thromboxane-a2 and Coronary-Artery-Disease

The crucial role of platelets in primary hemostasis and repair of injured endothelium is well established, as is their role in atherothrombosis. No other single cell type is responsible for as much morbidity and mortality, since death from ischemic heart disease or stroke is by far the leading cause of death worldwide. There is no doubt that our understanding of atherothrombosis has guided current antithrombotic strategies that have dramatically reduced ischemic complications and cardiovascular mortality within the last decades. Yet the rate of ischemic complications after optimal revascularization therapy remains disappointingly high. There is still a strong need for new and smart antiplatelet drugs. The ideal antithrombotic drug would spare physiological platelet function, hemostasis and vascular repair in order to avoid bleeding complications, but would exclusively target the pathological atherothrombotic process. As platelet activity might be determined early in the bone marrow, this review starts with insights into the birth of platelets, describes the essential and primary role of platelets in hemostasis with new evidence in signaling cascades, and closes with the deleterious role of platelets in atherosclerosis and atherothrombosis, with a focus on acute coronary syndromes.

Topics: Adenosine Diphosphate; Animals; Atherosclerosis; Blood Platelets; Coronary Artery Disease; Coronary Thrombosis; Fibrinolytic Agents; Hemostasis; Humans; Plaque, Atherosclerotic; Platelet Activation; Platelet Aggregation Inhibitors; Thrombin; Thrombosis; Thromboxane A2

In this study, we review the evidence for both long-standing and newer oral antiplatelet agents as secondary prevention in coronary artery disease, and give our opinion on where each agent's treatment role lies.. Platelets play a pathological role in acute coronary syndromes and are therefore a major therapeutic target. The caveat to this is that their physiological haemostatic role means there must be a careful balance between preventing ischaemia and not promoting bleeding. In addition to accepted oral agents (aspirin and clopidogrel), more potent antiplatelet agents have recently become available (prasugrel and ticagrelor) at a cost of increased bleeding.. There is now a choice of three antiplatelet agents to be used in conjunction with aspirin for secondary prevention with dual antiplatelet therapy. Clinicians must now 'tailor' the correct therapy for each patient, depending on their presentation, clinical features and stage of risk.

Topics: Adenosine; Aspirin; Clopidogrel; Coronary Artery Disease; Drug Interactions; Drug Therapy, Combination; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Risk Factors; Secondary Prevention; Thiophenes; Thromboxane A2; Ticagrelor; Ticlopidine

Platelets are major players in arterial thrombosis, and antiplatelet therapy has a clear clinical benefit in the treatment and prevention of cardiovascular events. In particular, aspirin and clopidogrel have become cornerstones in the treatment of patients with atherothrombosis. However, despite the proven efficacy of antiplatelet drugs, cardiovascular events remain an important cause of morbidity and mortality in these patients. Furthermore, a considerable variability in platelet reactivity during treatment with established oral antiplatelet therapy has prompted the search for novel drugs against platelet-dependent thrombosis. Possible benefits of upcoming drugs include a more efficient platelet inhibition and a reversible effect on platelet function. Aspirin, clopidogrel, prasugrel, ticagrelor, terutroban, E5555, SCH 530348 and cilostazol are discussed. This review highlights the rationale for important oral antiplatelet drugs in development and provides clinical perspectives on their pharmacological advantages and challenges.

Topics: Adenosine; Administration, Oral; Cardiovascular Diseases; Cilostazol; Coronary Artery Disease; Coronary Thrombosis; Drug Resistance; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Tetrazoles; Thiophenes; Thromboxane A2; Ticagrelor

The present review focuses on the roles of thromboxane A2 (TxA2) in arterial thrombosis, atherogenesis, vascular stent-related ischemic events and renal proteinuria. Particular emphasis is laid on therapeutic interventions targeting the TxA2 (TP) receptors and TxA2 synthase (TS), including dual TP-receptor antagonists and TS inhibitors. Their significant inhibitory efficacies on arterial thrombogenesis, atherogenesis, restenosis after stent placement, vasoconstriction and proteinuria indicate novel and improved treatments for cardiovascular and selected renal diseases. New therapeutic interventions of the TxA2 pathway may also be beneficial for patients with poor biological antiplatelet drug response, for example, to aspirin and/or clopidogrel. These new TP/TS agents offer novel improved treatments to efficiently and simultaneously interfere with thrombogenesis and atherogenesis, and to enlarge the existing panel of platelet inhibitors for efficient prophylaxis and treatment of arterial thrombosis and renal proteinuria.

Topics: Aspirin; Cardiovascular Diseases; Clopidogrel; Coronary Artery Disease; Coronary Restenosis; Humans; Kidney Diseases; Platelet Aggregation Inhibitors; Proteinuria; Receptors, Thrombin; Thrombosis; Thromboxane A2; Thromboxane-A Synthase; Ticlopidine

The early period following an acute coronary syndrome (ACS) is characterised by atherosclerotic plaque destabilisation and a pro-coagulant state, and is when patients are at highest risk for recurrent cardiovascular events and mortality. Statins decrease thrombus formation and increase fibrinolysis, inhibit platelet reactivity and aggregation, improve endothelial function in patients with coronary artery disease and have a major role in plaque stabilisation. Several studies showed that initiation of early statin therapy in these settings may have beneficial effects. This review summarises the current data on statins in the setting of ACSs. Known and other possible mechanisms of action are described. The pathophysiological mechanisms, histological features and biochemical characteristics of ACS are different than those with stable coronary disease, thereby suggesting that the mechanisms whereby statins exert their benefits in ACS may be distinct from those for stable CHD. Initiation of the therapy during hospitalisation rather than at the time of hospital discharge may provide protection against early recurrent cardiovascular events and also improve patients' compliance.

