Urinary thromboxane A2 metabolites in patients presenting in the emergency room with acute chest pain

Abstract. Objectives . The diagnosis of acute myocardial infarction (MI) is difficult in emergency rooms where large groups of patients present with chest pain. Confirmation of the diagnosis of MI based on the myocardial band of creatine phosphokinase may take a day. A more rapid diagnostic screening procedure is desirable and for this reason we evaluated urine thromboxane. Design . The study consisted of patients presenting with chest pain. Urine samples were obtained in the emergency room and on the following 5 days for those patients who were admitted to the hospital. The urine samples were used to determine the levels of immunoreactive 11-dehydro-thromboxane B₂ (i-11-dehydro-TXB₂) and 2,3-dinor-thromboxane B₂ (i-2,3-dinor-TXB₂). Myocardial infarction was defined as an increase in the myocardial band fraction of plasma creatine phosphokinase (> 5% of the total) and changes in the electrocardiogram. The patients' diagnoses were retrospectively correlated with thromboxane metabolite levels. Setting . The present study took place in the emergency rooms of two major hospitals: Georgetown University Medical Center. Washington DC, and Fairfax Hospital, Virginia, USA. Subjects . The study comprised 369 patients presenting with acute chest pain and consisted of 247 men and 122 women aged 30–94 years. Main outcome measures . The outcome measure of this study was the predictive value of i-11-dehydro TXB₂ and i-2,3-dinor-TXB₂, for the diagnosis of MI, in patients presenting in the emergency room with chest pain. Results . Patients undergoing an MI had significantly higher levels of both thromboxane metabolites in their urine in the emergency room, when compared to patients undergoing a cardiac event other than an MI or to patients with unstable angina. Thromboxane metabolite levels rapidly returned to normal on the days following admission to the hospital. Aspirin intake appeared to significantly decrease the levels of i-11-dehydro-TXB₂, but not that of i-2,3-dinor-TXB₂. Conclusions . The measurement of thromboxane metabolites in the urine may provide a more rapid, accurate and cost-effective means of diagnosing MIs in patients presenting with chest pain.     

Eicosanoids seasonally impact pulmonary function in asthmatic patients with Japanese cedar pollinosis

BackgroundCondition of asthma in patients with asthma and concomitant seasonal allergic rhinitis (SAR) deteriorates during the Japanese cedar pollen (JCP) season. However, the underlying mechanisms remain unclear.MethodsWe analyzed seasonal variations in eicosanoid levels in the airways of patients with asthma and concomitant SAR sensitized to JCP (N = 29, BA-SAR-JCP group) and those not sensitized (N = 13, BA-AR-non-JCP group) during the JCP season. The association between changes in eicosanoid concentrations and pulmonary function was assessed. Exhaled breath condensate (EBC) was collected, and pulmonary function tests were performed during the JCP and non-JCP seasons. The cysteinyl leukotriene (CysLT), thromboxane B₂ (TXB₂), prostaglandin D₂-methoxime (PGD₂-MOX), and leukotriene B₄ (LTB₄) levels in the collected EBC were measured via enzyme-linked immunosorbent immunoassays.ResultsThe log CysLT levels significantly increased in the BA-SAR-JCP group during the JCP season compared with the non-JCP season (1.78 ± 0.55, 1.39 ± 0.63 pg/mL, mean ± standard deviation, respectively, p = 0.01) and those in the BA-AR-non-JCP group during the JCP season (1.39 ± 0.38 pg/mL, p = 0.04). Moreover, the log TXB₂ levels seemed to increase. However, the log LTB₄ and log PGD₂-MOX levels did not increase. The changes in the log CysLT levels during the two seasons were negatively correlated to forced expiratory volume in one second (FEV₁) in the BA-SAR-JCP group (r = −0.52, p < 0.01).ConclusionsIn the BA-SAR-JCP group, seasonal increases in eicosanoid levels in the airway likely promoted deterioration in pulmonary function despite optimal maintenance treatment.     

Resolution of Corticosteroid-Induced Diabetes in Allergic Bronchopulmonary Aspergillosis with Omalizumab Therapy: A Novel Approach

There are substantial numbers of reports showing that leukotrienes (LTs) play important roles in adult asthma. No definite evidence has been demonstrated that LTs are involved in asthma attacks in children, although it is highly expected. In this report, we demonstrated that the levels of LTB₄ and LTC₄ but not thromboxane B₂ (TXB₂), a stable metabolite of TXA₂, were significantly elevated in the bronchoalveolar lavage fluid, which was obtained from intubated and mechanically ventilated children with severe asthma attacks. This is direct evidence that LTB₄ and LTC₄ predominantly participate in asthma attacks in pediatric patients.     

