In conclusion, recurrence of CVEs occurred independently of HTPR and residual COX-1 activity. Thus, our findings do not support the use of platelet or COX-1 functional testing for predicting clinical outcomes in stable cardiovascular patients.

Topics: Adult; Aged; Aged, 80 and over; Aspirin; Blood Platelets; Cardiovascular Diseases; Cohort Studies; Cyclooxygenase 1; Female; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Prospective Studies; Recurrence; Risk Factors; Secondary Prevention; Thromboxane B2

Mechanisms of accelerated atherothrombosis in patients with chronic kidney disease (CKD) are only partly characterized. The aims of this study were to evaluate the extent of thromboxane (TX)-dependent platelet activation in patients with CKD, and to characterize the determinants of altered TX biosynthesis in this setting, with particular reference to enhanced lipid peroxidation, low grade inflammation and CKD-related anemia.. A cross sectional comparison between urinary 8-iso-PGF2α and 11-dehydro-TXB2, in vivo markers of oxidative stress and platelet activation, respectively, was performed in 115 patients with stage 1-4 CKD.. Levels of both urinary 11-dehydro-TXB2 and 8-iso-PGF2α increased sequentially across the four CKD stages (P<0.0001, Kruskal-Wallis test). Both urinary prostanoids were inversely associated with either estimated glomerular filtration rate (eGFR, P<0.0001) or hemoglobin levels (P<0.0001). A significant direct correlation was also observed between urinary 11-dehydro-TXB2 and 8-iso-PGF2α (Rho=0.620, P<0.0001). On multivariate analysis, urinary 8-iso-PGF2α (β=0.459, P<0.0001), hemoglobin levels (β=- 0.261, P=0.002) and eGFR (β=-0.172, P=0.032) were independent predictors of urinary 11-dehydro-TXB2 (adjusted R(2)=0.488).. This study provides biochemical evidence of persistent platelet activation in patients with CKD. This condition occurs early in the natural history of the disease and is related to kidney function and oxidative stress. Moreover, we found an independent inverse relationship between hemoglobin levels and TX-dependent platelet activation. This finding may provide a mechanistic link between CKD-related anemia and increased cardiovascular risk.

Topics: Aged; Biomarkers; Cardiovascular Diseases; Cross-Sectional Studies; Dinoprost; Erythropoietin; Female; Glomerular Filtration Rate; Hemoglobins; Humans; Italy; Linear Models; Male; Middle Aged; Multivariate Analysis; Oxidative Stress; Platelet Activation; Prostaglandins; Renal Insufficiency, Chronic; Risk Assessment; Risk Factors; Thromboxane B2

Experimental studies demonstrated that glutathione peroxidase 3 (GPx3), an antioxidant enzyme that catabolizes hydrogen peroxide, protects against thrombosis. Little is known about its role in cardiovascular disease.. A prospective cohort study was conducted in 909 atrial fibrillation patients. Serum activities of GPx3, superoxide dismutase (SOD), and catalase were measured at baseline to assess the risk of cardiovascular events during a mean follow-up of 43.4 months (3291 person-years). Serum Nox2 and urinary excretion of 11-deydro-thromboxane B2 were also measured. During follow-up 160 cardiovascular events occurred (4.9%/year). Significantly lower values of GPx3 (P<0.001) and SOD (P=0.037) were detected in patients with, compared to those without, cardiovascular events. A lower survival rate was observed in patients with GPx3 (P<0.001) and SOD (P=0.010) activities below the median, as compared to those above. In a fully adjusted Cox regression model, GPx3 was the only antioxidant enzyme predictor of cardiovascular events (hazard ratio 0.647, 95% confidence interval 0.524-0.798, P<0.001). GPx3 was inversely associated with urinary 11-dehydro-thromboxane B2 (B -0.337, P<0.001) and serum Nox2 (B: -0.423, P<0.001). GPx3 activity progressively decreased with decades of age (P<0.001), with a progressive reduction in people aged ≥70 years.. This study provides evidence that a low antioxidant status, as depicted by reduced levels of GPx3, increases the risk of cardiovascular events in patients with atrial fibrillation. The age-related decline of GPx3 may represent a mechanism for the enhanced cardiovascular risk in the elderly population.

