The role of strict metabolic control by insulin infusion on fibrinolytic profile during an acute coronary event in diabetic patients

BACKGROUND: Many clinical and laboratory observations give support to the hypothesis that strict metabolic control by insulin infusion during acute coronary events may improve the ischemic damage and prognosis. HYPOTHESIS: We investigated the impact of intensive insulin treatment on fibrinolytic parameters during an acute ischemic myocardial event (unstable angina or acute myocardial infarction) in patients with type 2 diabetes mellitus. METHODS: The study group consisted of 48 type 2 diabetic patients, of whom 24 were randomized to conventional therapy plus intensive insulin treatment (Group 1) and 24 to conventional therapy only (Group 2). The two groups were comparable according to gender, age, body mass index, waist:hip ratio, duration of diabetes, previous antidiabetic treatment, type of ischemic events, concomitant therapy, and the classic risk factors for coronary disease. Insulin-treated patients were excluded from the study. Plasma levels of fibrinogen, tissue plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1) were measured on admission and discharge. Fibrinogen (fibr) was measured using the photometric method. PAI-1 and t-PA were measured by enzyme-linked immunosorbent assays. RESULTS: T-PA increased in both groups during hospitalization (t-PA(admission) vs. t-PA(discharge): Group 1: 15.42 +/- 4.4 ng x ml(-1) vs. 21.2 +/- 5.74 ng x ml(-1), p = 0.000037; Group 2: 14.47 +/- 6.31 ng x ml(-1) vs. 19.18 +/- 6.88 ng x ml(-1), p = 0.001). On the other hand, fibr and PAI-1 levels increased remarkably in controls (Group 2, fibr(admission) vs. fibr(discharge): 2.98 +/- 1.04 g x l(-1) vs. 3.59 +/- 1.01 g x l(-1), p = 0.002, and PAI-1admission vs. PAI-1 discharge: 30.6 +/- 17.34 ng x ml(-1) vs. 40.62 +/- 23.48 ng x ml(-1), p = 0.003). This finding was not observed in the intensive insulin treatment group (Group 1, fibr(admission) vs. fibr(discharge): 2.87 +/- 0.73 g x l(-1) vs. 2.67 +/- 0.72 g x l(-1), p = 0.101, and PAI-1 admission vs. PAI-1 discharge: 30.75 +/- 15.81 ng x ml(-1) vs. 27.75 +/- 6.43 ng x ml(-1), p = 0.484). CONCLUSION: Intensive insulin treatment during an acute coronary event improves fibrinolytic profile in patients with diabetes mellitus. This is a possible mechanism for the reduced short- and long-term mortality in diabetic patients treated with intensive insulin treatment protocol.     

Significance of changes in plasma adiponectin concentration after the implantation of stents in patients with stable angina

OBJECTIVE: Although plasma adiponectin levels may be a marker for the severity of coronary artery disease (CAD) and can help to predict future cardiovascular events in patients with CAD, the significance of changes in plasma adiponectin levels after the implantation of stents in patients with stable angina is unclear. METHODS: The subjects included 32 consecutive patients with stable angina who had undergone successful coronary stenting [bare metal stent (BMS, n=16) or sirolimus-eluting stent (SES, n=16)]. Blood sampling was performed at baseline, and at 24h, 48h, 14 days and 6 months after stenting. RESULTS: Plasma high-sensitivity C-reactive protein (hs-CRP) levels at baseline (0.16+/-0.15mg/dl) were significantly increased at 24h (0.36+/-0.45mg/dl, p=0.011) and 48h (1.01+/-1.01mg/dl, p<0.001), and plasma adiponectin levels at baseline (6.7+/-4.2mug/ml) were significantly decreased at 24h (6.1+/-4.2mug/ml, p=0.019) and 48h (6.2+/-4.9mug/ml, p=0.010) in all subjects. Although there were no significant differences in changes in plasma hs-CRP and adiponectin levels between BMS and SES groups during the study period, BMS group (6.5+/-0.9mug/ml at baseline) showed a significant reduction of plasma adiponectin at 48h (5.8+/-1.1mug/ml, p=0.022) and 6 months after stenting (4.7+/-2.3mug/ml, p=0.011). Percent diameter stenosis (%DS) at 6 months after stenting was negatively correlated with changes in the plasma adiponectin levels within 6 months [Deltaadiponectin (6 months-baseline)]. In addition, multiple logistic regression analysis revealed that the %DS at 6 months after stenting was most closely correlated with Deltaadiponectin (6 months-baseline) after adjusting for age, sex and body mass index. CONCLUSIONS: Coronary stenting may decrease circulating adiponectin in association with an inflammatory response. The changes in plasma levels of adiponectin after stenting may also be a predictor of coronary restenosis in patients with CAD.     

