ABSTRACT
OBJECTIVES: The primary objective of this study was to assess the pharmacokinetic profiles of acetylsalicylic acid (ASA) and salicylic acid (SA) after administration of two different formulations of aspirin under fasting and fed conditions. MATERIALS AND METHODS: The study was a randomized, open-label, parallel-group, 2-arm crossover study conducted at a single center. Healthy subjects were randomized to receive 300 mg of aspirin in either a 15-mL oral solution (pre-packaged vial containing powder and solvent that are combined at the time of administration) or a single solid tablet to be chewed and swallowed with 150 mL of water. Treatment visits were separated by a 10-day wash-out period. RESULTS: At 3 minutes, ASA concentrations for the oral solution fed state and fasting state arms exceeded those for the chewed tablet (fed 299 vs. 139 ng/mL; fasting 356 vs. 204 ng/mL). Compared to the chewed tablet, the mean plasma ASA concentration was 74% greater with the oral solution under fasting conditions, and 115% greater under fed conditions. Similarly, at 3 minutes, the mean SA plasma concentration with the oral solution under fed and fasting conditions exceeded those for the chewed tablet (fed 310 vs. 160 ng/mL; fasting 330 vs. 185 ng/mL). Under fasting conditions, the mean plasma ASA AUC0-last, with the oral solutions was 168,076.8 min.ng/mL compared to 163,726.3 min.ng/mL with the chewed tablet. Under fed conditions, the mean plasma ASA AUC0-last, with the oral solutions was 179,116.7 min.ng/mL compared to 164,704.3 min.ng/mL with the chewed tablet. CONCLUSION: This phase 1 study showed that use of an aspirin oral solution provided more rapid exposure to higher plasma concentration levels of ASA and SA than chewing a solid tablet.
Subject(s)
Aspirin , Mastication , Administration, Oral , Area Under Curve , Cross-Over Studies , Fasting , Humans , Powders , Salicylic Acid , Solvents , Tablets , Therapeutic Equivalency , WaterSubject(s)
Hematology/history , Awards and Prizes , Blood Platelet Disorders/history , Dyslexia/history , Education, Medical/history , Erythrocytes, Abnormal , History, 20th Century , History, 21st Century , Ichthyosis/history , Migraine Disorders/history , Military Medicine/history , Miosis/history , Muscle Fatigue , Norway , Research/history , Spleen/abnormalities , Veterinary Medicine/historyABSTRACT
OBJECTIVES: Patients with various inflammatory rheumatic diseases (IRDs) have increased risk of atherothrombotic disease. Lipoprotein (a) (Lp(a)) is a risk factor for atherosclerosis but its role in IRD with accompanying coronary artery disease (CAD) is still unclear. We aimed to examine if serum Lp(a) levels differed between CAD patients with and without accompanying IRD. DESIGN: A cross-sectional observational, patient-based cohort study. SETTING: Referred centre for coronary artery bypass grafting in the South Eastern part of Norway. PARTICIPANTS: 67 CAD patients with IRD (CAD/IRD) and 52 CAD patients without IRD (CAD/non-IRD). All patients were Caucasians, aged >18 years, without any clinically significant infection or malignancy. METHODS: Lp(a) levels in serum were analysed by particle enhanced immunoturbidimetric assay, and Lp(a) levels were related to clinical and biochemical characteristics of the patient population. RESULTS: We found no differences in serum levels of Lp(a) between CAD patients with and without IRD. In general, we found that Lp(a) correlated poorly with clinical and biochemical parameters including C reactive protein with the same pattern in the CAD/non-IRD and CAD/IRD groups. CONCLUSIONS: Our data do not support a link between inflammation and Lp(a) levels in CAD and in general Lp(a) levels were not correlated with other risk factors for cardiovascular disease.