Topics: C-Reactive Protein; Cholesterol, LDL; Clinical Trials as Topic; Coronary Artery Disease; Dose-Response Relationship, Drug; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Myocardial Ischemia; Platelet Aggregation Inhibitors; Risk Factors; Syndrome; Thromboxane A2

Active smoking is a well known risk factor for the development of atherosclerosis and in particular coronary heart disease and peripheral vascular disease. The negative effects of active smoking demonstrated on platelet function, the eicosanoid system and platelet thromboxane A2 generation may contribute to the hemostatic imbalance reported. Recently, the problem of passive smoking as a health risk has been widely discussed. Detailed information on the role of passive smoking on hemostatic parameters, however, is still very limited. As far as present knowledge is concerned, platelet activation seems to be significantly involved in the deleterious vascular effects of passive smoking as well.

Topics: Arteriosclerosis; Blood Platelets; Coronary Artery Disease; Humans; Platelet Activation; Risk Factors; Smoking; Thromboxane A2; Tobacco Smoke Pollution

Rupture of the lipid-rich atheromatous plaque, intraplaque hemorrhage, and intraluminal thrombus are three pathological hallmarks most commonly recognized in the infarct-related coronary artery at the site of acute myocardial infarction. Rupture of the atheromatous plaque is closely related to but does not fully explain the genesis of occlusive intracoronary thrombus formation and thus the development of acute myocardial infarction. Besides a variety of hematologic disorders, one should emphasize the role of the platelet-derived mediators that promote an environment where thrombosis and vasoconstriction occur, including TXA2, serotonin, ADP, platelet-derived growth factor, tissue factor, and the diminished availability of those natural endogenous substances that inhibit platelet aggregation, such as EDRF, tissue plasminogen activator, and PGI2. PGI2 released from vascular endothelial cells is extremely unstable. Our group provided the first evidence that HDL stabilizes PGI2 through the newly discovered function of Apo A-I, which is associated with the surface of HDL particles and identified as PGI2 stabilizing factor. Decrease in HDL-associated Apo A-I in patients with unstable angina and during the acute phase of myocardial infarction indicates that HDL plays an important role in preventing coronary atherosclerosis and intracoronary thrombus formation by stabilizing PGI2 in addition to the generally accepted biochemical property of HDL to prevent the accumulation of cholesterol by mobilizing free cholesterol from tissues or macrophages. There is also a PGI2 synthesis-stimulating factor in serum that has not yet been identified chemically. EDRF or nitric oxide provides another important regulating system in the vessel wall. Lipoproteins are inhibitors of endothelium-dependent relaxation of rabbit aorta.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Apolipoprotein A-I; Apolipoprotein A-II; Coronary Artery Disease; Coronary Thrombosis; Coronary Vessels; Endothelium, Vascular; Epoprostenol; Humans; Myocardial Infarction; Nitric Oxide; Thromboxane A2

Aspirin's therapeutic action is via inhibition of platelet cyclooxygenase 1 (COX-1) thromboxane A2 (TxA2) production. The aim of this study was to evaluate TxA2 production, in the absence of platelet COX-1 activity, in coronary atherosclerotic heart disease patients with and without atherothrombotic myocardial infarction (MI).. TxA2 production, in the absence of platelet COX-1 activity, was evaluated in 44 patients taking aspirin on 3 commercially available assays that detect metabolites of TxA2 in the urine. Two assays measure urine 11-dehydro-thromboxane B2 (TxB2) alone and 1 measures urine 11-dehydro-TxB2 plus 11-dehydro-2,3-dinor-TxB2. Platelet COX-1 inhibition was confirmed on <10% platelet aggregation in response to ≥1 mmol/L arachidonic acid. Median urine 11-dehydro-TxB2 was no different in those with and without a diagnosis of atherothrombotic MI (325 vs. 311 pg/mg creatinine, P=0.59 via polyclonal ELISA) and (312 vs. 244 pg/mg creatinine, P=0.11 via LC-MS/MS). Median urine 11-dehydro-TxB2 plus 11-dehydro-2,3-dinor-TxB2, however, was higher in those with vs. those without a diagnosis of atherothrombotic MI (1,035 vs. 606 pg/mg creatinine, P=0.03 via monoclonal ELISA).. Differences in TxA2 production, in the absence of platelet COX-1 activity, between those with vs. without atherothrombotic MI were not observed when TxA2 generation was assessed on 11-dehydro-TxB2 production alone (polyclonal ELISA or LC-MS/MS), but differences were observed when TxA2 generation was assessed using 11-dehydro-TxB2 plus 11-dehydro-2,3-dinor-TxB2 (monoclonal ELISA). These findings highlight important differences between different commercially available assays for TxA2 generation and suggest that 11-dehydro-2,3-dinor-TxB2 may be critical to the biology of atherothrombosis.