Effect of a short antibiotic treatment with roxithromycin on circulating adhesion molecules after coronary stenting: a single-center pilot trial.

BACKGROUND: The aim of this study was to assess the effect of periprocedural antibiotic treatment with roxithromycin on circulating cell adhesion molecules and restenosis after coronary stent implantation. METHODS: Case-control study enrolling 25 consecutive patients submitted to coronary stenting for stable, single-vessel coronary artery disease, treated with 300 mg roxithromycin once daily for 5 days, starting 2 days before the procedure (group R). Twenty-five patients, matched for lesion site, length and diameter, as control group (group C). The serological status for Chlamydia pneumoniae (CP) infection (IgG, ELISA) was assessed in all patients. The plasma concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), E-selectin and C-reactive protein at 1 month after coronary stenting were compared with baseline values. Binary restenosis (> or = 50%) was also evaluated at 6 months. RESULTS: sICAM-1 significantly decreased at 1 month in group R vs group C (371 +/- 181 vs 573 +/- 273 ng/ml, p = 0.005). This decrease was more evident in patients with a positive serology for CP (CP+) (group R 373 +/- 131 vs group C 597 +/- 255 ng/ml, p = 0.014). Antibiotic treatment had no effects on circulating E-selectin levels at 1 month (56.7 +/- 97 vs 49.8 +/- 62 ng/ml, p = 0.54). The restenosis rate (9/50, 18%) was similar in the two groups (group R 5/25 [20%], group C 4/25 [16%]). The restenosis rate was similar in the CP+ vs CP- group (6/35 [17%] vs 3/15 [20%]). CONCLUSIONS: A short course of treatment with roxithromycin at the time of coronary stenting induces a significant reduction in the sICAM-1 levels at 1 month but apparently does not influence the restenosis rate.     

Changes of serum hepatocyte growth factor in coronary artery disease

Hepatocyte growth factor (HGF) is an endothelial cell specific growth factor involved in the repair of endothelial cells and collateral formation, however, the role for coronary artery disease is still unknown. We measured serum HGF level in various coronary artery diseases to examine the clinical significance. Serum HGF level was measured using the enzyme-linked immunosorbent assay method in patients with stable effort angina pectoris (n = 26), old myocardial infarction (n = 18), unstable angina pectoris (UAP; n = 10) and acute myocardial infarction (AMI; n = 21). As a control group, we selected 11 patients with neurocirculatory asthenia. Blood samples from peripheral veins were collected at cardiac catheterization before heparin administration. In the AMI group, blood samples were also collected at 48, 72 hr, 1, 2, 3 and 4 weeks from the peripheral veins and 48 and 72 hr after reperfusion from the coronary sinus. Serum HGF level was significantly higher in the UAP (0.41 +/- 0.12 ng/ml, p < 0.001) and AMI groups (0.38 +/- 0.26 ng/ml, p < 0.05) compared to the control group (0.19 +/- 0.09 ng/ml). Serum HGF level peaked 48 hr after reperfusion in both the peripheral veins (0.42 +/- 0.16 ng/ml) and coronary sinus (0.58 +/- 0.23 ng/ml) in the AMI group, with a significantly higher level in the coronary sinus than the peripheral veins (p < 0.05). No significant correlation between peak HGF level in the peripheral veins and peak creatine kinase (CK), CK-MB, ejection fraction and cardiac index was observed. Serum HGF was elevated in acute coronary syndrome, indicating advanced endothelial cell damage. HGF is produced, at least partially, in the heart in patients with AMI. Serum HGF level may be useful to detect endothelial cell damage rather than myocardial cell damage.     

