Substance P alterations in skin and brain of chronically stressed atopic-like mice.

BACKGROUND: Stress is known to worsen the symptoms of atopic eczema (AE). Substance P is likely to play an important role in the development and pathogenesis of AE. OBJECTIVE: To examine a possible connection between chronic mild stress and changes in the expression of substance P and its receptor (R) neurokinin (NK) 1 in the skin and stress-related brain regions in NC/Nga atopic-like mice. METHODS: The mice were divided into three groups (eight animals per group): SE (stressed eczematous), NSE (non-stressed eczematous) and SC (stressed control). Ears and brains of the mice were investigated using immunohistochemistry and RT-PCR. RESULTS: In the skin, there was a decrease in the number of substance P immunoreactive nerve fibres in SE compared with SC group. RT-PCR showed a strong tendency to an increase in mRNA for NK1R in the skin of SE compared with NSE mice. There was an increase in the number of mast cells and the degree of their degranulation in the SE compared with both other groups. A decrease in substance P immunoreactivity in medial hippocampus was found in SE compared with NSE animals. In prefrontal cortex and central amygdala, there were no significant differences in substance P immunoreactivity between the three groups. CONCLUSION: Exposure to chronic mild stress in NC/Nga atopic-like mice may result in altered expression patterns of substance P in the skin and hippocampus.

Release of protein as well as activity of MMP-9 from unstable atherosclerotic plaques during percutaneous coronary intervention.

OBJECTIVES: Few studies have investigated the composition of unstable coronary plaques in vivo in humans. The aims of this study were to investigate if substances released from plaques during percutaneous coronary intervention (PCI) under distal protection could give information about plaque composition and also indicate possible biomarkers in plasma that may be used to identify patients at risk. METHODS AND RESULTS: Twenty patients with acute coronary syndromes undergoing PCI with distal protection were included. Plasma samples were taken before, during, and after the PCI in the aortic root, locally in the culprit vessel and intravenously. Plasma was analysed for possible markers of plaque instability. During PCI, local increases were observed for matrix metalloproteinase 9 (MMP-9), protein (P < 0.001) as well as activity (P < 0.001), interleukin 6 (IL-6; P < 0.01) and oxidized low-density lipoprotein (oxLDL; P = 0.01) in the culprit coronary artery. A systemic inflammatory response was also seen with increased levels of IL-10, MMP-3, serum amyloid A and C-reactive protein, but with no increase in MMP-9. CONCLUSIONS: Our study shows that local sampling of blood under distal protection may be used to analyse coronary plaques and to identify biomarkers for unstable plaques. Our results suggest that MMP-9 is a potential biomarker, and that IL-6, MMP9 and possibly oxLDL are released from plaques.

Abciximab in the treatment of acute myocardial infarction eligible for primary percutaneous transluminal coronary angioplasty. Results of the Glycoprotein Receptor Antagonist Patency Evaluation (GRAPE) pilot study.

OBJECTIVES: We sought to study the effect of early infusion of abciximab on coronary patency before primary angioplasty in patients with acute myocardial infarction. BACKGROUND: Glycoprotein IIb/IIIa antagonists have proved to be effective in reducing ischemic events associated with coronary angioplasty. The present study explores whether abciximab alone, without administration of thrombolytic therapy, may induce reperfusion in patients with acute myocardial infarction. METHODS: In the Glycoprotein Receptor Antagonist Patency Evaluation pilot study 60 patients with less than 6 h signs and symptoms of acute myocardial infarction eligible for primary angioplasty received in the emergency room a bolus of abciximab 250 microg/kg followed by a 12-h infusion of 10 microg/min. All patients were also treated with an oral dose of 160 mg aspirin and 5,000 IU of heparin intravenously. As soon as possible a diagnostic angiography was performed to evaluate the patency of the infarct-related artery. RESULTS: The median time between onset of symptoms and the administration of the abciximab bolus was 150 min (range 45 to 345), and the median time between abciximab bolus and first contrast injection in the infarct-related artery was 45 min (range 10 to 150). In 24 patients (40%, 95% confidence interval 28% to 52%) Thrombolysis in Myocardial Infarction (TIMI) flow grade 2 or 3 was observed at a median time of 45 min (range 10 to 150) after abciximab bolus; TIMI flow grade 3 was observed in 11 patients (18%, 95% confidence interval 9% to 28%). There was no difference in percentage of TIMI flow grade 2 or 3 between patients who received abciximab within 2.5 h after onset of symptoms or thereafter. CONCLUSIONS: Abciximab therapy given in the emergency room in patients awaiting primary angioplasty is associated with full reperfusion (TIMI flow grade 3) in about 20% and with TIMI flow grade 2 or 3 in about 40% of the patients at a median time of 45 min. These figures are higher than those in primary angioplasty trials without such pretreatment. Randomized controlled trials of very early infusion of abciximab, either prehospital or in-hospital, in patients eligible for angioplasty are warranted.