Subject(s)
Coronary Artery Disease/blood , Lipoprotein(a)/blood , Rheumatic Diseases/blood , Adult , Aged , Cohort Studies , Coronary Artery Disease/complications , Cross-Sectional Studies , Female , Humans , Inflammation/blood , Inflammation/complications , Male , Middle Aged , Rheumatic Diseases/complications , Risk FactorsABSTRACT
BACKGROUND: The purpose of this study was to investigate mediators of inflammation and haemostasis in patients with chronic necrotizing pulmonary aspergillosis (CNPA), a locally, destructive process of the lung due to invasion by Aspergillus species. METHODS: Measurements of selected biomarkers in 10 patients with CNPA and 19 healthy, matched controls were performed with enzyme-linked immunosorbent assay (ELISA) and multiplex methodology. The gene expressions of relevant biomarkers were analyzed with real-time quantitative RT-PCR. RESULTS: Increased concentrations of circulating mediators of inflammation interleukin (IL)-6, IL-8, RANTES, TNF-α, ICAM-1 and mediators involved in endothelial activation and thrombosis (vWF, TF and PAI-1) were observed in patients with CNPA. The concentration of the anti-inflammatory cytokine IL-10 was increased both in plasma and in PBMC in the patient population. The gene expression of CD40L was decreased in PBMC from the patient group, accompanied by decreased concentrations of soluble (s) CD40L in the circulation. CONCLUSIONS: The proinflammatory response against Aspergillus may be counteracted by reduced CD40L and sCD40L, as well as increased IL-10, which may compromise the immune response against Aspergillus in patients with CNPA.
Subject(s)
Biomarkers/blood , Blood Coagulation Factors/analysis , Cytokines/blood , Invasive Pulmonary Aspergillosis/pathology , Aged , Case-Control Studies , Enzyme-Linked Immunosorbent Assay , Female , Gene Expression Profiling , Humans , Male , Middle Aged , Real-Time Polymerase Chain ReactionABSTRACT
BACKGROUND: Fast platelet function tests can identify weak clopidogrel responders, but data on variability over time in clopidogrel responsiveness in several clinical settings are lacking. We wanted to explore long-term variability of multiple electrode aggregometry (MEA) measurements and the agreement between MEA and light transmission aggregometry (LTA) in patients with non-ST elevation myocardial infarction (NSTEMI) treated with aspirin and clopidogrel. METHODS: Parallel MEA and LTA were performed at baseline and after 6 and 12 weeks in 31 patients treated with percutaneous coronary intervention after NSTEMI. Adenosine diphosphate (ADP) concentrations 2 µM, 6.5 µM and 10 µM were used. Parallel testings in both arterial and venous blood were performed at baseline. MEA and LTA cut-off levels were applied to discriminate aggregation values suggesting presence or absence of high platelet reactivity (HPR). RESULTS: Arterial and venous MEA and LTA aggregation were similar. Within-subject variability in both MEA and LTA aggregation throughout the study was moderate. According to MEA, eight patients had HPR at baseline (MEA aggregation > 47 U). Defining > 47% as the LTA aggregation HPR cut-off level, the same number of patients (eight) had HPR according to LTA. Of the 93 MEA/LTA observations 81 (87.1%) gave the same HPR classification. MEA vs. LTA agreement at baseline was slightly inferior to that obtained after 12 weeks. CONCLUSIONS: MEA and LTA aggregation in arterial and venous blood seem similar. Within-subject variability over time was moderate, and the agreement between LTA and MEA was good, and stable in most patients.
Subject(s)
Aspirin/therapeutic use , Myocardial Infarction/drug therapy , Platelet Aggregation Inhibitors/therapeutic use , Platelet Aggregation/drug effects , Ticlopidine/analogs & derivatives , Aged , Aspirin/pharmacology , Clopidogrel , Female , Humans , Male , Middle Aged , Platelet Aggregation Inhibitors/pharmacology , Platelet Function Tests , Reproducibility of Results , Ticlopidine/pharmacology , Ticlopidine/therapeutic useABSTRACT
OBJECTIVE: The purpose of this study was to measure the in vivo platelet activation and thrombin generation in arterial blood after passing a subintimal conduit. METHODS: Subintimal percutaneous transluminal angioplasty (SPTA) is a technique where a subintimal channel is created, allowing recanalization of long peripheral arterial occlusion. From 10 patients with intermittent claudication, undergoing successful SPTA for femoropopliteal occlusive disease, we collected antecubital venous blood samples immediately before treatment, preprocedural arterial blood samples taken at the entry level proximal to the vessel occlusion, and subsequently at the reentry level after successful recanalization. Venous follow-up blood samples were taken after 24 hours. Plasma concentrations of ß-thromboglobulin (ß-TG), RANTES, and Prothrombin fragment (F1 + 2), were determined by immunoassay. Fibrinogen binding to platelets, leukocyte-platelet adhesion, and P-selectin were determined by flow cytometry. RESULTS: We found a statistically significant transluminal increase in the plasma concentrations of RANTES, ß-TG and F1 + 2 (p = 0.002, 0.001 and 0.001 respectively), which all normalized within 24 hours. Platelet-leukocyte aggregates significantly decreased after 24 hours compared with preprocedural and preentry levels (3.26% versus 5.26 %, p = 0.017). P-selectin expression on circulating platelets was statistically significantly increased in the blood sample taken at the re-entry level compared with the pre-procedural and pre-entry level (p = 0.007). After 24 hours there was no statistically significant difference to pre-procedural levels. There was no significant change in platelet fibrinogen binding at any levels. CONCLUSION: When passing a subintimal conduit, in vivo sampled blood demonstrated an extremely rapid and substantial uniform platelet activation and thrombin generation.