The effect of heparin on tissue factor and tissue factor pathway inhibitor in patients with acute myocardial infarction

We examined plasma TF and free TFPI levels in 26 consecutive patients with AMI, 26 patients with stable exertional angina, and 25 patients with chest pain syndrome. In patients with AMI, blood samples were obtained immediately after admission and at 4, 8, 16, 24, and 48 h, and the third, fifth, seventh, and fourteenth day after initiation of reperfusion therapy. Plasma TF levels in patients with AMI on admission were significantly higher than in the chest pain syndrome and stable exertional angina groups (248.0+/-117. 4 vs. 179.5+/-29.2 vs. 189.5+/-29.6 pg/ml, P<0.01). In patients with AMI, the level subsequently decreased after heparin administration and was maintained at significantly lower levels compared to those on admission. Plasma free TFPI levels in patients with AMI on admission were significantly higher than in the chest pain syndrome and stable exertional angina groups [33.5+/-12.4 vs. 26.0+/-7.6 ng/ml (P<0.01) vs. 27.5+/-6.3 ng/ml, P<0.05]. In patients with AMI, it reached the maximum level at 4 h after the administration of heparin, and gradually decreased over the time course. These data indicated that continuous administration of a low dose of heparin was effective in decreasing TF levels without affecting TFPI levels. Our results elucidate one of the mechanisms by which the administration of heparin is beneficial in AMI patients undergoing percutaneous revascularization.     

Hepatocyte growth factor production may be related to the inflammatory response in patients with acute myocardial infarction.

Hepatocyte growth factor (HGF) is a well-known powerful proliferative factor of vascular endothelial cells and it has been reported that plasma HGF concentrations are increased in acute myocardial infarction (AMI), although the mechanisms are not yet well delineated. Serum HGF levels and C-reactive protein (CRP) were measured in 22 patients with unstable angina pectoris (UAP) (15 males, 7 females; class IIb or IIIb of the Braunwald classification), 60 patients with AMI (37 males, 23 females; average time from the onset of symptoms to admission 4.6+/-0.7h, range, 0.5-12h), and 20 normal subjects. Immediate angioplasties were performed in 51 patients with AMI, and the time course of the HGF levels were measured in 31 patients among them. Heparin dramatically increased the HGF level and it declined to the normal range 18h after heparin injection. Blood samples were taken before heparin treatment, or at least 24h after. Serum HGF levels on admission was significantly increased in UAP (mean+/-SE: 0.30+/-0.03ng/ml, p<0.01), and AMI (0.27+/-0.02ng/ml, p<0.01) compared with the normal subjects (0.19+/-0.01 ng/ml). Even in the early stage (within 3 h of onset of symptoms to admission, average time was 1.8+/-0.1 h), serum HGF levels were already elevated (0.25+/-0.02 ng/ml, p<0.05). There was no significant difference between the HGF levels in UAP and AMI. Fifty-one of the 60 patients with AMI underwent immediate percutaneous transluminal coronary angioplasty and blood samples were obtained from 31 of them on days 7, 14, and 21 after MI. Serum HGF levels peaked on day 7 (0.34+/-0.04ng/ml, p<0.01) and there was a weak relationship between peak creatine kinase and serum HGF levels at that time. A statistically significant correlation was found between peak CRP and serum HGF levels on day 7 (r=0.62: p<0.001). Serum HGF levels decreased to nearly normal by day 21 (0.22+/-0.01 ng/ml). The study shows that serum HGF levels during the early stage of AMI increased significantly and peaked by day 7 after the onset, at which time there was a strong correlation with peak CRP levels. These data suggest that HGF production may be related to the inflammatory response in AMI.     

Fibrin formation and platelet aggregation in patients with acute myocardial infarction: effects of intravenous and subcutaneous low-dose heparin

Fibrinopeptide A (FPA) and beta thromboglobulin (BTG) were measured in 42 patients with acute myocardial infarction (AMI) allocated on admission to one of three groups: 14 patients received a heparin bolus injection of 5000 IU intravenously followed by a 2-hour intravenous infusion (830 IU/hr) (group 1), 14 patients received a heparin bolus of 5000 IU subcutaneously (group 2), and the remaining 14 patients received no anticoagulant treatment (group 3). In group 1 the initially elevated FPA level of 5.8 +/- 1.8 ng/ml dropped to 2.0 +/- 1.5 ng/ml 30 minutes after the intravenous heparin bolus injection of 5000 IU (p less than 0.001) and returned to normal (1.9 +/- 0.8 ng/ml) in 8 of 14 patients. The initially elevated BTG level of 64 +/- 21 ng/ml did not change significantly during intravenous heparin treatment, whereas there was a rapid but only transitory increase in platelet factor 4, (PF4) from 25 +/- 9 to 74 +/- 16 ng/ml (p less than 0.01) after the intravenous heparin bolus. In group 2 the initial FPA of 5.0 +/- 2.3 ng/ml was similarly elevated as in group 1 and dropped to 2.7 +/- 1.7 and 3.3 +/- 1.5 ng/ml 2 and 4 hours after 5000 IU subcutaneously (p less than 0.05), whereas 6 and 8 hours after subcutaneous heparin bolus the mean FPA levels were 4.2 +/- 1.7 and 5.5 +/- 2.0 ng/ml and no more significantly different from the initial FPA values. BTG and PF4 did not change significantly after the subcutaneous heparin bolus. In group 3 the initially elevated mean FPA level of 4.9 +/- 2.4 ng/ml did not change significantly during the first 8 hours after admission, whereas the FPA level 24 hours after admission was 8.4 +/- 3.9 ng/ml and higher than the initial value (p less than 0.01). We conclude that heparin may reduce the elevated FPA level in plasma found in patients with AMI; however, neither subcutaneous nor intravenous heparin in a dosage frequently used is sufficient to consistently normalize the elevated rate of fibrin formation found in these patients.     

