Albert Schömig

The clinical benefit of coronary-artery stenting performed in conjunction with coronary angioplasty is limited by the risk of thrombotic occlusion of the stent as well as hemorrhagic and vascular complications of intensive anticoagulation. We compared antiplatelet therapy with conventional anticoagulant therapy with respect to clinical outcomes 30 days after coronary-artery stenting.

Whether the two drug-eluting stents approved by the US Food and Drug Administration-a sirolimus-eluting stent and a paclitaxel-eluting stent-are associated with increased risks of death, myocardial infarction, or stent thrombosis compared with bare-metal stents is uncertain. Our aim was to compare the safety and effectiveness of these stents.We searched relevant sources from inception to March, 2007, and contacted investigators and manufacturers to identify randomised controlled trials in patients with coronary artery disease that compared drug-eluting with bare-metal stents, or that compared sirolimus-eluting stents head-to-head with paclitaxel-eluting stents. Safety outcomes included mortality, myocardial infarction, and definite stent thrombosis; the effectiveness outcome was target lesion revascularisation. We included 38 trials (18,023 patients) with a follow-up of up to 4 years. Trialists and manufacturers provided additional data on clinical outcomes for 29 trials. We did a network meta-analysis with a mixed-treatment comparison method to combine direct within-trial comparisons between stents with indirect evidence from other trials while maintaining randomisation.Mortality was similar in the three groups: hazard ratios (HR) were 1.00 (95% credibility interval 0.82-1.25) for sirolimus-eluting versus bare-metal stents, 1.03 (0.84-1.22) for paclitaxel-eluting versus bare-metal stents, and 0.96 (0.83-1.24) for sirolimus-eluting versus paclitaxel-eluting stents. Sirolimus-eluting stents were associated with the lowest risk of myocardial infarction (HR 0.81, 95% credibility interval 0.66-0.97, p=0.030 vs bare-metal stents; 0.83, 0.71-1.00, p=0.045 vs paclitaxel-eluting stents). There were no significant differences in the risk of definite stent thrombosis (0 days to 4 years). However, the risk of late definite stent thrombosis (>30 days) was increased with paclitaxel-eluting stents (HR 2.11, 95% credibility interval 1.19-4.23, p=0.017 vs bare-metal stents; 1.85, 1.02-3.85, p=0.041 vs sirolimus-eluting stents). The reduction in target lesion revascularisation seen with drug-eluting stents compared with bare-metal stents was more pronounced with sirolimus-eluting stents than with paclitaxel-eluting stents (0.70, 0.56-0.84; p=0.0021).The risks of mortality associated with drug-eluting and bare-metal stents are similar. Sirolimus-eluting stents seem to be clinically better than bare-metal and paclitaxel-eluting stents.

Long-QT syndromes are heritable diseases associated with prolongation of the QT interval on an electrocardiogram and a high risk of sudden cardiac death due to ventricular tachyarrhythmia. In long-QT syndrome type 1, mutations occur in the KCNQ1 gene, which encodes the repolarizing potassium channel mediating the delayed rectifier IKs current.

The long-term effects of treatment with sirolimus-eluting stents, as compared with bare-metal stents, have not been established.We performed an analysis of individual data on 4958 patients enrolled in 14 randomized trials comparing sirolimus-eluting stents with bare-metal stents (mean follow-up interval, 12.1 to 58.9 months). The primary end point was death from any cause. Other outcomes were stent thrombosis, the composite end point of death or myocardial infarction, and the composite of death, myocardial infarction, or reintervention.The overall risk of death (hazard ratio, 1.03; 95% confidence interval [CI], 0.80 to 1.30) and the combined risk of death or myocardial infarction (hazard ratio, 0.97; 95% CI, 0.81 to 1.16) were not significantly different for patients receiving sirolimus-eluting stents versus bare-metal stents. There was a significant reduction in the combined risk of death, myocardial infarction, or reintervention (hazard ratio, 0.43; 95% CI, 0.34 to 0.54) associated with the use of sirolimus-eluting stents. There was no significant difference in the overall risk of stent thrombosis with sirolimus-eluting stents versus bare-metal stents (hazard ratio, 1.09; 95% CI, 0.64 to 1.86). However, there was evidence of a slight increase in the risk of stent thrombosis associated with sirolimus-eluting stents after the first year.The use of sirolimus-eluting stents does not have a significant effect on overall long-term survival and survival free of myocardial infarction, as compared with bare-metal stents. There is a sustained reduction in the need for reintervention after the use of sirolimus-eluting stents. The risk of stent thrombosis is at least as great as that seen with bare-metal stents.

The aim of this study was to test whether the left ventricular assist device (LVAD) Impella LP2.5 (Abiomed Europe GmbH, Aachen, Germany) provides superior hemodynamic support compared with the intra-aortic balloon pump (IABP).Cardiogenic shock caused by left ventricular failure is associated with high mortality in patients with acute myocardial infarction (AMI). An LVAD may help to bridge patients to recovery from left ventricular failure.In a prospective, randomized study, 26 patients with cardiogenic shock were studied. The primary end point was the change of the cardiac index (CI) from baseline to 30 min after implantation. Secondary end points included lactic acidosis, hemolysis, and mortality after 30 days.In 25 patients the allocated device (n = 13 IABP, n = 12 Impella LP2.5) could be safely placed. One patient died before implantation. The CI after 30 min of support was significantly increased in patients with the Impella LP2.5 compared with patients with IABP (Impella: DeltaCI = 0.49 +/- 0.46 l/min/m(2); IABP: DeltaCI = 0.11 +/- 0.31 l/min/m(2); p = 0.02). Overall 30-day mortality was 46% in both groups.In patients presenting with cardiogenic shock caused by AMI, the use of a percutaneously placed LVAD (Impella LP 2.5) is feasible and safe, and provides superior hemodynamic support compared with standard treatment using an intra-aortic balloon pump. (Efficacy Study of LV Assist Device to Treat Patients With Cardiogenic Shock [ISAR-SHOCK]; NCT00417378).

Increased thrombogenicity and smooth muscle cell proliferative response induced by the metal struts compromise the advantages of coronary stenting. The objective of this randomized, multicenter study was to assess whether a reduced strut thickness of coronary stents is associated with improved follow-up angiographic and clinical results.A total of 651 patients with coronary lesions situated in native vessels >2.8 mm in diameter were randomly assigned to receive 1 of 2 commercially available stents of comparable design but different thickness: 326 patients to the thin-strut stent (strut thickness of 50 microm) and 325 patients to the thick-strut stent (strut thickness of 140 microm). The primary end point was the angiographic restenosis (>/=50% diameter stenosis at follow-up angiography). Secondary end points were the incidence of reinterventions due to restenosis-induced ischemia and the combined rate of death and myocardial infarctions at 1 year. The incidence of angiographic restenosis was 15.0% in the thin-strut group and 25.8% in the thick-strut group (relative risk, 0.58; 95% CI, 0.39 to 0.87; P=0.003). Clinical restenosis was also significantly reduced, with a reintervention rate of 8.6% among thin-strut patients and 13.8% among thick-strut patients (relative risk, 0.62; 95% CI, 0.39 to 0.99; P=0.03). No difference was observed in the combined 1-year rate of death and myocardial infarction.The use of a thinner-strut device is associated with a significant reduction of angiographic and clinical restenosis after coronary artery stenting. These findings may have relevant implications for the currently most widely used percutaneous coronary intervention.

Background— Multislice computed tomography angiography (CTA) is a promising technology for imaging patients with suspected coronary artery disease. Compared with 16-slice CTA, the improved spatial and temporal resolution of 64-slice CTA (0.6- versus 1.0-mm slice thickness and 330- versus 420-ms gantry rotation time) is associated with an increase in radiation dose. The objective of this retrospective investigation was to compare the estimated dose received during 16- and 64-slice CTA in daily practice and to investigate the impact of different scan protocols on dose and image quality. Methods and Results— Radiation dose was estimated for 1035 patients undergoing coronary CTA. Scanning algorithms with and without an ECG-dependent dose modulation and with a reduced tube voltage were investigated on dose estimates and image quality. In the entire patient cohort, radiation dose estimates were 6.4±1.9 and 11.0±4.1 mSv for 16- and 64-slice CTA, respectively ( P <0.01). The reduction in radiation dose estimates ranged between 37% and 40% and between 53% and 64% with the use of ECG-dependent dose modulation and with the combined use of the dose modulation and a reduced tube voltage, respectively. The reduction in dose estimates was not associated with a reduction in diagnostic image quality as assessed by the signal-to-noise ratio and by the frequency of coronary segments with diagnostic image quality. Conclusions— The increase in spatial and temporal resolution with 64-slice CTA is associated with an increased radiation dose for coronary CTA. Dose-saving algorithms are very effective in reducing radiation exposure and should be used whenever possible.

Objectives. The objective of this study was to identify clinical, lesional and procedural factors that can predict restenosis after coronary stent placement. Background. Coronary stent placement reduces the restenosis rate compared with that after percutaneous transluminal coronary angioplasty (PTCA). However, restenosis remains an unresolved issue, and identification of its predictive factors may allow further insight into the underlying process. Methods. All patients with successful coronary stent placement were eligible for this study unless they had had a major adverse cardiac event during the 1st 30 days after the procedure. Of the 1,349 eligible patients (1,753 lesions), follow-up angiography at 6 months was performed in 80.4% (1,084 patients, 1,399 lesions). Demographic, clinical, lesional and procedural data were prospectively recorded and analyzed for any predictive power for the occurrence of late restenosis after stenting. Restenosis was evaluated by using three outcomes at follow-up: binary restenosis as a diameter stenosis ≥50%, late lumen loss as lumen diameter reduction and target lesion revascularization (TLR) as any repeat PTCA or coronary artery bypass surgery involving the stented lesion. Results. Multivariate analysis demonstrated that diabetes mellitus, placement of multiple stents and minimal lumen diameter (MLD) immediately after stenting were the strongest predictors of restenosis. Diabetes increased the risk of binary restenosis with an odds ratio (OR) [95% confidence interval] of 1.86 [1.56 to 2.16] and the risk of TLR with an OR of 1.45 [1.11 to 1.80]. Multiple stents increased the risk of binary restenosis with an OR of 1.81 [1.55 to 2.06] and that of TLR with an OR of 1.94 [1.66 to 2.22]. An MLD <3 mm at the end of the procedure augmented the risk of binary restenosis with an OR of 1.81 [1.55 to 2.06] and that of TLR with an OR of 2.05 [1.77 to 2.34]. Classification and regression tree analysis demonstrated that the incidence of restenosis may be as low as 16% for a lesion without any of these risk factors and as high as 59% for a lesion with a combination of these risk factors. Conclusions. Diabetes, multiple stents and smaller final MLD are strong predictors of restenosis after coronary stent placement. Achieving an optimal result with a minimal number of stents during the procedure may significantly reduce this risk even in patients with adverse clinical characteristics such as diabetes.

For patients undergoing percutaneous coronary intervention, the administration of a clopidogrel loading dose ranging from 300 to 600 mg is currently recommended. It is unknown, though, whether loading doses higher than 600 mg exert additional suppression of platelet function.Sixty patients with suspected or documented coronary artery disease admitted to our hospital for coronary angiography were included in this trial. They were allocated to 1 of 3 clopidogrel loading doses (300, 600, or 900 mg) in a double-blinded, randomized manner. Plasma concentrations of the active thiol metabolite, unchanged clopidogrel, and the inactive carboxyl metabolite of clopidogrel were determined before and serially after drug administration. Optical aggregometry was performed before and 4 hours after administration of clopidogrel. Loading with 600 mg resulted in higher plasma concentrations of the active metabolite, clopidogrel, and the carboxyl metabolite compared with loading with 300 mg (P< or =0.03) and lower values for adenosine diphosphate-induced (5 and 20 micromol/L) platelet aggregation 4 hours after drug administration (P=0.01 and 0.004). With administration of 900 mg, no further increase in plasma concentrations of active metabolite and clopidogrel (P> or =0.38) and no further suppression of adenosine diphosphate-induced (5 and 20 micromol/L) platelet aggregation 4 hours after drug administration was achieved when compared with administration of 600 mg (P=0.59 and 0.39).Single doses of clopidogrel higher than 600 mg are not associated with an additional significant suppression of platelet function because of limited clopidogrel absorption.

The aim of this prospective trial was to assess whether platelet reactivity to clopidogrel assessed with multiple electrode platelet aggregometry (MEA) correlates with the risk of early drug-eluting stent thrombosis (ST).Studies using light transmission aggregometry (LTA) have shown that insufficient suppression of platelet reactivity to adenosine diphosphate (ADP) after clopidogrel treatment is associated with an increased risk of adverse cardiovascular events after percutaneous coronary intervention (PCI). However, LTA is time- and labor-intensive and inconvenient for the routine. A point-of-care assay with similar predictive power would be of great value.Between February 2007 and April 2008, a total of 1,608 consecutive patients with coronary artery disease and planned drug-eluting stent implantation were enrolled. Before PCI, all patients received 600 mg clopidogrel. Blood was obtained directly before PCI. The ADP-induced platelet aggregation was assessed in whole blood with MEA on a Multiplate analyzer (Dynabyte, Munich, Germany). The primary end point was definite ST at 30 days.The upper quintile of patients according to MEA measurements (n = 323) was defined as clopidogrel low responders. Compared with normal responders (n = 1,285), low responders had a significantly higher risk of definite ST within 30 days (2.2% vs. 0.2%; odds ratio [OR]: 9.4; 95% confidence interval [CI]: 3.1 to 28.4; p < 0.0001). Mortality rates were 1.2% in low versus 0.4% in normal responders (OR: 3.2; 95% CI: 0.9 to 11.1; p = 0.07). The composite of death or ST was higher in low versus normal responders (3.1% vs. 0.6%; OR: 5.1; 95% CI: 2.2 to 11.6; p < 0.001).Low response to clopidogrel assessed with MEA is significantly associated with an increased risk of ST. Further studies are warranted to evaluate the ability of MEA to guide antiplatelet therapy in patients undergoing PCI.

In patients with de novo coronary lesions, drug-eluting stents have drastically reduced restenosis risk compared with bare metal stents and conventional balloon angioplasty. It is less clear whether drug-eluting stents are superior to conventional balloon angioplasty for the treatment of patients with in-stent restenosis.To assess if drug-eluting stents are a more effective treatment of in-stent restenosis than conventional balloon angioplasty, and to assess the relative merits of 2 drug-eluting stents, a sirolimus-eluting stent and a paclitaxel-eluting stent.Randomized, open-label, active-controlled trial conducted among 300 patients with angiographically significant in-stent restenosis in 2 tertiary German centers from June 1, 2003, to October 20, 2003.After pretreatment with 600 mg of clopidogrel for at least 2 hours before intervention, all patients were randomly assigned to 1 of 3 treatment groups: sirolimus stent, paclitaxel stent, or balloon angioplasty (100 patients in each group).Primary end point: angiographic restenosis (diameter stenosis > or =50%) at 6-month follow-up angiography based on "in-segment" analysis. Primary analysis was comparison between stent groups and balloon angioplasty groups; a secondary analysis compared sirolimus and paclitaxel stents.Follow-up angiography was performed in 275 (92%) of 300 patients. The incidence of angiographic restenosis was 44.6% (41/92) in the balloon angioplasty group, 14.3% (13/91) in the sirolimus stent group (P<.001 vs balloon angioplasty), and 21.7% (20/92) in the paclitaxel stent group (P = .001 vs balloon angioplasty). When compared with balloon angioplasty, receiving a sirolimus stent had a relative risk (RR) of angiographic restenosis of 0.32 (95% confidence interval [CI], 0.18-0.56); a paclitaxel stent had an RR of 0.49 (95% CI, 0.31-0.76). The incidence of target vessel revascularization was 33.0% (33/100) in the balloon angioplasty group, 8.0% (8/100) in the sirolimus stent group (P<.001 vs balloon angioplasty), and 19.0% (19/100) in the paclitaxel stent group (P = .02 vs balloon angioplasty). The secondary analysis showed a trend toward a lower rate of angiographic restenosis (P = .19) and a significantly lower rate of target vessel revascularization (P = .02) among sirolimus stent patients compared with paclitaxel stent patients.In patients with in-stent restenosis, a strategy based on sirolimus- or paclitaxel-eluting stents is superior to conventional balloon angioplasty for the prevention of recurrent restenosis. Sirolimus-eluting stents may be superior to paclitaxel-eluting stents for treatment of this disorder.

Whether the glycoprotein IIb/IIIa inhibitor abciximab is beneficial in patients undergoing elective percutaneous coronary intervention after pretreatment with clopidogrel is unknown.We enrolled 2159 patients with coronary artery disease who underwent a percutaneous coronary intervention: 1079 patients were randomly assigned in a double-blind manner to receive abciximab and 1080 patients to receive placebo. All patients were pretreated with a 600-mg dose of clopidogrel at least two hours before the procedure. The primary end point of the trial was the composite of death, myocardial infarction, and urgent target-vessel revascularization within 30 days after randomization.The incidence of the primary end point was 4 percent (45 patients) in the abciximab group, as compared with 4 percent (43 patients) in the placebo group (relative risk, 1.05; 95 percent confidence interval, 0.69 to 1.59; P=0.82). Most adverse events were myocardial infarctions: the incidence was 4 percent (40 patients) in the abciximab group and 4 percent (41 patients) in the placebo group (P=0.91). Twelve patients (1 percent) in the abciximab group and eight patients (1 percent) in the placebo group had major bleeding complications (P=0.37). Profound thrombocytopenia occurred in 10 patients (1 percent) in the abciximab group but in none in the placebo group (P=0.002).Our data suggest that in patients at low-to-intermediate risk who undergo elective percutaneous coronary intervention after pretreatment with a high loading dose of clopidogrel, abciximab is associated with no clinically measurable benefit within the first 30 days.

Decreased vagal activity after myocardial infarction results in reduced heart-rate variability and increased risk of death. To distinguish between vagal and sympathetic factors that affect heart-rate variability, we used a signal-processing algorithm to separately characterise deceleration and acceleration of heart rate. We postulated that diminished deceleration-related modulation of heart rate is an important prognostic marker. Our prospective hypotheses were that deceleration capacity is a better predictor of risk than left-ventricular ejection fraction (LVEF) and standard deviation of normal-to-normal intervals (SDNN).We quantified heart rate deceleration capacity by assessing 24-h Holter recordings from a post-infarction cohort in Munich (n=1455). We blindly validated the prognostic power of deceleration capacity in post-infarction populations in London, UK (n=656), and Oulu, Finland (n=600). We tested our hypotheses by assessment of the area under the receiver-operator characteristics curve (AUC).During a median follow-up of 24 months, 70 people died in the Munich cohort and 66 in the London cohort. The Oulu cohort was followed-up for 38 months and 77 people died. In the London cohort, mean AUC of deceleration capacity was 0.80 (SD 0.03) compared with 0.67 (0.04) for LVEF and 0.69 (0.04) for SDNN. In the Oulu cohort, mean AUC of deceleration capacity was 0.74 (0.03) compared with 0.60 (0.04) for LVEF and 0.64 (0.03) for SDNN (p<0.0001 for all comparisons). Stratification by dichotomised deceleration capacity was especially powerful in patients with preserved LVEF (p<0.0001 in all cohorts).Impaired heart rate deceleration capacity is a powerful predictor of mortality after myocardial infarction and is more accurate than LVEF and the conventional measures of heart-rate variability.

The cytochrome P450 (CYP) 2C19 isoenzyme plays an important role in clopidogrel metabolization. A recently explored CYP2C19*17 allelic variant has been linked to increased transcriptional activity, resulting in extensive metabolization of CYP2C19 substrates, which may lead to an enhanced platelet response to clopidogrel treatment. The aim of this study was to assess the impact of CYP2C19*17 on ADP-induced platelet aggregation, the risk of bleeding, and stent thrombosis in clopidogrel-treated patients undergoing percutaneous coronary intervention.The study population included 1524 patients undergoing percutaneous coronary intervention after pretreatment with 600 mg clopidogrel. Genotypes were determined with a TaqMan assay. ADP-induced platelet aggregation was assessed on a Multiplate analyzer. The primary clinical safety end point was the 30-day incidence of bleeding defined according to Thrombolysis in Myocardial Infarction criteria, and the primary clinical efficacy end point was the 30-day incidence of stent thrombosis. For both heterozygous (*wt/*17; n=546) and homozygous (*17/*17; n=76) allele carriers, significantly lower ADP-induced platelet aggregation values were found compared with wild-type homozygotes (*wt/*wt; n=902; P=0.039 and P=0.008, respectively). CYP2C19*17 allele carriage was significantly associated with an increased risk of bleeding; the highest risk was observed for CYP2C19*17 homozygous patients (P=0.01, chi(2) test for trend). Multivariate analysis confirmed the independent association of CYP2C19*17 allele carriage with platelet aggregation values (P<0.001) and the occurrence of bleeding (P=0.006). No significant influence of CYP2C19*17 on the occurrence of stent thrombosis was found (P=0.79).CYP2C19*17 carrier status is significantly associated with enhanced response to clopidogrel and an increased risk of bleeding.