Endoscopic Comparison of the Gastroduodenal Safety and the Effects on Arachidonic Acid Products between Meloxicam and Piroxicam in the Treatment of Osteoarthritis

Our objective was to evaluate the efficacy, the gastroduodenal safety, and the effects on arachidonic acid products of meloxicam, a new acidic enolic non-steroidal anti-inflammatory drug which preferentially inhibits cyclo-oxygenase-2 over cyclo-oxygenase-1, versus piroxicam in patients with osteoarthritis of the knee. Meloxicam 7.5 mg or piroxicam 20 mg daily was administered for 4 weeks in this double-blind parallel-groups randomised study. The efficacy for pain relief of the two tested medications was assessed by means of visual analogue scale and other clinical parameters. Pre- and post-treatment endoscopies were performed, and the findings were scored and recorded. The gastric fluid was aspirated at each time and prostaglandin E₂, thromboxane B₂ and leukotriene B₄ were determined by ELISA. There was no significant difference between the groups regarding the primary efficacy. Changes in endoscopic findings by means of Lanza score showed statistically significant differences between the two treatment groups in favour of meloxicam at all sites – gastric, duodenal and total. Within-group comparisons showed a statistically significant difference (worsening) in gastric and total score with piroxicam, but no significant difference with meloxicam. The frequency of clinically relevant cases (total score >2) also showed a statistically significant worsening in the piroxicam group. The better GI tolerability of meloxicam was also suggested by fewer adverse GI events and no withdrawals due to adverse events compared with piroxicam. The pre-/post-study gastric juice concentration of PGE₂, TXB₂, and LTB₄ in the meloxicam group was 135.2 ± 85.8/71.2 ± 32.2, 116.3 ± 81.7/99.4 ± 107.5 and 388 ± 321/223 ± 98 pg/ml respectively. The pre-/post-study gastric juice concentration of PGE₂, TXB₂ and LTB₄ in the piroxicam group was 105.7 ± 43.1/68.2 ± 34.9, 94.0 ± 50.9/105.9 ± 121.1 and 625 ± 1574/828 ± 1464 pg/ml, respectively. Both meloxicam and piroxicam significantly inhibited gastric PGE₂ levels after 4 weeks’ treatment; however, there was no difference between these two groups. Neither of these medications had an effect on TXB₂. Only meloxicam inhibited LTB₄ concentration significantly, and the between-groups difference was significant. Meloxicam 7.5 mg once daily had better gastrointestinal tolerability and an efficacy comparable to that of piroxicam 20 mg over 4 weeks in patients with osteoarthritis of the knee. Received: 18 April 2000 / Accepted: 17 August 2000     

Attenuation of the Inflammatory Response in an Animal Colitis Model by Neutrophil Inhibitory Factor,a Novel β2-Integrin Antagonist

Background: Neutrophils are significant effector cells in acute inflammatory bowel disease. Recruitment of these cells is dependent on β₂-integrin-mediated adhesion and transmigration. The efficacy of neutrophil inhibitory factor (NIF), an antagonist of the β₂-integrin CD11b/CD18, in ameliorating inflammation was tested in an animal model of acute colitis. Method: Immune-complex colitis was induced in groups of rabbits by using various formalin concentrations (2%, 0.75%, and 0.5%). Animals were treated with rNIF, 10 mg/kg. After they had been killed the mucosal appearance was scored, and tissue saved for histology and quantitation of myeloperoxidase (MPO), leukotriene B₄ (LTB₄), prostaglandin E₂ (PGE₂), and thromboxane B₂ (TXB₂). Results: In the 2% formalin group therapy with rNIF resulted in lower LTB₄ (p < 0.05) levels. For the 0.75% and 0.5% groups, MPO was lower with rNIF treatment (p < 0.03 and p < 0.05, respectively), as were LTB₄ concentrations (both, p < 0.04). PGE₂ and TXB₂ levels remained unchanged. Histology showed polymorphonuclear cell infiltration to be reduced by rNIF in the 2% and 0.75% formalin-treatment groups (p < 0.05). Conclusion: These results suggest that blockade of CD11b/CD18-mediated mucosal neutrophil recruitment may form part of a strategy for targeted therapeutic intervention in inflammatory bowel disease.     