Impaired forearm reactive hyperemia is related to late restenosis after coronary stenting

To investigate whether systemic endothelial function on forearm resistance vessels is related to angiographic restenosis after coronary stenting, 47 men who underwent elective coronary stenting were divided into 2 groups according to the presence (n = 20) or absence (n = 27) of in-stent restenosis 6 months after the procedure. Another 19 risk factor-matched men with normal coronary angiograms served as the control group. Forearm blood flow was assessed by venous occlusive plethysmography. Basal forearm blood flow was similar between restenosis, nonrestenosis, and control groups (2.63 +/- 0.19, 2.58 +/- 0.14, and 3.23 +/- 0.13 ml/100 ml forearm tissue per minute, respectively). In all 3 groups, forearm blood flow increased significantly during reactive hyperemia (5.75 +/- 0.7, 11. 32 +/- 1.23, and 14.52 +/- 1.36 ml/100 ml forearm tissue per minute, p <0.05, respectively) and remained unchanged after sublingual administration of nitroglycerin. The percentage change of forearm blood flow during reactive hyperemia was significantly lower in the restenosis group (117.3 +/- 18.3%) than in the nonrestenosis group (354.2 +/- 46.5%, p <0.01). This difference was still present after sublingual nitroglycerin (37.6 +/- 21.2% vs 226.4 +/- 40.5%, p <0. 01). In contrast, percentage change of hyperemic forearm blood flow was significantly lower in patients with angina (117.5 +/- 49.5%) than in those without angina (290.1 +/- 37.4%, p <0.05) at follow-up. In all patients, the angiographic loss index was correlated negatively to the percentage change of hyperemic forearm blood flow (r = -0.33, p <0.01) and positively to the percentage change of forearm vascular resistance during reactive hyperemia (r = 0.33, p <0.01). In patients with angiographic restenosis after coronary stenting, forearm reactive hyperemia was more impaired compared with those without angiographic restenosis. Systemic endothelial dysfunction might be either a marker or one of the confounding factors in the development of late restenosis after coronary stenting.     

择期冠脉支架置入术对急性心肌梗死患者血清细胞色素C水平的影响

目的：观察择期冠状动脉支架置入术对急性心肌梗死（AMI）患者血清细胞色素C（Cyt C）水平的影响。方法：入选AMI并于梗死后10-14d行冠状动脉支架置入术的患者30例作为AMI组;另选择经冠脉造影排除冠心病（CHD）的患者30例作为非CHD对照组,采用酶联免疫吸附（ELISA）方法测定患者在冠状动脉支架置入术前,术后48h、72h血清Cyt C浓度。结果：1.冠脉支架置入术前AMI组血清Cyt C水平显著高于非CHD对照组[（1.18±0.71）ng/ml比（0.25±0.03）ng/ml,P〈0.01];2.冠状动脉支架置入术后48h、72h血清Cyt C水平[（0.68±0.29）ng/ml、（0.66±0.25）ng/ml]显著低于冠状动脉支架置入术前（P〈0.01）。结论：择期冠脉支架置入术能改善急性心肌梗死患者心肌细胞的凋亡。     