Topics: Aged; Aspirin; Blood Platelets; Coronary Artery Disease; Creatinine; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Female; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation; Thrombosis; Thromboxane A2; Thromboxane B2

Platelets, long believed to be incapable of de novo protein synthesis, may retain their ability to form the cyclooxygenase (COX) enzyme once it has been inactivated by aspirin. This may explain the inefficacy of the drug to induce sustained platelet inhibition in certain patients. We evaluated the stability of platelet inhibition following once-daily enteric-coated aspirin administration.. Platelet responsiveness to aspirin was evaluated in 11 stable coronary artery disease patients on chronic aspirin therapy before and 1, 3, 8, and 24h after observed ingestion of 80-mg enteric-coated aspirin. Inhibition of the COX pathway was measured pharmacologically through plasma thromboxane (Tx) B(2) levels, and functionally by light transmission aggregometry in response to arachidonic acid. COX-independent platelet activity was measured in response to adenosine diphosphate, epinephrine and collagen.. Plasma TxB(2) levels showed profound inhibition of TxA(2) formation, which was stable throughout 24h, in all but 1 subject. This subject had optimal response to aspirin (inhibition of platelet TxA(2) production within 1h), but recovered the ability to synthesize TxA(2) within 24h of aspirin ingestion. Arachidonic acid-induced platelet aggregation closely mirrored TxB(2) formation in this patient, portraying a functional ability of the platelet to aggregate within 24h of aspirin ingestion. COX-independent platelet aggregation triggered TxA(2) production to a similar extent in all patients, likely through signal-dependent protein synthesis.. COX-dependent platelet activity is recovered in certain individuals within 24h of aspirin administration. Further research should consider increasing aspirin dosing frequency to twice daily, to allow sustained inhibition in such subjects.

Topics: Adult; Aspirin; Coronary Artery Disease; Cyclooxygenase Inhibitors; Female; Genetic Heterogeneity; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Prostaglandin-Endoperoxide Synthases; Thromboxane A2; Thromboxane B2

Acute vigorous exercise, associated with increased release of plasma catecholamines, transiently increases the risk of primary cardiac arrest. We tested the effect of acute submaximal exercise on vasoactive substances and their combined result on platelet function.. Healthy volunteers, hypertensive patients and patients with coronary artery disease (CAD) performed a modified treadmill exercise test. We determined plasma catecholamines, thromboxane A2, prostacyclin, endothelin-1 and platelet aggregation induced by adenosine diphosphate (ADP) and collagen at rest and during exercise.. Our results during exercise showed a) platelet activation (increased thromboxane B2, TXB2), b) increased prostacyclin release from endothelium and c) decreased platelet aggregation in all groups, significantly more in healthy volunteers than in patients with CAD (with hypertensives lying in between these two groups).. Despite the pronounced activation of Sympathetic Nervous System (SNS) and increased TXB2 levels during acute exercise platelet aggregation decreases, possibly to counterbalance the prothrombotic state. Since this effect seems to be mediated by the normal endothelium (through prostacyclin and nitric oxide), in conditions characterized by endothelial dysfunction (hypertension, CAD) reduced platelet aggregation is attenuated, thus posing such patients in increased risk for thrombotic complications.

Topics: Adult; Catecholamines; Coronary Artery Disease; Endothelin-1; Endothelium, Vascular; Epoprostenol; Exercise; Female; Humans; Hypertension; Male; Platelet Activation; Platelet Aggregation; Thromboxane A2

Recently, we cloned from platelet mRNA a novel cyclooxygenase (COX)-2 splice variant, designated COX-2a, which is characterized by a partial deletion of exon 5. Preliminary studies of mRNA distribution of COX-2 isoforms in platelets from coronary artery bypass grafting (CABG) patients showed a variable increase in COX-2a mRNA expression after cardiac surgery. Thus, we assessed whether this variant may play a functional role in these patients. We report a marked (about 200-fold) increase in the expression of COX-2a mRNA after CABG. Evidence is presented that ribosomal frame-shifting may correct the coding sequence resulting in the expression of a full-length COX-2a protein. In addition, a reading frame-corrected COX-2a mutant (COX-2a delta G) was generated by site-directed mutagenesis and expressed in COS-7 cells using an adenoviral expression system. However, COX-2a protein was not active in terms of prostaglandin formation. Thus, alternative mRNA splicing might represent an intriguing posttranscriptional mechanism to oppose a transcriptional activation of the COX-2 gene. Evolutionary, this mechanism may prevent COX-2-dependent thromboxane synthesis in the platelet, which would potentiate the likelihood of thrombosis; pharmacologically, this mechanism would prevent an aspirin-insensitive pathway of thromboxane formation.