Radioimmunoassay for leukotriene B4

A rabbit immunized with leukotriene B₄ [LTB₄; (5S,12R)-6, 14-cis-8, 10-trans-icosatetraenoic acid] coupled to bovine serum albumin via the 12-oxy function of the lipid produced antibodies having an average association constant (K_a) for [14,15-³H]LTB₄ of 3.2 × 10⁹ M^-1 at 37°C and in a concentration of 0.37 μg/ml of the immune plasma. When 10 μl of anti-LTB₄ and 3.9 nCi of [14,15-³H]LTB₄ (28 Ci/mmol; 1 Ci = 3.7 × 10¹⁰ becquerels) were incubated in a volume of 250 μl, 50% inhibition of radioligand binding was achieved with 0.31 ng of LTB₄ and with 1.95 ng of (5S,12S)-6-trans-8-cis-LTB₄. The sulfidopeptide leukotrienes, LTC₄ and LTD₄, displaced the radioligand from this antibody with less than 1/100th the activity of LTB₄, and the diastereoisomers of 6-trans-LTB₄, 5-L-hydroxy-6-trans-8,11,14-cis-icosatetraenoic acid (5-HETE), and three prostaglandins were minimally effective. The specificity of this radioimmunoassay was further shown by assessment of the immunoreactive products generated from calcium ionophore (A23187)-activated rat serosal mast cells and human neutrophils after reversed-phase HPLC. Resolution of the supernatants from each cell type yielded a single immunoreactive peak that coeluted with synthetic LTB₄ and quantitatively correlated with the physical measurement by integrated A₂₆₉ in that peak; UV-absorbing peaks eluting at other retention times were not immunoreactive. The immunoreactive LTB₄ generated averaged 4.6 ng per 10⁶ rat mast cells and resolution of the supernatants by reversed-phase HPLC without a prior extraction step gave a recovery of 54%, validating the direct applicability of this sensitive and specific assay for LTB₄, a highly potent chemotactic factor, to unfractionated biologic fluids.     

Effects of perfluorohexane vapor in the treatment of experimental lung injury

RationaleWe investigated the effects of vaporized perfluorohexane (PFH) on pulmonary vascular tone, pulmonary vascular resistance and peak inspiratory pressure as well as lipid mediator formation in the treatment of calcium ionophore induced lung injury in a model of the isolated perfused and ventilated rabbit lungs.MethodsLung injury was induced in isolated perfused and ventilated rabbit lungs by calcium ionophore A23187. Lungs were treated with either 4.5 vol.% (4.5 vol.% PFH; n = 6) or 18 vol.% (18 vol.% PFH; n = 6) PFH. Six lungs remained untreated (Control). In addition 5 lungs (PFH-sham) remained uninjured receiving 18 vol.% PFH only. Mean pulmonary artery pressure (mPAP), peak inspiratory pressure (P_max), and lung weight (weight) were monitored for 120 min. Experiments were terminated before when the increase in lung weight exceeded 40 g. Perfusate samples were taken at regular intervals for analysis of TXB₂, 6-keto-PGF₁ and LTB₄.ResultsControls reached the study end point significantly earlier than both PFH groups. Significant differences were found for a weight gain of 10 g and 20 g between the control and the 4.5 vol.% PFH and the 18 vol.% PFH. Differences in mPAP were more pronounced in the 4.5 vol.% PFH. However increases in P_max were more marked in 4.5 vol.% PFH. TXA₂-, PGI₂-, and LTB₄-levels were significantly lower in PFH groups. Uninjured lungs remained unaffected by the presence of 18 vol.% PFH.ConclusionInflammatory lung injury was attenuated by the treatment with 4.5 vol.% PFH and 18 vol.% PFH vapor in the isolated perfused rabbit lung. Therapeutic effects were more pronounced with a concentration of 4.5 vol.% PFH.     

Impact of myocardial infarction on cardiac autonomic function in diabetic rats

AimsWe evaluated autonomic and hemodynamic parameters and maximal oxygen consumption (VO₂max) as possible determinants of mortality in streptozotocin (STZ) diabetic rats after myocardial infarction (MI).MethodMale Wistar rats were divided into (n = 8 of each): control sham (CS), diabetes sham (DS), MI (I), and diabetes + MI (DI). MI was induced 15 days after STZ induction. VO₂max was measured at 3 (basal), 30, 60, and 91 days after MI. Hemodynamic and autonomic parameters were evaluated 92 days after MI.ResultsMI area was similar in infarcted groups (~ 44%). Mortality rate increased in the DI (70%) compared with I (53%) group. Cardiopulmonary baroreflex, sympathetic (48%) and vagal (33%) tonus, low frequency (LF) band (57%), and LF/high frequency (HF) band ratio (53%) were reduced in DI compared with I animals. Furthermore, cardiac output (CO), peripheral vascular resistance (PVR) impairment, and VO₂max reductions were observed in the DI compared with the I group.ConclusionsOur data suggest that the CO and PVR changes as well as VO₂max reduction were probably associated with additional cardiac autonomic control impairment, and, consequently, increased mortality rate in diabetic rats after a chronic myocardial infarction.     