Intracoronary serotonin release after high-pressure coronary stenting

It is known that platelet-derived serotonin at the site of coronary angioplasty induces an increase in coronary tone and plays a role in vasoconstriction after balloon angioplasty. The goal of the present investigation was to compare local release of serotonin with changes in coronary tone after coronary stenting and coronary angioplasty. Twenty patients with significant stenosis (> or =50% diameter narrowing) of the left anterior descending coronary artery were referred to traditional coronary angioplasty (10 patients; group 1) or high-pressure coronary stenting (10 patients; group 2). An additional 16 patients with similar angiographic characteristics were referred to the coronary angioplasty group (8 patients; group 1a) or stenting group (8 patients; group 2a) after pretreatment with ketanserin. Serotonin plasma levels in coronary sinus and coronary cross-sectional area distal to the site of dilatation were measured before and after bath revascularization procedures. In groups 1 and 1a, plasma serotonin levels in coronary sinus increased from basal values of 3.2+/-0.8 and 3.2+/-0.5 ng/ml to 29.5+/-13 and 25.6+/-9 ng/ml after ballooning (p <0.001 vs baseline). In groups 2 and 2a, plasma serotonin levels in coronary sinus increased from basal values of 3.5+/-0.3 and 3.5+/-0.7 ng/ml to 114.6+/-34 and 113+/-29 ng/ml after stenting (p <0.001 vs baseline and vs postangioplasty values in groups 1 and 1a). Coronary cross-sectional area distal to the site of dilatation significantly decreased after angioplasty in group 1 (from 4.33+/-0.4 to 3.32+/-0.3 mm2; p <0.001), and after stenting in group 2 (from 4.27+/-0.3 to 2.86+/-0.2 mm2; p <0.001 vs baseline, and p <0.02 vs values after coronary angioplasty in group 1). Pretreatment with ketanserin significantly reduced distal coronary vasoconstriction after angioplasty and stenting. It is concluded that the higher local serotonin release after coronary stenting may explain the more marked coronary constriction observed after prosthesis deployment with respect to traditional coronary angioplasty. Ketanserin is able to significantly attenuate the increase in distal coronary tone induced by both revascularization procedures.     

Association of patency of the infarct-related coronary artery with plasma levels of plasminogen activator inhibitor activity in acute myocardial infarction.

To examine the fibrinolytic capacity in patients with acute myocardial infarction (AMI), baseline levels of plasma plasminogen activator inhibitor (PAI) activity and tissue-type plasminogen activator (t-PA) antigen were measured in 47 patients with Q-wave AMI who underwent emergent coronary angiography 3.0 +/- 0.2 hours after the symptom onset. They received intracoronary injection of urokinase if their infarct-related arteries were occluded. They were classified into 3 groups according to the patency of the infarct-related artery before and after thrombolytic therapy: the patent group (13 patients), the recanalized group (23 patients) and the occluded group (11 patients). The mean level of plasma PAI activity (IU/ml) was higher in patients with AMI as a whole than in the control group (12.8 +/- 1.6 vs 5.4 +/- 0.5, p less than 0.01). The level was lower in the patent group (3.0 +/- 1.1) and higher in the recanalized (18.6 +/- 2.2) and occluded (10.8 +/- 2.5) groups than in the control group (each p less than 0.01). The level was lower in the occluded than in the recanalized group (p less than 0.01) and 62% of the patients in the occluded group had levels within range of the control group. The mean level of plasma t-PA antigen (ng/ml) was higher in patients with AMI as a whole than in the control group (10.3 +/- 0.8 vs 5.8 +/- 0.3, p less than 0.01). There was no difference in the level among the 3 groups with AMI.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pentraxin3 is a novel marker for stent-induced inflammation and neointimal thickening

Inflammation in the injured vessel wall plays an essential role in the mechanism of restenosis. Pentraxin3 (PTX3) is synthesized at the inflammatory site in response to primary inflammatory stimuli. To establish the clinical significance of plasma PTX3 levels in the pathophysiology of inflammation in the injured vessels, we serially measured the levels in 20 patients undergoing elective coronary stenting. Plasma PTX3 levels increased 15 min after coronary stenting, and reached a maximum at 24h in the coronary sinus (P<0.001 versus baseline) and peripheral blood (P<0.001 versus baseline). The transcardiac gradient of PTX3 at 15 min after PCI was higher in patients with than those without restenosis (0.40+/-0.64 versus -0.19+/-0.33 ng/ml, P=0.02). Furthermore, the increase in PTX3 at 24h was positively correlated with the increase in activated Mac-1 on the surface of neutrophils at 48 h (r=0.48, p<0.05) in the coronary sinus. Stepwise multiple regression analysis demonstrated that the relative increase in PTX3 at 24h was the most powerful predictor of late lumen loss (r=0.547, P=0.007). Coronary stenting enhanced circulating PTX3 levels in association with an inflammatory response. PTX3 may be a useful marker for evaluation of inflammatory reaction and neointimal thickening after vascular injury.     