Subject(s)
Angioplasty , Atherosclerosis/blood , Platelet Activation , Thrombin/metabolism , Aged , Aged, 80 and over , Atherosclerosis/therapy , Blood Platelets/metabolism , Blood Platelets/pathology , Chemokine CCL5/blood , Female , Femoral Artery/pathology , Humans , Intermittent Claudication/blood , Intermittent Claudication/therapy , Male , Middle Aged , Monocytes/pathology , P-Selectin/blood , Popliteal Artery/pathology , beta-Thromboglobulin/metabolismABSTRACT
BACKGROUND: We investigated whether the heparin-coated AN69 ST hemodialysis (HD) filter induced less hypercoagulability during HD than a conventional polysulfone filter (F×8). METHODS: In a crossover design, 11 patients were treated alternately with AN69 ST and F×8 filters (45 sessions). All filters were primed with unfractionated heparin (UFH) and unadsorbed UFH was removed by saline flushing. Half the conventional dalteparin dose was given as a bolus dose at the start of HD. Clotting was evaluated hourly in the venous air trap. Prothrombin fragments 1 and 2 (PF1 + 2), antithrombin (AT), ß-TG and anti-FXa activity were repeatedly measured. RESULTS: One patient treated with enalapril had two repeated adverse reactions to the AN69 ST filter and was excluded from the study. Use of the AN69 ST filter did not decrease the mean clot score or PF1 + 2, but decreased ß-TG compared to the F×8 filter. CONCLUSION: The heparin-coated AN69 ST filter did not induce less coagulation when compared to the F×8 filter.
Subject(s)
Anticoagulants/pharmacology , Blood Coagulation/drug effects , Coated Materials, Biocompatible , Heparin/pharmacology , Membranes, Artificial , Polymers , Renal Dialysis/instrumentation , Sulfones , Adult , Aged , Aged, 80 and over , Cross-Over Studies , Female , Humans , Male , Middle Aged , Renal Dialysis/methodsABSTRACT
OBJECTIVE: We hypothesized a role for the inflammatory protein YKL-40 in atherogenesis and plaque destabilization based on its role in macrophage activation, tissue remodeling, and angiogenesis. METHODS: Serum YKL-40 levels were measured by enzyme immunoassay in 89 patients with carotid atherosclerosis and 20 healthy controls. Carotid expression of YKL-40 was examined by real time RT-PCR in 57 of the patients. Regulation and effect of YKL-40 were examined in THP-1 monocytes. RESULTS: Our main findings were: (1) serum YKL-40 levels were significantly elevated in patients with carotid atherosclerosis, with particularly high levels in those with symptomatic disease; (2) patients with recent ischemic symptoms (within 2 months) had higher YKL-40 mRNA levels in carotid plaque than other patients; (3) in vitro, the beta-adrenergic receptor agonist isoproterenol, toll-like receptor (TLR) 2 and TLR4 agonists, and in particular releasate from activated platelets significantly increased the expression of YKL-40 in THP-1 monocytes and (4) in vitro, YKL-40 increased matrix metalloproteinase-9 expression and activity in THP-1 monocytes, involving activation of p38 mitogen-activated protein kinase. CONCLUSIONS: Our findings suggest that YKL-40 might be a marker of plaque instability, potentially reflecting macrophage activation and matrix degradation within the atherosclerotic lesion.