Topics: Administration, Oral; Alternative Splicing; Animals; Aspirin; Base Sequence; Blood Platelets; Chlorocebus aethiops; Coronary Artery Bypass; Coronary Artery Disease; COS Cells; Cyclooxygenase 2; Drug Resistance; Epoprostenol; Frameshifting, Ribosomal; Humans; Isoenzymes; Molecular Sequence Data; Mutagenesis, Site-Directed; Nucleic Acid Conformation; Platelet Aggregation; Platelet Aggregation Inhibitors; RNA, Messenger; Thromboxane A2; Transfection; Treatment Outcome; Up-Regulation

To evaluate whether aspirin reduces the incidence and frequency of daily life myocardial ischaemia in a cohort of patients with chronic stable coronary artery disease.. Tertiary referral centre.. 60 patients with chronic stable coronary artery disease underwent 48 hour Holter monitoring to assess the incidence and frequency of daily life myocardial ischaemia. Those with myocardial ischaemia (40/60) entered a double blind, crossover trial of aspirin (300 mg/day for three weeks) versus placebo. After each treatment arm, 48 hour Holter monitoring was repeated and urinary thromboxane (Tx) B2, 11-dehydro-TxB2, plasma prothrombin fragment F1+2, macrophage colony stimulating factor (MCSF), and interleukin (IL)-6 were measured.. Aspirin reduced the total number and duration of ischaemic episodes from 339 to 251 and from 1765 to 1365 minutes, respectively (p < 0.01 for both). TxB2 was also reduced from 0.2 to 0.1 ng/mg creatinine, 11-dehydro-TxB2 from 3.3 to 1.3 ng/mg creatinine, F1+2 from 1.5 to 1.2 nmol/l, MCSF from 991 to 843 pg/ml, and IL-6 from 3.5 to 2.9 pg/ml (p < 0.05 for all). 11-dehydro-TxB2 excretion with and without aspirin was related to MCSF concentrations (p < 0.01), and the percentage reduction of MCSF by aspirin was related to the reduction of 11-dehydro-TxB2 (p < 0.05) and the reduction of the ischaemic burden compared with placebo (p < 0.05).. In patients with daily life ischaemia, aspirin reduces the incidence and frequency of ischaemic episodes as well as the systemic concentrations of haemostatic/inflammatory markers. Aspirin may prevent transient coronary flow reductions through platelet, thrombin, and cytokine inhibition.

Topics: Adult; Aged; Aspirin; Biomarkers; Cohort Studies; Coronary Artery Disease; Cross-Over Studies; Double-Blind Method; Electrocardiography, Ambulatory; Female; Humans; Interleukin-6; Macrophage Colony-Stimulating Factor; Male; Middle Aged; Myocardial Ischemia; Peptide Fragments; Platelet Aggregation Inhibitors; Prothrombin; Thromboxane A2; Thromboxane B2

We evaluated whether renin-angiotensin system (RAS) blockade attenuates cardiovascular events.. Because inflammation and enhanced thrombogenesis are hallmarks of atherosclerosis, we assessed whether RAS inhibition elicits anti-inflammatory and anti-aggregatory effects.. Interleukin 6 (IL-6), high-sensitivity C-reactive protein (hsCRP), metalloprotease 9 (MMP-9), and interleukin 10 (IL-10) were determined in patients with coronary artery disease (CAD) and arterial hypertension six to eight weeks after coronary angioplasty (low-density lipoprotein serum levels <150 mg/dl). Patients were randomized double-blind to either 20 mg enalapril (ENAL, n = 27) or 300 mg irbesartan (IRB, n = 21) for 3 months. Blood samples were drawn at baseline and at three months. Thromboxane A2-induced platelet aggregation was determined turbidimetrically; urine bicyclo-prostaglandin E2 (PGE(2)) and inflammatory markers were measured by enzyme-linked immunosorbent assay technique.. Both treatment regimens enhanced serum IL-10 levels (IRB p < 0.001, ENAL p < 0.03) and reduced serum MMP-9 protein (IRB p < 0.001, ENAL p < 0.05) and MMP-9 activity (IRB p < 0.005, ENAL p < 0.05). Only IRB reduced serum IL-6 and hsCRP levels significantly compared with baseline (p < 0.01), whereas ENAL did not (hsCRP p < 0.02 IRB vs. ENAL, p < 0.01 IRB vs. ENAL). Platelet aggregation was only reduced by IRB (p < 0.001, ENAL p < 0.06, IRB vs. ENAL p < 0.001) while urine PGE(2) levels remained unchanged.. Angiotensin-converting enzyme (ACE) inhibition and angiotensin II type 1 receptor (AT1) blockade reduced serum MMP-9 protein/activity to a similar extent, and only AT1 blockade reduced hsCRP, IL-6, and platelet aggregation in patients with CAD. Thus, AT1-blockade appears to exert stronger systemic anti-inflammatory and anti-aggregatory effects compared with ACE inhibition.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Biphenyl Compounds; C-Reactive Protein; Coronary Artery Disease; Dinoprostone; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Inflammation; Interleukin-10; Interleukin-6; Irbesartan; Male; Matrix Metalloproteinase 9; Middle Aged; Platelet Aggregation; Tetrazoles; Thromboxane A2