Effect of glycoprotein IIb/IIIa receptor blockade with abciximab on clinical and angiographic restenosis rate after the placement of coronary stents following acute myocardial infarction

OBJECTIVES: In the Intracoronary Stenting and Antithrombotic Regimen-2 trial (ISAR-2), we sought to investigate the effect of abciximab on angiographic and clinical restenosis after stenting following acute myocardial infarction (AMI). We also intended to assess the impact of abciximab on clinical outcome in this setting. BACKGROUND: It is unclear whether abciximab reduces neointima formation after stenting. Such an effect may be particularly prominent in thrombus-containing lesions. METHODS: Patients undergoing stenting within 48 h after onset of AMI were randomly assigned to receive either standard-dose heparin or abciximab plus reduced-dose heparin. Of 401 patients randomized, 366 without 30-day adverse events were eligible for six-month angiographic follow-up. Scheduled angiography was performed in 80% of these patients. RESULTS: By 30 days, the composite clinical end point of death, reinfarction, and target lesion revascularization (TLR) was reached in 5.0% of the abciximab group and in 10.5% of the control group (p = 0.038). At one year, absolute reduction in the composite clinical end point by abciximab was still 5.7% but had lost its statistical significance. Our primary end point, late lumen loss, was 1.26+/-0.85 mm with abciximab and 1.21+/-0.74 mm with standard heparin (p = 0.61), and binary angiographic restenosis rates were 31.1% and 30.6%, respectively (p = 0.92). CONCLUSIONS: In patients undergoing stenting following AMI, abciximab exerted beneficial effects by substantially reducing the 30-day rate of major adverse cardiac events. During one-year follow-up, there was no additional benefit from a reduction in TLR nor did abciximab reduce angiographic restenosis.     

Increased circulating platelet-derived microparticles are associated with stent-induced vascular inflammation

Inflammation as well as platelet activation at the site of local vessel-wall injury plays an essential role in the mechanism of restenosis after Percutaneous coronary intervention (PCI). Platelet-derived microparticles (PDMPs) released from activated platelets are thought to play a role in the inflammatory process, possibly interacting with leukocyte integrin Mac-1. We serially measured circulating PDMPs, high-sensitive C-reactive protein (hs-CRP) and activated Mac-1 on the surface of neutrophils in 61 patients undergoing coronary stenting. PDMPs, hs-CRP and Mac-1 increased after coronary stenting in a time-dependent manner with the maximum response at 48 h in coronary sinus blood (PDMPs: 10.3+/-8.9-32.8+/-13.8 U/ml; P<0.001, hs-CRP: 0.27+/-0.23-1.46+/-0.99 mg/dl; P<0.001, activated Mac-1, 134+/-19% relative increase, P<0.001). PDMPs were correlated with hs-CRP (R=0.58, P<0.001) and the relative increase in Mac-1 (R=0.69, P<0.001) 48 h after coronary stenting. Multiple regression analysis showed that each of PDMPs (R=0.40, P<0.05), hs-CRP (R=0.33, P<0.05) and Mac-1 (R=0.48, P<0.01) was an independent predictor of the late lumen loss. Coronary stenting enhanced circulating PDMPs in association with an inflammatory response in the injured vessel wall. PDMPs may be a useful marker for evaluation of stent-induced inflammatory status and a powerful predictor of restenosis equivalent to activated Mac-1.     

Increased plasma fibrinolysis and tissue-type plasminogen activator/tissue-type plasminogen activator inhibitor ratios after ethanol withdrawal in chronic alcoholics.

The effects of alcohol withdrawal on fibrinolysis were studied in 10 middle-aged male chronic alcoholics institutionalized for withdrawal therapy. All patients were sampled on admission [day 1 (D1)] and 21 days after alcohol withdrawal [day 22 (D22)]. The overall plasma fibrinolytic capacity (OFC) was assayed by measuring the ability of patient plasma to generate D-dimers from a standardized fibrin clot, and tissue-type plasminogen activator (t-PA) and t-PA inhibitor (PAI-1) levels were assayed together with serum cholesterol, triglyceride and cholesterol fractions. At D22, the OFC significantly increased in seven patients [D1 = 10 +/- 0.7 microg/h (mean +/- SD), D22 = 17 +/- 7.4 microg/h; P < 0.01], while t-PA and PAI-1 levels decreased in all patients but two (t-PA: D1 = 16.6 +/- 5 ng/ml, D22 = 10.2 +/- 3.8 ng/ml; P < 0.001; and PAI-1: D1 = 46 +/- 39 ng/ml, D22 = 21 +/- 28 ng/ml; P < 0.01). This study clearly demonstrates an increase in overall fibrinolytic activity after alcohol withdrawal, which is mainly due to a decrease in PAI-1 levels. These changes induced by alcohol abstinence might provide clear benefit by reducing the risk of thromboembolic events and particularly of stroke associated with elevated PAI-1 levels described in heavy drinkers.     