Treatment effects on serum lipoprotein lipids, apolipoproteins and low density lipoprotein particle size and relationships of lipoprotein variables to progression of coronary artery disease in the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT).

OBJECTIVES: To investigate the mechanisms by which bezafibrate retarded the progression of coronary lesions in the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT), we examined the relationships of on-trial lipoproteins and lipoprotein subfractions to the angiographic outcome measurements. BACKGROUND: BECAIT, the first double-blind, placebo-controlled, randomized serial angiographic trial of a fibrate compound, showed that progression of focal coronary atherosclerosis in young survivors of myocardial infarction could be retarded by bezafibrate treatment. METHODS: A total of 92 dyslipoproteinemic men who had survived a first myocardial infarction before the age of 45 years were randomly assigned to treatment for 5 years with bezafibrate (200 mg three times daily) or placebo; 81 patients underwent baseline and at least one post-treatment coronary angiography. RESULTS: In addition to the decrease in very low density lipoprotein (VLDL) cholesterol (-53%) and triglyceride (-46%) and plasma apolipoprotein (apo) B (-9%) levels, bezafibrate treatment resulted in a significant increase in high density lipoprotein-3 (HDL3) cholesterol (+9%) level and a shift in the low density lipoprotein (LDL) subclass distribution toward larger particle species (peak particle diameter +032 nm). The on-trial HDL3 cholesterol and plasma apo B concentrations were found to be independent predictors of the changes in mean minimum lumen diameter (r=-0.23, p < 0.05), and percent (%) stenosis (r = 0.30, p < 0.01), respectively. Decreases in small dense LDL and/or VLDL lipid concentrations were unrelated to disease progression. CONCLUSIONS: Our results suggest that the effect of bezafibrate on progression of focal coronary atherosclerosis could be at least partly attributed to a rise in HDL3 cholesterol and a decrease in the total number of apo B-containing lipoproteins.

Coagulation activity and clinical outcome in unstable coronary artery disease.

In the current study, we investigated molecular markers of coagulation activity, ie, prothrombin fragment 1+2 (F1+2), thrombin-antithrombin (TAT) complex, soluble fibrin (SF), and D-dimer, and their relation to death, myocardial infarction, and refractory angina during and after anticoagulant treatment in unstable coronary artery disease. Patients with unstable coronary artery disease (N=320) were randomized to a 72-hour infusion with either inogatran, a low-molecular-mass direct thrombin inhibitor, or unfractionated heparin. During the 30-day follow-up, a 40% lower event rate was seen in patients with high compared with low baseline levels of TAT or SF. High baseline levels of coagulation activity were correlated with a larger decrease during treatment. Patients with decreased compared with raised F1+2 or TAT levels after 6 hours of treatment had a 50% lower event rate at 30 days (F1+2, P=0.04; TAT, P=0.02). At the cessation of antithrombin treatment, there was a clustering of cardiac events that tended to be related to a rise in the levels of TAT and the other markers. During long-term follow-up (median, 29 months), there was a relation between higher baseline levels of D-dimer (P=0.003) and increased mortality. High baseline levels of molecular markers of coagulation activity might identify patients with a thrombotic condition (as the major cause of instability) who are good responders to anticoagulant therapy, with a larger decrease in coagulation activity during treatment and a decreased risk of ischemic events. However, this early benefit is lost during long-term follow-up when high baseline levels of coagulation activity are associated with a raised risk of early reactivation and increased mortality.

Antithrombotic activity of inogatran, a new low-molecular-weight inhibitor of thrombin, in a closed-chest porcine model of coronary artery thrombosis.