Background —Apart from its established effects on vessel patency after percutaneous coronary revascularization, glycoprotein IIb/IIIa receptor blockade by abciximab may improve myocardial perfusion by inhibition of the interaction of platelets and platelet aggregates with the microvasculature. We investigated the effect of abciximab with stent placement in acute myocardial infarction. Methods and Results —In a prospective randomized trial, patients undergoing stenting in acute myocardial infarction within 48 hours after onset of symptoms were randomly assigned to receive either standard-dose heparin or abciximab plus low-dose heparin. Immediately after the procedure and at 14-day angiographic follow-up, we assessed flow velocity in the recanalized vessel with the Doppler wire and regional wall motion by the centerline method. End points were changes in papaverine-induced peak flow velocities and in wall motion indices. We assigned 98 patients to standard heparin and 102 to abciximab. We obtained 152 paired flow measurements and 151 paired left ventricular function studies. Residual stenoses of the treated lesions did not differ between the 2 groups. Improvement of peak flow velocity (mean [95% CI]: 18.1 cm/s [13.6 to 22.6 cm/s], n=80, versus 10.4 cm/s [5.4 to 15.4 cm/s], n=72, P =0.024) and wall motion index (0.44 SD/chord [0.29 to 0.59 SD/chord], n=79 versus 0.15 SD/chord [0.00 to 0.30 SD/chord], n=72, P =0.007) was significantly greater in patients assigned to abciximab than in those on heparin alone. At follow-up, the abciximab group had a higher global left ventricular ejection fraction than the heparin group (62% [59% to 65%] versus 56% [53% to 59%], P =0.003). Conclusions —Abciximab had important effects beyond the maintenance of large-vessel patency. It improved the recovery of microvascular perfusion and concomitantly enhanced the recovery of contractile function in the area at risk.

Drug-eluting stents are highly effective in reducing the rate of in-stent restenosis. It is not known whether there are differences in the effectiveness of currently approved drug-eluting stents in the high-risk subgroup of patients with diabetes mellitus.We enrolled 250 patients with diabetes and coronary artery disease: 125 were randomly assigned to receive paclitaxel-eluting stents, and 125 to receive sirolimus-eluting stents. The primary end point was in-segment late luminal loss. Secondary end points were angiographic restenosis (defined as in-segment stenosis of at least 50 percent at follow-up angiography) and the need for revascularization of the target lesion during a nine-month follow-up period. The study was designed to show noninferiority of the paclitaxel stent as compared with the sirolimus stent, defined as a difference in the extent of in-segment late luminal loss of no more than 0.16 mm.The extent of in-segment late luminal loss was 0.24 mm (95 percent confidence interval, 0.09 to 0.39) greater in the paclitaxel-stent group than in the sirolimus-stent group (P=0.002). In-segment restenosis was identified on follow-up angiography in 16.5 percent of the patients in the paclitaxel-stent group and 6.9 percent of the patients in the sirolimus-stent group (P=0.03). Target-lesion revascularization was performed in 12.0 percent of the patients in the paclitaxel-stent group and 6.4 percent of the patients in the sirolimus-stent group (P=0.13).In patients with diabetes mellitus and coronary artery disease, use of the sirolimus-eluting stent is associated with a decrease in the extent of late luminal loss, as compared with use of the paclitaxel-eluting stent, suggesting a reduced risk of restenosis.

The objectives of this study were to analyze the clinical and angiographic outcome of diabetic patients with successful coronary stent placement and to compare these results with those achieved after stenting in nondiabetic patients.The outcome of diabetic patients treated with stent placement due to coronary artery disease has not been assessed comprehensively.This study analyzes a consecutive series of patients with successful stent placement comprising 715 patients with diabetes and 2,839 patients without diabetes. Clinical one year follow-up and angiographic control at 6 months were part of the protocol. Death, myocardial infarction and target lesion revascularization were considered as adverse events. An automated edge detection system was used for the angiographic assessment. The primary clinical endpoint was event-free survival at one year. The primary angiographic endpoint was restenosis rate at 6 months (> or = 50% diameter stenosis).Event-free survival was significantly lower in diabetic than in nondiabetic patients (73.1 vs. 78.5%, p < 0.001). Survival free of myocardial infarction was also significantly reduced in the diabetic group (89.9 vs. 94.4% in nondiabetics, p < 0.001). The incidence of both restenosis (37.5 vs. 28.3%, p < 0.001) and stent vessel occlusion (5.3 vs. 3.4%, p = 0.037) was significantly higher in diabetic patients. Diabetes was identified as an independent risk factor for adverse clinical events and restenosis in multivariate analyses.Patients with diabetes mellitus have a less favorable clinical outcome at one year after successful stent placement as compared to the nondiabetic patients. The clinical follow-up was characterized by a higher incidence of death, myocardial infarction and reinterventions. Diabetic patients also demonstrated an increased risk for restenosis.

Prevention of myocardial damage is the main goal of all reperfusion therapies in patients with acute myocardial infarction. The relative efficacy of various reperfusion strategies is under intensive investigation. We assessed whether coronary stenting combined with the blockade of platelet glycoprotein IIb/IIIa receptors produces a greater degree of myocardial salvage than fibrinolysis with an accelerated infusion of alteplase, a tissue plasminogen activator, in patients with acute myocardial infarction.A total of 140 patients were enrolled in the randomized trial; 71 were assigned to receive a stent plus abciximab, and 69 to receive intravenous alteplase. The primary end point was the degree of myocardial salvage, determined by means of serial scintigraphic studies with technetium Tc 99m sestamibi. The secondary end point was a composite of death, reinfarction, and stroke within six months after randomization.In the group that received a stent plus abciximab, the median size of the final infarct was 14.3 percent of the left ventricle (25th and 75th percentiles, 6.8 and 24.5 percent), as compared with a median of 19.4 percent (25th and 75th percentiles, 7.9 and 34.2 percent) in the alteplase group (P=0.02). This difference was due to the larger salvage index (the percentage of the left ventricle that was salvaged, divided by the percentage that was compromised by the initial perfusion defect) in the stent group: 0.57 (25th and 75th percentiles, 0.35 and 0.69), as compared with 0.26 (25th and 75th percentiles, 0.09 and 0.61; P<0.001). The cumulative incidence of death, reinfarction, or stroke at six months was lower in the stent group than in the alteplase group (8.5 vs. 23.2 percent. P=0.02; relative risk, 0.34; 95 percent confidence interval, 0.13 to 0.88).In patients with acute myocardial infarction, coronary stenting plus abciximab leads to a greater degree of myocardial salvage and a better clinical outcome than does fibrinolysis with a tissue plasminogen activator.

We tested the hypothesis that thinner-strut stents are associated with a reduced rate of restenosis when comparing two stents with different design. We have previously shown that, for two stents with similar design, the risk for restenosis is dependent on the strut thickness. It is unknown whether strut thickness preserves its relevance as a determinant of restenosis even in the presence of different stent designs. A total of 611 patients with symptomatic coronary artery disease were randomly assigned to receive either the thin-strut ACS RX Multilink stent (Guidant, Advanced Cardiovascular Systems, Santa Clara, California) (strut thickness 50 μm, interconnected ring design; n = 309) or the thick-strut BX Velocity stent (Cordis Corp., Miami, Florida) (strut thickness 140 μm, closed cell design; n = 302). The primary end point was angiographic restenosis (≥50% diameter stenosis at follow-up angiography). Secondary end points were the incidence of target-vessel revascularization (TVR) and the combined rate of death and myocardial infarction (MI) at one year. The incidence of angiographic restenosis was 17.9% in the thin-strut group and 31.4% in the thick-strut group, relative risk, 0.57 (95% confidence interval, 0.39 to 0.84), p < 0.001. A TVR due to restenosis was required in 12.3% of the thin-strut group and 21.9% of the thick-strut group, relative risk, 0.56 (95% confidence interval, 0.38 to 0.84), p = 0.002. No significant difference was observed in the combined incidence of death and MI at one year. When two stents with different design are compared, the stent with thinner struts elicits less angiographic and clinical restenosis than the thicker-strut stent.

The aim of the study was to investigate the relationship between bleeding within the 30 days after percutaneous coronary interventions (PCI) and 1-year mortality and to assess the appropriateness of inclusion of the periprocedural bleeding in a quadruple composite end point to assess PCI outcome.Periprocedural bleeding is one of the most frequent complications of PCI.This study included 5,384 patients from 4 randomized placebo-controlled trials on the value of abciximab after pre-treatment with 600 mg of clopidogrel: ISAR-REACT, -SWEET, -SMART-2, and -REACT-2. Bleeding--defined according to the Thrombolysis In Myocardial Infarction criteria--included all bleeding events within 30 days after enrollment. The primary end point was 1-year mortality.In the 4 trials, within the first 30 days there were 42 deaths (0.8%), 314 myocardial infarctions (MIs) (5.8%), 52 urgent revascularizations (1.0%), and 215 bleeding complications (4.0%). Mortality at 1 year was 3.6% (n = 197). A Cox proportional hazards model revealed that the 30-day occurrence of bleeding (hazard ratio [HR] 2.96, 95% confidence interval [CI] 1.96 to 4.48; p < 0.001), MI (HR 2.29, 95% CI 1.52 to 3.46; p < 0.001) and urgent revascularization (HR 2.49, 95% CI 1.16 to 5.35; p = 0.019) independently predicted 1-year mortality. The c statistic was 0.79 for bleeding, 0.78 for MI, and 0.78 for urgent revascularization, demonstrating a comparable discriminatory power of these adverse events for predicting 1-year mortality.Our study demonstrates a strong relationship between the 30-day frequency of bleeding and 1-year mortality after PCI and supports the inclusion of periprocedural bleeding in a 30-day quadruple end point for the assessment of outcome after PCI.

Background In animal models of myocardial infarction (MI), inflammatory responses compromise microcirculation during reperfusion and restrict functional recovery. To investigate cardiac inflammatory responses in patients with acute MI, we examined the cardiac release of cytokines, the expression on neutrophils of the β 2 -integrin Mac-1 (CD11b/CD18) and L-selectin (CD62L), and the cardiac release of thrombomodulin as a marker of endothelial injury. Methods and Results In 12 patients with acute anterior MI, blood samples were obtained from the coronary sinus and from the aorta immediately before and after recanalization of the coronary occlusion by balloon angioplasty. Twelve patients undergoing elective balloon angioplasty served as control subjects. Plasma concentrations of interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α, and thrombomodulin were determined by immunoassay, and surface expression of CD11b and CD62L was assessed by flow cytometry. Differences in coronary sinus and arterial blood were found in IL-6 before (median, 6.3 ng/L, P =.01) and after (13.4 ng/L, P =.002) recanalization and in IL-8 after recanalization (10.7 ng/L, P =.02). The cardiac release of both cytokines significantly ( P ≤.03) increased with reperfusion. Cytokine release after reperfusion was associated with significant transcardiac gradients in surface expression on neutrophils of CD11b (10.1 mean channel of fluorescence intensity [mean fl], P =.01) and CD62L (−8.7 mean fl, P =.007) and with a thrombomodulin release (4.5 μg/L, P =.004). Transcardiac gradients in IL-1β and tumor necrosis factor-α were not found. None of the changes found in MI were detectable in the control group. Conclusions As evidence of cardiac inflammatory responses in reperfused acute MI, the study demonstrates cardiac neutrophil activation with signs of endothelial injury and a release of the proinflammatory cytokines IL-8 and IL-6. These findings may assist in the design of pharmacological interventions aimed at reducing microvascular reperfusion injury.

Background —The role of coronary stenting in the treatment of patients with small vessels is not well defined. The purpose of this study was to investigate the influence of vessel size on long-term clinical and angiographic outcome after coronary stent placement. Methods and Results —The study comprised 2602 patients with successful stent implantation for symptomatic coronary artery disease. Patients were subdivided into 3 equally sized groups (tertiles) according to vessel size, with respective ranges of &lt;2.8, 2.8 to 3.2, and &gt;3.2 mm. Event-free survival at 1 year was 69.5% in the group with smaller vessels, 77.5% in the second group, and 81% in the group with larger vessels ( P &lt;0.001). Late lumen loss was similar between the 3 groups (1.12±0.73, 1.12±0.79, and 1.09±0.88 mm, respectively). Angiographic restenosis rate was significantly higher in the small-vessel group (38.6%, 28.4%, and 20.4% in groups 1, 2, and 3, respectively; P &lt;0.001). The analysis identified subgroups with different risk for restenosis even among patients with small vessels. Within this group, the restenosis rate may be as low as 29.6% in patients without additional risk factors and as high as 53.5% in patients with diabetes and complex lesions. Conclusions —Patients with small vessels present a higher risk for an adverse outcome after coronary stent placement because of a higher incidence of restenosis. However, the unusually high risk for restenosis is confined to those patients with small vessels who have concomitant risk factors such as diabetes and complex lesions.

In unstable coronary syndromes, catheter intervention is frequently preceded by antithrombotic treatment to reduce periprocedural risk; however, evidence from clinical trials to support antithrombotic pretreatment is sparse.To test the hypothesis that prolonged antithrombotic pretreatment improves the outcome of catheter intervention in patients with acute unstable coronary syndromes compared with early intervention.Randomized controlled trial conducted from February 27, 2000, to April 8, 2002, and including patients admitted to 2 German tertiary care centers with symptoms of unstable angina plus either ST-segment depression or elevation of cardiac troponin T levels.Patients were randomly allocated to antithrombotic pretreatment for 3 to 5 days or to early intervention after pretreatment for less than 6 hours. In both groups, antithrombotic pretreatment consisted of intravenous unfractionated heparin (60-U/kg bolus followed by infusion adjusted to maintain partial thromboplastin time of 60 to 85 seconds), aspirin (500-mg intravenous bolus followed by 100-mg twice-daily oral dose), oral clopidogrel (600-mg loading dose followed by 75-mg twice-daily dose), and intravenous tirofiban (10- microg/kg bolus followed by continuous infusion of 0.10 microg/kg per min).Composite 30-day incidence of large nonfatal myocardial infarction or death from any cause.Of the 410 patients enrolled, 207 were allocated to receive prolonged antithrombotic pretreatment and 203 to receive early intervention. Elevated levels of cardiac troponin T were present in 274 patients (67%), while 268 (65%) had ST-segment depression. The antithrombotic pretreatment and the early intervention groups were well matched with respect to major baseline characteristics and definitive treatment (catheter revascularization: 133 [64.3%] vs 143 [70.4%], respectively; coronary artery bypass graft surgery: 16 [7.7%] vs 16 [7.9%]). The primary end point was reached in 11.6% (3 deaths, 21 infarctions) of the group receiving prolonged antithrombotic pretreatment and in 5.9% (no deaths, 12 infarctions) of the group receiving early intervention (relative risk, 1.96 [95% confidence interval, 1.01-3.82]; P =.04). This outcome was attributable to events occurring before catheterization; after catheterization, both groups incurred 11 events each (P =.92).In patients with unstable coronary syndromes, deferral of intervention for prolonged antithrombotic pretreatment does not improve the outcome compared with immediate intervention accompanied by intense antiplatelet treatment.

The objective of this study was to investigate the impact of no-reflow phenomenon on 5-year mortality among patients with acute ST-segment elevation myocardial infarction (STEMI) treated by primary percutaneous coronary intervention (PCI). This impact was also assessed in relation to infarct size.The impact of no-reflow on long-term mortality in patients with STEMI has been insufficiently studied.This study included 1,406 patients with STEMI treated by primary PCI. No-reflow was diagnosed using angiographic criteria. Infarct size was measured with single-photon emission computed tomography imaging 7 to 14 days after the acute event. The primary outcome was 5-year mortality.The no-reflow phenomenon was diagnosed in 410 patients (29%). Infarct size was 15.0% (6.0% to 29.0%) of the left ventricle in the no-reflow group versus 8.0% (2.0% to 21.0%) of the left ventricle in the reflow group (p < 0.001). There were 132 deaths during follow-up. Of them, 59 deaths occurred among patients with no-reflow and 73 deaths occurred among patients with reflow (Kaplan-Meier estimates of 5-year mortality 18.2% and 9.5%, respectively; odds ratio: 2.02; 95% confidence interval: 1.44 to 2.82; p < 0.001). The Cox proportional hazards model adjusting for infarct size among other variables identified the no-reflow phenomenon as an independent correlate of 5-year mortality (hazard ratio: 1.66; 95% confidence interval: 1.17 to 2.36; p = 0.004).In patients with STEMI treated by primary PCI, no-reflow phenomenon is a strong predictor of 5-year mortality. No-reflow phenomenon after PCI provides prognostic information that is independent of and beyond that provided by infarct size.

AimsSeveral studies have demonstrated that the mutant *2 allele of the CYP2C19 681G>A loss-of-function polymorphism is associated with diminished metabolization of clopidogrel into its active thiol metabolite and an attenuated platelet response to clopidogrel treatment. It is not known whether patients carrying the mutant CYP2C19*2 allele have a higher risk of stent thrombosis (ST) compared with homozygous CYP2C19*1 wild-type allele carriers following percutaneous coronary intervention (PCI). The aim of this study was to assess the impact of the CYP2C19 681G>A loss-of-function polymorphism on ST following PCI performed after pre-treatment with clopidogrel.

Objective The antiplatelet activity of clopidogrel is characterized by considerable interindividual differences. Variable intestinal absorption is suggested to contribute to the inconsistencies in response. We tested the hypothesis that the intestinal efflux transporter P-glycoprotein (P-gp) limits the oral bioavailability of clopidogrel and that variance in the MDR1 gene encoding P-gp predicts absorption variability. Methods and Results P-gp-mediated transport of clopidogrel was assessed by transflux, influx, and efflux experiments by use of Caco-2 cells. Inhibition of P-gp activity by different modulators increased the absorptive clopidogrel flux across Caco-2 monolayers from 0.51 ± 0.19 pmol/cm2 (mean ± SD) at baseline by a maximum of 5- to 9-fold (P < .001) and the intracellular accumulation from 0.99 ± 0.11 pmol/mg protein by a maximum of 2.5-fold (P < .001) in response to 1-μmol/L clopidogrel and decreased clopidogrel efflux to the level of passive diffusion. In 60 patients with coronary artery disease who underwent percutaneous coronary intervention, the peak plasma concentration (Cmax) and the total area under the plasma concentration-time curve (AUC) of clopidogrel and its active metabolite after a single oral loading dose of 300, 600, or 900 mg were tested for correlation with the MDR1 genotype. In the 300-mg and 600-mg groups (but not in the 900-mg group) Cmax and AUC values were lower in subjects homozygous for the MDR1 3435T variant compared with subjects with the 3435C/T and 3435C/C genotypes. After the 600-mg loading dose, Cmax values (mean ± SD) of clopidogrel and its active metabolite in 3435T/T carriers were 13.3 ± 5.2 ng/mL and 2.5 ± 1.2 ng/mL, respectively, compared with 49.7 ± 41.6 ng/mL (P = .001) and 6.6 ± 3.6 ng/mL (P = .011), respectively, in 3435C/T and 3435C/C carriers; AUC values were 1502 ± 463 ng/mL × min for clopidogrel and 209 ± 99 ng/mL × min for its active metabolite in 3435T/T carriers compared with 7057 ± 5443 ng/mL × min (P = .0006) and 744 ± 541 ng/mL × min (P = .011), respectively, in 3435C/T and 3435C/C carriers. Conclusions Clopidogrel absorption and thereby active metabolite formation are diminished by P-gp-mediated efflux and are influenced by the MDR1 C3435T genotype. Clinical Pharmacology & Therapeutics (2006) 80, 486–501; doi: 10.1016/j.clpt.2006.07.007

In patients receiving aspirin, the optimal duration of clopidogrel therapy after drug-eluting stent (DES) implantation remains unclear.This multicentre, randomized, double-blind, placebo-controlled trial tested the hypothesis that in patients undergoing DES implantation, 6 months of clopidogrel is non-inferior to 12 months in terms of clinical outcomes. At 6 months after DES implantation, patients on clopidogrel were randomly assigned to either a 6-month period of placebo or an additional 6-month period of clopidogrel. The primary endpoint was the composite of death, myocardial infarction, stent thrombosis, stroke, and thrombolysis in myocardial infarction major bleeding at 9 months after randomization.Owing to slow recruitment and low event rates, the trial was stopped prematurely after enrolment of 4005 of 6000 planned patients. Of 4000 patients included in the final analysis, 1997 received 6 months of clopidogrel and 2003 received 12 months. The primary endpoint occurred in 29 patients (1.5%) assigned to 6 months of clopidogrel and 32 patients (1.6%) assigned to 12 months, observed difference -0.1%, upper limit of one-sided 95% confidence interval (CI) 0.5%, limit of non-inferiority 2%, Pfor noninferiority <0.001. Stent thrombosis was observed in five patients (0.3%) assigned to 6 months of clopidogrel and three patients (0.2%) assigned to 12 months; hazard ratio (HR) 1.66, 95% CI: 0.40-6.96, P = 0.49. Thrombolysis in myocardial infarction major bleeding was observed in 4 patients (0.2%) assigned to 6 months clopidogrel and 5 patients (0.3%) assigned to 12 months; HR 0.80, 95% CI: 0.21-2.98, P = 0.74.In the present trial, characterized by low event rates, we did not observe a significant difference in net clinical outcome between 6 and 12 months of clopidogrel therapy after DES implantation. However, the results of the trial must be considered in view of its premature termination and lower than expected event rates. The trial is registered with ClinicalTrials.gov, Identifier: NCT00661206.