Pre-procedural plasma levels of C-reactive protein and interleukin-6 do not predict late coronary angiographic restenosis after elective stenting.

AIMS: Inflammatory markers may serve as an important prognostic predictor in patients with coronary heart diseases. In patients undergoing coronary interventions, it has been shown that baseline C-reactive protein (CRP) could predict late clinical restenosis. Only a few small studies have examined the possible relationship with angiographic restenosis. In patients with stable angina pectoris,we examined whether baseline CRP and IL-6 predict late coronary angiographic restenosis after stenting. METHODS AND RESULTS: Pre-procedural plasma levels of CRP and IL-6 were measured in 216 patients with stable angina pectoris undergoing elective coronary stenting. Angiographic follow-up was performed in all patients at 6 months. Baseline CRP levels were 6.15 +/- 0.78 mg/L versus 5.24 +/- 1.17 mg/L in the patent and restenosis groups, respectively (P=0.64). IL-6 levels were 0.46 +/- 0.03 ng/L versus 0.40 +/- 0.07 ng/L in the patent and restenosis groups, respectively (P=0.50). CRP levels were obtained again at the time of angiographic follow-up and were found to be similar in both groups (2.89 +/- 0.29 mg/L versus 2.61 +/- 0.63 mg/L, P=0.72). Moreover, in a sub-group of 43 patients, serial blood samples were obtained at several time points after the procedure up to 6 months. Both CRP and IL-6 plasma levels increased significantly in response to the procedure. CRP levels peaked at 3 days (11.27 +/- 1.53 mg/L versus 4.26 +/- 0.72 mg/L at baseline, P<0.0001). IL-6 levels reached maximum values after 24 h (1.08 +/- 0.14 ng/L versus 0.53 +/- 0.08 ng/L at baseline, P<0.0001). However, in this sub-group of patients, neither peak CRP nor IL-6 levels were found to predict late angiographic restenosis. CONCLUSIONS: Coronary stenting is associated with transient increases in both CRP and IL-6 levels. However, pre-procedural CRP and IL-6 levels do not predict late coronary angiographic restenosis.     

Effect of elevated homocysteine levels on clinical restenosis following percutaneous coronary intervention

Since hyperhomocysteinemia confers a prothrombotic effect and promotes proliferation of smooth muscle cells in response to vascular injury, it might be implicated in the pathogenesis of restenosis after percutaneous coronary intervention (PCI). Our study comprised 55 patients who underwent successful PCI in the acute myocardial infarction (AMI) course. Homocysteine levels were determined within 24 h of admission. During a 1-year follow-up, 16 patients (31%) underwent repeated coronary angiography for recurrent angina or re-infarction, which demonstrated re-narrowing of > or =50% at the qualifying PCI site (clinical restenosis). Irrespective of stent deployment, clinical restenosis was not associated with higher homocysteine levels (12 +/- 7 vs. 14 +/- 11 micromol/l, p = 0.77). There was no correlation between homocysteine levels and time to restenosis (r(2) = 0.06, p = 0.35). In conclusion, elevated homocysteine levels do not predict a higher incidence of restenosis after PCI.     