Topics: Aged; Aged, 80 and over; Aging; Atrial Fibrillation; Cardiovascular Diseases; Catalase; Cohort Studies; Female; Follow-Up Studies; Glutathione Peroxidase; Humans; Ischemic Attack, Transient; Male; Middle Aged; Myocardial Infarction; Myocardial Revascularization; NADPH Oxidase 2; Prognosis; Proportional Hazards Models; Prospective Studies; Stroke; Superoxide Dismutase; Thromboxane B2

Patients with Klinefelter syndrome (KS) exhibit an increased cardiovascular risk, but underlying mechanisms are largely unknown. The present cross-sectional study has been conducted to evaluate platelet reactivity and the expression of platelet activation markers (8-iso-prostaglandin F2α[8-iso-PGF2α] and 11-dehydro-thromboxane-B₂[11-dehydro-TXB2]) in KS patients and healthy controls. Twenty-three consecutive KS patients under testosterone replacement therapy have been included as case group and 46 age-matched healthy males recruited among hospital staff served as controls. Light transmission aggregometry was performed in both cases and controls and maximal platelet aggregation (max-A%) was defined as maximal light transmittance reached within 5 min after the addition of 0.2 or 0.4 mm arachidonic acid (AA). A ≥ 50% irreversible light transmittance (LT-50%) following platelet stimulation defined an adequate platelet aggregation and AC-50% was defined as the minimal agonist concentration needed to achieve LT-50%. The AC-50% was 0.26 mm AA for KS and 0.36 mm for controls (p < 0.001). Whereas AA (0.2 mm) induced LT-50% in 69.6% of KS and in 15.2% of controls (p < 0.001), the stimulation with AA (0.4 mm) determined LT-50% in all cases and controls. However, max-A% was higher in KS than in controls both after AA (0.2 mm) (65.61% vs. 46.30%, p = 0.002,) and after AA (0.4 mm) (96.43% vs. 81.04%, p < 0.001). 8-iso-PGF2α and 11-dehydro-TXB2 were higher in KS than in controls (446.54 pg/mg creatinine vs. 230.00 pg/mg creatinine, p < 0.001 and 1278.36 pg/mg creatinine vs. 595.08 pg/mg creatinine, p = 0.001, respectively) and AC-50% inversely correlated with 8-iso-PGF2α (ρ = -0.548, p < 0.001) and with 11-dehydro-TXB2 (ρ = -0.523, p < 0.001). In a linear regression model, KS independently predicted a lower AC-50% (β = -0.597, p < 0.001) and higher levels of 8-iso-PGF2α (β = 0.709, p < 0.001) and 11-dehydro-TXB2 (β = 0.605, p < 0.001). In contrast, no correlation has been found between max-A%, testosterone and estradiol levels in KS. We observed increased platelet reactivity in KS. This might, at least in part, explain the increased thrombotic risk associated with this disease.

Topics: Adult; Blood Platelets; Cardiovascular Diseases; Creatinine; Cross-Sectional Studies; Dinoprost; Estradiol; Humans; Klinefelter Syndrome; Male; Platelet Activation; Platelet Aggregation; Risk Factors; Testosterone; Thromboxane B2

We performed a cross-sectional, multicentre study in Japan to detect the differences in biomarkers of exposure and cardiovascular biomarkers between smokers and non-smokers. Several clinically relevant cardiovascular biomarkers differed significantly between smokers and non-smokers, including lipid metabolism (high-density lipoprotein cholesterol concentrations - lower in smokers), inflammation (fibrinogen and white blood cell count - both higher in smokers), oxidative stress (8-epi-prostaglandin F2α - higher in smokers) and platelet activation (11-dehydro-thromboxane B2 - higher in smokers) (p ≤ 0.0001). These results provide further evidence showing that cardiovascular biomarkers can discriminate smokers from non-smokers, and could be used to evaluate the risks associated with tobacco products.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Asian People; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Cholesterol, HDL; Cotinine; Cross-Sectional Studies; Dinoprost; Female; Fibrinogen; Humans; Japan; Male; Middle Aged; Smoking; Thromboxane B2