Subject(s)
Carotid Artery Diseases/blood , Glycoproteins/biosynthesis , Lectins/biosynthesis , Adipokines , Adult , Aged , Aged, 80 and over , Case-Control Studies , Chitinase-3-Like Protein 1 , Female , Gene Expression Regulation , Humans , Inflammation , Macrophage Activation , Macrophages/metabolism , Male , Matrix Metalloproteinase 9/metabolism , Middle Aged , Monocytes/cytology , Neovascularization, Pathologic , Stroke/pathology , Ventricular Remodeling , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
BACKGROUND: Evaluation of clopidogrel therapy by in vitro methods has limitations which may be of clinical importance. We wanted to explore the variability in aggregometry response in aspirin sensitive patients before and after initiation of clopidogrel therapy. METHODS: ADP 9.37 microM, AA 1.2mM and TRAP 25 mM stimulated light transmissions aggregometry (LTA) were performed twice before (Exams 1 and 2; 3 weeks apart)-and within one year after-initiation of clopidogrel therapy (Exam 3) in 79 patients treated with PCI. Repeated ADP aggregometry was also performed in 16 healthy volunteers in order to estimate LTA measurement error. RESULT: Inter-individual differences in ADP aggregation e.g. at Exam 1 were substantial (range 17-77%, SD 15.8%). Intra-individual changes between Exams 1 and 2 were significant (-27 to +36%, SD 14.6%, p<0.05). Inter-individual differences at Exam 3 (on clopidogrel treatment) were larger than expected from Exams 1 and 2 (p<0.01). AA aggregation was the same before and during clopidogrel treatment. In controls, inter-individual differences were smaller at ADP 10 than at ADP 5 microM. CONCLUSIONS: Inter-individual differences in ADP aggregation were significant both before and during clopidogrel therapy, and there were significant intra-individual variations over time. Therefore, prediction of aggregometry response before or during clopidogrel therapy based on single tests may be unreliable. Inter-individual differences in healthy controls are smaller at high concentrations of ADP, and comparisons of aggregometry response should be performed with caution unless ADP concentrations are standardized.
Subject(s)
Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation/drug effects , Platelet Function Tests/methods , Ticlopidine/analogs & derivatives , Adenosine Diphosphate/pharmacology , Arachidonic Acid/pharmacology , Aspirin/pharmacology , Case-Control Studies , Clopidogrel , Demography , Female , Humans , Male , Middle Aged , Peptide Fragments/pharmacology , Reproducibility of Results , Ticlopidine/pharmacologyABSTRACT
Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by defective immunoglobulin production and high frequency of bacterial infections, autoimmunity and manifestations of chronic inflammation. The urokinase plasminogen activator (uPA), its cell bound and soluble receptor (uPAR, suPAR) have complex biological functions involving innate immune defense mechanisms and regulation of inflammation. Based on this dual role, we hypothesized that the uPA system could be affected in CVID, and examined expression of components of the uPA system in subgroups of CVID. All CVID-patients had increased plasma levels of suPAR with particularly high levels in those with splenomegaly and thrombocytopenia. Plasma uPA levels were also raised in these patients, and both suPAR and uPA levels correlated with the monocyte activation marker neopterin. Monocytes from CVID patients had increased expression of uPAR. We show an increased activation of the uPA system possibly contributing to the inflammatory phenotype seen in subgroups of CVID patients.
Subject(s)
Common Variable Immunodeficiency/immunology , Monocytes/immunology , Receptors, Urokinase Plasminogen Activator/blood , Urokinase-Type Plasminogen Activator/blood , Adult , Common Variable Immunodeficiency/blood , Common Variable Immunodeficiency/metabolism , Female , Humans , Male , Middle Aged , Monocytes/metabolismABSTRACT
The interaction between inflammatory cytokines and endothelial cells is a critical step in atherogenesis leading to endothelial dysfunction and inflammation. We have previously reported that the tumor necrosis factor superfamily member LIGHT could be involved in atherogenesis through its ability to promote vascular inflammation. In the present study we identified proteinase-activated receptor (PAR)-2 as an inflammatory mediator that was markedly enhanced by LIGHT in endothelial cells. We also found that LIGHT acted synergistically with PAR-2 activation to promote enhanced release of the proatherogenic chemokines interleukin-8 and monocyte chemoattractant protein-1, underscoring that the interaction between LIGHT and PAR-2 is biologically active, promoting potent inflammatory effects. We showed that the LIGHT-mediated upregulation of PAR-2 in endothelial cells is mediated through the HVEM receptor, involving Jun N-terminal kinase signaling pathways. A LIGHT-mediated upregulation of PAR-2 mRNA levels was also found in human monocytes when these cells were preactivated by tumor necrosis factor alpha. We have previously demonstrated increased plasma levels of LIGHT in unstable angina patients, and here we show a similar pattern for PAR-2 expression in peripheral blood monocytes. We also found that LIGHT, LIGHT receptors, and PAR-2 showed enhanced expression, and, to some degree, colocalization in endothelial cells and macrophages, in the atherosclerotic plaques of ApoE(-/-) mice, suggesting that the inflammatory interaction between LIGHT and PAR-2 also may be operating in vivo within an atherosclerotic lesion. Our findings suggest that LIGHT/PAR-2-driven inflammation could be a pathogenic loop in atherogenesis potentially representing a target for therapy in this disorder.