Implementation of high sensitivity cardiac troponin T measurement in the emergency department

BackgroundWe examined the diagnostic performance of high sensitivity cardiac troponin T (cTnThs) measurement and its ability to predict risk in unselected patients presenting to the emergency department with acute chest pain.MethodsWe conducted a retrospective analysis of 137 consecutive patients with chest pain (age range, 66 ± 16 years; 64% male). A final diagnosis of acute myocardial infarction was made using the “old” (cTnT fourth-generation assay, ≥0.04 μg/L) or the “new” cutpoint (cTnThs ≥0.014 μg/L).ResultsThe adjudicated final diagnosis of acute myocardial infarction significantly increased from 20 to 35 patients (a 75% increase) and troponin-positive nonvascular cardiac chest pain from 10 to 30 (a 200% increase) using cTnThs. The number of patients with unstable angina or troponin-negative nonvascular cardiac chest pain significantly decreased (P <.05). Diagnostic performance of cTnThs levels at admission was significantly higher compared to cTnT levels (area under the curve [AUC] 0.85 vs AUC 0.70; P <.05). cTnThs levels below the detection limit (<0.003 μg/L) had a negative predictive value of 100% to exclude acute myocardial infarction. The event rate during 6 months of follow-up was low in patients with cTnThs levels <0.014 μg/L, while patients with cTnT levels ≥0.04 μg/L were at increased, and patients with cTnThs ≥0.014 μg/L and cTnT <0.04 μg/L at intermediate risk of death or recurrent myocardial infarction (P = .002). Risk was highest in chest pain patients with dynamic changes of cTnThs levels >30%.ConclusionThe introduction of cTnThs assay displays an excellent diagnostic performance for the workup of patients with chest pain at the time of their initial presentation. Even small increases of cTnThs indicate increased risk for death or myocardial infarction during follow-up.     

Aerobic exercise training delays cardiac dysfunction and improves autonomic control of circulation in diabetic rats undergoing myocardial infarction

BackgroundExercise training (ET) has been used as a nonpharmacological strategy for treatment of diabetes and myocardial infarction (MI) separately. We evaluated the effects ET on functional and molecular left ventricular (LV) parameters as well as on autonomic function and mortality in diabetics after MI.Methods and ResultsMale Wistar rats were divided into control (C), sedentary-diabetic infarcted (SDI), and trained-diabetic infarcted (TDI) groups. MI was induced after 15 days of streptozotocin-diabetes induction. Seven days after MI, the trained group underwent ET protocol (90 days, 50-70% maximal oxygen consumption-VO₂max). LV function was evaluated noninvasively and invasively; baroreflex sensitivity, pulse interval variability, cardiac output, tissue blood flows, VEGF mRNA and protein, HIF1-α mRNA, and Ca²⁺ handling proteins were measured. MI area was reduced in TDI (21 ± 4%) compared with SDI (38 ± 4%). ET induced improvement in cardiac function, hemodynamics, and tissue blood flows. These changes were probable consequences of a better expression of Ca²⁺ handling proteins, increased VEGF mRNA and protein expression as well as improvement in autonomic function, that resulted in reduction of mortality in TDI (33%) compared with SDI (68%) animals.ConclusionsET reduced cardiac and peripheral dysfunction and preserved autonomic control in diabetic infarcted rats. Consequently, these changes resulted in improved VO₂max and survival after MI.     