OBJECTIVE: To characterize the antithrombotic activity of inogatran per se in a porcine model of copper-coil-induced coronary artery thrombosis and to compare its effect with that of heparin and ASA. METHODS: Forty-eight pigs were assigned to one of the following groups: (1) saline; (2) heparin, (a) 75 and (b) 150 IU/kg/h; (3) acetylsalicylic acid (ASA), 12.5 mg/kg; (4) ASA 12.5 mg/kg + inogatran, 0.06 mg/kg/h; (5) ASA 12.5 mg/kg + inogatran, 0.30 mg/kg/h; (6) inogatran, 0.30 mg/kg/h; (7) inogatran, 0.60 mg/kg/h; (8) inogatran, 1.5 mg/kg/h. Computerized vectorcardiography was applied to monitor coronary occlusion and reperfusion. RESULTS: Cumulative time in which coronary arteries were patent, expressed as a percentage of the treatment time (i.e., 90 min) in heparin- and ASA-treated pigs, was 8 +/- 6 and 14 +/- 7%, respectively. This is not significantly different from placebo-treated pigs. Inogatran-treated pigs showed a dose-dependent antithrombotic effect, and the average patency rates were 34 +/- 39, 54 +/- 37 and 80 +/- 32%, in groups 6, 7 and 8, respectively. Combined treatment with inogatran and ASA did not significantly improve the antithrombotic effect. A partial antithrombotic effect of inogatran was maintained for, on average, at least 150 min after the end of treatment, as evidenced by patency rates of 31 +/- 43, 52 +/- 48 and 62% +/- 44, in groups 6, 7, and 8, respectively. CONCLUSION: Inogatran inhibits the formation of arterial thrombosis more effectively than heparin or ASA. Inhibition of clot-bound thrombin and thrombin-induced platelet activation may be the mechanisms behind this effect. Our findings also suggest that a thrombus formed in the presence of inogatran is more susceptible to spontaneous endogenous fibrinolysis.

Effect of bezafibrate treatment over five years on coronary plaques causing 20% to 50% diameter narrowing (The Bezafibrate Coronary Atherosclerosis Intervention Trial [BECAIT]).

Recent reports indicate that most coronary events originate from plaques causing <50% diameter stenosis. A subgroup analysis of the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) data was undertaken to determine the effects of bezafibrate in relation to baseline narrowing. BECAIT included 92 male postacute myocardial infarction patients <45 years of age. Each received double-blind treatment with bezafibrate (200 mg 3 times daily) or placebo for 5 years, together with a low-fat diet. Coronary angiography was performed at baseline and after 2 and 5 years. The mean minimum lumen diameter of lesions causing 20% to <50% diameter stenosis at baseline did not narrow over 5 years in the bezafibrate group and decreased by 0.15 mm in the placebo group (p <0.05). In segments with > or =50% diameter stenosis at baseline, no change was seen in either of the 2 groups. In the analysis including only segments with 20% to <50% stenosis at baseline, coronary events were seen in 7 of 40 patients with a progression in minimum lumen diameter of more than the median value and in 3 of 41 patients with a change less than the median value. Thus, bezafibrate had a preferential effect in slowing the progression of narrowings causing <50% stenosis at baseline in young men followed up for a 5-year period after acute myocardial infarction.

Thrombin inhibitors suppress the thrombin-thrombomodulin-mediated generation of activated protein C.

In the treatment of unstable coronary artery disease, direct thrombin inhibitors have shown no or only limited benefit as compared with heparin, despite theoretical advantages. One explanation may be that the direct thrombin inhibitors to a greater extent than heparin have an inhibiting effect on the generation and activity of activated protein C. In the present study, this hypothesis was tested in an in vitro, "purified" system, where human protein C underwent activation to activated protein C by the thrombin-thrombomodulin complex. Direct thrombin inhibitors, inogatran and hirudin, unfractionated heparin+antithrombin, or dalteparin+antithrombin, were added to the system before activation to evaluate their inhibitory effect on the generation of activated protein C. At inhibitor concentrations well below the achieved plasma levels in major clinical trials, the thrombin-thrombomodulin-mediated activation of protein C was inhibited by all the studied inhibitors in a dose-dependent manner, but, contrary to our hypothesis, to a greater extent by unfractionated heparin+antithrombin and dalteparin+antithrombin than by the direct thrombin inhibitors, hirudin and inogatran. Despite difficulties to draw conclusions for the in vivo situation, the in vitro inhibition, by all studied inhibitors, of the generation of activated protein C, found in this study may be a possible explanation for ongoing cardiovascular events despite adequate treatment with thrombin inhibitors, in patients with unstable coronary artery disease. This inhibition of the generation of activated protein C may also contribute to the rebound in cardiovascular events after withdrawal of effective antithrombotic treatment.