Subject(s)
Atherosclerosis/etiology , Endothelial Cells/metabolism , Endothelium, Vascular/pathology , Receptor, PAR-2/physiology , Receptors, Tumor Necrosis Factor, Member 14/physiology , Tumor Necrosis Factor Ligand Superfamily Member 14/physiology , Vasculitis/metabolism , Aged , Angina Pectoris/metabolism , Angina Pectoris/pathology , Angina, Unstable/metabolism , Angina, Unstable/pathology , Animals , Atherosclerosis/metabolism , Atherosclerosis/pathology , Cells, Cultured/metabolism , Chemokine CCL2/metabolism , Endothelial Cells/pathology , Female , Gene Expression Regulation , Humans , Interleukin-8/metabolism , JNK Mitogen-Activated Protein Kinases/physiology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Nitric Oxide Synthase Type III/metabolism , Receptor, PAR-2/agonists , Recombinant Fusion Proteins/physiology , Signal Transduction/physiology , Tumor Necrosis Factor Ligand Superfamily Member 14/genetics , Vasculitis/complications , Vasculitis/pathologyABSTRACT
BACKGROUND: Platelet microparticles (PMPs) possess proatherogenic and procoagulant properties which may play a role in atherogenesis and subsequent thromboembolic complications. The present study was conducted to investigate the possible relationship between carotid atherosclerosis and plasma concentrations of PMPs, and elucidate if plasma levels of PMPs were affected by postprandial hypertriglyceridemia. METHODS AND RESULTS: Subjects with ultrasound-assessed carotid atherosclerotic plaques (echogenic; n=20 and echolucent; n=20), assessed by ultrasonography, and subjects without carotid plaques (n=20) were recruited from a population-based study and underwent a standard fat tolerance test. Subjects with carotid plaques had significantly higher levels of large PMPs than subjects without carotid atherosclerotic plaques (96.7+/-50.4 microg/l versus 56.1+/-34.9 microg/l), after adjustments for traditional cardiovascular risk factors and use cardiovascular drugs (p=0.021). Plasma PMPs were not associated with plaque echogenicity. Postprandial hypertriglyceridemia induced a similar increase in plasma PMPs within all groups. Significant correlations were found between an increase in plasma triglycerides and percent elevation in total PMPs (r=0.29, p<0.05) and large PMPs (r=0.34, p<0.01) in the postprandial phase. CONCLUSIONS: Individuals with echogenic and echolucent carotid atherosclerotic plaques have statistically significant elevation of large plasma PMPs compared to age/sex-matched normal controls. Postprandial hypertriglyceridemia induces a significant, similar increase in plasma PMPs in individuals with and without carotid atherosclerotic plaques which could be of pathophysiological importance in atherogenesis.
Subject(s)
Blood Platelets/physiology , Blood Platelets/ultrastructure , Carotid Artery Diseases/blood , Postprandial Period/physiology , Aged , Carotid Artery Diseases/diagnostic imaging , Carotid Artery Diseases/etiology , Carotid Stenosis/blood , Carotid Stenosis/diagnostic imaging , Carotid Stenosis/etiology , Case-Control Studies , Dietary Fats/administration & dosage , Female , Humans , Hypertriglyceridemia/blood , Hypertriglyceridemia/etiology , Male , Triglycerides/blood , UltrasonographyABSTRACT
Platelet microparticles (PMPs) are highly procoagulant and might therefore be important in the pathogenesis of arterial thrombotic diseases. The aim of this study was to determine plasma levels of PMPs in survivors of myocardial infarction (MI) and their relation to activation of primary (sCD40L) and secondary (thrombin-antithrombin (TAT) complexes) haemostasis. An observational, population-based case control study was conducted in 61 MI patients 1-4 years after the MI and 61 age-matched and sex-matched healthy controls. PMPs were quantified using an immunoassay that discriminates between small and large PMPs. MI patients had significantly higher total PMPs (314.3 microg/L, 273.1-361.4 microg/L versus 225.8 microg/L, 168.8-273.1 microg/L, p=0.009) (geometric mean and 95% CI) and larger PMPs (181.3 microg/L, 160.7-204.3 microg/L versus 134.3 microg/L, 104.6-174.9 microg/L) than controls. The differences between groups remained significant after adjustments for use of cardiovascular drugs, body mass index, blood pressure and serum lipids, but were weakened when smoking was included in the analysis. Multiple regression analysis revealed a significant independent association between large PMPs and plasma TAT and soluble CD40 ligand (sCD40L) in MI patients, but not in healthy controls. The independent association between large PMPs and thrombin generation supports the concept that formation of PMPs is important for increased coagulation activation in MI patients.