Summary Patients receiving dual antiplatelet treatment with aspirin and clopidogrel are commonly treated with proton pump inhibitors (PPIs). Attenuating effects on platelet response to clopidogrel have been reported solely for the PPI omeprazole. PPIs differ in their metabolisation properties as well as their potential for drug-drug interactions. The aim of this study was to investigate the impact of different PPIs (pantoprazole, omeprazole, esomeprazole) on platelet response to clopidogrel in patients with previous coronary stent placement under chronic clopidogrel treatment. In a cross-sectional observational study, consecutive patients under clopidogrel maintenance treatment (n=1,000) scheduled for a control coronary angiography were enrolled. Adenosine diphosphate (ADP)-induced platelet aggregation (in AU*min) was measured with multiple electrode platelet aggregometry (MEA). From the entire study population, 268 (26.8%) patients were under PPI treatment at the time point of platelet function testing (pantoprazole, n=162; omeprazole, n=64; esomeprazole, n=42). Platelet aggregation (median [interquar-tile range]) was significantly higher in patients with omeprazole treatment (295.5 [193.5–571.2] AU*min) compared to patients without PPI treatment (220.0 [143.8–388.8] AU*min; p=0.001). Platelet aggregation was similar in patients with pantoprazole (226.0 [150.0–401.5] AU*min) or esomeprazole (209.0 [134.8–384.8] AU*min) treatment compared to patients without PPI treatment (p=0.69 and p=0.88, respectively). Attenuating effects of concomitant PPI treatment on platelet response to clopidogrel were restricted to the use of omeprazole. No attenuating effects on platelet response to clopidogrel were observed for pantoprazole or esomeprazole. Specifically designed and randomized clinical studies are needed to define the impact of concomitant PPI treatment on adverse events after percutaneous coronary intervention.

AimsThe efficacy of durable polymer drug-eluting stents (DES) is delivered at the expense of delayed healing of the stented vessel. Biodegradable polymer DES aim to avoid this shortcoming and may potentially improve long-term clinical outcomes, with benefit expected to accrue over time. We sought to compare long-term outcomes in patients treated with biodegradable polymer DES vs. durable polymer sirolimus-eluting stents (SES).

The accumulation of endogenous catecholamines within the extracellular space of the ischemic myocardium has been studied in the isolated perfused (Langendorff) heart of the rat subjected to various periods of complete ischemia, with subsequent collection of the reperfusate. Catecholamines and deaminated metabolites were measured by radioenzymatic methods, or high pressure liquid chromatography. Ischemic periods of less than 10 minutes are not associated with an increased overflow of catecholamines or metabolites. Longer periods of ischemia are accompanied by the overflow of noradrenaline and its deaminated metabolite 3,4-dihydroxyphenylglycol. This overflow increases with lengthening of the preceding ischemic period (10 minutes: 2.5 +/- 0.6, 20 minutes: 209.8 +/- 17.2, 60 minutes: 1270.5 +/- 148.1 pmol noradrenaline/g heart). Noradrenaline concentration is highest during the first minute of reperfusion, suggesting that the noradrenaline detected during reperfusion is released into the extracellular space of the myocardium during ischemia and is subsequently eluted. Experiments with variation of extracellular calcium concentration and with neuronal uptake (uptake1) blocking agents suggest that different mechanisms of catecholamine release are acting during the course of ischemia. A calcium-independent carrier-mediated efflux of noradrenaline from the nerve terminals is of major importance, using the same carrier as is normally responsible for transporting noradrenaline from the synaptic clefts into the neuronal varicosities. Thus, various uptake1-blocking agents diminish the noradrenaline overflow following ischemic periods of between 10 and 40 minutes. The noradrenaline overflow following longer periods of ischemia is unaffected by uptake1-blocking agents, and additional noradrenaline release at this time is probably consequent upon dissolution of cell membranes. Overflow of adrenaline and dopamine occurs to a minor degree (less than 5% of the corresponding noradrenaline overflow), and only after ischemic periods of more than 15 minutes.

To compare the efficacy and safety of drug-eluting stents vs. bare-metal stents in patients with acute ST-segment elevation myocardial infarction.We performed a meta-analysis of eight randomized trials comparing drug-eluting stents (sirolimus-eluting or paclitaxel-eluting stents) with bare-metal stents in 2786 patients with acute ST-segment elevation myocardial infarction. All patients were followed up for a mean of 12.0-24.2 months. Individual data were available for seven trials with 2476 patients. The primary efficacy endpoint was the need for reintervention (target lesion revascularization). The primary safety endpoint was stent thrombosis. Other outcomes of interest were death and recurrent myocardial infarction. Drug-eluting stents significantly reduced the risk of reintervention, hazard ratio of 0.38 (95% CI, 0.29-0.50), P < 0.001. The overall risk of stent thrombosis: hazard ratio of 0.80 (95% CI, 0.46-1.39), P = 0.43; death: hazard ratio of 0.76 (95% CI, 0.53-1.10), P = 0.14; and recurrent myocardial infarction: hazard ratio of 0.72 (95% CI, 0.48-1.08, P = 0.11) was not significantly different for patients receiving drug-eluting stents vs. bare-metal stents.The use of drug-eluting stents in patients with acute ST-segment elevation myocardial infarction is safe and improves clinical outcomes by reducing the risk of reintervention compared with bare-metal stents.

Data on the comparative value of the circumferential pulmonary vein and the segmental pulmonary vein ablation for interventional treatment of atrial fibrillation are limited. We hypothesized that the circumferential pulmonary vein ablation approach was superior to the segmental pulmonary vein ablation approach.One hundred patients with highly symptomatic atrial fibrillation were randomly assigned to undergo either circumferential (n=50) or segmental pulmonary vein ablation (n=50). Freedom from atrial tachyarrhythmias in a 7-day Holter monitoring at 6 months was the primary end point. Secondary end points were freedom of arrhythmia-related symptoms and a composite of pericardial tamponade, thromboembolic complications, and pulmonary vein stenosis (safety end point). On the basis of the results of the 7-day Holter monitoring at 6 months, 21 patients (42%) after circumferential pulmonary vein ablation and 33 patients (66%) after segmental pulmonary vein ablation (P=0.02) were free of atrial tachyarrhythmia episodes. During the 6-month follow-up period, 27 patients (54%) after circumferential pulmonary vein ablation and 41 patients (82%) after segmental pulmonary vein ablation remained free of arrhythmia-related symptoms (P<0.01). No significant difference was found in the safety end point (6 versus 7 events; P=0.77) in the circumferential versus segmental pulmonary vein ablation group, respectively.This study demonstrates no superiority of the circumferential pulmonary vein ablation over segmental pulmonary vein ablation for treatment of atrial fibrillation in terms of efficacy and safety.

Whether bivalirudin is superior to unfractionated heparin in patients with stable or unstable angina who undergo percutaneous coronary intervention (PCI) after pretreatment with clopidogrel is unknown.

Activated platelets tether and activate myeloid leukocytes. To investigate the potential relevance of this mechanism in acute myocardial infarction (AMI), we examined cytokine induction by leukocyte-platelet adhesion and the occurrence of leukocyte-platelet conjugates in patients with AMI.We obtained peripheral venous blood samples in 20 patients with AMI before and daily for 5 days after direct percutaneous transluminal coronary angioplasty (PTCA) and in 20 patients undergoing elective PTCA. Throughout the study period, CD41 immunofluorescence of leukocytes (flow cytometry) revealed increased leukocyte-platelet adhesion in patients with AMI compared with control patients (mean +/- SE of fluorescence [channels] before PTCA: 77 +/- 16 versus 35 +/- 9; P = .003). In vitro, thrombin-stimulated fixed platelets bound to neutrophils and monocytes. Within 2 hours, this resulted in increased mRNA for interleukin (IL),1 beta, IL-8, and monocyte chemoattractant protein (MCP)-1 in unfractionated leukocytes. After 4 hours, IL-1 beta and IL-8 concentration of the cell-free supernatant had increased by 268 +/- 36% and 210 +/- 7%, respectively, and cellular MCP-1 content had increased by 170 +/- 8%. Addition of activated platelets to adherent monocytes had a similar effect and was associated with nuclear factor-kappa B activation. Inhibition of binding by anti-P selectin antibodies reduced the effect of activated platelets on cytokine production.In patients with AMI, leukocyte-platelet adhesion is increased. Binding of activated platelets induces IL-1 beta, IL-8, and MCP-1 in leukocytes. Our findings suggest that leukocyte-platelet adhesion contributes to the regulation of inflammatory responses in AMI.

The glycoprotein IIb/IIIa receptor inhibitor abciximab has improved the efficacy of primary percutaneous coronary interventions in patients with acute myocardial infarction. However, it is not known whether abciximab remains beneficial after adequate clopidogrel loading in patients with acute ST-segment-elevation myocardial infarction.A total of 800 patients with acute ST-segment-elevation myocardial infarction within 24 hours from symptom onset, all treated with 600 mg clopidogrel, were randomly assigned in a double-blind fashion to receive either abciximab (n=401) or placebo (n=399) in the intensive care unit before being sent to the catheterization laboratory. The primary end point, infarct size measured by single-photon emission computed tomography with technetium-99m sestamibi before hospital discharge, was 15.7+/-17.2% (mean+/-SD) of the left ventricle in the abciximab group and 16.6+/-18.6% of the left ventricle in the placebo group (P=0.47). At 30 days, the composite of death, recurrent myocardial infarction, stroke, or urgent revascularization of the infarct-related artery was observed in 20 patients in the abciximab group (5.0%) and 15 patients in the placebo group (3.8%) (relative risk, 1.3; 95% CI, 0.7 to 2.6; P=0.40). Major bleeding complications were observed in 7 patients in each group (1.8%).Upstream administration of abciximab is not associated with a reduction in infarct size in patients presenting with acute myocardial infarction within 24 hours of symptom onset and receiving 600 mg clopidogrel.

Our purpose was to make a synthesis of the available evidence on the relative efficacy and safety of 2 drug-eluting stents (DES)—sirolimus-eluting stent (SES) and paclitaxel-eluting stent (PES)—in patients with coronary artery disease. It is not known whether there are differences in late outcomes between the 2 most commonly used DES: SES and PES. Sixteen randomized trials of SES versus PES with a total number of 8,695 patients were included in this meta-analysis. A full set of individual outcome data from 5,562 patients was also available. Mean follow-up period ranged from 9 to 37 months. The primary efficacy end point was the need for reintervention (target lesion revascularization). The primary safety end point was stent thrombosis. Secondary end points were death and recurrent myocardial infarction (MI). No significant heterogeneity was found across trials. Compared with PES, SES significantly reduced the risk of reintervention (hazard ratio [HR] 0.74; 95% confidence interval [CI] 0.63 to 0.87, p < 0.001) and stent thrombosis (HR 0.66; 95% CI 0.46 to 0.94, p = 0.02) without significantly impacting on the risk of death (HR 0.92; 95% CI 0.74 to 1.13, p = 0.43) or MI (HR 0.84; 95% CI 0.69 to 1.03, p = 0.10). Sirolimus-eluting stents are superior to PES in terms of a significant reduction of the risk of reintervention and stent thrombosis. The risk of death was not significantly different between the 2 DES, but there was a trend toward a higher risk of MI with PES, especially after the first year from the procedure.

<h3>Summary</h3> <i>Background:</i> In patients undergoing percutaneous coronary intervention (PCI), a link between bleeding and excess mortality has been demonstrated. A potential association of platelet response to clopidogrel and bleeding has not been well established yet. <i>Objectives:</i> The aim of the present study was to assess the impact of clopidogrel responsiveness on the risk of bleeding in clopidogrel‐treated patients undergoing PCI. <i>Methods:</i> Patients (<i>n</i> = 2533) undergoing PCI after pretreatment with 600 mg of clopidogrel were enrolled in this study. Blood was obtained directly before PCI. Adenosine‐diphosphate (ADP)‐induced platelet aggregation was assessed on a Multiplate analyzer. The primary endpoint was the incidence of in‐hospital Thrombolysis in Myocardial Infarction (TIMI) major bleeding and the secondary endpoint was in‐hospital TIMI minor bleeding. Receiver‐operator curve (ROC) analysis was used to derive the optimal platelet aggregation value defining enhanced clopidogrel responders for the association of measurements with major bleeding. <i>Results:</i> Thirty‐four (1.3%) major bleeding events and 137 (5.4%) minor bleeding events were observed. The risk of a major bleeding was significantly higher in patients (<i>n</i> = 975) with an enhanced response to clopidogrel as compared with the remaining patients (<i>n</i> = 1558) (2.2 vs. 0.8%, unadjusted odds ratio (OR) 2.6, 95% confidence interval (CI) 1.3–5.2, <i>P</i> = 0.005; adjusted OR 3.5, 95% CI 1.6–7.3, <i>P</i> = 0.001). No significant differences between both groups were observed for the occurrence of minor bleeding events (<i>P</i> = 0.68). <i>Conclusions:</i> Enhanced clopidogrel responsiveness is associated with a higher risk of major bleeding. Whether guidance of antiplatelet treatment based on platelet function testing proves useful for avoiding bleeding events warrants further investigation.

To compare the effectiveness and safety of three types of stents (sirolimus eluting, paclitaxel eluting, and bare metal) in people with and without diabetes mellitus.Collaborative network meta-analysis.Electronic databases (Medline, Embase, the Cochrane Central Register of Controlled Trials), relevant websites, reference lists, conference abstracts, reviews, book chapters, and proceedings of advisory panels for the US Food and Drug Administration. Manufacturers and trialists provided additional data.Network meta-analysis with a mixed treatment comparison method to combine direct within trial comparisons between stents with indirect evidence from other trials while maintaining randomisation. Overall mortality was the primary safety end point, target lesion revascularisation the effectiveness end point.35 trials in 3852 people with diabetes and 10,947 people without diabetes contributed to the analyses. Inconsistency of the network was substantial for overall mortality in people with diabetes and seemed to be related to the duration of dual antiplatelet therapy (P value for interaction 0.02). Restricting the analysis to trials with a duration of dual antiplatelet therapy of six months or more, inconsistency was reduced considerably and hazard ratios for overall mortality were near one for all comparisons in people with diabetes: sirolimus eluting stents compared with bare metal stents 0.88 (95% credibility interval 0.55 to 1.30), paclitaxel eluting stents compared with bare metal stents 0.91 (0.60 to 1.38), and sirolimus eluting stents compared with paclitaxel eluting stents 0.95 (0.63 to 1.43). In people without diabetes, hazard ratios were unaffected by the restriction. Both drug eluting stents were associated with a decrease in revascularisation rates compared with bare metal stents in people both with and without diabetes.In trials that specified a duration of dual antiplatelet therapy of six months or more after stent implantation, drug eluting stents seemed safe and effective in people both with and without diabetes.

The combination of glycoprotein IIb/IIIa inhibitors and heparin has not been compared with bivalirudin in studies specifically involving patients with non–ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention (PCI). We compared the two treatments in this patient population.

The efficacy of drug-eluting stents in reducing restenosis risk has not been uniform across patient subsets. Identifying predictive factors of restenosis may help improve outcomes after percutaneous coronary interventions.All patients who underwent successful implantation of sirolimus- or paclitaxel-eluting stents in native vessels for de novo lesions between August 2002 and December 2004 were eligible for this study. All data were prospectively collected. Angiographic restenosis was defined as diameter stenosis > or =50% at follow-up in the in-segment area. Target lesion revascularization was defined as any revascularization procedure involving the target lesion. Included in this study were 1845 patients with 2093 target lesions. Multivariable analysis showed that vessel size, final diameter stenosis, and drug-eluting stent type were the strongest predictors of restenosis. A 0.5-mm decrease in vessel size was associated with adjusted odds ratios (ORs) of 1.74 (95% CI, 1.31 to 2.32) for angiographic restenosis and 1.65 (95% CI, 1.22 to 2.23) for target lesion revascularization. A 5% increase in final diameter stenosis was associated with adjusted ORs of 1.30 (95% CI, 1.15 to 1.47) for angiographic restenosis and 1.18 (95% CI, 1.03 to 1.35) for target lesion revascularization. Compared with paclitaxel-eluting stent, sirolimus-eluting stent was associated with adjusted ORs of 0.60 (95% CI, 0.44 to 0.81) for angiographic restenosis and 0.67 (95% CI, 0.49 to 0.91) for target lesion revascularization.Vessel size and drug-eluting stent type are the most important predictors of angiographic and clinical restenosis, with drug-eluting stent type having a particular impact on restenosis of small coronary vessels.

Summary The level of platelet aggregation, measured with light transmission aggregometry (LTA) in platelet rich plasma (PRP), has been shown to predict outcomes after percutaneous coronary intervention (PCI). However, measuring parameters of platelet function with LTA is time consuming and weakly standardized. Thus, a fast and standardized method to assess platelet function after clopidogrel treatment would be of great value for clinical practice. A new method, multiple electrode platelet aggregometry (MEA), to rapidly measure platelet aggregation in whole blood has recently been developed. The aim of this study was to assess parameters of platelet function with MEA and LTA before and after administration of 600 mg clopidogrel. Blood samples from 149 patients scheduled for coronary angiography were taken after clopidogrel treatment; in addition, in 60 of the patients samples were available before clopidogrel treatment. ADP-induced platelet aggregation was measured with LTA and simultaneously in whole blood with MEA on the Multiplate analyzer. Platelet aggregation measured with MEA decreased significantly after clopidogrel treatment (P&lt;0.0001). ADP-induced platelet aggregation assessed with MEA and LTA correlated significantly (Spearman rank correlation coefficient=0.71; P&lt;0.0001).The results of MEA, a fast and standardized method to assess the platelet response to ADP prior to and after clopidogrel treatment, correlate well with LTA.