Predictors of recurrent restenosis after coronary stenting: an analysis of 197 patients

One of the major limitations in coronary stenting is in-stent restenosis. This study was aimed to identify clinical, angiographic, and procedural factors that may be related to recurrent in-stent restenosis. We analyzed consecutive 197 patients who underwent coronary stenting. Follow-up angiography was available in 170 patients and repeat balloon angioplasty was performed for in-stent restenosis. These patients were subdivided into 3 groups: group A consisted of 100 patients that were never restenosed, group B had 49 patients restenosed once, and in group C were 21 patients restenosed more than twice. Group C was more often female (48%) and included diabetes mellitus patients (52%). Lesion location, reference vessel size and diameter stenosis were similar for all groups. However, the incidence of calcified lesions tended to be higher (50% vs. 29%; p = 0.07), and lesion length was longer in group C than in group A (11.9+/- 5.4 mm vs. 9.0+/- 3.9 mm; p < 0.01). Diameter stenosis after predilation as well as after stenting was significantly higher in group C than in group A (50+/- 10% vs 39+/- 10%; p < 0.01, 32+/- 8% vs. 19+/- 10%; p < 0.01). The incidence of diffuse type of in-stent restenosis was significantly higher in group C than in group B (62% vs. 14%; p < 0.01). Multivariate logistic regression analysis identified diameter stenosis after stenting (p = 0.0022), female (p = 0.0135), and diameter stenosis after predilatation (p = 0.0233) as the significant correlate of recurrent in-stent restenosis. In conclusion, the major recurrent in-stent restenosis predictors identified included female gender, final diameter stenosis, and diameter stenosis after predilatation.     

Increased expression of plasminogen activator inhibitor-1 by mediators of the acute phase response: a potential progenitor of vasculopathy in hypertensives.

Hypertension is an important risk factor for coronary atherosclerosis, which is accelerated by inflammation and diminished fibrinolysis. We have previously shown that levels of plasminogen activator inhibitor-1 (PAI-1), the major physiologic inhibitor of fibrinolysis, are increased with atherogenic metabolic derangement. Because the liver is one of the major sources of circulating PAI-1, we here examined the effects of two proinflammatory cytokines, interleukin (IL)-1beta, and IL-6, on PAI-1 production in a human hepatoma cell line, HepG2. IL-1beta (1 ng/ml) and IL-6 (1 ng/ml) increased the accumulation of PAI-1 in the conditioned media over 24 h (IL-1beta: 2.1 +/- 0.2 (mean +/- SD) fold over the control; IL-6:1.4 +/- 0.2 fold; Western blot, p < 0.05). The increase in PAI-1 protein accumulation correlated with the increased expression of PAI-1 mRNA (Northern blot). An HMG-CoA reductase inhibitor (mevastatin, 10 micromol/l) attenuated the PAI-1 production induced by IL-1beta and IL-6. The plasma PAI-1 activity level was higher in hypertensives than in normotensives (10.0 +/- 9.8 AU/ml vs. 6.2 +/- 4.5 AU/ml, p < 0.05). The plasma PAI-1 antigen level was also higher in hypertensives than in normotensives (30.9 +/- 22.4 ng/ml vs. 24.4 +/- 13.3 ng/ml, p < 0.05). Thus, 1) IL-1beta and IL-6 can increase PAI-1 production in hepatic cells and 2) mevastatin may exert anti-thrombotic effects by decreasing the PAI-1 protein production induced by these proinflammatory cytokines. These results provide further insights into how inflammation is involved in the atherothrombotic complications observed in hypertensives, which may be ameliorated by HMG-CoA reductase inhibitors.     

Predictors of sub-acute stent thrombosis in acute myocardial infarction patients following primary coronary stenting with bare metal stent.

BACKGROUND: The aim of the present study was to identify the relationship between sub-acute stent thrombosis (SAT) and acute-phase inflammatory reactants, such as high-sensitivity C-reactive protein (hs-CRP) and serum amyloid-A protein (SAA), in patients with acute myocardial infarction (AMI) successfully treated with primary coronary stenting. METHODS AND RESULTS: The 381 consecutive AMI subjects were reperfused by primary coronary stenting within 24 h of onset. SAT was confirmed angiographically in 10 patients (2.6%). There were no significant differences between the patients with or without SAT in terms of patient characteristics, Killip classification on admission, or stent diameter, nor were there significant differences between the 2 groups in terms of left ventricular function soon after stenting (left ventricular ejection fraction) or end-diastolic volume index. The plasma levels of both hs-CRP and SAA were significantly higher in the SAT patients than in the others (hs-CRP: 6.7+/-6.7 mg/dl vs 3.3+/-3.8 mg/dl, p=0.007; SAA: 699+/-812 mug/dl vs 208+/-273 mug/dl, p<0.0001). Multivariate analysis identified SAA as an independent predictor of SAT (risk ratio: 4.9, 95% confidence interval: 1.7-14.9, p<0.05). CONCLUSION: In patients with AMI who are treated with primary coronary stenting, inflammation may be closely related to SAT, for which SAA is a useful predictor.