Subject(s)
Blood Platelets , Cell-Derived Microparticles , Myocardial Infarction/blood , Adult , Female , Humans , Male , Middle Aged , Models, Biological , Survival RateABSTRACT
OBJECTIVE: Both animal and human studies demonstrate activation of coagulation during cardiac arrest. Prearrest anticoagulation is used routinely in many experimental studies. We studied the hemodynamic effects of prearrest anticoagulation with a low-molecular-weight heparin suitable for clinical use during cardiopulmonary resuscitation in pigs. DESIGN: Randomized and blinded experimental animal study. SETTING: University hospital-affiliated research laboratory. SUBJECTS: Sixteen female domestic pigs. INTERVENTIONS: Three minutes before electrically induced ventricular fibrillation, enoxaparin 1 mg/kg or physiologic saline was blinded and administered intravenously. After 10 mins of untreated ventricular fibrillation, advanced cardiac life support was initiated with continuous mechanical chest compressions and interposed manual ventilation with 100% oxygen. Epinephrine was administered after 2 mins of advanced cardiac life support followed by attempted defibrillation 1 min thereafter. Advanced cardiac life support was continued for 10 mins following international guidelines. Electrocardiogram was recorded continuously and ventricular fibrillation waveform was analyzed (median slope). Animals with return of spontaneous circulation were observed for ten more minutes. Blood specimens were drawn for analysis of coagulation activation (thrombin-antithrombin complex) and drug effect (anti-factor Xa activity). MEASUREMENTS AND MAIN RESULTS: Six of eight (75%) pigs in each group achieved return of spontaneous circulation. Thrombin-antithrombin complex levels were significantly lower in pigs that received enoxaparin. There was no significant difference either in measured hemodynamics between the groups during advanced cardiac life support and after return of spontaneous circulation or in median slope values during ventricular fibrillation. Epinephrine caused a significant decrease in femoral and increase in cerebral cortical blood flow with no difference between the groups. CONCLUSIONS: Prearrest anticoagulation with enoxaparin did not influence either hemodynamics during advanced cardiac life support and after return of spontaneous circulation or the frequency of return of spontaneous circulation in porcine cardiac arrest.
Subject(s)
Cardiopulmonary Resuscitation , Fibrinolytic Agents/pharmacology , Heart Arrest/therapy , Hemodynamics/drug effects , Heparin, Low-Molecular-Weight/pharmacology , Animals , Female , SwineABSTRACT
BACKGROUND AND PURPOSE: Although cerebral microemboli are often detected by transcranial Doppler ultrasonography in mechanical heart valve patients, the clinical significance of such microemboli is unclear. The aim of this study was to determine the frequency and composition of cerebral microemboli in a prosthetic heart valve population and to correlate these findings to cerebrovascular symptoms, blood inflammation, and coagulation parameters. METHODS: Seventy-six consecutive patients with a total of 81 prosthetic (54 mechanical, 27 biologic) heart valves were monitored for cerebral microemboli by multifrequency transcranial Doppler ultrasonography 1 year after valve replacement. Cerebrovascular events in the first year were recorded by a neurologist. Inflammation and coagulation markers were measured by immunoassays. RESULTS: Microemboli were detected in mechanical heart valve patients only (28 patients, 56%). Twelve percent were solid, occurring in 17 (34%) of the mechanical heart valve population. The presence of solid cerebral microemboli was the only variable that was associated with cerebrovascular symptoms after a final regression analysis (P=0.026). The plasma monocyte chemotactic protein-1 level was raised in patients with solid microemboli (P=0.014). CONCLUSIONS: Solid cerebral microemboli were detected by multifrequency transcranial Doppler ultrasonography in 35% of a mechanical heart valve population, and the frequency was higher in patients who experienced cerebrovascular events during the first year after valve replacement. The results suggest that the detection of solid cerebral microemboli may be helpful in predicting the risk of ischemic stroke in mechanical heart valve patients.