We assessed the rate of cardiac events after detection or exclusion of obstructive coronary artery disease (CAD) by coronary computed tomography angiography (CCTA). Several studies have demonstrated a high diagnostic accuracy of CCTA for detection of obstructive CAD compared with invasive angiography, but data regarding the clinical prognostic value of CCTA are limited. In all, 1,256 consecutive patients with suspected CAD undergoing 64-slice CCTA in our institution between October 2004 and September 2006 were observed prospectively for the occurrence of severe cardiac events (cardiac death, myocardial infarction, or unstable angina requiring hospitalization: primary study end point) and all cardiac events (additionally including revascularization >90 days after CCTA). The observed rate of all cardiac events was compared with the event rate predicted by the Framingham risk score. Obstructive CAD was defined as ≥50% diameter stenosis in any coronary artery. During a median follow-up of 18 months (interquartile range 14 to 25 months), the overall rates of severe and all cardiac events were 0.6% and 1.8%, respectively. In 802 patients without obstructive CAD, there were 4 cardiac events, of which 1 was severe, whereas in 348 patients with obstructive CAD, there were 17 cardiac events, of which 5 were severe. The difference between the 2 groups was highly significant both for severe events (odds ratio: 17.3, 95% confidence interval: 3.6 to 82.5) and for all cardiac events (odds ratio: 16.1, 95% confidence interval: 7.2 to 36.0; both p < 0.001). The rate of all cardiac events in patients without obstructive CAD was significantly lower than predicted by the Framingham risk score (p = 0.01). In patients with suspected CAD, CCTA has a significant prognostic impact on the prediction of cardiac events for the subsequent 18 months. The exclusion of obstructive CAD by CCTA identifies a patient population with an event risk lower than predicted by conventional risk factors.

Background— The Bleeding Academic Research Consortium (BARC) has recently proposed a unified definition of bleeding in patients receiving antithrombotic therapy. We investigated the relationship between bleeding events as defined by BARC and 1-year mortality in patients undergoing percutaneous coronary intervention (PCI) and assessed whether the BARC bleeding definition is superior to existing bleeding definitions in regard to mortality prediction in patients after PCI procedures. Methods and Results— This study represents a patient-level pooled analysis of 12 459 patients recruited in 6 randomized trials of patients undergoing PCI. Bleeding events were assessed with the use of BARC, Thrombolysis in Myocardial Infarction (TIMI), and Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) trial criteria. The primary outcome was 1-year mortality. Bleeding occurred in 1233 patients (9.9%) according to BARC (679 patients or 5.4% with BARC class ≥2 bleeding), in 374 patients (3.0%) according to TIMI, and in 491 patients (3.9%) according to REPLACE-2 criteria. There were 340 deaths (2.7%) over the first year after PCI. BARC class ≥2 bleeding was associated with a significant increase in 1-year mortality (adjusted hazard ratio 2.72; 95% confidence interval, 2.03–3.63). The predictivity of a multivariable model for 1-year mortality was significantly improved after inclusion of bleeding defined according to BARC to an extent comparable to that provided by TIMI and REPLACE-2 criteria. Conclusions— The present study demonstrated a close association between bleeding events defined according to BARC and 1-year mortality after PCI.

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.It is unclear whether abciximab reduces neointima formation after stenting. Such an effect may be particularly prominent in thrombus-containing lesions.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.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).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.

Coronary stent implantation is being performed in an increasing number of patients with a wide spectrum of clinical and lesion characteristics. A variety of stent designs are now available and continuous efforts are being made to improve the stent placement procedure. The objective of this study was to perform a comprehensive analysis of the relation between clinical, lesion, and procedural factors, and restenosis after intracoronary stenting in a large and unselected population of patients. A consecutive series of 4,510 patients with coronary stent placement was analyzed. Exclusion criteria were only a failed procedure and an adverse outcome within the first month after the intervention. Follow-up angiography was performed in 80% of patients at 6 months. Clinical, lesion, and procedural data from all 3,370 patients (4,229 stented lesions) with follow-up angiography were analyzed in a logistic regression model for restenosis (> or =50% diameter stenosis). Clinical factors contributed to the predictive power of the model much less than lesion and procedural factors. The strongest risk factor for restenosis was a small vessel size, with a 79% increase in the risk for a vessel of 2.7 mm versus a vessel of 3.4 mm in diameter. Stent design was the second strongest factor; the incidence of restenosis ranged from 20.0% to 50.3% depending on the stent type implanted. In conclusion, this study demonstrates the predominant role of lesion and procedural factors in determining the occurrence of restenosis after coronary stent placement. Among these factors, stent design appears to play a particularly important role in the hyperplastic response of the vessel wall.

Diabetic patients are at increased risk of adverse outcomes after percutaneous coronary interventions. Although subset analyses suggest particular benefit from the administration of abciximab in diabetic patients, no dedicated large randomized trials have been performed in diabetic patients undergoing percutaneous coronary intervention, and certainly not after pretreatment with a high loading dose of clopidogrel.This study (Intracoronary Stenting and Antithrombotic Regimen: Is Abciximab a Superior Way to Eliminate Elevated Thrombotic Risk in Diabetics [ISAR-SWEET] Study) enrolled 701 diabetic patients with coronary artery disease who underwent an elective percutaneous coronary intervention after pretreatment with a 600-mg dose of clopidogrel >2 hours before the procedure: 351 patients were randomly assigned to abciximab and 350 patients to placebo. The primary end point of the trial was the composite incidence of death and myocardial infarction at 1 year. The frequency of angiographic restenosis (diameter stenosis > or =50%) was the secondary end point. The incidence of death or myocardial infarction was 8.3% in the abciximab group and 8.6% in the placebo group (P=0.91), with a relative risk of 0.97 (95% CI, 0.58 to 1.62). The incidence of angiographic restenosis was 28.9% in the abciximab group and 37.8% in the placebo group (P=0.01), with a relative risk of 0.76 (95% CI, 0.62 to 0.94). The incidence of target lesion revascularization was 23.2% in the abciximab group and 30.4% in the placebo group (P=0.03).The findings of this study do not support a significant impact of abciximab on the risk of death and myocardial infarction in diabetic patients undergoing percutaneous coronary interventions after pretreatment with a 600-mg loading dose of clopidogrel at least 2 hours before the procedure. The present findings suggest, however, that abciximab reduces the risk of restenosis in diabetic patients receiving coronary bare metal stents.

ContextPlacement of sirolimus-eluting stents or paclitaxel-eluting stents has emerged as the predominant percutaneous treatment strategy in patients with coronary artery disease (CAD). Whether there are any differences in efficacy and safety between these 2 drug-eluting stents is unclear.ObjectiveTo compare outcomes of sirolimus-eluting and paclitaxel-eluting coronary stents on the basis of data generated by randomized head-to-head clinical trials.Data SourcesPubMed and the Cochrane Central Register of Controlled Trials, conference proceedings from major cardiology meetings, and Internet-based sources of information on clinical trials in cardiology from January 2003 to April 2005.Study SelectionRandomized trials comparing the sirolimus-eluting stent with the paclitaxel-eluting stent in patients with CAD reporting the outcomes of interest (target lesion revascularization, angiographic restenosis, stent thrombosis, myocardial infarction [MI], death, and the composite of death or MI) during a follow-up of at least 6 months.Data ExtractionTwo reviewers independently identified studies and abstracted data on sample size, baseline characteristics, and outcomes of interest.Data SynthesisSix trials, including 3669 patients, met the selection criteria. No significant heterogeneity was found across trials. Target lesion revascularization, the primary outcome of interest, was less frequently performed in patients who were treated with the sirolimus-eluting stent (5.1%) vs the paclitaxel-eluting stent (7.8%) (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.49-0.84; P = .001). Similarly, angiographic restenosis was less frequently observed among patients assigned to the sirolimus-eluting stent (9.3%) vs the paclitaxel-eluting stent (13.1%) (OR, 0.68; 95% CI, 0.55-0.86; P = .001). Event rates for sirolimus-eluting vs paclitaxel-eluting stents were 0.9% and 1.1%, respectively, for stent thrombosis (P = .62); 1.4% and 1.6%, respectively, for death (P = .56); and 4.9% and 5.8%, respectively, for the composite of death or MI (P = .23).ConclusionsPatients receiving sirolimus-eluting stents had a significantly lower risk of restenosis and target vessel revascularization compared with those receiving paclitaxel-eluting stents. Rates of death, death or MI, and stent thrombosis were similar.

Background —Platelet/endothelium interaction plays an important role in the pathophysiology of inflammation and atherosclerosis. The role of platelets for monocyte chemotactic protein-1 (MCP-1) secretion and surface expression of intercellular adhesion molecule-1 (ICAM-1) on endothelial cells has been assessed. Methods and Results —Monolayers of human umbilical vein endothelial cells were incubated with nonstimulated or ADP-activated platelets for 6 hours, and secretion of MCP-1 and surface expression of ICAM-1 were determined by ELISA and flow cytometry, respectively. In the presence of ADP-activated platelets, both MCP-1 secretion and ICAM-1 surface expression were significantly increased compared with nonstimulated platelets ( P &lt;0.02). Activation of the transcription factor nuclear factor-κB (NF-κB) determined by electrophoretic mobility shift assay and κB-dependent transcriptional activity was enhanced in the presence of activated platelets. In addition, ADP-activated platelets induced MCP-1 and ICAM-1 promoter–dependent transcription. Liposomal transfection of a double-stranded κB phosphorothioate oligonucleotide, but not of the mutated form, inhibited MCP-1 secretion and surface expression of ICAM-1 on activated endothelium ( P &lt;0.05). Conclusions —The present study indicates that activated platelets modulate chemotactic (MCP-1) and adhesive (ICAM-1) properties of endothelial cells via an NF-κB–dependent mechanism. Platelet-induced activation of the NF-κB system might contribute to early inflammatory events in atherogenesis.

In acute myocardial infarction (AMI), platelets play a key role in thrombotic processes that limit the patency of the recanalized, infarct-related coronary artery and contribute to reperfusion injury. Platelet function in the course of AMI treated by direct percutaneous transluminal coronary angioplasty (PTCA) has not been evaluated.In 15 patients with anterior AMI, peripheral venous blood samples were obtained before and 4, 8, 24, and 48 hours after recanalization of the occluded artery by PTCA. Fifteen patients who had stable coronary heart disease and were undergoing elective balloon angioplasty served as control subjects. Fibrinogen receptor function and surface expression of P-selectin on platelets were determined by flow cytometry. In addition, we evaluated generation of platelet-derived microparticles and the effect of systemic plasma from patients with AMI on normal platelet function and on platelet adhesion to human endothelial cells in culture. We found fibrinogen receptor activity and P-selectin expression on circulating platelets 8 hours after direct PTCA are decreased (P < .01). This coincided with a decrease in peripheral platelet count (P < .05) and an increase in generation of microparticles (P < .002). Twenty-four to 48 hours after PTCA, fibrinogen receptor activity and P-selectin expression increased again. Systemic plasma obtained before and after direct PTCA sensitized normal platelets to hyperaggregate in vitro (P < .001) and stimulated platelet adhesion to endothelial cells in culture (P < .01). None of the changes found in AMI were detectable in the control group.After transient apparent deactivation of circulating platelet, probably caused by sequestration of hyperactive platelets, the level of platelet activation increases in patients with AMI treated by direct PTCA. These findings underscore the need for novel antiplatelet strategies in AMI.

No specifically designed studies have addressed the role of primary percutaneous coronary intervention in patients with acute ST-segment elevation myocardial infarction (STEMI) presenting more than 12 hours after symptom onset. Current guidelines do not recommend reperfusion treatment in these patients.To assess whether an immediate invasive treatment strategy is associated with a reduction of infarct size in patients with acute STEMI, presenting between 12 and 48 hours after symptom onset, vs a conventional conservative strategy.International, multicenter, open-label, randomized controlled trial conducted from May 23, 2001, to December 15, 2004, of 365 patients aged 18 to 80 years without persistent symptoms admitted with the diagnosis of acute STEMI between 12 and 48 hours after symptom onset.Random assignment to either an invasive strategy (n=182) based predominantly on coronary stenting with abciximab or a conventional conservative treatment strategy (n=183).The primary end point was final left ventricular infarct size according to single-photon emission computed tomography study with technetium Tc 99m sestamibi performed between 5 and 10 days after randomization in 347 patients (95.1%). Secondary end points included composite of death, recurrent MI, or stroke at 30 days.The final left ventricular infarct size was significantly smaller in patients assigned to the invasive group (median, 8.0%; interquartile range [IQR], 2.0%-15.8%) vs those assigned to the conservative group (median, 13.0%; IQR, 3.0%-27.0%; P<.001). The mean difference in final left ventricular infarct size between the invasive and conservative groups was -6.8% (95% confidence interval [CI], -10.2% to -3.5%). The secondary end points of death, recurrent MI, or stroke at 30 days occurred in 8 patients in the invasive group (4.4%) and 12 patients in the conservative group (6.6%) (relative risk, 0.67; 95% CI, 0.27-1.62; P = .37).An invasive strategy based on coronary stenting with adjunctive use of abciximab reduces infarct size in patients with acute STEMI without persistent symptoms presenting 12 to 48 hours after symptom onset.

Interleukin (IL)-6 and IL-8 are important regulators of inflammatory responses in myocardial infarction. Induction of monocyte procoagulant activity (PCA) by these cytokines could present a mechanism that links inflammatory responses to thrombotic events. We therefore investigated the effect of IL-6 and IL-8 on monocyte tissue factor (TF) expression. Recombinant human IL-6 and IL-8 caused a time- and dose-dependent increase in PCA (recalcification time) of monocytic U937 cells and of mononuclear leukocytes. Using blocking anti-TF monoclonal antibodies and factor VII-deficient control plasma, this PCA was shown to be TF dependent. Compared with unstimulated cells, mononuclear cell PCA increased by 4.5-fold to 17 +/- 2 mU/5x10(5) cells after exposure to 100 ng/L IL-6 for 4 hours and by 6.6-fold to 27 +/- 4 mU/5x10(5) cells after exposure to IL-8 under the same conditions. Northern blot analysis showed an increase in TF mRNA after stimulation with IL-6 or IL-8 for 2 hours, and after 4 hours an increase in cellular TF protein content was found by immunoassay. Flow cytometry demonstrated that IL-6 and IL-8 induced an increase in TF surface expression on monocytes. Thus, IL-6 and IL-8 induce monocyte PCA by increasing mRNA, protein content, and surface expression of TF.

Abrupt vessel closure after percutaneous transluminal coronary angioplasty (PTCA) is associated with major adverse events. Different surgical and nonsurgical approaches have been advocated to treat or prevent this complication. This study summarizes our 4-year experience with Palmaz-Schatz stenting for the management of 339 patients with present or threatened occlusion after PTCA.Stent implantation was attempted in a total of 339 and 4959 patients with PTCA during the study period and was successful in 327 (96.5%). During the follow-up, events like death, myocardial infarction, need for revascularization (bypass surgery and repeat in-stent angioplasty), and major vascular complications were recorded. Angiographic follow-up at 6 months was performed in 89.3% of the eligible patients. As part of an initial policy, stenting was intended as a bridge to nonemergency bypass surgery in 26 patients. In 301 patients for whom stenting was intended as permanent treatment, early clinical course (first 4 weeks) was characterized by a 1.3% cardiac mortality and a 4.0% nonfatal myocardial infarction rate; bypass surgery was necessary in 1%, and 6.3% required early repeat PTCA. Surgical repair for peripheral vascular complications was required in 5.6%, and major bleeding events were encountered in 9%. The incidence of subacute stent closure was 6.9%, with subsequent recanalization successful in 86%; subacute stent closure was predicted by presence of vessel occlusion before stenting and localization of the stent in a vessel other than the right coronary artery. Survival rate at 2 years was 95.4%, survival without myocardial infarction was 91.1%, and event-free survival was 70.7%. Survival at 2 years was lower for patients with stents in bypass vein grafts and with myocardial infarction after stenting. Six-month control angiography revealed a restenosis rate of 29.6%.Patients with present or threatened occlusion after PTCA may benefit from Palmaz-Schatz stenting. It is associated with a low mortality and myocardial infarction rate and with a long-term event-free rate comparable to that of uncomplicated PTCA.

Retrospective postinfarction studies revealed that decreased heart rate turbulence (HRT) indicates increased risk for subsequent death. This is the first prospective study to validate HRT in a large cohort of the reperfusion era.One thousand four hundred fifty-five survivors of an acute myocardial infarction (age <76 years) in sinus rhythm were enrolled. HRT onset (TO) and slope (TS) were calculated from Holter records. Patients were classified into the following HRT categories: category 0 if both TO and TS were normal, category 1 if either TO or TS was abnormal, or category 2 if both TO and TS were abnormal. The primary end point was all-cause mortality. During a follow-up of 22 months, 70 patients died. Multivariately, HRT category 2 was the strongest predictor of death (hazard ratio, 5.9; 95% CI, 2.9 to 12.2), followed by left ventricular ejection fraction (LVEF) < or =30% (4.5; 2.6 to 7.8), diabetes mellitus (2.5; 1.6 to 4.1), age > or =65 years (2.4; 1.5 to 3.9), and HRT category 1 (2.4; 1.2 to 4.9). LVEF < or =30% had a sensitivity of 27% at a positive predictive accuracy level of 23%. The combined criteria of LVEF < or =30%, HRT category 2 or LVEF >30%, age > or =65 years, diabetes mellitus, and HRT category 2 had a sensitivity of 24% at a positive predictive accuracy level of 37%. The combined criteria of LVEF < or =30% or LVEF >30%, age > or =65 years, diabetes mellitus, and HRT category 1 or 2 had a sensitivity of 44% at a positive predictive accuracy level of 23%.HRT is a strong predictor of subsequent death in postinfarction patients of the reperfusion era.

This prospective randomized study investigated platelet-induced upregulation of Mac-1 on monocytes and its inhibition by glycoprotein (GP) IIb/IIIa blockage in patients with acute myocardial infarction (AMI).In experimental AMI, Mac-1 on leukocytes is the pivotal adhesion molecule for detrimental inflammatory responses. In vitro, platelet adhesion to monocytes upregulates Mac-1.Patients undergoing stenting in AMI within 48 h after onset of symptoms were randomly assigned to receive either standard-dose heparin (n = 50) or abciximab plus low-dose heparin (n = 50). In serial blood samples, we assessed platelet-monocyte interaction and Mac-1 surface expression by triple color immunofluorescence flow cytometry.Compared with platelet-negative monocytes, Mac-1 surface expression on monocytes with attached platelets was upregulated (median fluorescence intensity [interquartile range]: 259 [179 to 367] vs. 135 [78 to 195] arbitrary units, p < 0.001). As an indicator of platelet-monocyte interaction, mean fluorescence of the platelet marker GP Ib alpha in the monocytes population decreased after abciximab, although it remained unaffected by heparin alone. Abciximab achieved this effect by a reduction in platelet mass attached to monocytes (GP Ib alpha fluorescence intensity of heterotypic aggregates at 24 h [arbitrary units]: 187 [143 to 236] after abciximab vs. 228 [156 to 332] after heparin, p = 0.02), whereas it did not affect the percentage of monocytes with adherent platelets. Reduction of platelet-monocyte interaction resulted in decreased Mac-1 surface expression (fluorescence intensity at 24 h [arbitrary units]: 116 [68 to 153] after abciximab vs. 162 [117 to 239] after heparin, p = 0.001).In patients with AMI, platelet-leukocyte interactions modulate Mac-1 expression on monocytes. Glycoprotein IIb/IIIa blockade is a therapeutic option to interfere with this mechanism.

Platelets and alterations of chemotactic and adhesive properties of endothelium play an important role in the pathophysiology of atherosclerosis. We investigated the effect of platelets on secretion of monocyte chemotactic protein-1 (MCP-1) and on surface expression of intercellular adhesion molecule-1 (ICAM-1) of cultured endothelium. Pretreatment of cultured monolayers of endothelial cells with alpha-thrombin-activated platelets significantly enhanced secretion of MCP-1 and ICAM-1 surface expression (P<0.01) that could be inhibited by interleukin-1 (IL-1) antagonists by approximately 40%. Activation of transcription factor nuclear factor-kappaB (NF-kappaB) which regulates transcription of early inflammatory response genes such as MCP-1, was significantly increased in endothelial cells treated with activated platelets via an IL-1 mediated mechanism as determined by electrophoretic mobility shift assay (EMSA) and kappaB-dependent transcriptional activity. In trans-well experiments, alpha-thrombin-activated platelets enhanced IL-1-dependent surface expression of vitronectin receptor (alpha(v)beta(3)) on the luminal aspect of endothelial monolayers and promoted alpha(v)beta(3)-mediated platelet/endothelium adhesion that could be inhibited by the antiadhesive peptides GRGDSP and c(RGDfV). We conclude that activated platelets induce significant changes in chemotactic (secretion of MCP-1) and adhesive (surface expression of ICAM-1 and alpha(v)beta(3)) properties of cultured endothelium. These findings imply a potential pathophysiological mechanism of platelets in an early stage of atherogenesis.