There is no effect on remodeling of vascular wall 4 weeks after local delivery of antithrombin in a porcine model of coronary overstretching.

BACKGROUND: Antithrombin III is an effective endogenous inhibitor of thrombin with antiproliferative and anti-inflammatory capabilities. Systematic administration of direct thrombin inhibitors as well as of antithrombin has proven effective at reducing formation of neointima after injury to vessel wall in various animal models. Local delivery of antithrombin attenuates deposition of platelets after balloon injury to porcine coronary vessels. OBJECTIVE: To test our hypothesis that local delivery of antithrombin affects remodeling of vessel wall after balloon injury to the left anterior descending artery (LAD) in pigs. METHODS: With a balloon:vessel diameter ratio of 1.5 deep vessel-wall injury was performed with conventional balloon angioplasty in the LAD in 16 pigs. After balloon injury the pigs were administered locally two doses of 2.5 ml antithrombin (250 U) or, as a control, two doses of 2.5 ml albumin (10 mg). All pigs were administered 200 U/kg bodyweight heparin before catheterization. The animals were then kept in stalls and fed normal grain. After approximately 4 weeks the animals were killed and lesions were assessed by computer-assisted image analysis. The areas of each vessel-wall layer and the percentage area stenosis were calculated. As a measure of injury, the length of rupture of the lamina elastica interna was measured. RESULTS: The injury was found to be equally profound in pigs of these groups. There was no significant difference between the groups concerning the areas of vessel-wall layers. The percentage area stenosis was similar for pigs in these two groups (36.5 +/- 14.9% for pigs in the antithrombin group versus 35.4 +/- 16.2% for pigs in the control group, NS). CONCLUSIONS: Local delivery of 250 U antithrombin to the LAD in pigs did not affect remodeling of the vessel wall 4 weeks after balloon injury.

Thrombin inhibition with inogatran for unstable angina pectoris: evidence for reactivated ischaemia after cessation of short-term treatment.

BACKGROUND: The acute coronary syndromes of unstable angina and non-Q-wave infarction are initiated by coronary plaque rupture and subsequent thrombus formation. Thrombin is central to this response as it activates platelets and the coagulation system. In an open design study we assessed the tolerability and safety of the low molecular weight thrombin inhibitor, inogatran, for unstable angina or non-Q-wave infarction. METHODS: Thirty-seven patients, treated within 72 h of symptoms, were allocated consecutively to groups to receive a 4 h infusion with one of three doses of inogatran. Thrombin generation and activity were measured with plasma markers at baseline, after the 4 h treatment period and 4 h later. Ischaemia was monitored using continuous vectorcardiography during the 4 h of treatment and during the subsequent 4 h after inogatran infusion had been stopped, to detect any increase in ischaemic events after the period of treatment. In addition, 12 patients received inogatran as an infusion for 72 h. RESULTS: Inogatran was tolerated well. There were no adverse haemodynamic effects or allergic reactions. Minor bleeding events were detected in 37% of the patients. The biochemical and vectorcardiographic findings indicated suppression of thrombin generation after the 4 h treatment period compared with baseline. During the first 4 h after inogatran treatment, thrombin activity and episodes of ischaemia were increased compared with during the treatment period. CONCLUSION: Inogatran was tolerated well and was safe, but its discontinuation was followed by a reactivation of thrombin activity and ischaemia. Whether this reactivation represented a rebound phenomenon, or merely resulted from the discontinuation of an effective therapy, cannot be established from the present study.

Local delivery of antithrombin inhibits platelet deposition after balloon injury in a porcine coronary model.