Role of FLAP and PDE4D in myocardial infarction and stroke: Target discovery and future treatment options

Opinion statement Biomarkers such as C-reactive protein (CRP) and myeloperoxidase (MPO) are elevated in patients with coronary artery disease and confer risk of acute cardiovascular events, such as myocardial infarction (MI) and stroke. More recently, variants in the 5-lipoxygenase-activating protein (FLAP) gene were shown to confer risk to both MI and stroke, effects that appear to be mediated through elevated LTB₄, a chemoattractant mediator shown to be upregulated in patients with MI. Another gene in the leukotriene (LT) pathway, LTA ₄ hydrolase, was subsequently found to confer increased risk to MI, effects that were ethnicity-specific with an approximately threefold higher risk in African Americans than in whites. In another study, markers in the phosphodiesterase (PDE) 4D gene were found to confer risk to large-vessel occlusive and cardiogenic stroke. Interestingly, there is a cross-link between the 5-LO and the PDE4D pathways with converging biology. To address the role of an inhibitor of FLAP on biomarkers of MI risk, a randomized placebocontrolled phase II trial was conducted in patients with MI. This trial showed that LTB₄ and MPO production was reduced in whole blood leukocytes that were stimulated with ionomycin and the effects of the inhibitor were dose dependent. Serum CRP and plasma MPO were also reduced at the highest dose, which was well tolerated. These data suggest that LTB₄ is a risk factor of MI and that inhibition of FLAP and the LT pathway produces suppression of biomarkers that are associated with MI risk, including but not limited to LTB₄, MPO, and CRP, supporting the notion that the LTB₄ arm of the LT pathway may play a fundamental role in heart attacks and stroke.     

A distinctive role of the leukotriene B4 receptor BLT1 in osteoclastic activity during bone loss

Although leukotriene B₄ (LTB₄) is produced in various inflammatory diseases, its functions in bone metabolism remain unknown. Using mice deficient in the high-affinity LTB₄ receptor BLT1, we evaluated the roles of BLT1 in the development of two bone resorption models, namely bone loss induced by ovariectomy and lipopolysaccharide. Through observations of bone mineral contents and bone morphometric parameters, we found that bone resorption in both models was significantly attenuated in BLT1-deficient mice. Furthermore, osteoclasts from BLT1-deficient mice showed reduced calcium resorption activities compared with wild-type osteoclasts. Osteoclasts expressed BLT1, but not the low-affinity LTB₄ receptor BLT2, and produced LTB₄. LTB₄ changed the cell morphology of osteoclasts through the BLT1-Gi protein-Rac1 signaling pathway. Given the causal relationship between osteoclast morphology and osteoclastic activity, these findings suggest that autocrine/paracrine LTB₄ increases the osteoclastic activity through the BLT1-Gi protein-Rac1 signaling pathway. Inhibition of BLT1 functions may represent a strategy for preventing bone resorption diseases.     

Bile salts determine leukotriene B4 synthesis in a human intestinal cell line (CaCo-2)

The ability of a human colonic epithelial cell line (CaCo-2) to synthesize leukotriene B₄ (LTB₄) in response to bile salt stimulation was examined, as was the dependency of such stimulation on the hydrophobic-hydrophilic balance of the bile salts. We demonstrate for the first time in this human intestinal epithelial cell line the ability of bile salts to stimulate synthesis of LTB₄. CaCo-2 cell monolayers were incubated with a series of bile salts ranging in concentration from 0.5 µM to 1 mM. This resulted in a dose- and hydrophobicity-dependent increase in LTB₄ synthesis. Hydrophobic bile salts (glycine and taurine conjugates of lithocholate and deoxycholate) caused LTB₄ synthesis to be stimulated 27% and 35%, respectively, above control levels. In contrast, hydrophilic bile salts (glycine and taurine conjugates of ursodeoxycholate) increased LTB₄ synthesis only 11.2% and 16.1%. Under basal conditions pretreatment with dexamethasone significantly inhibited bile salt-induced LTB₄ synthesis by 38% compared to control. With more hydrophobic bile salts, chenodeoxycholate and deoxycholate, dexamethasone inhibited LTB₄ synthesis to levels significantly below those observed with dexamethasone under basal conditions. Unlike A23187 calcium ionophore-induced LTB₄ synthesis, bile salt-induced stimulation of LTB₄ synthesis was not found to be dependent on the presence of extracellular calcium. Variations in bile salt stimulation of LTB₄ by intestinal epithelial cells could be important in modulating cellular responses. The synthesis of chemotactic factors, such as LTB₄, by the human colonic adenocarcinoma epithelial cell line now needs to be extended to normal human intestinal epithelium, as it may play a role in many of the functional disturbances which characterize intestinal inflammatory conditions.This work was funded by the Canadian Foundation for Ileitis and Colitis (CFIC).     