In this prospective study, we investigated the prevalence and characteristics of clearly discernible noncalcified coronary plaques in a patient population with suspected significant coronary artery disease (CAD) by using 64-slice computed tomography (CT).The assessment of noncalcified coronary plaques by noninvasive strategies may be important to improve cardiovascular risk stratification.To rule out significant stenosis, high-resolution 64-slice coronary CT (0.6-mm collimation, 330-ms gantry rotation time) was performed in 161 consecutive patients with an intermediate risk for having CAD. Computed tomography data sets were evaluated for presence of coronary calcifications, noncalcified plaques, and/or lumen narrowing.Noncalcified coronary plaques were detected in 48 (29.8%) of 161 enrolled patients. Although noncalcified plaques together with coronary calcifications were present in 38 of 161 (23.6%) patients, the prevalence of noncalcified plaques as the only manifestation of CAD was 6.2% (10 of 161 patients). Patients with noncalcified plaques were characterized by significantly higher total cholesterol, low-density lipoprotein, and C-reactive protein levels as well as a trend for more diabetes mellitus. The majority of noncalcified plaques resulted in lumen narrowing of <50%. Of the remaining 113 patients, CAD and coronary calcifications were ruled out in 53 of 161 (32.9%) patients, whereas 60 of 161 (37.3%) patients presented with calcifications in the absence of noncalcified plaque.With the use of 64-slice CT, clearly discernible noncalcified atherosclerotic coronary plaques can be detected in a large group of patients with an intermediate risk for having CAD. The assessment of these plaques by CT angiography may allow for improved cardiovascular risk stratification.

To assess the incidence, timing, and relation of drug-eluting stent (DES) thrombosis to discontinuation of clopidogrel therapy. This prospective observational cohort study included 6816 consecutive patients that underwent successful DES implantation. Primary endpoint was definite stent thrombosis (ST). During 4 years of follow-up, definite ST was observed in 73 patients, corresponding to a cumulative incidence of 1.2%. Cumulative incidence of ST at 30 days was 0.5 and 0.8% at 1 year, respectively. Discontinuation of clopidogrel therapy was significantly associated with ST only in the first 6 months after the procedure (P < 0.001). During that period, the median time interval from clopidogrel discontinuation to ST was 9 days [interquartile range (IQR) 5.5–22.5] while thereafter it was 104.3 days (IQR 7.4–294.8). The 4 year incidence of ST after DES implantation is low. A relevant number of ST occur early after discontinuation of clopidogrel therapy. The dependence of ST on discontinuation of clopidogrel therapy seems to be mostly confined to the first 6 months after DES implantation. However, specifically designed randomized studies are required to establish the optimal length of clopidogrel therapy after DES implantation.

The purpose of this study was to evaluate image quality and radiation dose using a 100 kVp tube voltage scan protocol compared with standard 120 kVp for coronary computed tomography angiography (CTA).Concerns have been raised about radiation exposure during coronary CTA. The use of a 100 kVp tube voltage scan protocol effectively lowers coronary CTA radiation dose compared with standard 120 kVp, but it is unknown whether image quality is maintained.We enrolled 400 nonobese patients who underwent coronary CTA: 202 patients were randomly assigned to a 100 kVp protocol and 198 patients to a 120 kVp protocol. The primary end point was to demonstrate noninferiority in image quality with the 100 kVp protocol, which was assessed by a 4-point grading score (1 = nondiagnostic, 4 = excellent image quality). For the noninferiority analysis, a margin of -0.2 image quality score points for the difference between both scan protocols was pre-defined. Secondary end points included radiation dose and need for additional diagnostic tests during follow-up.The mean image quality scores in patients scanned with 100 kVp and 120 kVp were 3.30 ± 0.67 and 3.28 ± 0.68, respectively (p = 0.742); image quality of the 100 kVp protocol was not inferior, as demonstrated by the 97.5% confidence interval of the difference, which did not cross the pre-defined noninferiority margin of -0.2. The 100 kVp protocol was associated with a 31% relative reduction in radiation exposure (dose-length product: 868 ± 317 mGy × cm with 120 kVp vs. 599 ± 255 mGy × cm with 100 kVp; p < 0.0001). At 30-day follow-up, the need for additional diagnostic studies did not differ (13.4% vs. 19.2% for 100 kVp vs. 120 kVp, respectively; p = 0.114).A coronary CTA protocol using 100 kVp tube voltage maintained image quality, but reduced radiation exposure by 31% as compared with the standard 120 kVp protocol. Thus, 100 kVp scan protocols should be considered for nonobese patients to keep radiation exposure as low as reasonably achievable. (Prospective Randomized Trial on Radiation Dose Estimates of Cardiac CT Angiography in Patients Scanned With a 100 kVp Protocol [PROTECTION II]; NCT00611780).

Summary The adenosine diphosphate (ADP) receptor P2Y12 blocking agent clopidogrel is clinically proven to be efficient in preventing thrombotic events. However, its therapeutic value is limited by an, as yet poorly explained, interindividual heterogeneity in platelet inhibition. To evaluate possible pharmacokinetic determinants of this response variability, we developed a sensitive and specific liquid chromatography tandem mass spectrometry (LC-MS/MS) assay for quantification of unmodified inactive clopidogrel, its inactive carboxyl metabolite, and its active thiol metabolite in plasma. Analyte concentrations and platelet aggregation were assessed in ten healthy volunteers receiving an oral load of 600 mg clopidogrel. Subjects showed marked inter-individual differences in maximal platelet inhibition and in plasma pharmacokinetics. Univariate regression revealed linear correlations between maximal antiplatelet effect and peak plasma concentrations (cmax) of unchanged clopidogrel (r=0.76; p=0.01), of the carboxyl metabolite (r=0.70; p=0.03), and of the thiol metabolite (r=0.73; p=0.02), as well as linear correlations between cmax values of clopidogrel and its metabolites. This indicates that the response variability is predominantly caused by individual differences in clopidogrel absorption and that other factors, such as ADP receptor reactivity or differences in bioactivation of clopidogrel, do not play a major role.

Sirolimus- and paclitaxel-eluting stents effectively reduce restenosis in small coronary vessels. The relative efficacy of these drug-eluting stents in this high-risk subset is not known.A total of 360 patients undergoing percutaneous coronary intervention for de novo lesions in native coronary vessels with a diameter of <2.80 mm received randomly paclitaxel-eluting stents (n=180) or sirolimus-eluting stents (n=180). The primary endpoint was in-stent late luminal loss. Secondary endpoints were angiographic restenosis and need of target lesion revascularization. The study intended to show that the paclitaxel-eluting stent is not inferior to the sirolimus-eluting stent with respect to the primary endpoint. The non-inferiority margin was set at 0.16 mm. Follow-up angiography was performed in 87% of the patients. In-stent late luminal loss in the paclitaxel-eluting stent group was 0.32 mm (upper 95% boundary, 0.42 mm), which was greater than that in the sirolimus-eluting stent group, failing to show the non-inferiority of the paclitaxel-eluting stent to the sirolimus-eluting stent (P>0.99). Angiographic restenosis was found in 19.0% of the lesions in the paclitaxel-eluting stent group and 11.4% of the lesions in the sirolimus-eluting stent group (P=0.047). Target lesion revascularization was performed in 14.7% of the lesions treated with paclitaxel-eluting stents and 6.6% of the lesions treated with sirolimus-eluting stents (P=0.008).The paclitaxel-eluting stent is associated with a greater late luminal loss and is less effective in reducing restenosis in small coronary vessels than the sirolimus-eluting stent.

The length of a coronary lesion is a significant predictor of restenosis after balloon angioplasty. The influence of lesion length has not comprehensively been assessed after coronary stent placement. This study includes 2,736 consecutive patients with coronary stent placement. Only patients with recent or chronic occlusions before the intervention were excluded. Patients were divided in 2 groups: 573 patients with long lesions (≥15 mm) and 2,163 patients with short lesions (<15 mm). There were no significant differences between the groups with respect to the procedural success rate and incidence of subacute thrombosis. One-year event-free survival was lower in patients with long lesions (73.3% vs 80.0%, p = 0.001). Six-month angiography was performed in 82.5% of the eligible patients. The incidence of binary restenosis (≥50% diameter stenosis) was higher in patients with long lesions (36.9% vs 27.9%, p <0.001). Similarly, patients with long lesions presented more late lumen loss than those with short lesions (1.29 ± 0.89 vs 1.07 ± 0.77 mm, p <0.001). Multivariate models for both binary restenosis and late lumen loss demonstrated that lesion length was an independent risk factor for restenosis. The risk was further increased by multiple stent placement and overlapping stents that were also independent risk factors of restenosis. Stented segment length did not show any independent effect. Therefore, long lesions represent an independent risk factor for restenosis after coronary stent placement. The results of this study suggest that a possible way to reduce the risk is to cover the lesion with a minimal number of nonoverlapping stents.

The aim of this study was to determine the impact of a reduced 100-kV tube voltage on image quality and radiation exposure in a pre-defined subgroup analysis of the international, multicenter radiation dose survey PROTECTION I (Prospective Multicenter Study on RadiaTion Dose Estimates Of Cardiac CT AngIOgraphy I) study. Cardiac computed tomography angiography (CCTA) has become a frequently used diagnostic tool in clinical practice. Despite continually improving CT technology, there remain concerns regarding the associated radiation exposure. A reduced tube voltage of 100 kV has been proposed as an effective means for dose reduction in nonobese patients. The study assessed the relevant radiation dose parameters as well as quantitative and qualitative diagnostic image quality data in a subgroup of 321 patients (100 kV: 82 patients; 120 kV: 239 patients), who were scanned at study sites that applied a 100-kV tube voltage in at least 1 patient. Diagnostic image quality was assessed by an experienced CCTA investigator with a 4-point score (1: nondiagnostic to 4: excellent image quality). Effective radiation dose was estimated from the dose-length-product of each CCTA study. The use of the 100-kV scan protocol was associated with 53% reduction in CCTA median radiation dose estimates, when compared with the conventional 120-kV scan protocol (p < 0.001). Although image noise significantly increased by 26.3% with 100 kV, signal- as well as contrast-to-noise ratios also increased by 7.9% (p = 0.254) and 10.8% (p = 0.027), respectively. Reduction of tube voltage did not impair diagnostic image quality (median diagnostic score: 3.5 [3.25 to 3.75] vs. 3.5 [3.0 to 3.75] for 100 kV vs. 120 kV; p = 0.22). In this nonrandomized PROTECTION I dose survey, reducing the CCTA tube voltage to 100 kV in nonobese patients is associated with a significant reduction in radiation exposure while maintaining diagnostic image quality. Thus, the 100-kV scan technique should be considered for CCTA dose reduction in adequately selected patients.

To the Editor: Platelet response to clopidogrel is characterized by large interindividual response variability ([1][1]). Numerous studies have linked low responsiveness to clopidogrel with the occurrence of thrombotic events, and more recently, data have emerged linking an enhanced response to

For patients with sirolimus-eluting stent (SES) restenosis requiring reintervention, we compared a strategy of repeat SES (Cypher, Cordis, Miami Lakes, Florida) implantation with paclitaxel-eluting stent (PES) (Taxus, Boston Scientific, Natick, Massachusetts) implantation.Despite their high anti-restenotic efficacy, the widespread utilization of SES therapy has led to a significant absolute number of patients presenting with SES treatment failure. The optimal treatment strategy for such patients remains unclear.The ISAR-DESIRE 2 (Intracoronary Stenting and Angiographic Results: Drug Eluting Stents for In-Stent Restenosis 2) study was a randomized, open-label, active-controlled trial conducted among 450 patients with clinically significant in-SES restenosis at 2 centers in Munich, Germany. After pre-treatment with 600 mg clopidogrel, all patients were randomly assigned to either SES or PES implantation. The primary end point was late lumen loss, based on in-stent analysis, at 6- to 8-month follow-up angiography. Secondary end points were binary angiographic restenosis (diameter stenosis >50%) at 6- to 8-month follow-up, target lesion revascularization, the composite of death or myocardial infarction, and definite stent thrombosis at 12 months.Regarding anti-restenotic efficacy, there were no differences between SES and PES in late loss (0.40 +/- 0.65 mm vs. 0.38 +/- 0.59 mm; p = 0.85), binary restenosis (19.6% vs. 20.6%; p = 0.69), or target lesion revascularization (16.6% vs. 14.6%; p = 0.52). In terms of safety outcomes, the rates of death/myocardial infarction (6.1% vs. 5.8%; p = 0.86) and stent thrombosis (0.4% vs. 0.4%; p > 0.99) were also similar.In cases of SES restenosis, treatment with either repeat SES or switch to PES was associated with a comparable degree of efficacy and safety. Drug resistance at an individual patient level may play a contributory role to the somewhat higher than expected late loss observed with the SES in the current study. (Intracoronary Stenting and Angiographic Results: Drug-Eluting Stents for In-Stent Restenosis 2 [ISAR-DESIRE 2]; NCT00598715).

Patients with acute myocardial infarction might benefit from the addition of glycoprotein IIb/IIIa inhibitors to fibrinolytic or mechanical reperfusion strategies. We compared two strategies, stenting and fibrinolysis, both combined with abciximab, in terms of their ability to salvage myocardium in patients with acute myocardial infarction.We enrolled 162 patients with acute myocardial infarction within 12 h of onset of symptoms, assigning 81 stenting plus abciximab and 81 alteplase plus abciximab. Technetium-99m sestamibi scintigraphy was done at admission and after a median of 11 days to calculate initial perfusion defect, final infarct size, and degree of myocardial salvage. The primary endpoint was the salvage index (the ratio of the degree of myocardial salvage to the initial perfusion defect). Major adverse clinical events within 6 months from randomisation were also compared between the two treatments.Paired scintigraphic measurements were available for 70 patients in the stent group and 71 in the alteplase group. Stenting was associated with greater myocardial salvage than alteplase (median 13.6% [IQR 5.9-23.9] vs 8.0% [2.5-16.0] of the left ventricle; p=0.007). Salvage index was greater in the stent group than in the alteplase group (median 0.60 [0.37-0.82] vs 0.41 [0.13-0.58]; p=0.001). The 6-month mortality rate was 5% (four deaths) in the stent group and 9% (seven deaths) in the alteplase group (relative risk 0.56 [95% CI 0.17-1.88]; p=0.35).In patients with acute myocardial infarction, a reperfusion strategy based on stenting with abciximab produced more myocardial salvage than the combination of fibrinolysis plus abciximab. Larger studies are needed to assess whether these effects translate into clinical benefit.

We sought to test whether an increase in the clopidogrel maintenance dose results in increased inhibition of platelet aggregation.Sixty patients after pre-treatment with 600 mg of clopidogrel and within 12 h after successful PCI were included in this trial. They were allocated to receive one of two clopidogrel daily maintenance doses (75 or 150 mg) for 30 days in a double-blind randomized manner. Platelet function was evaluated 30 days after the intervention with optical aggregometry and with a new point-of-care test (VerifyNowtrade mark P2Y12 assay). Maximal 5 microM ADP-induced platelet aggregation 30 days after PCI in the group treated with 150 mg/day clopidogrel (45.1 +/- 20.9%) was significantly lower than in the group treated with 75 mg/day (65.3 +/- 12.1%; P < 0.001). The VerifyNowtrade mark P2Y12 assay also indicated a higher degree of platelet function inhibition in the group treated with 150 mg/day (60.0 +/- 72.0 P2Y12 Reaction Units) than in the group treated with 75 mg/day (117.0 +/- 64.3 P2Y12 Reaction Units; P = 0.004).Administration of a 150 mg oral maintenance dose of clopidogrel results in more intense inhibition of platelet aggregation than administration of the currently recommended 75 mg maintenance dose.

A recent genome-wide association study identified a haplotype block on chromosome 4q25 associated with atrial fibrillation (AF). We sought to replicate this association in four independent cohorts.The Framingham Heart Study and Rotterdam Study are community-based longitudinal studies. The Vanderbilt AF Registry and German AF Network (AFNet) are case-control studies. Participants with AF (n = 3508) were more likely to be male and were older than referent participants (n = 12 173; Framingham 82 +/- 10 vs. 71 +/- 13 years; Rotterdam 73 +/- 8 vs. 69 +/- 9 years; Vanderbilt 54 +/- 14 vs. 57 +/- 14 years; AFNet 62 +/- 12 vs. 49 +/- 14 years). Single nucleotide polymorphism (SNP) rs2200733 was associated with AF in all four cohorts, with odds ratios (ORs) ranging from 1.37 in Rotterdam [95% confidence interval (CI) 1.18-1.59; P = 3.1 x 10(-5)] to 2.52 in AFNet (95% CI 2.22-2.8; P = 1.8 x 10(-49)). There also was a significant association between AF and rs10033464 in Framingham (OR 1.34; 95% CI 1.03-1.75; P = 0.031) and AFNet (OR 1.30; 95% CI 1.13-1.51; P = 0.0002), but not Vanderbilt (OR 1.16; 95% CI 0.86-1.56; P = 0.33). A meta-analysis of the current and prior AF studies revealed an OR of 1.90 (95% CI 1.60-2.26; P = 3.3 x 10(-13)) for rs2200733 and of 1.36 (95% CI 1.26-1.47; P = 6.7 x 10(-15)) for rs10033464.The non-coding SNPs rs2200733 and rs10033464 are strongly associated with AF in four cohorts of European descent. These results confirm the significant relations between AF and intergenic variants on chromosome 4.

It is not known whether further suppression of platelet function can be achieved with clopidogrel beyond that provided by currently recommended loading and maintenance doses. We performed a comparative assessment of the antiplatelet effects of a 600-mg loading dose of clopidogrel given to patients with and without chronic clopidogrel therapy.Those eligible for this prospective study were aspirin-treated patients with suspected or documented coronary artery disease admitted to hospital for coronary angiography. Two series of 20 consecutive patients each were assessed in this study. The first series included patients who had never received clopidogrel (first-use group); the second series included patients on chronic therapy with a daily dose of 75 mg clopidogrel for > or =1 month (chronic therapy group). Blood samples were drawn before and 6 hours after oral administration of 600 mg clopidogrel for aggregometry and flow cytometry studies. In the first-use group, loading with 600 mg clopidogrel inhibited ADP 5 micromol/L-induced platelet aggregation from 90+/-9% to 51+/-19% (P<0.001). In the chronic therapy group, loading with 600 mg clopidogrel yielded further inhibition of ADP 5 micromol/L-induced platelet aggregation in addition to that achieved by the maintenance dose of 75 mg/d, from 52+/-14% to 33+/-12% (P<0.001). In both groups, 600 mg clopidogrel loading significantly inhibited ADP-induced expression of glycoprotein IIb/IIIa and P-selectin receptors.Further platelet inhibition can be achieved with clopidogrel in addition to that provided by currently recommended loading and maintenance doses. Higher doses may be warranted after assessment of their clinical efficacy and safety.

AimsAlthough biodegradable polymer drug-eluting stent (DES) platforms have potential to enhance long-term clinical outcomes, data concerning their efficacy are limited to date. We previously demonstrated angiographic antirestenotic efficacy with a microporous, biodegradable polymer DES. In the current study, we hypothesized that at 12 months, its clinical safety and efficacy would be non-inferior to that of permanent polymer DES.

This study assessed the impact on long-term mortality of percutaneous coronary intervention (PCI) versus medical treatment in patients with symptoms or signs of myocardial ischemia but no acute coronary syndrome. The impact of PCI on the long-term prognosis of patients with stable coronary artery disease has not been established. We identified 17 randomized trials comparing a PCI-based invasive treatment strategy with medical treatment in 7,513 patients with symptoms or signs of myocardial ischemia but no acute coronary syndrome. Of these patients, 3,675 were assigned to the PCI group and 3,838 to the medical treatment group. The primary end point was all-cause death. The length of follow-up was in the range between 12 and 122 months, 51 months on average. In the PCI group, 271 patients died compared with 335 patients in the medical treatment group, which corresponds to a 20% reduction in the odds ratio (OR) of all-cause death (OR: 0.80; 95% confidence interval [CI]: 0.64 to 0.99, p = 0.263 for heterogeneity across the trials). Allocation to the PCI group was associated with a nonsignificant 26% reduction in the OR of cardiac death (OR: 0.74, 95% CI: 0.51 to 1.06). In the PCI group, 319 patients had a nonfatal myocardial infarction after randomization compared with 357 patients in the medical treatment group (OR: 0.90, 95% CI: 0.66 to 1.23). These findings suggest that a PCI-based invasive strategy may improve long-term survival compared with a medical treatment-only strategy in patients with stable coronary artery disease.