Omega-3 fatty acids suppress Thromboxane A(2) (TxA(2)) generation via mechanisms independent to that of aspirin therapy. We sought to evaluate whether baseline omega-3 fatty acid levels influence arachidonic acid proven platelet-cyclooxygenase-1 (COX-1) independent TxA(2) generation (TxA(2) generation despite adequate aspirin use).. Subjects with acute myocardial infarction, stable CVD or at high risk for CVD, on adequate aspirin therapy were included in this study. Adequate aspirin action was defined as complete inhibition of platelet-COX-1 activity as assessed by <10% change in light transmission aggregometry to ≥1 mmol/L arachidonic acid. TxA(2) production was measured via liquid chromatography-tandem mass spectrometry for the stable TxA(2) metabolite 11-dehydro-thromboxane B2 (UTxB2) in urine. The relationship between baseline fatty acids, demographics and UTxB(2) were evaluated. Baseline omega-3 fatty acid levels were not associated with UTxB(2) concentration. However, smoking was associated with UTxB(2) in this study.. Baseline omega-3 fatty acid levels do not influence TxA(2) generation in patients with or at high risk for CVD receiving adequate aspirin therapy. The association of smoking and TxA(2) generation, in the absence of platelet COX-1 activity, among aspirin treated patients warrants further study.

Topics: Aged; Aspirin; Biomarkers; Blood Platelets; Cardiovascular Diseases; Chromatography, Liquid; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Fatty Acids, Omega-3; Female; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Function Tests; Smoking; Tandem Mass Spectrometry; Thromboxane A2; Thromboxane B2

Dickkopf-1 (DKK-1) is a major regulator of the Wnt signaling pathway, involved in inflammation, atherogenesis, and the regulation of glucose metabolism. Because platelets are major contributors to circulating levels of DKK-1 in other clinical settings, we aimed at characterizing the platelet contribution to DKK-1 in type 2 diabetes mellitus (T2DM) and evaluating associations of DKK-1 with glucose metabolism, platelet activation, and endothelial dysfunction.. A cross-sectional comparison of DKK-1, soluble CD40L (sCD40L; reflecting platelet-mediated inflammation), asymmetric dimethylarginine (ADMA; marker of endothelial dysfunction), and urinary 11-dehydro-thromboxane B2 (in vivo marker of platelet activation) was performed among 214 diabetic patients (90 receiving aspirin at 100 mg/day) and 30 healthy controls. Plasma DKK-1 levels were markedly higher in patients with T2DM than in healthy patients (P<0.0001). DKK-1 levels were significantly lower in diabetic patients receiving compared with those not on aspirin treatment (P=0.008); in the latter, DKK-1 was significantly correlated with 11-dehydro-thromboxane B2, ADMA, and CD40L (ρ=0.303. P<0.0001, ρ=0.45. P<0.0001, and ρ=0.37, P<0.0001, respectively) but not with glycemic control or DM duration. Among patients not receiving aspirin, improvement of metabolic control in a subgroup of newly diagnosed patients treated with acarbose for 20 weeks and in a group treated with rosiglitazone for 24 weeks was associated with concurrent significant reductions in DKK-1 (P=0.005 and P=0.004) and 11-dehydro-thromboxane B2 (P=0.005 and P=0.004).. Circulating DKK-1 is increased in T2DM and associated with endothelial dysfunction and platelet activation. Plasma DKK-1 levels are reduced with improvement of glycemic control and low-dose aspirin treatment.

Topics: Aged; Arginine; Aspirin; Biomarkers; Cardiovascular Diseases; Case-Control Studies; CD40 Ligand; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Intercellular Signaling Peptides and Proteins; Male; Middle Aged; Platelet Activation; Platelet Aggregation Inhibitors; Thromboxane B2; Wnt Signaling Pathway