In this study, we evaluated the effect of S 18886, a specific thromboxane A(2) receptor antagonist, on endothelial function in patients with coronary artery disease (CAD).. Impaired release of endothelial vasodilator substances and increased release of vasoconstrictor prostanoids both contribute to endothelial dysfunction in atherosclerosis. One unresolved question is whether vasoconstrictor prostanoids are still produced and affect vascular tone or alter endothelium-dependent vasodilation in patients treated with aspirin.. Twenty patients with stable CAD treated with 100 mg/day aspirin were evaluated in a randomized, double-blinded, placebo-controlled study. Twelve patients received a single oral dose of 10 mg S 18886, and eight patients received placebo. Before and 60 min after a single oral dose of S 18886 or placebo, flow-mediated vasodilation (FMD) was evaluated using an echo-tracking device. Venous occlusion plethysmography was used to evaluate the effects on forearm blood flow (FBF) of a brachial artery infusion of acetylcholine (ACh), sodium nitroprusside (SNP), or norepinephrine before and after treatment.. Baseline FBF was not affected by S 18886 or placebo. The vasodilator response to ACh was significantly potentiated by S 18886 as compared with placebo (p = 0.03 by analysis of co-variance), whereas the effects of norepinephrine and SNP were unchanged. Flow-mediated dilation increased from 2.50 +/- 1.14% to 3.84 +/- 1.80% (p < 0.01) after S 18886, but was unchanged after placebo.. Single administration of S 18886 improved FMD and ACh-induced vasodilation in aspirin-treated patients with CAD. These results suggest that release of endogenous agonists of TP receptors may contribute to endothelial dysfunction, despite aspirin treatment, in patients with atherosclerosis.

Topics: Acetylcholine; Aged; Aspirin; Coronary Artery Disease; Cyclooxygenase Inhibitors; Double-Blind Method; Endothelium, Vascular; Forearm; Humans; Male; Middle Aged; Naphthalenes; Nitroprusside; Norepinephrine; Propionates; Receptors, Thromboxane; Regional Blood Flow; Tetrahydronaphthalenes; Thromboxane A2; Treatment Outcome; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

The transmural biodegradable polycaprolactone/poly(D,L-lactic/glycolic acid) (PCL/PLGA) scaffold is a promising modality for diffuse coronary atherosclerosis cases that are not suitable for bypass grafting. The purpose of this study was to evaluate the long-term performance of the PCL/PLGA scaffold in vivo in the setting of polymer and heparin degradation.. After mechanical drilling through the ventricular wall was performed in the whole ventricular wall, two scaffolds were implanted into the ventricular wall. Animals were grouped into the single drilling group (SD group), the blank scaffold group (BS group), and the heparinized scaffold group (HS group) and were allowed to survived for 6 mo. Next, the patency and integrity of the scaffolds were evaluated by echocardiography and 3D-DOCTOR software. Endothelium coverage of the lumen was evaluated by scanning electron microscopy. Neovessels and collagen fiber within the scaffolds were identified by histologic staining. Metabolite production of prostacyclin (PGI2) and thromboxane A2 (TXA2) in the plasma was measured by an enzyme-linked immunosorbent assay. The expression levels of PGI2 synthase and cyclooxygenase 2 (COX-2) involved in PGI2 production and COX-1 involved in TXA2 production were measured by Western blot analysis.. The heparinized scaffolds were patent for up to 6 mo and the lumen was covered with confluent endothelial cells. Histologic staining revealed collagen fiber remodeling and reconstruction of the neovascular network immediately surrounding the lumen. The expression of PGI2 synthase and COX-2 in the HS group was significantly higher compared with the SD and BS groups (P < 0.01). The expression of COX-1 was similar in the three groups (P > 0.05). Consistent with synthetase expression, a PGI2 metabolite (6-keto-PGF1a) also showed a significant increase in the HS group relative to the SD and BS groups (P = 0.021 and P = 0.015, respectively). Concomitantly, as a PGI2 antagonist, the TXA2 metabolite (TXB2) did not exhibit a significant difference among the three groups (P = 0.17).. Despite polymer and heparin degradation, the scaffold could continuously maintain the structural integrity and lumen patency for up to 6 mo by reinforcement of host collagen fiber and the balance of PGI2/TXA2.

Topics: Absorbable Implants; Animals; Anticoagulants; Biocompatible Materials; Coronary Artery Disease; Cyclooxygenase 1; Cyclooxygenase 2; Echocardiography; Endothelial Cells; Epoprostenol; Heparin; Lactic Acid; Microscopy, Electron, Scanning; Polyesters; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Swine; Swine, Miniature; Thromboxane A2; Tissue Scaffolds; Vascular Patency

Topics: Arachidonic Acid; Aspirin; Blood Platelets; Coronary Artery Disease; Drug Administration Schedule; Drug Monitoring; Drug Resistance; Humans; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Predictive Value of Tests; Thromboxane A2; Time Factors; Treatment Outcome