Gold is a highly biocompatible material. Experimental evidence suggests that coating the stent with a gold layer may have a beneficial influence. In this randomized trial, we assessed whether gold-coated stents were associated with a better clinical and angiographic outcome after coronary placement.Patients with symptomatic coronary artery disease were randomly assigned to receive either a gold-coated Inflow stent (n = 367) or an uncoated Inflow stainless steel stent (n = 364) of identical design. Follow-up angiography was routinely performed at 6 months. The primary end point of the study was the occurrence of any adverse clinical event (death, myocardial infarction, or target-vessel revascularization) during the first year after stenting. At 30 days, there was no significant difference in the combined incidence of adverse events, with 7.9% in the gold-stent group versus 5.8% in the steel-stent group (P = 0.25). The incidence of angiographic restenosis (> or =50% diameter stenosis) was 49.7% in the gold-stent group and 38.1% in the steel-stent group (P = 0.003). One-year survival free of myocardial infarction was 88.6% in the gold-stent group and 91.8% in the steel-stent group (P = 0.14). One-year event-free survival was significantly less favorable in the gold-stent group (62.9% versus 73.9% in the steel-stent group; P = 0.001).Coating steel stents with gold had no significant influence on the thrombotic events observed during the first 30 days after the intervention. However, gold-coated stents were associated with a considerable increase in the risk of restenosis over the first year after stenting.

Recent clinical studies that investigated the efficacy of the two U.S. Food and Drug Administration-approved drug-eluting stent (DES) platforms Cypher (Cordis, Johnson and Johnson, Miami Lakes, Florida) and Taxus (Boston Scientific, Boston, Massachusetts) suggest that there are differences between both DES concerning neointimal growth. Both DES elute compounds that inhibit the cell cycle, but at different stages: Cypher stents elute sirolimus, which induces G1 cell cycle inhibition, and Taxus stents release paclitaxel, which predominantly leads to M-phase arrest. In an attempt to explain the differences observed in human studies, the properties of these stent-based compounds on critical molecular and cellular events associated with the pathophysiology of in-stent restenosis are discussed in detail with the conclusion that both sirolimus and paclitaxel are different in their pleiotropic anti-restenotic effects. This may be in part responsible for the differences observed in recent clinical studies.

The aim of this trial was to compare the safety and efficacy of paclitaxel-eluting stents (PES) and sirolimus-eluting stents (SES) for treatment of unprotected left main coronary artery (uLMCA) disease. Both PES and SES have reduced the risk of restenosis, particularly in high-risk patient and lesion subsets. However, their comparative performance in uLMCA lesions is not known. In this randomized study, 607 patients with symptomatic coronary artery disease undergoing percutaneous coronary intervention for uLMCA were enrolled: 302 were assigned to receive a PES (Taxus, Boston Scientific, Natick, Massachusetts) and 305 assigned to receive a SES (Cypher, Cordis, Johnson & Johnson, New Brunswick, New Jersey). The primary end point was the combined incidence of death, myocardial infarction, and target lesion revascularization (TLR) at 1 year. The secondary end point was angiographic restenosis on the basis of the LMCA area analysis at follow-up angiography. At 1 year the cumulative incidence of death, myocardial infarction, or TLR was 13.6% in the PES and 15.8% in the SES group (relative risk [RR]: 0.85, 95% confidence interval [CI]: 0.56 to 1.29, p = 0.44). One patient in the PES group (0.3%) and 2 patients in the SES group (0.7%) experienced definite stent thrombosis (p = 0.57). Mortality at 2 years was 10.7% in the PES and 8.7% in the SES group (RR: 1.14, 95% CI: 0.66 to 1.95, p = 0.64). Angiographic restenosis was 16.0% with PES and 19.4% with SES (RR: 0.82, 95% CI: 0.57 to 1.19, p = 0.30). Implantation of either PES or SES in uLMCA lesions is safe and effective; both of these drug-eluting stents provide comparable clinical and angiographic outcomes. (Drug-Eluting-Stents for Unprotected Left Main Stem Disease [ISAR-LEFT-MAIN]; NCT00133237)

AimsThe objective of this study was to assess the non-inferiority, in terms of anti-restenotic efficacy, of both biodegradable-polymer (BP) and polymer-free (PF) stents compared with permanent-polymer rapamycin-eluting (PP; Cypher) stent.

Platelet interaction with endothelium plays an important role in the pathophysiology of coronary microcirculation. We assessed the role of the vitronectin receptor (integrin alpha(v)beta3) in platelet/endothelium adhesion.We investigated the effect on platelet/endothelium adhesion of plasma obtained from patients with acute myocardial infarction during reperfusion (before and 8, 24, 48, and 72 hours and 5 to 7 days after direct angioplasty) and with pretreatment with alpha-thrombin (2 U/mL) and recombinant human interleukin-1beta. Platelet/endothelium adhesion was significantly enhanced by approximately 20% after pretreatment of endothelium with patient plasma for 4 hours (P<.05) compared with endothelium treated with pooled control plasma. Plasma-induced platelet/endothelium adhesion was, in part, RGD peptide dependent. Pretreatment of endothelial cells with alpha-thrombin or recombinant human interleukin-1beta enhanced platelet/endothelium adhesion and surface expression of alpha(v)beta3 on the luminal aspect of endothelium (P<.05). The adhesion of platelets, isolated platelet microparticles, and Chinese hamster ovary cells bearing human recombinant alpha(IIb)beta3 (platelet glycoprotein IIb-IIIa) to activated endothelial cells was inhibited by antiadhesive peptides GRGDSP and c(RGDfV) and monoclonal antibodies 4F10, LM609, and 7E3.The expression of vitronectin receptor exposed on the luminal aspect of activated endothelium is enhanced and mediates platelet/endothelium adhesion. Vitronectin receptor-mediated platelet attachment to activated endothelium during reperfusion may contribute to reperfusion injury and could be a target for antiadhesive therapy.

The release of endogenous noradrenaline and its deaminated metabolite dihydroxyphenylglycol in the myocardium have been studied in the isolated perfused heart of the rat subjected to three models of energy depletion: ischemia, anoxia, and cyanide intoxication. Anoxia and cyanide intoxication were combined with substrate deficiency at constant perfusion flow. All three energy-depleting procedures caused a similar overflow of noradrenaline which, following a constant delay of 10 minutes without increased release, amounted to more than 25% of total heart content within 40 minutes. This noradrenaline overflow was not diminished in the absence of extracellular calcium and was inhibited by the uptake1 blocker desipramine in all three experimental models, indicating a common and nonexocytotic release mechanism. In the presence of glucose, neither anoxia nor cyanide intoxication resulted in a measurable noradrenaline overflow. Conversely, blockade of glycolysis or glucose depletion prior to ischemia or cyanide poisoning accelerated the noradrenaline overflow, demonstrating a key role of the sympathetic nerve cells' energy status in causing nonexocytotic catecholamine release. Blockade of energy metabolism in the presence of oxygen (cyanide model) resulted in the overflow of high amounts of dihydroxyphenylglycol that was not inhibited by uptake1 blockade. The release of the lipophilic dihydroxyphenylglycol by diffusion reflects deamination of axoplasmic noradrenaline by monoamine oxidase. Since saturation of the enzyme could be excluded in this model dihydroxyphenylglycol release can be taken as a mirror of cytoplasmic noradrenaline concentration. The results obtained by these studies indicate that nonexocytotic catecholamine release is a two-step process induced by energy deficiency in the sympathetic varicosity. In a first step, noradrenaline is lost from storage vesicles, resulting in increasing axoplasmic concentrations. The second step is the rate-limiting transport of intracellular noradrenaline across the cell membrane by the uptake1 carrier that has reversed its normal net transport direction.

In clopidogrel-treated patients undergoing coronary stenting, high on-treatment platelet reactivity was linked to a higher risk of stent thrombosis (ST). Platelet response to clopidogrel is significantly influenced by genetic factors. Recently published findings showed a highly significant impact of a common polymorphism (Q192R) within the paraoxonase-1 (PON1) gene on clopidogrel treatment efficacy but no influence of the CYP2C19*2 genetic variant as previously demonstrated. The aim of this study was to assess the impact of the PON1 Q192R genotype in parallel to that of CYP2C19*2 on the antiplatelet effect of clopidogrel and the risk of ST in clopidogrel-treated patients. In 1524 patients undergoing percutaneous coronary intervention, ADP-induced platelet aggregation was assessed in relation to PON1 Q192R and CYP2C19*2 genotypes. The clinical impact of genetic variants was investigated by comparing genotype frequencies of both genetic variants in a registry of 127 cases with early ST vs. an early ST-free control cohort (n = 1439). For PON1 Q192R genotypes, platelet aggregation values were similar across all genotype groups (P = 0.65). For CYP2C19*2 genotypes, significantly higher aggregation values were found in CYP2C19 wt/*2 and *2/*2 patients when compared with wt/wt allele carriers (P < 0.0001). Comparing genotype frequencies between ST cases and controls, no differences were observed for PON1 Q192R genotype distributions (P = 0.23), whereas the genotype distribution differed for CYP2C19*2 genotypes (P = 0.019). The PON1 Q192R genotype did not influence platelet response to clopidogrel or the risk of ST in clopidogrel-treated patients, whereas the CYP2C19*2 genotype impacted on both antiplatelet effect of clopidogrel and risk of coronary ST.

To investigate the combination of heart rate turbulence (HRT) and deceleration capacity (DC) as risk predictors in post-infarction patients with left ventricular ejection fraction (LVEF) > 30%.We enrolled 2343 consecutive survivors of acute myocardial infarction (MI) (<76 years) in sinus rhythm. HRT and DC were obtained from 24 h Holter recordings. Patients with both abnormal HRT (slope < or = 2.5 ms/RR and onset > or = 0%) and abnormal DC (< or =4.5 ms) were considered suffering from severe autonomic failure (SAF) and prospectively classified as high risk. Primary and secondary endpoints were all-cause, cardiac, and sudden cardiac mortality within the first 5 years of follow-up. During follow-up, 181 patients died; 39 deaths occurred in 120 patients with LVEF < or = 30%, and 142 in 2223 patients with LVEF>30% (cumulative 5-year mortality rates of 37.9% and 7.8%, respectively). Among patients with LVEF > 30%, SAF identified another high-risk group of 117 patients with 37 deaths (cumulative 5-year mortality rates of 38.6% and 6.1%, respectively). Merging both high-risk groups (i.e. LVEF < or = 30% and/or SAF) doubled the sensitivity of mortality prediction compared with LVEF < or = 30% alone (21.1% vs. 42.1%, P < 0.001) while preserving 5-year mortality rate (38.2%).In post-MI patients with LVEF>30%, SAF identifies a high-risk group equivalent in size and mortality risk to patients with LVEF < or = 30%.

Inflammation plays an important role in the pathogenesis of atherosclerosis and acute coronary syndromes. Cytokines IL-10 and TNF-α exert opposite functions in inflammatory reactions, IL-10 acting predominantly as an antiinflammatory and TNF-α as a proinflammatory factor. Functional single nucleotide polymorphisms in the genes of IL-10, TNF-α, and TNF-β are associated with gene expression and plasma levels of IL-10 and TNF-α. The aim of the study was to assess whether these IL-10 and TNF gene polymorphisms are related to the risk of coronary artery disease (CAD) and myocardial infarction (MI). Consecutive, angiographically examined patients with significant coronary stenoses but without symptoms or signs of old or acute MI constituted the group with CAD (n=998) and patients with old or acute MI constituted the group with MI (n=793). Subjects with neither angiographic CAD nor symptoms or signs of MI (n=340) served as controls. They were matched with the patients for age and sex. Genotyping was performed with techniques based on the polymerase chain reaction. Allele frequencies, genotype distributions, and frequencies of allele combinations for three IL-10 promoter polymorphisms, −1082G/A, −819C/T and −592C/A, were similar between CAD patients, MI patients, and matched controls. Similarly, genetic analysis did not reveal group-specific differences for the TNF-α promoter polymorphisms −863C/A and −308G/A, as well as for the TNF-β intron 1 polymorphism 252G/A. In addition, no relationship was found between specific combinations of IL-10 and TNF alleles, indicative of low IL-10 and high TNF-α production, respectively, and CAD or MI. The lack of association persisted also after adjusting for other cardiovascular risk factors. Our findings suggest that six different and functionally relevant polymorphisms of the genes coding for IL-10, TNF-α, and TNF-β are neither separately nor in cooperation associated with the risk of CAD or MI in angiographically examined patients.

In this prospective evaluation we investigated the accuracy of 64-slice computed tomography angiography (CTA) in an unselected but symptomatic patient population for detection of stenoses in bypass grafts when compared with invasive angiography. The assessment of significant stenosis in bypass grafts is important for patients with recurrent angina symptoms after bypass surgery. High-resolution 64-slice computed tomography (0.6 mm collimation, 330 ms gantry rotation time) and invasive angiography were performed in 138 consecutive patients with a total of 418 bypass grafts. Relevant stenosis was defined as diameter reduction ≥50%. During CTA, arrhythmias were present in 42 (30%) patients who were not excluded from the analysis. The assessment of stenosis or occlusion of bypass grafts resulted in a sensitivity of 97%, specificity of 97%, and positive and negative predictive values of 93% and of 99%, respectively. The diagnostic accuracy for the detection of graft occlusion or stenosis did not differ between arterial and venous grafts. The evaluability of bypass grafts was significantly lower in patients with arrhythmias or with heart rates ≥65 beats/min during scanning. However, in the assessment of evaluable bypass grafts, no significant differences were detected in the diagnostic accuracy in these subgroups. This large prospective study demonstrates that 64-slice CTA is a reliable method for the assessment of bypass graft patency and stenoses even in an unselected “real-world” patient population.

Comparative assessment of clinical outcomes after use of drug-eluting stents versus bare-metal stents for treatment of aortocoronary saphenous vein graft lesions has not been undertaken in large randomised trials. We aimed to undertake a comparison in a randomised trial powered for clinical endpoints.In this randomised superiority trial, patients with de-novo saphenous vein graft lesions were assigned by computer-generated sequence (1:1:1:3) to receive either drug-eluting stents (one of three types: permanent-polymer paclitaxel-eluting stents, permanent-polymer sirolimus-eluting stents, or biodegradable-polymer sirolimus-eluting stents) or bare-metal stents. Randomisation took place immediately after crossing of the lesion with a guidewire, and was stratified for each participating centre. Investigators assessing data were masked to treatment allocation; patients were not masked to allocation. The primary endpoint was the combined incidence of death, myocardial infarction, and target lesion revascularisation at 1 year. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00611910.610 patients were allocated to treatment groups (303 drug-eluting stent, 307 bare-metal stent). Drug-eluting stents reduced the incidence of the primary endpoint compared with bare-metal stents (44 [15%] vs 66 [22%] patients; hazard ratio [HR] 0.64, 95% CI 0.44-0.94; p=0.02). Target lesion revascularisation rate was reduced by drug-eluting stents (19 [7%] vs 37 [13%] patients; HR 0.49, 95% CI 0.28-0.86; p=0.01). No significant differences were seen between drug-eluting stents and bare-metal stents regarding all-cause mortality (15 [5%] vs 14 [5%] patients; HR 1.08, 95% CI 0.52-2.24; p=0.83), myocardial infarction (12 [4%] vs 18 [6%]; HR 0.66, 95% CI 0.32-1.37; p=0.27), or definite or probable stent thrombosis (2 [1%] in both groups; HR 1.00, 95% CI 0.14-7.10; p=0.99).In patients undergoing percutaneous coronary intervention for de-novo saphenous vein graft lesions, drug-eluting stents are the preferred treatment option because they reduce the risk of adverse events compared with bare-metal stents.Deutsches Herzzentrum.

The effects of exogenous and endogenous adenosine on exocytotic noradrenaline release were studied in rat hearts perfused in situ. Exocytotic release of endogenous noradrenaline (determined by high pressure liquid chromatography) was induced by electrical stimulation of the left cervicothoracic ganglion. Exogenous adenosine significantly reduced noradrenaline overflow from the heart. This suppression of noradrenaline overflow was not influenced by desipramine, indicating a mechanism independent from noradrenaline reuptake. The A1 subtype specific agonists cyclohexyladenosine and R-phenylisopropyladenosine had inhibitory effects at lower concentrations than adenosine and S-phenylisopropyladenosine, suggesting the relevance of presynaptic inhibitory adenosine receptors of the A1 subtype. Short ischemic periods of 3 minutes resulted in a marked coronary venous overflow of adenosine during reperfusion. This was accompanied by an inhibition of noradrenaline release evoked by nerve stimulation during ischemia. The adenosine antagonists theophylline and 8-phenyltheophylline prevented this suppression of noradrenaline release. Blockade of oxidative phosphorylation by cyanide in combination with glucose-free perfusion induced an increased formation of endogenous adenosine and suppression of stimulation-evoked noradrenaline overflow. Again, in the presence of the adenosine antagonists theophylline or 8-phenyltheophylline, this suppression was abolished. These results indicate that adenosine is a potent inhibitor of exocytotic noradrenaline release in the heart with relevance during conditions of increased endogenous adenosine formation such as myocardial ischemia.

A genetically defined molecular heterogeneity of haptoglobin, characterized by the major phenotypic forms Hp 1-1, Hp 2-1, and Hp 2-2, has been associated with distinct clinical manifestations. To enable the use of DNA samples for the study of this polymorphism, we established a haptoglobin genotyping method based on PCR.Taking advantage of the selectivity of PCR, we amplified DNA segments specifically representing haptoglobin alleles Hp 1 and Hp 2 from genomic DNA. The products were analyzed by agarose gel electrophoresis. Haptoglobin phenotyping of plasma samples was performed by polyacrylamide gel electrophoresis and peroxidase staining.Exploiting the known size difference between Hp 1 and Hp 2, we amplified allele-specific DNA molecules with one pair of oligonucleotide primers. As an alternative, we used separate primer pairs to generate amplification products indicative of alleles Hp 1 and Hp 2. Because of the primer design, genotype determination was not compromised by sequence variations specifying haptoglobin allele subtypes S and F. For the same reason, the sequence similarity between the haptoglobin gene and the haptoglobin-related gene did not interfere with the accuracy of genotyping. Analysis with restriction enzymes demonstrated the authenticity of the allele-specific DNA products. Haptoglobin DNA genotyping and protein phenotyping, performed in parallel, yielded fully corresponding results. In a group of 249 individuals, the haptoglobin genotype distribution was as follows: 14.5% Hp 1-1, 48.2% Hp 2-1, and 37.3% Hp 2-2.The new method can be used for genotyping of a common haptoglobin polymorphism.

We sought to assess changes in antirestenotic efficacy of drug-eluting stents (DES) by restudying subjects at 2 time points after coronary stenting (6 to 8 months and 2 years) and to compare differences in time courses of late luminal loss (LLL) between 3 different DES platforms in use at our institution.DES therapy is associated with low levels of LLL at 6 to 8 months. The temporal course of neointimal formation after this time point remains unclear.This prospective, observational, systematic angiographic follow-up study was conducted at 2 centers in Munich, Germany. Patients underwent stenting with permanent-polymer rapamycin-eluting stents (RES), polymer-free RES, or permanent-polymer paclitaxel-eluting stents (PES). The primary end point was delayed LLL (the difference in in-stent LLL between 6 to 8 months and 2 years).Of 2,588 patients undergoing stenting, 2,030 patients (78.4%) had 6- to 8-month angiographic follow-up and were enrolled in the study. Target lesion revascularization was performed in 259 patients; these patients were not considered for further angiographic analysis. Of 1,771 remaining patients, 1,331 had available 2-year reangiographic data (75.2%). Overall mean (SD) delayed LLL was 0.12 +/- 0.49 mm (0.17 +/- 0.50 mm, 0.01 +/- 0.42 mm, and 0.13 +/- 0.50 mm in permanent-polymer RES, polymer-free RES, and permanent-polymer PES groups, respectively [p < 0.001]). In multivariate analysis, only stent type (in favor of polymer-free RES) predicted delayed LLL.Ongoing erosion of luminal caliber beyond 6 to 8 months after the index procedure is observed following DES implantation. Absence of permanent polymer from the DES platform seems to militate against this effect.