The prevalence of cardiovascular diseases in women increases sharply after menopause. In postmenopausal women, thromboxane production increases while prostacyclin decreases. Low dose aspirin reduces the production of both thromboxane and prostacyclin. The present study was an open-label clinical trial with two parallel groups of 15 premenopausal women and 15 postmenopausal women. Twenty-four hours urine was collected from each subject before and after aspirin 100 mg daily for 7 days. The concentration of thromboxane and prostacyclin was measured as their metabolites (11-dehydro-thromboxane B(2) and 2,3-dinor-6-keto-prostaglandin-F(1α)) in urine using enzyme immunoassay methods. This study showed that aspirin significantly reduced thromboxane in both groups with significantly larger percentage reduction in postmenopausal women compared to premenopausal women (73.32 vs. 61.13%, p = 0.021). This study also showed that aspirin reduced prostacyclin significantly in both groups, but the percentage reduction between the groups was not significantly different. The decrease in the ratio of 11-dTXB(2)/2,3-dinor-6-keto-PGF(1α) should be compared to assess aspirin efficacy as an antithrombotic. Calculation of the ratio of 11-dTXB(2)/2,3-dinor-6-keto-PGF(1α) before aspirin consumption was higher in postmenopausal women than in premenopausal women. The decrease in 11-dTXB(2)/2,3-dinor-6-keto-PGF(1α) ratio by aspirin was greater in postmenopausal women than in premenopausal women (1.91 vs. 0.17; p = 0.022). It was concluded that aspirin reduced thromboxane and prostacyclin significantly in each group with significant 11-dTXB(2) percentage reduction between groups and non-significant 2,3-dinor-6-keto-PGF(1α) percentage reduction between groups, but reduced the 11-dTXB(2)/2,3-dinor-6-keto-PGF(1α) ratio much larger in postmenopausal women compared to that in premenopausal women.

Topics: Adult; Aspirin; Cardiovascular Diseases; Female; Humans; Middle Aged; Platelet Aggregation Inhibitors; Postmenopause; Premenopause; Prostaglandins F; Thromboxane B2

Thromboxane B2 (TxB2) and particularly 11-dehydrothromboxane B2 (11-dTxB2) are widely used as prognostic risk markers of platelet activation in cardiovascular diseases. The main errors in TxB2 and 11-dTxB2 determination include either low concentrations of circulating TxB2 (1 - 2 pg/mL) and 11-dTxB2 (0.9 - 4.3 pg/mL) or rather high transiency (mean TxB2 half-life is approximately 5 minutes) as well as an incorrect pre-analytical phase set up. The aim of this study was to investigate the impact of a widely used purification step on the results of enzyme immunosorbent assay (EIA)--based measurement of the two selected thromboxanes.. For the purpose of this study, 20 plasma samples (10 healthy donors, 10 patients under treatment with acetylsalicylic acid) were screened for TxB2 and 11-dTxB2 concentrations using commercial competitive EIA kits (Cayman Chemicals, Tallinn, Estonia; Neogen, Lexington, KY, USA) with or without the introduction of the purification procedure.. The purification step does not significantly affect the results of EIA measurements of the two of TxA2 metabolites (TxB2, 11-dTxB2) in human plasma. The levels of TxB2 and 11-dTxB2 determined in the plasma samples were not significantly changed (p < 0.05) when the purification step was omitted compared to the purified samples.. This study establishes a protocol allowing for reliable and reproducible plasma TxB2 and 11-dTxB2 EIA measurement for routine basic screening of platelet function.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Blood Platelets; Cardiovascular Diseases; Humans; Immunoenzyme Techniques; Platelet Activation; Prognosis; Reagent Kits, Diagnostic; Reproducibility of Results; Solid Phase Extraction; Thromboxane B2

The receptor for advanced glycation end-products (RAGE) has been implicated in obesity-related metabolic disease and accelerated atherothrombosis.. We tested the hypothesis that changes in endogenous secretory (es)RAGE levels as a result of excess adiposity and oxidative stress may contribute to enhancing platelet activation in obese women, thus increasing the cardiovascular risk.. Eighty otherwise healthy obese women and 20 nonobese women were studied.. esRAGE and plasma adiponectin were reduced in obese women [median (interquartile range), 0.18 (0.13-0.26) vs. 0.38 (0.20-0.48) ng/ml, P = 0.003; and 4.4 (2.8-6.4) vs. 10.0 (6.9-12.5) μg/ml, P < 0.0001, respectively] who also displayed higher urinary 11-dehydro-thromboxane B(2) (11-dehydro-TXB(2)) [795 (572-1089) vs. 211 (135-301) pg/mg creatinine; P < 0.0001] and 8-iso-prostaglandin F(2α) (8-iso-PGF(2α)) [544 (402-698) vs. 149 (98-219) pg/mg creatinine; P < 0.0001] compared to nonobese women. Direct correlations between plasma adiponectin and esRAGE (Rho = 0.43; P < 0.0001) and between urinary 8-iso-PGF(2α) and 11-dehydro-TXB(2) (Rho = 0.36; P = 0.001) were observed in obese women. Moreover, plasma esRAGE and urinary 11-dehdro-TXB(2) were inversely related (Rho = -0.29; P = 0.008). On multiple linear regression analysis, urinary 8-iso-PGF(2α) and plasma esRAGE were independent predictors of urinary 11-dehydro-TXB(2). In five obese women, a short-term weight loss program gave a significant increase in esRAGE and decrease in urinary 8-iso-PGF(2α) and 11-dehydro-TXB(2).. In otherwise healthy obese women, low plasma esRAGE levels are associated with reduced circulating adiponectin and enhanced thromboxane biosynthesis, which is in part mediated by increased lipid peroxidation. Thus, excess adiposity may be implicated in RAGE hyperactivation and thromboxane-dependent platelet activation, contributing to obesity-related metabolic and vascular disease.