BACKGROUND: Thrombin activation and initiation of the coagulation process can lead to thrombotic complications after coronary angioplasty. A therapeutic approach may be effectively to inhibit thrombin activity at the site of the vessel wall injury. OBJECTIVE: The aim of the present study was to investigate the short-term effects of local delivery of antithrombin on coronary vessel wall injury in pigs. METHODS: A coronary balloon angioplasty was performed in the left anterior descending artery. Twenty-four hours before the procedure, platelets were marked with Indium 111 and infused into the pig. Before catheterisation 100 U/kg of heparin was administered. Eight pigs received 250 U (5 ml) of antithrombin and, as a control, eight received 10 mg of albumin (5 ml) delivered using a local drug delivery balloon catheter. Microscopic preparation of the injured part of the vessel was performed, and the amount of radioactivity was measured, giving the number of platelets per cm2. Plasma antithrombin level was measured before and after local delivery. The amount of antithrombin in the vessel wall was measured using a semi-quantitative method involving anti-antithrombin antibodies. RESULTS: The number of platelets per cm2 was significantly lower in the antithrombin group (mean 2.3 x 10(6)) than in the control group (6.3 x 10(6), P= 0.02 ). No macroscopic thrombus was detected in the antithrombin group, whereas three out of eight pigs in the control group had visible thrombus formation (NS). There was an increase in the plasma concentration of antithrombin after local delivery. In the antithrombin group, antithrombin was detected in the intima, the lumen part of the media and in the vasa vasorum. CONCLUSION: Antithrombin can be administered and deposited locally in the coronary vessel wall thereby reducing platelet deposition after balloon injury.

Influence of percutaneous transluminal coronary angioplasty on cardiac release of endothelin, neuropeptide Y and noradrenaline.

In the present study, the cardiac outflow of endothelin, noradrenaline and neuropeptide Y was investigated in 13 patients undergoing first time coronary angioplasty (PTCA) due to stenosis of the left anterior descending coronary artery. During PTCA there was an increase in the coronary sinus levels of endothelin but no detectable changes in neuropeptide Y or noradrenaline concentrations. It is therefore concluded that endothelial damage rather than myocardial ischaemia is the cause of endothelin release during PTCA.

The postcardiac injury syndrome following percutaneous transluminal coronary angioplasty.

A 57-year-old man, who had suffered an anterior Q-wave myocardial infarction complicated with typical post-cardiac injury syndrome (PCIS) 9 years earlier, underwent percutaneous transluminal coronary angioplasty (PTCA) without any immediate clinical, laboratory, or radiological signs of complications. After 4 days he recognized the recurrence of the earlier symptoms of PCIS. The diagnosis was supported by slight fever, elevated inflammatory parameters, and improvement when oral corticosteroids were given. The observations suggest that milder cardiac injury than previously considered, that is, without demonstrated structural damage to pericardium or myocardium, may precipitate PCIS in predisposed individuals. The case adds a differential diagnosis to chest pain and malaise following PTCA.

[Fibrinolysis or angioplasty in acute myocardial infarction?]. / Fibrinolys eller angioplastik vid akut hjärtinfarkt?

Early reperfusion during myocardial infarction limits myocardial injury and reduces mortality. Fibrinolysis (with streptokinase, or tissue or recombinant plasminogen activators) is today an established method for the treatment of myocardial infarction patients manifesting ST-segment elevation or left bundle branch block at ECG (electrocardiography), effective reperfusion being obtained in fifty per cent of cases. Extensive developments are under way, both of fibrinolytic substances and of various adjuvant treatments. A satisfactory alternative treatment to fibrinolysis is percutaneous transluminal coronary angioplasty (PTCA), a method which can be used when fibrinolysis is contraindicated or during cardiogenic shock, or when there is no sign of reperfusion in response to fibrinolytic treatment. Provided the facilities and competence are available, PTCA can even be used as primary treatment instead of fibrinolysis.

[Primary PTCA or thrombolysis in acute myocardial infarction?]. / Primär PTCA eller trombolys vid akut hjärtinfarkt?

In acute ST-elevation infarction two different reperfusion strategies--thrombolytic medication and acute coronary angiography--have proved to improve the prognosis. The clinical course for patients with ST-elevation infarction is described in relation to whether they received thrombolytic medication or underwent acute coronary angiography with the aim of mechanical revascularization. The one-year mortality was high (20 percent) regardless of treatment strategy. In terms of morbidity there were no clear differences between the two treatment groups.