AimsCoronary computed tomography angiography (CCTA) has a high accuracy for detection of obstructive coronary artery disease (CAD). Several studies also showed a good predictive value for subsequent cardiac events. However, the follow-up period of these studies was limited to ∼2 years and long-term follow-up data on prognosis out to 5 years are very limited.

Background— Although drug-eluting stents (DESs) constitute a major achievement in preventing restenosis, concerns remain regarding the increased inflammatory and thrombogenic responses associated with the polymers used. Recently, we showed that a nonpolymer on-site coating with rapamycin not only is feasible and safe but also leads to a dose-dependent reduction in restenosis. Methods and Results— To assess whether polymer-free stents coated on-site with 2% rapamycin solution are inferior to polymer-based paclitaxel-eluting stents for the prevention of restenosis, we randomly assigned a total of 450 patients with de novo lesions in native coronary vessels, excluding the left main trunk, to either the polymer-free, rapamycin-coated Yukon DES (rapamycin stent) or the polymer-based, paclitaxel-eluting Taxus stent (paclitaxel stent). The primary end point was in-stent late lumen loss. Secondary end points were angiographic restenosis and target lesion revascularization. The study was designed to test the noninferiority of the rapamycin stent compared with the paclitaxel stent with respect to late lumen loss according to a noninferiority margin of 0.13 mm. Follow-up angiography was completed in 81% of the patients. The mean difference in in-stent late lumen loss between the rapamycin-stent group and the paclitaxel-stent group was 0.002 mm, and the upper limit of the 1-sided 95% confidence interval was 0.10 mm ( P =0.02 from test for noninferiority). No significant differences were observed regarding angiographic restenosis rates (14.2% with the rapamycin stent and 15.5% with the paclitaxel stent) and target lesion revascularization rates due to restenosis (9.3% in both groups). Conclusions— The polymer-free, rapamycin-coated stent has an antirestenotic effect that is not inferior to that observed with the polymer-based paclitaxel-eluting stent.

A higher mortality risk for women with acute myocardial infarction (AMI) is a common finding in studies that compare the postinfarction outcome of women vs men. It is not clear, however, whether sex is an independent predictor of death among patients systematically treated with aggressive reperfusion and medical strategies.To assess the impact of patient's sex on outcome in a consecutive series of patients with AMI treated with a reperfusion strategy largely based on percutaneous coronary interventions.Inception cohort of 1937 patients (502 women and 1435 men) who were admitted with a diagnosis of AMI to a tertiary referral institution between January 1995 and December 2000.Mortality at 1 year after AMI.Compared with men, women were older (70 vs 61 years; P<.001) and had known diabetes or hypertension more often. Both men and women received essentially identical therapy with the majority of patients (86%) receiving reperfusion therapy via percutaneous coronary interventions. There were no significant differences in 1-year Kaplan-Meier death rates with 13.8% (68 cases) among women and 12.9% (184 cases) among men (unadjusted hazard ratio, 1.06; 95% confidence interval, 0.80-1.39; P =.70). After age adjustment, women had a lower risk of death (hazard ratio, 0.65; 95% confidence interval, 0.49-0.87; P =.004).Despite their more advanced age and greater prevalence of diabetes or hypertension, women with AMI who were treated with a reperfusion strategy largely based on percutaneous coronary interventions show a similar outcome as men.

We sought to synthesize the available evidence on the effectiveness of drug-eluting stents for bare-metal in-stent restenosis.Although there is clinical evidence that drug-eluting stents are associated with better results than other treatments for in-stent restenosis, they are not yet approved for this indication. Meta-analysis of randomized trials may yield more precise estimates of treatment effects and enable a rapid adoption of effective treatments in clinical practice.Data sources included PubMed and conference proceedings. Prespecified criteria were met by 4 randomized studies comparing sirolimus- or paclitaxel-eluting stents versus balloon angioplasty or vascular brachytherapy in 1,230 patients with bare-metal in-stent restenosis. Studies reported the clinical outcomes of efficacy and safety during a minimum of 9 months. The primary outcome was target lesion revascularization.No significant heterogeneity was found across trials, thus showing a similar effect size regardless of the use of balloon angioplasty or vascular brachytherapy as comparators. The risk of target lesion revascularization (odds ratio 0.35, 95% confidence interval [CI] 0.25 to 0.49; p < 0.001) and that of angiographic restenosis (odds ratio 0.36, 95% CI 0.27 to 0.49; p = 0.001) were markedly lower in patients treated with drug-eluting stents. There were no differences between patients treated with drug-eluting stents and those treated with other techniques with respect to the composite of death or myocardial infarction (odds ratio 1.04, 95% CI 0.54 to 2.03; p = 0.55).Drug-eluting stents are markedly superior to conventional techniques (balloon angioplasty and vascular brachytherapy) and should be considered as first-line treatment for patients with bare-metal in-stent restenosis.

The purpose of this study was to evaluate image quality and radiation dose using a prospectively electrocardiogram (ECG)-triggered axial scan protocol compared with standard retrospective ECG-gated helical scanning for coronary computed tomography angiography.B A C K G R O U N D Concerns have been raised regarding radiation exposure during coronary computed tomography angiography.Although the use of prospectively ECG-triggered axial scan protocols may effectively lower radiation dose compared with helical scanning, it is unknown whether image quality is maintained in a clinical setting. M E T H O D SIn a prospective, multicenter, multivendor trial, 400 patients with low and stable heart rates were randomized to either an axial or a helical coronary computed tomography angiography scan protocol.The primary endpoint was to demonstrate noninferiority in image quality with the axial scan protocol, which was assessed on a 4-point scale (1 ϭ nondiagnostic, 4 ϭ excellent image quality).Secondary endpoints included radiation dose and the rate of downstream testing during 30-day follow-up. R E S U L T SImage quality in patients scanned with the axial scan protocol (score 3.36 Ϯ 0.59) was not inferior compared with helical scan protocols (3.37 Ϯ 0.59) (p for noninferiority Ͻ0.004).Axial scanning was associated with a 69% reduction in radiation exposure (dose-length product [estimated effective dose] 252 Ϯ 147 mGy • cm [3.5 Ϯ 2.1 mSv] vs. 802 Ϯ 419 mGy • cm [11.2 Ϯ 5.9 mSv] for axial vs. helical scan protocols, p Ͻ 0.001).The rate of downstream testing did not differ (13.8% vs. 15.9% for axial vs. helical scan protocols, p ϭ 0.555).C O N C L U S I O N S In patients with stable and low heart rates, the prospectively ECG-triggered axial scan protocol maintained image quality but reduced radiation exposure by 69% compared with helical scanning.Axial computed tomography data acquisition should be strongly recommended in suitable patients to avoid unnecessarily high radiation exposure.(Prospective Randomized Trial on Radiation Dose Estimates of CT Angiography in Patients Scanned With a Sequential Scan Protocol [PROTECTION-III];

We examined clinical outcomes in the Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment (ISAR-REACT) trial based on the duration of pretreatment with a 600-mg loading dose of clopidogrel.The influence of the treatment duration with a 600-mg dose of clopidogrel before percutaneous coronary revascularization on early outcomes remains uncertain.Among 2,159 patients with coronary disease who underwent percutaneous coronary intervention (PCI) in the ISAR-REACT trial, we examined clinical outcomes relative to the duration of pretreatment with a 600-mg dose of clopidogrel: (2 to 3 h, 3 to 6 h, 6 to 12 h, or >12 h). Patients were randomly assigned to adjunctive therapy with abciximab or placebo at the beginning of the study. The primary end point was a composite of death, myocardial infarction, or urgent revascularization within 30 days after randomization.No significant differences were observed between patient groups regarding the duration of pretreatment, irrespective of assignment to abciximab or placebo (p = 0.27 for interaction among abciximab/clopidogrel and placebo/clopidogrel treatment at each time interval). Occurrence of major bleeding also did not differ according to time of initial clopidogrel dosing.For low-to-intermediate risk patients treated with a 600-mg loading dose of clopidogrel before PCI, incremental clinical benefit within the first 30 days from durations of pretreatment >2 to 3 h was not evident.