Study of the role of leukotriene B4 in abnormal function of human subchondral osteoarthritis osteoblasts: Effects of cyclooxygenase and/or 5‐lipoxygenase inhibition

Objective

To compare the effect of licofelone, NS‐398 (an inhibitor of cyclooxygenase 2 [COX‐2]), and BayX‐1005 (an inhibitor of 5‐lipoxygenase activating protein) on the production of leukotriene B₄ (LTB₄) and prostaglandin E₂ (PGE₂), and on cell biomarkers by human osteoarthritis (OA) subchondral osteoblasts.

Methods

Primary in vitro osteoblasts were prepared from subchondral bone specimens obtained from OA patients and autopsy subjects. LTB₄ and PGE₂ levels were measured by enzyme‐linked immunosorbent assay in conditioned media of osteoblasts incubated in the presence or absence of licofelone, NS‐398, or BayX‐1005. The effect of these drugs or of the addition of LTB₄ on alkaline phosphatase (AP) activity and osteocalcin release by OA and normal osteoblasts was determined. The presence of LTB₄ receptors in normal and OA osteoblasts was evaluated by Western blot analysis.

Results

OA osteoblasts produced variable levels of PGE₂ and LTB₄ compared with normal osteoblasts. Licofelone, at the maximal dose used, inhibited production of PGE₂ and LTB₄ by OA osteoblasts by a mean ± SEM of 61.2 ± 6.4% and 67.0 ± 7.6%, respectively. NS‐398 reduced PGE₂ production by 75.8 ± 5.3%. BayX‐1005 inhibited LTB₄ production in OA osteoblasts by 38.7 ± 14.5% and marginally affected PGE₂ levels (reduction of 14.8 ± 5.3%). Licofelone dose‐dependently stimulated 1,25‐dihydroxyvitamin D‐induced AP activity while inhibiting osteocalcin release. BayX‐1005 partly reproduced these effects, but NS‐398 failed to affect them. LTB₄ dose‐dependently inhibited AP activity in OA osteoblasts, while its effect on osteocalcin depended on endogenous LTB₄ levels in these cells. In normal osteoblasts, LTB₄ dose‐dependently stimulated osteocalcin, whereas it failed to influence AP. LTB₄ receptors BLT1 and BLT2 were present in normal and OA osteoblasts.

Conclusion

Licofelone inhibits the production of PGE₂ and LTB₄. Selective effects of licofelone on AP and osteocalcin occur via its role on LTB₄ production. Because LTB₄ can modify cell biomarkers in OA and normal osteoblasts, our results suggest licofelone could modify abnormal bone remodeling in OA.

     

Utility of cardiac troponin I,creatine kinase-MBmass,myosin light chain 1, and myoglobin in the early in-hospital triage of "high risk" patients with chest pain

OBJECTIVE—To evaluate the use of cardiac troponin I (cTnI), creatine kinase-MB_mass (CK-MB_mass), myosin light chain 1 (MLC 1), and myoglobin in identifying "high risk" patients with chest pain who will experience serious cardiac events (SCEs) in hospital.
DESIGN—Prospective study.
SETTING—University affiliated medical centre in Philadelphia, USA.
PATIENTS—208 patients with chest pain, at > 7% risk of acute myocardial infarction (MI), but without new ST segment elevation on their presenting ECG.
INTERVENTIONS—cTnI, CK-MB_mass, MLC 1, and myoglobin concentrations were obtained on admission (0 hour) and at 4, 8, 16, and 24 hours.
MAIN OUTCOME MEASURES—The sensitivity, specificity, positive and negative predictive value, and pre- and post-test probabilities of patients suffering an SCE in hospital were determined. SCEs included cardiac death, acute MI, cardiac arrest, life threatening cardiac arrhythmia, cardiogenic shock, and urgent coronary revascularisation.
RESULTS—Admission concentrations of all markers were poor predictors of SCEs in hospital but improved substantially at subsequent timepoints. cTnI and CK-MB_mass were consistently the most useful prognostic indicators. If both were negative at 0, 4, and 8 hours, then 99% (95% confidence interval 96% to 100%) of patients remained free from SCEs. The only SCEs not thus predicted were revascularisation procedures and associated complications. Additional tests after 8 hours, or the inclusion of additional markers, did not improve predictive accuracy further.
CONCLUSIONS—Patients with high risk clinical features on admission who have negative cTnI and CK-MB_mass concentrations at 0, 4, and 8 hours later have a favourable in-hospital prognosis and could be considered for early triage out of coronary care units.