Topics: Adiponectin; Adult; Anthropometry; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Dinoprost; Female; Humans; Linear Models; Lipid Peroxidation; Lipids; Middle Aged; Obesity; Oxidative Stress; Platelet Activation; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Risk; Thromboxane B2; Weight Loss

The methylenetetrahydrofolate reductase (MTHFR) 677 C→T polymorphism may be associated with elevated total homocysteine (tHcy) levels, an independent risk factor for cardiovascular disease. It was the study objective to evaluate in vivo lipid peroxidation and platelet activation in carriers of the MTHFR 677 C→T polymorphism and in non-carriers, in relation to tHcy and folate levels. A cross-sectional comparison of urinary 8-iso-prostaglandin (PG)F(2α) and 11-dehydro-thromboxane (TX)B(2) (markers of in vivo lipid peroxidation and platelet activation, respectively) was performed in 100 carriers and 100 non-carriers of the polymorphism. A methionine-loading test and folic acid supplementation were performed to investigate the causal relationship of the observed associations. Urinary 8-iso-PGF(2α) and 11-dehydro-TXB(2) were higher in carriers with hyperhomocysteinaemia than in those without hyperhomocysteinaemia (p<0.0001). Hyperhomocysteinaemic carriers had lower folate levels (p=0.0006), higher urinary 8-iso-PGF(2α) (p<0.0001) and 11-dehydro-TXB(2) (p<0.0001) than hyperhomocysteinaemic non-carriers. On multiple regression analysis, high tHcy (p<0.0001), low folate (p<0.04) and MTHFR 677 C→T polymorphism (p<0.001) independently predicted high rates of 8-iso-PGF(2α) excretion. Methionine loading increased plasma tHcy (p=0.002), and both urinary prostanoid metabolites (p=0.002). Folic acid supplementation was associated with decreased urinary 8-iso-PGF(2α) and 11-dehydro-TXB2 excretion (p<0.0003) in the hyperhomocysteinaemic group, but not in the control group, with substantial inter-individual variability related to baseline tHcy level and the extent of its reduction. In conclusion, hyperhomocysteinaemia due to the MTHFR 677 C→T polymorphism is associated with enhanced in vivo lipid peroxidation and platelet activation that are reversible, at least in part, following folic acid supplementation. An integrated biomarker approach may help identifying appropriate candidates for effective folate supplementation.

Topics: Biomarkers; Cardiovascular Diseases; Comorbidity; Cross-Sectional Studies; Diabetes Mellitus; Dinoprost; Dyslipidemias; Folic Acid; Homocystinuria; Humans; Hyperhomocysteinemia; Lipid Peroxidation; Methionine; Methylenetetrahydrofolate Reductase (NADPH2); Muscle Spasticity; Oxidative Stress; Platelet Activation; Polymorphism, Single Nucleotide; Psychotic Disorders; Smoking; Thromboxane B2