Subject(s)
Heart Valve Prosthesis/adverse effects , Intracranial Embolism/diagnostic imaging , Intracranial Embolism/epidemiology , Stroke/diagnostic imaging , Stroke/epidemiology , Ultrasonography, Doppler, Transcranial , Adolescent , Adult , Aged , Aged, 80 and over , Amaurosis Fugax/diagnostic imaging , Amaurosis Fugax/epidemiology , Blood Coagulation , Embolism, Air/diagnostic imaging , Embolism, Air/epidemiology , Female , Humans , Incidence , Inflammation/epidemiology , Ischemic Attack, Transient/diagnostic imaging , Ischemic Attack, Transient/epidemiology , Male , Middle Aged , Platelet Activation , Predictive Value of Tests , Risk FactorsABSTRACT
RATIONALE: Thrombus formation and inflammation are involved in the pathogenesis of pulmonary arterial hypertension (PAH), and LIGHT (Lymphotoxin-like Inducible protein that competes with Glycoprotein D for Herpesvirus entry mediator on T lymphocytes) has been shown to promote vascular inflammation. OBJECTIVES: We sought to investigate the role of the tumor necrosis factor superfamily ligand LIGHT in the pathogenesis of PAH. METHODS: We studied 73 patients with severe PAH and 10 control subjects. LIGHT and pro- and antithrombotic markers were assessed by enzyme immunoassays. MEASUREMENTS AND MAIN RESULTS: (1) Patients with idiopathic PAH (n = 21), patients with PAH related to risk factors or associated conditions (n = 31), and those with chronic thromboembolic PAH (n = 21) all had raised serum levels of LIGHT compared with control subjects (n = 10). (2) LIGHT levels in femoral artery were significantly related to mortality in the patients with PAH. (3) Immunostaining of LIGHT and its receptors was seen in alveolar macrophages, vascular smooth muscle cells, and endothelial cells in lungs from patients with PAH. (4) Thirteen patients received prostacyclin infusion (3 mo), and all showed hemodynamic improvement, accompanied by decreased LIGHT levels. (5) Prostacyclin abolished the release of LIGHT from activated platelets in vitro, suggesting that the decrease in LIGHT during prostacyclin therapy could involve direct effects on platelets. (6) LIGHT increased tissue factor and plasminogen activator inhibitor type 1 and decreased thrombomodulin levels in endothelial cells, inducing a prothrombotic state in these cells. CONCLUSIONS: Our findings suggest prothrombotic effects of LIGHT in PAH involving endothelium-related mechanisms, potentially contributing to the progression of this disorder.
Subject(s)
Hypertension, Pulmonary/etiology , Thrombosis/etiology , Tumor Necrosis Factor Ligand Superfamily Member 14/physiology , Biomarkers/blood , Disease Progression , Humans , Ligands , Tumor Necrosis Factor Ligand Superfamily Member 14/analysis , Tumor Necrosis Factor Ligand Superfamily Member 14/blood , Umbilical Veins/cytologyABSTRACT
Increased echolucency of carotid plaques is associated with an increased risk of ischemic stroke. Inflammation and apoptosis of vascular smooth muscle cells in the arterial wall are involved in the atherosclerotic process and destabilization of the plaque. Granzyme B (GrB) is a key mediator of T cell-mediated cytotoxicity, and we therefore hypothesized that this protease could distinguish echolucent from other plaques. Ultrasound-determined echolucency of atherosclerotic plaques was assessed prior to carotid endarterectomy/angioplasty in 57 consecutively recruited patients with high-grade internal carotid stenosis. Plasma levels of GrB were measured by enzyme immunoassay prior to surgery. Patients with carotid atherosclerosis had significantly higher plasma levels of GrB compared to healthy controls (n=16) (p<0.01), with particularly high levels in those with an echolucent lesion. While there were no differences in traditional cardiovascular risk factors or CRP between those with echolucent (n=16) and those with echogenic/heterogeneous (n=41) plaques, the echolucent group had markedly raised plasma levels of GrB (p<0.01). Patients with high levels of circulating granzyme B also had more ischemic lesions on cerebral MRI prior to surgery. Raised plasma levels of GrB in echolucent carotid plaques with increased frequency of cerebrovascular events suggest that GrB may be a marker of plaque instability.