     

Alterations in plasma lecithin:cholesterol acyltransferase and myeloperoxidase in acute myocardial infarction: Implications for cardiac outcome

Background

The cholesterol esterifying enzyme, lecithin:cholesterol acyltransferase (LCAT), plays a key role in HDL maturation and remodeling. Myeloperoxidase (MPO) may compromise LCAT enzymatic activity. We tested the extent to which plasma LCAT activity is altered in acute myocardial infarction (MI) in conjunction with abnormal MPO levels. We also assessed the impact of LCAT and MPO on newly developed major adverse cardiovascular events (MACE).

Methods

Two-hundred one consecutive patients referred for acute chest pain of whom 134 had MI (95 with ST-elevation) participated. Forty-five new MACE were ascertained during 1203 (range 13–1745) days of follow-up among 185 patients. Plasma LCAT activity was measured using an exogenous substrate assay. MPO mass was assayed by chemiluminescent microparticle immunoassay.

Results

Plasma LCAT activity was decreased by 15%, coinciding with 7-fold increased MPO levels in acute MI patients vs. patients with non-cardiac chest pain (p < 0.001 for both; correlation: r = −0.343, p < 0.001). MI at admission was associated independently with both lower plasma LCAT activity and higher MPO (age- and sex-adjusted odds ratio per 1 SD increment: 0.46 (95% CI, 0.31–0.68), p < 0.001 and 7.58 (95% CI, 3.34–17.11), p < 0.001, respectively). In an analysis with LCAT and MPO together these associations were modestly attenuated. MPO mass (hazard ratio: 1.59 (95% CI, 1.15–2.19), p = 0.004), but not LCAT activity (hazard ratio: 0.87 (95% CI, 0.65–1.19), p = 0.39), predicted newly manifest MACE.

Conclusion

In acute MI patients, plasma LCAT activity is decreased coinciding with increased MPO levels. Higher MPO but not lower LCAT activity prospectively predicts adverse cardiac outcome.     

Increased neutrophil migration in smokers with or without chronic obstructive pulmonary disease

Background and objective: The number of airway neutrophils is increased in chronic obstructive pulmonary disease (COPD), and this may have a central pathophysiological role in the disease. In addition, activation of neutrophils increases their migration into sites of injury. We hypothesize that circulating neutrophils are activated in smokers. Methods: Peripheral blood neutrophils were isolated from healthy non‐smokers (n = 15), and smokers with (n = 15) or without COPD (n = 15), who were matched with regard to cumulative tobacco exposure, and chemotactic responses to N‐formyl‐methionyl‐leucyl‐phenylalanine (fMLP), interleukin‐8 (IL‐8, CXCL8) and leukotriene B₄ (LTB₄) were assessed using the ChemoTx System (Neuro Probe Inc., Gaithersburg, MD, USA). Serum tumour necrosis factor‐α (TNF‐α) concentrations were measured by ELISA. Surface expression of the neutrophil activation marker, CD11b, was measured by flow cytometry. Results: The chemotactic response to CXCL8 was increased in smokers with or without COPD (P < 0.05). Migration towards LTB₄ was increased in smokers without COPD compared with non‐smokers (P < 0.05), whereas there was no difference in fMLP‐induced chemotaxis between the groups. There was a correlation between serum TNF‐α levels and migration induced by IL‐8 (Rho = 0.442; P = 0.038) and LTB₄ (Rho = 0.428; P = 0.044) in the smokers. Furthermore, there was a tendency towards higher CD11b expression in the COPD group (P = 0.057). Conclusions: Chemotaxis of circulating neutrophils towards CXCL8, and partly towards LTB₄, is increased in smokers, indicating a systemic influence of smoking on cell activation, irrespective of the presence of airflow limitation. The relationship between TNF‐α and chemotactic response suggests that TNF‐α is involved in neutrophil activation, resulting in enhanced migration.     

Variability of exhaled breath condensate leukotriene B4 and 8-isoprostane in COPD patients