Elevated urine 11-dehydro TXB(2), an indicator of persistent thromboxane generation in aspirin-treated patients, correlates with adverse cardiovascular outcome and has recently been identified as an independent risk factor for vein graft thrombosis after cardiac bypass surgery in the Reduction in Graft Occlusion Rates (RIGOR) study. The polyclonal antibody-based ELISA used to measure 11-dehydro TXB(2) in these previous studies is no longer clinically available and has been supplanted by a Food and Drug Administration (FDA)-cleared second-generation monoclonal antibody-based ELISA.. To compare the laboratory and clinical performance of the first- and second-generation assays in a well-defined study population.. 11-dehydro TXB(2) was quantified in 451 urine samples from 229 Reduction in Graft Occlusion Rates (RIGOR) subjects using both ELISA. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and spiking studies were used to investigate discordant assay results. The association of 11-dehydro TXB(2) to clinical outcome was assessed for each assay using multivariate modeling.. Median 11-dehydro TXB(2) levels were higher by monoclonal antibody- compared with polyclonal antibody-based ELISA (856 vs. 399 pg mg(-1) creatinine, P < 0.000001), with the latter providing values similar to UPLC-MS/MS. This discrepancy was predominantly as a result of cross-reactivity of the monoclonal antibody with 11-dehydro-2,3-dinor TXB(2), a thromboxane metabolite present in a similar concentration but with a poor direct correlation with 11-dehydro TXB(2). In contrast to the first-generation ELISA, 11-dehydro TXB(2) measured by the monoclonal antibody-based ELISA failed to associate with the risk of vein graft occlusion.. Quantification of urine 11-dehydro TXB(2) by monoclonal antibody-based ELISA was confounded by interference from 11-dehydro-2,3-dinor TXB(2) which reduced the accuracy and clinical utility of this second-generation assay.

Topics: Antibodies, Monoclonal; Antibody Specificity; Cardiovascular Diseases; Chromatography, Liquid; Cross Reactions; Enzyme-Linked Immunosorbent Assay; Humans; Risk Factors; Sensitivity and Specificity; Tandem Mass Spectrometry; Thromboxane B2

Urinary 11-dehydro thromboxane B2 (d-TXB2) concentrations in the highest quartile have been associated with an increased risk of adverse outcomes in patients at high risk for atherothrombotic events. However, the determination of d-TXB2 is time consuming and not suitable for daily clinical routine. We therefore sought to determine the test correlating best with d-TXB2 to estimate aspirin-mediated platelet inhibition in 225 patients on dual antiplatelet therapy after percutaneous intervention with stent implantation. We selected light transmission aggregometry, the VerifyNow aspirin assay, the Platelet Function Analyzer-100, multiple electrode platelet aggregometry (MEA) and Impact-R for comparisons with d-TXB2. Cut-off values for high on-treatment residual arachidonic acid-inducible platelet reactivity (HRPR) were defined according to quartiles of each assay. Sensitivities and specificities of the different platelet function tests were based on d-TXB2 results. The results from all assays correlated poorly with d-TXB2. Only MEA showed a weak, but significant correlation with d-TXB2 (r = 0.14, p = 0.042). Further, the five platelet function tests showed a poor agreement with d-TXB2 regarding the determination of HRPR. Sensitivities and specificities for HRPR ranged from 17.5 to 44.6%, and from 70.8 to 77.9%, respectively. In conclusion, the evaluated assays did not mirror d-TXB2 results, suggesting that thromboxane inhibition can be circumvented in assays that determine platelet function. Therefore, large trials with clinical outcome data are needed to determine the diagnostic value of the various test systems and to define the gold standard method for assessing residual AA-inducible platelet reactivity.

Topics: Adult; Aged; Aged, 80 and over; Aspirin; Blood Platelets; Cardiovascular Diseases; Female; Humans; Male; Middle Aged; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Stents; Thromboxane B2; Treatment Outcome

To investigate tools for evaluation of smoking-associated disease initiation and progression, we examined basic clinical parameters and biomarkers of cardiovascular disease risk, in a group of healthy volunteers with an average 10-year smoking history. A small cross-sectional study of never-smokers, moderate smokers and smokers was performed. Caucasians were recruited to match pre-defined cigarette tar yields and cigarettes smoked per day. For haematological parameters, significant differences between never-smokers and all female smokers combined were seen for haemoglobin concentration, haematocrit, total leucocyte count, neutrophil count and lymphocyte count. For all male smokers combined, only total leucocyte count was statistically different. Analysis of exhaled CO and other smoke exposure biomarker (nicotine and its metabolites) data showed a statistically significant increase in all groups of smokers with a trend related to the number of cigarettes smoked per day. Thromboxane urinary metabolites 11-dehydro-thromboxane B(2) and 2,3-dinor-thromboxane B(2) were statistically significantly elevated in smokers. Significant statistical differences between smokers with approximately 10 years of smoking history and non-smokers in white cells count, hemoglobin and thromboxane turnover were seen, although they did not reach levels associated with overt diseases. These data could provide insight into early biomarkers predictive of risk for coronary and vascular disease.