Aspirin-induced cyclooxygenase (COX)-1 acetylation is irreversible and it is assumed that the platelet thromboxane-A2 aggregation pathway is inhibited for at least 24 hours (h) after aspirin ingestion. However, time course of biological efficacy of daily low-dose aspirin has rarely been assessed in patients with coronary artery disease (CAD). We aimed to assess the 24-h biological efficacy of daily low-dose aspirin in CAD patients. The peak and trough (2 h-24 h) effect of a chronic treatment with once daily dose aspirin were studied in 150 consecutive stable CAD patients. The main outcome measure was light transmission aggregometry (LTA) triggered with 0.5 mg/ml arachidonic acid (AA). In the last 47 consecutive patients, additional tests were conducted at 6, 12, 16, 20 h after last aspirin administration. 4.7% of the patients had significant aggregation (>20% maximal intensity LTA-AA) 2 h after aspirin ingestion and 24.7% at 24 h (p<0.0001). The more precise assessments in the last 47 patients showed that significant platelet aggregation progressively reappeared with time after aspirin intake (2 h--4% of patients, 6 h-- 4%, 12 h--11%, 16 h--16%, 20 h--19% and 24 h--28%). Concordant results were observed using production of thromboxane-B2 and other techniques evaluating AA-induced platelet aggregation/activation. No significant differences were found between lower (75-100 mg/day) and higher (>100 mg/day) dose aspirin. Such aspirin «resistance» at 24 h after ingestion was related to biological inflammatory markers, current smoking and diabetes. In conclusion, once daily aspirin does not provide stable 24-h antiplatelet protection in a significant proportion of CAD patients. Any biological assessment of aspirin efficacy should take time since last aspirin intake into consideration.

Topics: Aged; Arachidonic Acid; Aspirin; Blood Platelets; Chi-Square Distribution; Coronary Artery Disease; Drug Administration Schedule; Drug Monitoring; Drug Resistance; Female; Humans; Male; Middle Aged; Odds Ratio; Paris; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Predictive Value of Tests; Prospective Studies; Thromboxane A2; Time Factors; Treatment Outcome

In South Africa coronary artery disease (CAD) is less common in African than Indian or white subjects. Although the association between CAD and metabolic factors have been well documented, the role of genetic factors is as yet poorly understood. Specific polymorphisms in the platelet membrane glycoprotein (GP) IIIa gene Pl(A1/A2), have been implicated in the development of CAD.. The prevalence of platelet GPIIIa (Pl(A1/A2)) polymorphisms and their effect on platelet function was determined in 313 Indian, 267 white and 227 African subjects with and without a history of CAD.. In subjects without a history of CAD the frequency of the unfavourable Pl(A2) allele was 8.0%, 14.8% and 8.7% in the Indian, white and African populations respectively, with the frequency being significantly higher (p<0.05) in the white than both other groups. The frequency of the Pl(A2) allele was higher in subjects with (23.0%) than without (10.0%; p<0.0001) a history of CAD. Aggregation studies showed that platelets carrying the Pl(A2) allele were hypersensitive to the platelet aggregating agonists ADP and collagen and produced a higher amount of TXA(2) when stimulated with low concentrations of both these agonists.. The positive association observed between the platelet GPIIIa Pl(A1/A2) polymorphism and platelet function suggests that the GPIIIa Pl(A2) allele may be a genetic factor that contributes to the risk of sudden death from myocardial infarction in the absence of known risk factors but it does not explain ethnic differences in the prevalence of CAD.

Topics: Adenosine Diphosphate; Alleles; Blood Platelets; Collagen; Coronary Artery Disease; Dose-Response Relationship, Drug; Ethnicity; Female; Gene Frequency; Genotype; Humans; Integrin beta3; Male; Platelet Aggregation; Polymorphism, Genetic; Prevalence; South Africa; Thromboxane A2; Urban Population

To determine a) whether clinical response to electroconvulsive therapy (ECT) is associated with decreased platelet activation in patients with major depressive disorder (MDD) and b) if any medical/demographic characteristics predict response to ECT or changes in platelet activation. Increased platelet activation may underlie the increased risk of coronary artery disease (CAD) in patients with MDD.. Before their first and sixth ECT treatments, study patients (n = 44) completed the Beck Depression Inventory (BDI) to assess the severity of depressive symptoms. Activity of the platelet thromboxane (TBX) A(2) pathway was assessed by measuring the morning spot urinary concentrations of 11-dehydroxy-thromboxane B(2) (11-D-TBX B(2)), a major metabolite of platelet-derived TBX A(2).. Multivariate logistic regression analyses revealed that improvement on the BDI was significantly more likely in patients without a history of hypertension (p = .02) and in patients who were prescribed a greater number of "platelet-altering" medications (p = .03). During a course of ECT, a decrease in urinary 11-D-TBX B(2) was significantly more likely to occur in ECT nonresponders (p = .01) and younger patients (p = .02).. Clinical response to ECT coadministered may not be associated with decreases in platelet-derived TBX. Future studies will confirm which somatic "antidepression" treatments offer optimal thrombovascular benefits for depressed patients with multiple risk factors for, or clinically evident, cerebral disease or CAD.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Coronary Artery Disease; Depressive Disorder, Major; Electroconvulsive Therapy; Female; Humans; Hypertension; Male; Middle Aged; Multivariate Analysis; Personality Inventory; Platelet Activation; Risk Factors; Thromboxane A2; Thromboxane B2; Treatment Outcome