The reproducibility of exhaled breath condensate (EBC) mediators is not well documented in chronic obstructive pulmonary disease (COPD). This study assessed within assay (WA), within (WD) and between day (BD) reproducibility of EBC leukotriene B₄ (LTB₄) and 8-isoprostane. Three EBC samples were collected from 24 COPD patients separated by 1 h and 1 wk, to assess WD and BD reproducibility. WA reproducibility was assessed by sample analysis by enzyme immunoassay in triplicate. WA coefficient of variation for LTB₄ and 8-isoprostane (18.2% and 29.2%, respectively) was lower than corresponding values for WD (47.7% and 65.3%, respectively) and BD (75.7% and 79.1%, respectively). Repeatability coefficient for 8-isoprostane and LTB₄ assays were 18.6 pg/ml and 13.2 pg/ml, respectively. Group mean differences for WD and BD were small and statistically nonsignificant. Using the Bland Altman method, there were wide limits of agreement for WD (−51.6 to 47.2 for 8-isoprostane and −31.8 to 31.4 for LTB₄) and BD reproducibility (−61.4 to 75.7 for 8-isoprostane and −29.3 to 38.6 for LTB₄). This is the first study to fully report the variability of EBC 8-isoprostane and LTB₄ in COPD. WA variability and group mean changes were small. However, we observed considerable WD and BD variability for these biomarkers.     

Psychology of earthquake-induced stress cardiomyopathy, myocardial infarction and non-cardiac chest pain

Aims: To compare psychological factors in patients presenting to hospital with earthquake‐induced stress cardiomyopathy, myocardial infarction (MI) and non‐cardiac chest pain. We hypothesised that patients with stress cardiomyopathy and non‐cardiac chest pain would be more psychologically vulnerable than those with MI. Methods: Cardiology admitting staff in the week following the September 2010 Christchurch earthquake prospectively identified patients with earthquake‐precipitated chest pain. Males were excluded. All consenting women met diagnostic criteria for one of the three conditions. Patients underwent a semistructured interview with a senior clinical psychologist who was blind to the cardiac diagnosis. Premorbid psychological factors, experience of the earthquake and psychological response were assessed using a range of validated tools. Results: Seventeen women were included in the study, six with stress cardiomyopathy, five with MI and six with non‐cardiac chest pain. Earthquake experiences were notably similar across the groups. Patients with non‐cardiac chest pain scored high on the hospital anxiety and depression scale, the health anxiety questionnaire, the Eysenck neuroticism scale and the Impact of Event scale. Women with stress cardiomyopathy scored as the most psychologically robust. Depression and extroversion scores were the same across groups. Conclusion: Our hypothesis was incorrect. Women with non‐cardiac chest pain following an earthquake have higher anxiety and neuroticism scores than women with either MI or stress cardiomyopathy. Stress cardiomyopathy following an earthquake is not specific to psychologically vulnerable women. The psychology of natural disaster‐induced stress cardiomyopathy may differ from that of sporadic cases.     

Prediction of Recurrent Events by D-Dimer and Inflammatory Markers in Patients with Normal Cardiac Troponin I (PREDICT) Study

Background

The independent predictive value of d-dimer and inflammatory markers for the risk of recurrent adverse events in patients with acute chest pain but normal levels of cardiac troponin I (cTnI) remains unclear.

Methods

We studied 391 patients admitted to the hospital in 1 year with acute ischemic-type chest pain. Creatine kinase-myocardial band isoenzyme (CK-MB) mass and cTnI levels were measured in initial and 12-hour samples. Soluble intercellular adhesion molecule (sICAM)-1, vascular cell adhesion molecule (sVCAM)-1, sP-selectin, sE-selectin, high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL6), fibrinogen, and d-dimer levels were measured in initial samples. A 1-year incidence of death, myocardial infarction (MI), revascularization, or readmission with chest pain was determined (with death/MI as the primary end point).

Results

Patients with normal levels of CK-MB_mass and cTnI (195/391[50%]) were at a lower risk than patients with elevated levels of CK-MB_mass or cTnI, but still had an important incidence of events (77/195[39%]). Marker elevation was defined as >75th percentile (upper quartile). Elevated d-dimer levels (>580 ng/mL) was predictive of death/MI (odds ratio, 5.4; 95% CI, 1.5-20.2; P = .005). Elevated sP-selectin levels (>152 ng/mL; odds ratio, 3.2; 95% CI, 0.9-11.6; P = .06) trended to increased death/MI rates, with weaker trends for elevated levels of hsCRP (>7.1 mg/L), IL6 (>10.7 pg/mL), and ST depression. Other markers, other electrocardiogram changes, or classic risk factors were not predictive of death/MI. With a multivariate analysis, d-dimer and sP-selectin were found to be of independent significance for death/MI after adjustment for inflammatory, hemostatic, and electrocardiogram markers and d-dimer after adjustment for classic risk factors.

Conclusion

Normal cTnI levels after acute chest pain does not confer absence of future risk. Concurrent assessment of d-dimer and inflammatory markers may improve risk stratification.