Topics: Adult; Biomarkers; Cardiovascular Diseases; Cross-Sectional Studies; Disease Progression; Female; Hemoglobins; Humans; Leukocyte Count; Male; Risk Factors; Sex Factors; Smoking; Tars; Thromboxane B2; Thromboxanes; Young Adult

Topics: Aged; Aspirin; Cardiovascular Diseases; Cyclooxygenase Inhibitors; Double-Blind Method; Female; Follow-Up Studies; Humans; Internationality; Male; Middle Aged; Risk Factors; Survival Rate; Thromboxane B2; Thromboxanes

The phenomenon called aspirin resistance is being intensively discussed.. To evaluate the biochemical aspirin response, the method of urinary 11-dehydro TXB2 levels measurement was used. Quantitative detection of TXB2 in urine was determined by competitive enzyme immunoassay, using human Thromboxane B2 ELISA-kit. We investigated the urine samples from 69 patients.. The mean urinary levels of 11-dehydro TXB2 were significantly lower in patients in the primary and secondary types of aspirin prevention comparing with the control group of patients not taking aspirin. The difference in thromboxane concentrations between the two groups of patients taking aspirin did not reach statistical significance. Our results did not show significant differences in the biochemically measured aspirin response when comparing diabetics with non-diabetics. Similarly, the observed tendency to higher thromboxane levels in women did not show to be significantly different from men.. Our pilot study did not show any significant differences among patients at different cardiovascular risk. Since there is currently no standard laboratory method to detect aspirin non-responders available, the term aspirin resistance remains controversial and requires further research. Every effort should be done to improve patients' compliance and to prevent clinically relevant interactions of aspirin with ibuprofen. The elimination of these two factors as was the case in our study may provide better efficacy of the antithrombotic prevention by aspirin (Fig. 2, Tab. 4, Ref. 19). Full Text (Free, PDF) www.bmj.sk.

Topics: Aged; Aspirin; Cardiovascular Diseases; Diabetes Mellitus; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Risk; Thromboxane B2

We studied whether aspirin resistance, defined as failure of suppression of thromboxane generation, increases the risk of cardiovascular events in a high-risk population.. Baseline urine samples were obtained from 5529 Canadian patients enrolled in the Heart Outcomes Prevention Evaluation (HOPE) Study. Using a nested case-control design, we measured urinary 11-dehydro thromboxane B2 levels, a marker of in vivo thromboxane generation, in 488 cases treated with aspirin who had myocardial infarction, stroke, or cardiovascular death during 5 years of follow-up and in 488 sex- and age-matched control subjects also receiving aspirin who did not have an event. After adjustment for baseline differences, the odds for the composite outcome of myocardial infarction, stroke, or cardiovascular death increased with each increasing quartile of 11-dehydro thromboxane B2, with patients in the upper quartile having a 1.8-times-higher risk than those in the lower quartile (OR, 1.8; 95% CI, 1.2 to 2.7; P=0.009). Those in the upper quartile had a 2-times-higher risk of myocardial infarction (OR, 2.0; 95% CI, 1.2 to 3.4; P=0.006) and a 3.5-times-higher risk of cardiovascular death (OR, 3.5; 95% CI, 1.7 to 7.4; P<0.001) than those in the lower quartile.. In aspirin-treated patients, urinary concentrations of 11-dehydro thromboxane B2 predict the future risk of myocardial infarction or cardiovascular death. These findings raise the possibility that elevated urinary 11-dehydro thromboxane B2 levels identify patients who are relatively resistant to aspirin and who may benefit from additional antiplatelet therapies or treatments that more effectively block in vivo thromboxane production or activity.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Aspirin; Canada; Cardiovascular Diseases; Case-Control Studies; Cohort Studies; Comorbidity; Cyclooxygenase Inhibitors; Death, Sudden, Cardiac; Demography; Female; Follow-Up Studies; Humans; Male; Myocardial Infarction; Odds Ratio; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Secondary Prevention; Stroke; Thromboxane B2; Thromboxanes; Vitamin E