Patients with inadequate platelet inhibition by aspirin, referred to as aspirin resistance, might have an increased risk of suffering cardiovascular events. Therefore, identification of these patients by measuring platelet function is of great interest. Our objectives were to evaluate performance parameters of VerifyNow and to determine the agreement between VerifyNow and light transmission aggregometry (LTA) ad modum Born.. We included 21 healthy volunteers and 40 patients with stable coronary artery disease. Duplicate measurements of platelet aggregation were performed using VerifyNow and LTA (arachidonic acid 1.0 mM) in healthy volunteers before aspirin and in all participants on four consecutive days during treatment with non-enteric-coated aspirin 75 mg daily. VerifyNow test results were expressed in Aspirin Reaction Units (ARU) and LTA test results in percent of maximal aggregation. The cut-off for determination of aspirin resistance was > or =550 ARU and > or =20%, respectively.. All participants were compliant, confirmed by complete suppression of serum-thromboxane B(2). VerifyNow was highly repeatable with a coefficient of variance of 0.5% at baseline and 3.0% during aspirin treatment. No individuals were identified as aspirin resistant with VerifyNow, whereas seven (12%) individuals were identified with LTA. ROC analysis using LTA as the gold standard showed poor sensitivity and good specificity with a cut-off at 550 ARU.. VerifyNow was highly repeatable, but further studies are needed to investigate the relevance of the cut-off level at 550 ARU for detecting aspirin resistance.

Topics: Adult; Aspirin; Blood Platelets; Case-Control Studies; Coronary Artery Disease; Drug Resistance; Female; Hemoglobins; Humans; Interviews as Topic; Male; Patient Compliance; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Count; Platelet Function Tests; Reproducibility of Results; ROC Curve; Sensitivity and Specificity; Thromboxane A2

We sought to compare the results obtained from six major platelet function tests in the assessment of the prevalence of aspirin resistance in patients with stable coronary artery disease.. 201 patients with stable coronary artery disease receiving daily aspirin therapy (> or =80 mg) were recruited. Platelet aggregation was measured by: (i) light transmission aggregometry (LTA) after stimulation with 1.6 mM of arachidonic acid (AA), (ii) LTA after adenosine diphosphate (ADP) (5, 10, and 20 microM) stimulation, (iii) whole blood aggregometry, (iv) PFA-100, (v) VerifyNow Aspirin; urinary 11-dehydro-thromboxane B(2) concentrations were also measured. Eight patients (4%, 95% CI 0.01-0.07) were deemed resistant to aspirin by LTA and AA. The prevalence of aspirin resistance varied according to the assay used: 10.3-51.7% for LTA using ADP as the agonist, 18.0% for whole blood aggregometry, 59.5% for PFA-100, 6.7% for VerifyNow Aspirin, and finally, 22.9% by measuring urinary 11-dehydro-thromboxane B(2) concentrations. Results from these tests showed poor correlation and agreement between themselves.. Platelet function tests are not equally effective in measuring aspirin's antiplatelet effect and correlate poorly amongst themselves. The clinical usefulness of the different assays to classify correctly patients as aspirin resistant remains undetermined.

Topics: Adult; Aged; Aged, 80 and over; Aspirin; Blood Platelets; Coronary Artery Disease; Cyclooxygenase 1; Drug Resistance; Female; Humans; Male; Middle Aged; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Reference Values; Thromboxane A2

Aspirin resistance (AR) is estimated to be present in 5-75% of patients and is related to increased cardiovascular mortality. However, the underlying mechanisms are mostly unknown. In the present study, AR was detected in 14 out of 55 patients (25%) with coronary artery disease. The presence of concomitant anti-inflammatory drugs did not affect AR. Plasma levels of thromboxane B(2) as well as the markers for oxidative stress and known platelet activators 8-isoprostane and lipid peroxidation products were significantly higher in aspirin-resistant individuals (349.3 pg/ml, 53.9 pg/ml, and 538 micromol/l) compared to controls (113.7 pg/ml, 10.3 pg/ml, and 32.2 micromol/l; P < 0.05, respectively). Platelet cyclooxygenase-1 (COX-1) and COX-2 mRNA and protein expression were without significant differences between the two groups. DNA sequencing detected a novel platelet COX-1 single nucleotide polymorphism (SNP) resulting in amino acid exchange at position 8 (Arg8/Trp8). The wild-type as well as the heterozygous and homozygous SNP were present in both patient groups without significant differences. The aspirin binding (Arg120) and acetylation site (Ser529) were unaffected in the samples tested. Neither was AR related to the platelet integrin PlA(1)/A(2) polymorphism. In conclusion, AR appears to be unrelated to differences in platelet COX-1 and COX-2 expression or to a novel platelet COX-1 SNP and the PlA(1)/A(2) SNP. However, a correlation exists to elevated eicosanoids generated by oxidative stress indicating COX-1-independent pathways for the generation of platelet activating molecules represent a potential cause for AR.