Subject(s)
Carotid Stenosis/blood , Carotid Stenosis/diagnostic imaging , Granzymes/blood , Ultrasonography, Doppler, Color/methods , Adult , Aged , Aged, 80 and over , Biomarkers , Carotid Stenosis/classification , Case-Control Studies , Female , Humans , Male , Middle AgedABSTRACT
BACKGROUND: This prospective randomized study compared the inflammatory response in patients undergoing elective on-pump and off-pump coronary artery bypass grafting. PATIENTS AND METHODS: Forty-four patients undergoing elective coronary artery bypass grafting were recruited with 22 patients randomized to on-pump heart surgery and 22 patients to off-pump coronary bypass surgery. Plasma levels of C3bc, the terminal SC5b-9 complement complex, myeloperoxidase, beta-thromboglobulin and prothrombin fragment F1 + 2 were measured before the operation, intraoperatively, at termination of the operation, and two hours post-operatively. RESULTS: Complement was markedly activated in the on-pump group as indicated by a significant increase in C3bc and SC5b-9 (p < 0.001 for both), whereas no complement activation was seen in the off-pump group (p = 0.001 between the groups). In contrast, both groups showed significant activation of neutrophils, platelets and coagulation, as indicated by an early increase in myeloperoxidase and a post-operative increase in beta-thromboglobulin and F1 + 2, respectively. Notably, there were no intergroup differences with regard to neutrophil and platelet activation, whereas coagulation activation was more pronounced in the off-pump group (p < 0.01). CONCLUSIONS: Off-pump surgery completely eliminated the heart-lung machine-induced complement activation. Neutrophils and platelets were equally activated in both groups, whereas coagulation was enhanced post-operatively in the off-pump group.
Subject(s)
Complement Activation , Coronary Artery Bypass, Off-Pump , Heart Diseases/surgery , Blood Coagulation , Cardiopulmonary Bypass , Coronary Artery Bypass , Extracorporeal Circulation , Heart-Lung Machine , Humans , Neutrophil Activation , Platelet ActivationABSTRACT
Familial hypercholesterolemia (FH) is associated with heterogeneity of the onset and severity of coronary heart disease (CHD). In this study, we investigated different low-grade proinflammatory markers and the atheroprotective function of the HDL3 subfraction in FH-patients (n = 13) with identical LDL-receptor mutations and in age- and sex-matched healthy controls (n = 11). Compared with healthy controls, FH-patients had greater gene expressions of the proatherogenic mediators TNF-alpha and IL-8 in circulating peripheral blood mononuclear cells. In addition, they had a higher serum concentration of intercellular adhesion molecule-1 (ICAM-1) and a lower net antioxidant capacity. FH-derived HDL3 with a high level of triglycerides had a reduced capacity to inhibit the release of IL-8 from TNF-alpha-stimulated human umbilical vein endothelial cells (HUVEC) [1.864 mg/L (1.461-2.208 mg/L) vs. 1.466 mg/L (1.225-1.643 mg/L); P < 0.05; median (range)], and a reduced capacity to promote cholesterol efflux from lipid-loaded macrophages [12% (12-14%) vs. 15% (14-18%); P < 0.05; median (range)] compared with HDL3 with a lower triglyceride content. Notably, the degree of inhibition of IL-8 release from HUVEC by HDL3 was correlated with the ability of HDL3 to promote cholesterol efflux (r = -0.80, P = 0.03). In conclusion, compared with healthy controls, FH-patients are characterized by higher levels of low-grade proinflammatory markers, and FH-derived HDL3 with high triglyceride content may be more proatherogenic. These triglyceride rich-HDL3 might be partly responsible for the phenotypic variation among FH-patients with identical LDL-receptor mutations.
Subject(s)
Cholesterol/metabolism , Cytokines/blood , Hyperlipoproteinemia Type II/blood , Lipoproteins, HDL/blood , Lipoproteins, HDL/pharmacology , Triglycerides/blood , Adult , Cell Line, Tumor , Cells, Cultured , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Female , Humans , Hyperlipoproteinemia Type II/genetics , Interleukin-8/metabolism , Lipoproteins, HDL3 , Macrophages/metabolism , Male , Middle Aged , Mutation , Phenotype , Receptors, LDL/genetics , Tumor Necrosis Factor-alpha/pharmacology , Umbilical VeinsABSTRACT
Platelet-derived microparticles (PMPs) are considered a marker of platelet activation. They vary considerably in size, and flow cytometry, the predominant method used to assay PMPs, is only detecting larger PMPs (>0.1 microm). We describe here a method that quantifies the amount of PMP-located GPIIb antigen in detergent-treated platelet-free plasma (PPP) by means of a one-step time-resolved immunofluorometric assay (TR-IFMA). This assay uses a streptavidin-coated microwell plate and two different monoclonal antibodies to GPIIb (CD41), one conjugated to biotin and the other labeled with europium ion. A wide linear range standard curve with low background and a high sensitivity was obtained. Pre-assay ultracentrifugation or filtration of PPP extensively reduced the fluorometric signal, indicating that the GPIIb antigen is mainly particle-located. A strong correlation between the amount of GPIIb and PMP as detected by flow cytometry was found. Consequently, the assay can be used to study PMP-related phenomena and, in contrast to flow cytometry, can be used on frozen samples and is independent of PMP size.