This study investigates how strenuous arm exercise affects oxidized-low density lipoprotein (O(X)-LDL) mediated-platelet activation in patients with SCI. Ten patients with SCI and ten age- and sex-matched healthy subjects exercised strenuously using an arm crank ergometer. The following measurements were taken both when the subjects were at rest, and immediately after exercise: plasma lipid profile, O(X)-LDL mediated platelet aggregability and [Ca(2+)]i, urinary 11-dehydro-thromboxane B2 (11-dehydro-TXB2) and 8-iso-prostaglandin F(2alpha), (8-iso-PG F(2alpha)) contents, and plasma NO metabolite (nitrite plus nitrate) level. Based on these measurements, the major findings of this study can be summarized as follows: 1) the SCI group had higher urinary 8-iso-PGF(2alpha) and 11-dehydro-TXB2 contents, but a lower plasma nitrite plus nitrate level than the control group; 2) at rest, the SCI group had a higher platelet aggregability and [Ca(2+)]i, and O(X)-LDL-potentiated platelet activation than the control group; 3) O(X)-LDL-potentiated platelet aggregation was enhanced by strenuous arm exercise in both groups, but the effect of exercise was more pronounced in the SCI group than in the control group; 4) treating the platelet with L-arginine inhibited O(X)-LDL-potentiated platelet activation in both groups. The study concludes that individuals with SCI had more extensive resting and exercise-enhanced O(X)-LDL-potentiated platelet activation and greater amounts of preformed lipid peroxides than those without SCI. Therefore, supplementation therapy with antioxidants may be needed for patients with SCI, especially in a strenuous arm exercise period.

Topics: Adult; Arm; Arteriosclerosis; Calcium; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Dinoprost; Exercise Test; F2-Isoprostanes; Female; Humans; Lipid Peroxidation; Lipoproteins, LDL; Male; Nitrates; Nitric Oxide; Nitrites; Oxidative Stress; Platelet Activation; Platelet Aggregation; Platelet Count; Risk Factors; Spinal Cord Injuries; Thromboxane B2

F2-isoprostanes are bioactive prostaglandin (PG)-like compounds that are produced from arachidonic acid through a nonenzymatic process of lipid peroxidation catalyzed by oxygen free-radicals. 8-Epi-PGF2 alpha may amplify the platelet response to agonists, circulates in plasma, and is excreted in urine. We examined the hypothesis that the formation of 8-epi-PGF2 alpha is altered in patients with hypercholesterolemia and contributes to platelet activation in this setting. Urine samples were obtained from 40 hypercholesterolemic patients and 40 age- and sex-matched control subjects for measurement of immunoreactive 8-epi-PGF2 alpha. Urinary excretion of 11-dehydro-thromboxane (TX) B2, a major metabolite of TXA2, was measured as an in vivo index of platelet activation. Low-dose aspirin, indobufen, and vitamin E were used to investigate the mechanism of formation and effects of 8-epi-PGF2 alpha on platelet activation. Urinary 8-epi-PGF2 alpha was significantly (P = .0001) higher in hypercholesterolemic patients than in control subjects: 473 +/- 305 versus 205 +/- 95 pg/mg creatinine. Its rate of excretion was inversely related to the vitamin E content of LDL and showed a positive correlation with urinary 11-dehydro-TXB2. Urinary 8-epi-PGF2 alpha was unchanged after 2-week dosing with aspirin and indobufen despite complete suppression of TX metabolite excretion. Vitamin E supplementation was associated with dose-dependent reductions in both urinary 8-epi-PGF2 alpha and 11-dehydro-TXB2 by 34% to 36% and 47% to 58% at 100 and 600 mg daily, respectively. We conclude that the in vivo formation of the F2-isoprostane 8-epi-PGF2 alpha is enhanced in the vast majority of patients with hypercholesterolemia. This provides an aspirin-insensitive mechanism possibly linking lipid peroxidation to amplification of platelet activation in the setting of hypercholesterolemia. Dose-dependent suppression of enhanced 8-epi-PGF2 alpha formation by vitamin E supplementation may contribute to the beneficial effects of antioxidant treatment.

Topics: Antioxidants; Aspirin; Cardiovascular Diseases; Cross-Sectional Studies; Cyclooxygenase Inhibitors; Dinoprost; Female; Humans; Hypercholesterolemia; Isoindoles; Lipid Peroxidation; Lipoproteins, LDL; Male; Middle Aged; Phenylbutyrates; Platelet Activation; Platelet Aggregation Inhibitors; Reactive Oxygen Species; Thromboxane B2; Vitamin E