Topics: Antigens, Neoplasm; Aspirin; Blood Platelets; Coronary Artery Disease; Cyclooxygenase 1; Dinoprost; Drug Resistance; Humans; Integrin beta3; Lipid Peroxidation; Nephelometry and Turbidimetry; Oxidative Stress; Platelet Aggregation; Polymorphism, Genetic; Polymorphism, Single Nucleotide; RNA, Messenger; Thromboxane A2; Thromboxane B2

Topics: Aspirin; Coronary Artery Disease; Cyclooxygenase 1; Cyclooxygenase 2; Dose-Response Relationship, Drug; Drug Resistance; Enzyme Activation; Female; Flow Cytometry; Humans; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prevalence; Recurrence; Thromboxane A2; Time Factors; Treatment Refusal

Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Coronary Artery Disease; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprost; Humans; Isoenzymes; Membrane Proteins; Platelet Aggregation Inhibitors; Prostaglandin-Endoperoxide Synthases; Sulfonamides; Thromboxane A2

Constriction in response to serotonin is enhanced in the coronary arteries of atherosclerotic monkeys. The main objective of the present study was to determine whether abnormal responses to serotonin in atherosclerosis are reversed following removal of dietary cholesterol. In addition, we examined the effect of an atherogenic diet and reduction in dietary cholesterol on vascular responses to activation of ATP-sensitive K+ channels with aprikalim. Diameters of small coronary arteries were measured on the epicardial surface of the left ventricle in vivo by using stroboscopic illumination synchronized to the heart cycle to visually freeze the motion of the heart. Diameters were measured with a microscope-video system during topical application of two vasoconstrictor agonists, serotonin and the thromboxane mimetic U46619, and the vasodilator agonists aprikalim and nitroprusside. Responses were compared in normal (n = 9), atherosclerotic (n = 14; high-cholesterol diet), and regression (n = 8; high-cholesterol diet followed by normal diet) monkeys. Constriction of coronary arteries in response to serotonin was enhanced in monkeys on an atherogenic diet and was normal in regression monkeys. Vasoconstriction in response to U46619 and vasodilation in response to nitroprusside and aprikalim were not altered by atherosclerosis. Thus, abnormal vascular responses to serotonin in small coronary arteries of atherosclerotic monkeys without morphological evidence of disease can be reversed to normal by reducing dietary cholesterol.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine Triphosphate; Animals; Cholesterol, Dietary; Coronary Artery Disease; Coronary Vessels; Macaca fascicularis; Male; Nitroprusside; Picolines; Potassium Channels; Prostaglandin Endoperoxides, Synthetic; Pyrans; Serotonin; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

In the study was investigated whether the formation of prostanoids is changed in the different regions of aorta or in clotting whole blood in dependence on development of atherosclerosis. For this question New Zealand rabbits were fed for different periods with a cholesterol rich diet (0.5%). At the end of the different dietary periods the animals were killed and the following parameters estimated: blood: levels of total cholesterol, HDLcholesterol, VLDLcholesterol, cholesterol in the beta-migrating lipoprotein fraction, serum lipid peroxides, TXB2 formation capacity of clotting whole blood; aorta: surface of intima covered with fatty streaks, free and esterified cholesterol, triglycerides, collagen, formation of 6-keto-PGF1a and TXB2 by abdominal and thoracic aortas. The lipid parameter demonstrated a relatively strong correlation with the duration of cholesterol rich diet or the macroscopically detectable atherosclerosis, but the prostanoid formation remained unchanged.

Topics: Animals; Aorta; Cholesterol, Dietary; Coronary Artery Disease; Epoprostenol; Lipoproteins; Rabbits; Thromboxane A2

The examination of 194 patients with coronary heart disease concurrent with clinical manifestations of angina pectoris established that the development of coronary atherosclerosis was accompanied by suppressed prostacyclin (PGI2) synthesis and increased thromboxane A2 (TxA2) leukotriene (LT) synthesis. The activation of synthesis of the vasoconstrictor and proaggregate TxA2 depended on the severity of clinical signs of angina pectoris. The imbalance of PGI2 to- TxA2 metabolite ratios was associated with dyslipidemias and the extent of coronary atherosclerosis. Bicycle ergometry testing resulted in prostanoid imbalance. The determination of the dynamics of prostanoids was used to check the efficiency of antianginal therapy. The concomitant application of inhibitors of thromboxane synthetase and LT synthesis was recommended for secondary prevention of thrombotic complications in patients with coronary atherosclerosis.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aspirin; Coronary Artery Disease; Depression, Chemical; Drug Therapy, Combination; Humans; Leukotriene B4; Male; Middle Aged; Quercetin; Stimulation, Chemical; Thromboxane A2

Topics: Arachidonic Acids; Aspirin; Coronary Artery Disease; Coronary Disease; Coronary Vasospasm; Cyclooxygenase Inhibitors; Epoprostenol; Humans; Thromboxane A2

The effects of low dose indomethacin therapy in primary prevention of diet-induced atherosclerosis of rhesus monkeys was studied. The parameters studied were serum cholesterol concentration, thromboxane A2 (T x B2), prostacyclin (6-keto-PGF1 alpha) in serum/plasma, and the extent and intensity of coronary atherosclerosis. Although indomethacin did not affect serum cholesterol, it reduced serum T x B2 significantly (P less than 0.01). Plasma 6-keto-PGF1 alpha was not restored to the pretreatment level. A significant protective role of the drug was noted as far as coronary atherosclerosis is concerned (P less than 0.01).

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Body Weight; Cholesterol; Coronary Artery Disease; Diet, Atherogenic; Disease Models, Animal; Indomethacin; Macaca mulatta; Male; Thromboxane A2

Topics: Aspirin; Coronary Artery Disease; Coronary Disease; Coronary Thrombosis; Humans; Thromboxane A2