HomeCirculationVol. 109, No. 25Coronary and Myocardial Angiography Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBCoronary and Myocardial AngiographyAngiographic Assessment of Both Epicardial and Myocardial Perfusion C. Michael Gibson, MS, MD and Albert Schömig, MD C. Michael GibsonC. Michael Gibson From the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Harvard Medical School and Deutsches Herzzentrum, München, Germany. and Albert SchömigAlbert Schömig From the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Harvard Medical School and Deutsches Herzzentrum, München, Germany. Originally published29 Jun 2004https://doi.org/10.1161/01.CIR.0000134278.50359.CBCirculation. 2004;109:3096–3105Angiographic assessment of epicardial coronary artery blood flow has played a pivotal role in our understanding of the "time-dependent open artery hypothesis" and in the evaluation of reperfusion strategies over the past 2 decades.1–8 It has become increasingly apparent, however, that clinical outcomes are not only associated with angiographic flow in the epicardial artery, but also with angiographic flow in the myocardium.9–13 To this end, the goal of reperfusion therapies has shifted to include reperfusion downstream at the level of capillary bed, and it might be more appropriate that the hypothesis now be termed "the time dependent open artery and open microvascular hypothesis." The goal of this article is to review angiographic methods used to evaluate myocardial ischemia and infarction and to discuss the insights into the pathophysiology of acute coronary syndromes provided by these angiographic indexes of coronary artery blood flow and myocardial perfusion.TIMI Flow Grades (TFGs)For nearly 2 decades now, the Thrombolysis In Myocardial Infarction (TIMI) flow grade classification scheme has been successfully used to assess coronary blood flow in acute coronary syndromes1 (Table). It has been a valuable tool to compare angiographic outcomes following reperfusion, and the association of the TFGs with clinical outcomes (including mortality) has been well documented.2–8 The relationship between TFG and mortality does satisfy what some consider to be 3 criteria required to validate a surrogate end point for mortality, as follows: (1) There is an association between TIMI grade 3 flow and mortality, (2) an agent such as recombinant tissue plasminogen activator improves TIMI grade 3 flow by 22% over another agent such as streptokinase, and (3) the agent tissue plasminogen activator improves mortality 1.1% over streptokinase. Definitions of the TFG and the TMPG SystemsGradeCharacteristicsTFG, a grading system for epicardial coronary flow 0No perfusion; no antegrade flow beyond the point of occlusion 1Penetration without perfusion; the contrast material passes beyond the area of obstruction but "hangs up" and fails to opacify the entire coronary bed distal to the obstruction for the duration of the cine run 2Partial reperfusion; the contrast material passes across the obstruction and opacifies the coronary bed distal to the obstruction. However, the rate of entry of contrast into the vessel distal to the obstruction and/or its rate of clearance from the distal bed is perceptibly slower than its entry into and/or clearance from comparable areas not perfused by the culprit vessel (eg, the opposite coronary artery or coronary bed proximal to the obstruction) 3Complete perfusion; antegrade flow into the bed distal to the obstruction occurs as promptly as into the bed proximal to the obstruction and clearance of contrast material from the involved bed is as rapid as from an uninvolved bed in the same vessel or the opposite arteryTMPG, a grading system for myocardial perfusion 0Dye fails to enter the microvasculature; there is either minimal or no ground glass appearance ("blush") or opacification of the myocardium in the distribution of the culprit artery indicating lack of tissue level perfusion 1Dye slowly enters but fails to exit the microvasculature; there is the ground glass appearance ("blush") or opacification of the myocardium in the distribution of the culprit lesion that fails to clear from the microvasculature, and dye staining is present on the next injection (approximately 30 seconds between injections) 2Delayed entry and exit of dye from the microvasculature; there is the ground glass appearance ("blush") or opacification of the myocardium in the distribution of the culprit lesion that is strongly persistent at the end of the washout phase (ie, dye is strongly persistent after 3 cardiac cycles of the washout phase and either does not diminish or only minimally diminishes in intensity during washout) 3Normal entry and exit of dye from the microvasculature; there is the ground glass appearance ("blush") or opacification of the myocardium in the distribution of the culprit lesion that clears normally, and it is either gone or only mildly/moderately persistent at the end of the washout phase (ie, dye is gone or is mildly/moderately persistent after 3 cardiac cycles of the washout phase and noticeably diminishes in intensity during the washout phase), similar to that in an uninvolved artery; blush that is of only mild intensity throughout the washout phase but fades minimally is also classified as grade 3On the basis of this relationship between TIMI flow and mortality observed in the GUSTO I [Global Utilization of Streptokinase and Tissue plasminogen activator (alteplase) for Occluded coronary arteries] angiographic trial, it was anticipated that an additional 20% improvement in TIMI 3 flow would be required to further improve mortality by another 1%. The disparity between the early results of trials evaluating combination therapy [low-dose fibrinolysis combined with full-dose glycoprotein IIb IIIa (GP IIbIIIa) inhibition] and the lack of mortality benefit in subsequent large-scale clinical trials has raised questions regarding the relationship between improvements in TIMI grade 3 flow and clinical outcomes. Despite the initial optimism of early dose-escalation trials involving low-dose fibrinolytic combined with full-dose GP IIbIIIa inhibition, later results in blinded parallel dose-confirmation phases yielded a modest 8% average improvement in TIMI grade 3 flow at 60 minutes and an even more modest 4% improvement at 90 minutes among 948 patients studied (Figure 1). On the basis of approximately a 6% improvement in early TIMI grade 3 flow, a 0.3% improvement in mortality in a large-scale mortality trial might be expected (6% observed TFG 3 improvement/20% required TFG 3 improvement for 1% mortality reduction =0.3%). The results of GUSTO V are in keeping with this modest estimated reduction with mortality rates of 5.9% and 5.6% (n=16 588, P=NS).14Download figureDownload PowerPointFigure 1. Despite initial optimism after early reports of dose-escalation trials involving low-dose fibrinolytic combined with full-dose GP IIbIIIa inhibition, later results in blinded parallel dose-confirmation phases yielded a modest 8% average improvement in TIMI grade 3 flow at 60 minutes and an even more modest 4% improvement at 90 minutes among 948 patients studied. TNK indicates tenecteplase.Care must be taken when extrapolating the results of angiographic patency studies to estimate potential clinical benefits. For example, the association of TIMI grade 3 flow with mortality is confounded by the fact that the majority of TIMI grade 2 flow is observed in the left anterior descending artery (LAD) territory, whereas the majority of TIMI grade 3 flow is observed in the right coronary artery (RCA).7 Thus, improved outcomes among patients with TIMI grade 3 flow are explained at least in part by the fact that inferior myocardial infarction (MI) location is associated with a lower mortality rate.7 Use of a more precise angiographic measure such as the TIMI frame count does support the notion that improved epicardial flow is associated with improved clinical outcomes; however, the magnitude of the clinical improvement associated with TIMI grade 3 flow may have been overestimated and may be nonlinear. Greater clinical benefits may be observed if a closed artery (TIMI grade 0/1 flow) is opened (TIMI grade 2 flow) compared with the magnitude of improvement that might occur if an artery with TIMI grade 2 flow is converted to TIMI grade 3 flow. As more arteries with TIMI grade 2 flow are treated with adjunctive percutaneous coronary intervention (PCI), the prognosis associated with this flow grade may improve. Indeed, 2-year mortality in more recent analyses indicates that the survival advantage of TIMI grade 3 flow over TIMI grade 2 flow at 2 years may not be as great as it once was in the era before aggressive utilization of rescue and adjunctive (PCI).10Indeed, one of the benefits of rescue and adjunctive PCI following fibrinolytic administration may be to reduce reocclusion. The benefit of achieving early patency is greatly reduced if it is not sustained as a result of reocclusion. Reinfarction is associated with a doubling in mortality, which is due to an early divergence in mortality by 30 days.15,16 Although early randomized trials failed to demonstrate a benefit in the performance of conventional angioplasty soon after fibrinolytic administration, these trials preceded the use of stents, thienopyridines, platelet GP IIb/IIIa inhibitors, and the monitoring of activated clotting times. Among 20 101 patients enrolled in recent TIMI trials, performance of PCI during the index hospitalization was associated with a lower rate of in-hospital recurrent MI (1.6% versus 4.5%, P<0.001) and lower 2-year mortality (5.6% versus 11.6%, P<0.001).16 The rates of PCI were low (≈10%) in GUSTO V, and this may account for the modest benefits observed among patients treated with combination therapy. Somewhat paradoxically, although one of the benefits of combination therapy was touted to be a reduction in "urgent revascularization," if such revascularization is actually beneficial by virtue of stabilizing the lesion and reducing the risk of reocclusion, then clinical outcomes may in fact be worse if a more successful pharmacological strategy lowers the rate of urgent revascularization.17 It should also be noted that while these angiographic measures are indexes of flow, and although they are associated with the risk of reocclusion,18 other nonangiographic processes may also underlie the pathophysiology of reocclusion as well as other clinical outcomes.Although poorer TFGs and poorer clinical outcomes are clearly associated, the directionality of any causal relationship between the two has not been unequivocally demonstrated. For instance, it is not clear whether slower blood flow causes larger MIs or alternatively whether larger MIs cause slower blood flow as a result of greater edema or microvascular disruption in the myocardium. Furthermore, cessation of coronary blood flow in acute MI does not explain all deaths, as there are other pathophysiological mechanisms by which patients may die in acute MI, such as intracranial hemorrhage. Finally, as discussed below, successful restoration of epicardial patency in the absence of successful myocardial perfusion may not confer large clinical benefits.The Corrected TIMI Frame Count: A Measure of the Time for Dye to Go Down the ArteryAlthough the TFG classification scheme has been a valuable tool for comparing the efficacy of reperfusion strategies and in the identification of patients at higher risk for adverse outcomes in acute coronary syndromes, there are limitations to this classification scheme.7 To overcome these limitations, one of us (C.M.G.) developed a new, more objective and precise index of coronary blood flow called the corrected TIMI frame count (CTFC), in which the number of cineframes required for dye to reach standardized distal landmarks are counted; this is essentially a measure of the time for dye to go down the artery.7,8,10In the first frame used for TIMI frame counting, a column of dye touches both borders of the coronary artery and moves forward (Figure 2).7 In the last frame, dye begins to enter (but does not necessarily fill) a standard distal landmark in the artery (Figure 2). These standard distal landmarks are as follows: in the RCA, the first branch of the posterolateral artery; in the circumflex system, the most distal branch of the obtuse marginal branch, which includes the culprit lesion in the dye path; and in the LAD, the distal bifurcation, which is also known as the "moustache," "pitchfork" or "whale's tail" (Figure 2). These frame counts are corrected for the longer length of the LAD by dividing by 1.7 to arrive at the CTFC.7 Knowing the time for dye to go down the artery from the CTFC (CTFC/30=seconds), and length of the artery (either from an angioplasty guide wire or by planimetry), dye velocity (cm/s) can also be calculated in a more refined fashion.19 This refined measure allows calculation of the velocity proximal and distal to the lesion.19Download figureDownload PowerPointFigure 2. TIMI frame-counting method. In the first frame (lower left panel), a column of near or fully concentrated dye touches both borders of the coronary artery and moves forward. In the last frame (second column), dye begins to enter (but does not necessarily fill) a standard distal landmark in the artery. These standard distal landmarks are as follows: the first branch of the posterolateral artery in the RCA (third column, top panel); in the circumflex system, the most distal branch of the obtuse marginal branch that includes the culprit lesion in the dye path (third column , middle panel); and in the LAD the distal bifurcation, which is also known as the moustache, pitchfork, or whale's tail (third column, bottom panel). Adapted from Gibson et al.7In contrast to the conventional TFG classification scheme, the CTFC is quantitative rather than qualitative, it is objective rather than subjective, it is a continuous rather than a categorical variable, and it is reproducible.7 Using the CTFC, coronary blood flow is unimodally distributed as a continuous variable.7 Thus, any division of flow into normal and abnormal categories is somewhat arbitrary. It should be noted that if an epicardial artery is occluded, then a frame count of 100 is imputed. This value of 100 lies near the 99th percentile for frame counts among open arteries in the ST-elevation MI (STEMI) setting. If values are imputed for closed arteries, then nonparametric analyses (eg, Wilcoxon rank sum tests) should be utilized because the dataset often follows a nonparametric distribution.In multiple studies, the CTFC has been shown to be quite reproducible with a 1- to 2-frame difference between observers.20–32 Similarly, 2 experienced angiographic core laboratories (GUSTO and TIMI) have analyzed the same films from a fibrinolytic trial with discrepancies in 21% of TFG readings (41/194, Kappa=0.76); however, excellent concordance in trial results were seen using the CTFC (overall median difference=0 frames).32 The CTFC is also accurate in that it is highly correlated with Doppler velocity wire measure of coronary flow reserve, distal velocity, average peak velocity, and volumetric flow, 21–23 as well as fractional flow reserve (r=0.85).24Technical Factors Influencing the CTFCNormally 21 frames are required for dye to traverse the human coronary artery.7 Despite differences in the length of the coronary arteries, the force of injections, the diameter of the arteries, heart rates, cardiac output, and catheter engagement, there is only a 3.1-frame standard deviation among patients with normal flow, and the 95% confidence interval for normal flow extends from >14 frames to <28 frames.7 Faster than normal or hyperemic flow is therefore defined as a CTFC <14 frames and constitutes what we now term "TIMI grade 4 flow."7 Although the CTFC is not used to determine the TFGs, in a retrospective analysis, the TIMI Angiographic Core Laboratory tended to classify flow as TIMI grade 2 flow if the CTFC was >40 (≈1.3 seconds).7A variety of technical and physiological variables impact the CTFC.20,33–36 Use of a power injector to change the force of injection (cc/sec) from the 10th to the 90th percentile of human injection rates lowers the CTFC by only 2 frames,33 nitrate administration significantly increases the CTFC by ≈6 frames (P<0.001),20 dye injection at the beginning of diastole significantly decreases the CTFC by 3 to 6 frames,20 and increasing the heart rate by 20 bpm significantly decreases the CTFC by ≈5 frames (P<0.001).20 It is for this reason that administration of nitrates is often standardized in trials assessing the CTFC as an end point. The mechanical force of injection alone in a closed artery following fibrinolytic therapy will open ≈10% of closed arteries,34 but the dye type used for injection is not associated with changes in the CTFC.35Relation of the CTFC to Clinical OutcomesThe CTFC following fibrinolytic administration is related to a variety of clinical outcomes.7,8,10,25–30 Flow in the infarct-related artery in survivors is significantly faster than in patients who die (49.5 versus 69.6 frames; P=0.0003).8 Mortality increases by 0.7% for every 10-frame rise in CTFC (P<0.001).8 None of the patients in the TIMI studies who have had a CTFC <14 (hyperemic or TIMI grade 4 flow) died by 30 days.8 Likewise, in patients with unstable angina (UA) or non-ST-elevation MI (NSTEMI), the post-PCI culprit flow among survivors is significantly faster than among those patients who died (CTFCs 20.4 versus 33.4 frames, P=0.017).37 Again, none of the 376 patients with a CTFC <14 following PCI died, underscoring the fact that, even within the subgroup of patients with "normal flow," there may be further subgroups with even better flow and even better mortality.37 Multiple studies have now documented an association between the CTFC and clinical outcomes among patients treated with primary PCI also, and the CTFC has demonstrated greater sensitivity in detecting improvements in epicardial flow compared with the use of TIMI grade 3 flow among patients treated with new device interventions.38–42With respect to other end points, the CTFC has also been related to a lower rate of restenosis, even when postprocedure diameters were corrected for.37 Thus, not only is "bigger better," but "faster is better" also. 37 Stankovic et al22 have built on these observations further by dividing the CTFC by the minimum lumen diameter to demonstrate that this measure, which integrates both anatomic and functional flow data, is the strongest predictor of restenosis in their study, and we have demonstrated that the ratio is associated with post-PCI death or MI.37 Slower CTFCs on surveillance angiography are also associated with higher rates of transplant rejection.43Insights Into the Pathophysiology of STEMI and UA/NSTEMI Based on the CTFCUntil recently, it was assumed that flow in nonculprit arteries in the setting of acute coronary syndromes was "normal." However, the CTFC in uninvolved arteries in acute STEMI (30.5 frames) is in fact 40% slower than normal (21 frames, P<0.001).7,44–46 In the setting of STEMI, adjunctive and rescue PCI restores flow in culprit vessels that is nearly identical to that of nonculprit arteries in the setting of acute MI (30.5 versus 30.5 frames, p=NS),44 but this flow remains slower than normal. PCI of the culprit lesion is also associated with improvements in the nonculprit artery after the intervention in both the STEMI and UA/NSTEMI settings.44,45 If abnormal flow was present in the nonculprit artery at baseline (ie, CTFC >28), then the improvements in nonculprit flow were more dramatic (10 frames).44 It is notable that slower flow throughout all 3 arteries in STEMI is associated with a higher risk of adverse outcomes,44 poorer wall motion in remote territories, 44 poorer tissue perfusion on digital subtraction angiography (DSA),45 and a greater magnitude of ST depression in remote territories such as the anterior precordium in inferior MI.47 It could be speculated that the poorer flow in nonculprit arteries may be the result of more extensive necrosis in shared microvasculature, or a result of vasoconstriction mediated through either a local neurohumoral or paracrine mechanism. Indeed, Gregorini et al48 have demonstrated that the CTFC and fractional wall shortening is improved in both the culprit and nonculprit arteries after administration of α-blockers, indicating that "α-adrenergic storm" may play a role. Finally, Willerson and others49–55 have demonstrated over the past 2 decades that a wide range of vasoconstrictors including thromboxane A2, serotonin, endothelin, oxygen-derived free radicals, and thrombin are all released in the setting of vessel injury and thrombosis.It has long been assumed that the residual stenosis in the setting of STEMI is largely responsible for the delay in flow. However, despite a 13% residual diameter stenosis and the relief of intraluminal obstruction that would be anticipated after stent placement, flow remains persistently delayed to 26 frames poststent, and likewise 34% of stented vessels remain with abnormal flow with a CTFC ≥28 (the 95th percentile of the upper limit of normal).56 This persistent delay is unlikely to be due to either the residual stenosis or intraluminal obstruction and points to the fact that there are other determinants of delayed epicardial blood flow. Multiple determinants of coronary blood flow at 90 minutes after fibrinolysis have been identified,56 and a map of their multiple interrelationships or colinearities observed in an expanded dataset is shown in Figure 3. All variables on the chart are related to impaired epicardial blood flow following fibrinolytic administration, and overlap of the Venn diagram among variables indicates which variables are related to each other. While the presence of pulsatile flow (systolic flow reversal), and a greater percentage of the vessel to the stenosis is associated with slower flow in the epicardial artery, these 2 variables are likewise associated with LAD infarct artery location. Likewise, poorer tissue perfusion (TMPG), tighter percent diameter stenoses, and a shorter duration of patency by 90 minutes (delayed opening in response to a fibrinolytic agent) are all associated with a longer duration of symptoms before arrival to the hospital. Download figureDownload PowerPointFigure 3. Multiple variables determine flow at 90 minutes, and they are often related to each other. These interassociations and their overall influence on flow are demonstrated in the figure as intersecting ellipses with directionality on improvements in flow illustrated by plus or minus signs.Obviously, the residual percent stenosis plays a critical role, with the average 70% stenosis increasing the CTFC by ≈17 frames.56 The presence of residual thrombus adds ≈4 frames.56 There are also unanticipated contributors to delayed flow such as the timing of reperfusion; ie, those patients who were patent at 60 minutes had 15 frames faster flow than those patients who achieved flow between 60 and 90 minutes. LAD infarcts had slower flow by 8 frames than infarcts in other locations. It could be speculated that left system infarcts have slower flow as a result of the fact that they have lesions that are located more proximally, they subtend the thicker left ventricular wall, and there is higher wall stress in the left ventricle than in the right ventricle.56Myocardial Angiography: The TIMI Myocardial Perfusion Grade (TMPG)Restoration of epicardial flow does not necessarily lead to restoration of tissue level or microvascular perfusion, as elegantly documented by Ito et al12,13 on myocardial contrast echocardiography. Perfusion of the myocardium can also be assessed using the angiogram. In the TMPG system, TMPG 0 represents minimal or no myocardial blush; in TMPG 1, dye stains the myocardium, and this stain persists on the next injection; in TMPG 2, dye enters the myocardium but washes out slowly so that dye is strongly persistent at the end of the injection; and in TMPG 3, there is normal entrance and exit of dye in the myocardium (Table). Another method of assessing myocardial perfusion on the angiogram is the myocardial blush grade (MBG) developed by van't Hof et al.57 A grade of 0 (no blush) and a grade of 3 (normal blush) are the same in the TMPG and MBG systems. An MBG grade 1 or 2 represents diminished intensity in the myocardium and corresponds to a value of 0.5 in the expanded TMPG grading system. A TMPG of 1 or a stain in the TIMI system is subsumed within the value of a 0 in the MBG system. Thus, normal perfusion in the myocardium carries a score of 3 in both the TMPG and MBG systems, and a closed muscle carries a score of 0 in both systems. Lepper et al58 have demonstrated that angiographic and echocardiographic myocardial perfusion are closely related, and among patients undergoing primary PCI for acute MI, impaired MBG was the best multivariate predictor of nonreperfusion on myocardial contrast echocardiography.Independent of flow in the epicardial artery and other covariates such as age, blood pressure, and pulse, the TMPG has been shown to be multivariate predictors of mortality in acute STEMI at 2 years.10 The TMPG permits risk stratification even within epicardial TIMI grade 3 flow. Despite achieving epicardial patency with normal TIMI grade 3 flow, those patients whose microvasculature fails to open (TMPG 0/1) have a 7-fold increase in mortality compared with those patients with both TIMI grade 3 flow in the epicardial artery. Achievement of both TIMI grade 3 flow in both the artery and the myocardium is associated with a mortality under 1%10 (Figure 4). Likewise, in the setting of primary PCI, both van't Hof et al57 and Haager et al59 have demonstrated an association between impaired myocardial perfusion and early and late mortality. These improvements in early and late mortality may be mediated by improvements in myocardial salvage.60 As Dibra et al60 have demonstrated, restoration of TMPG 2/3 is associated with a higher salvage index (0.49±0.42 versus 0.34±0.49, P=0.01) and a smaller final infarct size (15.4±15.5% versus 22.1±16.2% of the left ventricle, P=0.001). Indeed, second only to stent placement, restoration of TMPG 2/3 was the next most powerful independent determinant of the myocardial salvage index, and was more closely associated with higher salvage indexes than the TFGs.60Download figureDownload PowerPointFigure 4. The TMPG assesses tissue-level perfusion using the angiogram and is a multivariate predictor of mortality in acute MI. The TMPG permits risk stratification even within epicardial TIMI grade 3 flow. Despite achieving epicardial patency with normal TIMI grade 3 flow, those patients whose microvasculature fails to open (TMPG 0/1) have a persistently elevated mortality of 5.4% at 30 days. In contrast, those patients with both TIMI grade 3 flow in the epicardial artery and TMPG 3 have a mortality under 1% [0.7% [1/137] vs 4.7% [15/318]; P=0.05 using Fisher's exact test for TMPG 3 vs grades 0, 1, and 2). Adapted from Gibson et al.9The association between a prolonged duration of symptoms before treatment in ST-elevation MI with poorer clinical and angiographic outcomes has led to the phrase "time is myocardium." Indeed, the angiographic data do now provide mechanistic data to support this common notion. The association between increased time from symptom onset to treatment, worsened myocardial perfusion, and increased mortality rate has been demonstrated both in patients treated with fibrinolytic therapy61 and in those treated with primary angioplasty.62,63 Impaired myocardial perfusion on the angiogram has in turn been associated with greater left ventricular end-diastolic pressure64 and the presence of overt congestive heart failure on presentation.65 Among patients presenting with cardiogenic shock, a restoration of normal myocardial perfusion is associated with improved survival.66There are data associating abnormal myocardial perfusion on the angiogram with slower Doppler velocity measurements in the epicardial artery.67 Does abnormal myocardial perfusion slow epicardial flow, or, alternatively, does abnormal epicardial flow impair myocardial perfusion? Although there is likely a bidirectional nature to any causal relationship between the two, after restoration of full epicardial patency (eg, after the scaffolding of the lesion by intracoronary stent placement), it is likely that impaired myocardial perfusion may play a major role in reducing antegrade flow in the epicardial artery. A variety of drugs are available to treat abnormal myocardial perfusion, but aside from adenosine, their association with improved clinical outcomes remains largely untested.68Association of Electrocardiographic Findings With Angiographic Findings in STEMIThe ECG (ST resolution) and the angiogram provide insight into myocardial perfusion. It is notable that both the ST segment resolution and the TMPG provide independent prognostic information with respect to SPECT infarct size.11 Likewise, with respect to clinical outcomes, 2 additional studies have now documented the complementary prognostic information provided by the ECG (degree of ST resolution) and the angiographic blush, with failure to achieve ST resolution and a closed myocardium on angiography following primary PCI carrying a particularly poor prognosis.59,69 These data suggest a potential electromechanical dissociation between microvascular blood flow and myocyte function. Whereas the angiogram may reflect mechanical patency of the microvasculature and the integrity of the endothelium, the

Despite recent advances in interventional cardiology, including the introduction of drug-eluting stents for de novo coronary lesions, the treatment of in-stent restenosis (ISR) remains a challenging clinical issue. Given the efficacy of systemic sirolimus administration to prevent neointimal hyperplasia in animal models and to halt and even reverse the progression of allograft vasculopathy, the aim of the present double-blind, placebo-controlled study was to evaluate the efficacy of a 10-day oral sirolimus treatment with 2 different loading regimens for the prevention of recurrent restenosis in patients with ISR.Three hundred symptomatic patients with ISR were randomly assigned to 1 of 3 treatment arms: placebo or usual-dose or high-dose sirolimus. Patients received a cumulative loading dose of 0, 8, or 24 mg of sirolimus 2 days before and the day of repeat intervention followed by maintenance therapy of 2 mg/d for 7 days. Angiographic restenosis at 6-month angiography was the primary end point of the study. Restenosis was significantly reduced from 42.2% to 38.6% and to 22.1% in the placebo, usual-dose, and high-dose sirolimus groups, respectively (P=0.005). Similarly, the need for target vessel revascularization was reduced from 25.5% to 24.2% and to 15.2% in the placebo, usual-dose, and high-dose groups, respectively (P=0.08). The sirolimus blood concentration on the day of the procedure correlated significantly with the late lumen loss at follow-up (P<0.001).In patients with ISR, an oral adjunctive sirolimus treatment with an intensified loading regimen before coronary intervention resulted in a significant improvement in the angiographic parameters of restenosis.

The prodrug clopidogrel requires activation by cytochrome P-450 (CYP) enzymes for its antiplatelet effect. The genes encoding enzymes for clopidogrel activation are polymorphic, leading to reduced or increased function, depending on the respective genotype. Reduced-function alleles have been associated with an increase in cardiovascular events.We tested the association of the presence of the ABCB1 (C/T) T-allele, CYP2C19*2 (G/A) A-allele, or CYP2C19*17 (C/T) T-allele with the primary end point of the need of clinically-driven target lesion revascularization (TLR) and the secondary end points of major adverse cardiovascular events (MACE; including death, myocardial infarction [MI], and TLR) at 1 year in a high-risk population of 928 patients with acute MI.Carriers of the CYP2C19*17 T-allele, with increased clopidogrel activation, had a 37% relative reduction in the TLR incidence, the primary end point (14.0% vs 22.3%, P = .002), and a 22% relative reduction of the secondary end point MACE (22.0% vs 28.1%, P = .04) compared with noncarriers, respectively. The association of the T-allele with TLR remained significant in the multivariate analysis (P = .001). The ABCB1 (C/T) and the CYP2C19*2 (G/A) polymorphisms were not associated with the incidence of TLR or MACE.Based on the genetic analysis in a high-risk population of acute MI patients with interventional treatment and continuous clopidogrel therapy, our study found a protective effect for carriers of an increased-function CYP2C19*17 T-allele with significantly lower rates of TLR and MACE. T-allele carriers with acute MI and increased clopidogrel activation had significantly reduced clinical event rates.

Matrix metalloproteinases (MMPs) are thought to promote progression of atherosclerosis and cardiovascular complications such as plaque rupture. It has been suggested that, on tumor cells, the extracellular MMP inducer (EMMPRIN) is involved in MMP synthesis by as yet unknown mechanisms. On cardiovascular cells, regulation of EMMPRIN in vivo or any functional relevance for MMP induction in vitro has not yet been studied. Thus, we studied EMMPRIN expression on monocytes in acute myocardial infarction (MI) and its potential relevance for MMP activation.In 20 patients with acute MI, surface expression of EMMPRIN was significantly enhanced on monocytes compared with in 20 patients with chronic stable angina. EMMPRIN upregulation was associated with increased expression of the membrane type 1 MMP (MT1-MMP) on monocytes (flow cytometry) as well as MMP-9 activity (gelatin zymography) in the plasma. At 6 months after successful revascularization, EMMPRIN, MT1-MMP, and MMP-9 had normalized. The secretion of MMP-9 by monocytes was induced by monocyte adhesion to immobilized recombinant EMMPRIN or to EMMPRIN-transfected Chinese hamster ovary cells. Moreover, adherent EMMPRIN-transfected monocytic cells stimulated MMP-2 activity of human vascular smooth muscle cells. Gene silencing of EMMPRIN by small-interfering RNA hindered lipopolysaccharide-induced monocyte secretion of MMP-9, indicating a predominant role of EMMPRIN in MMP-9 induction.EMMPRIN and MT1-MMP are upregulated on monocytes in acute MI. During cellular interactions, EMMPRIN stimulates MMP-9 in monocytes and MMP-2 in smooth muscle cells, indicating that EMMPRIN may display a key regulatory role for MMP activity in cardiovascular pathologies.

The investigation of no-reflow phenomenon after percutaneous coronary intervention (PCI) in patients with acute ST-segment-elevation myocardial infarction has therapeutic implications. We investigated the predictive factors, persistence in time, and impact of no reflow on myocardial salvage, ventricular function, and mortality.The study included 1140 patients with ST-segment-elevation myocardial infarction undergoing primary PCI and paired scintigraphic examinations (before intervention and 7 to 14 days thereafter). After primary PCI, 108 patients had no reflow and 1032 patients had normal coronary flow. The median salvage index was 0.34 (interquartile range, 0.15, 0.49) in patients with no reflow versus 0.55 (interquartile range, 0.29, 0.81) in patients with normal flow (P<0.001). Left ventricular ejection fraction at 6 months after PCI was 47.7+/-13.1% in the no-reflow group versus 54.2+/-13.9% in the group with normal flow after PCI (P<0.001). In 80.3% of patients with no reflow, normalization of blood flow >6 months after PCI occurred and correlated with improvement in the left ventricular ejection fraction. Independent predictors of no reflow were residual flow in the infarct-related artery (P<0.001), initial perfusion defect (P=0.03), C-reactive protein (P<0.001), and previous myocardial infarction (P=0.013). Kaplan-Meier estimates of 1-year mortality were 16.7% (n=18) in patients with no reflow versus 5.5% (n=56) in patients with normal flow (hazard ratio, 3.35; 95% CI, 1.97 to 5.69; P<0.001).No reflow after primary PCI was associated with reduced myocardial salvage, larger infarct size, worse left ventricular ejection fraction at 6 months, and increased risk of 1-year mortality. In 4 of 5 patients with no reflow after PCI, restoration of normal flow occurred 6 months after reperfusion.

The role of the sympathetic nervous systme and of arginine vasopressine (AVP) in the mediation of the central cardiovascular effects of angitotensin II (ANG II) and substance P (SP) was investigated. ANG II and SP caused dose-dependent blood pressure increases when injected into the lateral brain ventricle (i.c.v.) of conscious rats; ANG II was tenfold more potent than SP. Peripheral blockade of α-adrenoceptors with prazosin or blockade of the vasopressor action of AVP by the AVP antagonist d(CH2)5 VDAVP both partially inhibited the pressor responses to central ANG II. Combined treatment with the two blockers produced almost complete inhibition of the central ANG II responses. Substance P injected i.c.v. produced increases in noradrenaline and adrenaline but not AVP in the plasma. Peripheral α-receptor blockade by prazosin reversed the central pressor effects of SP to depressor responses. The AVP antagonist did not alter the cardiovascular responses to SP. It is concluded that in onscious animals, stimulation of the sympathetic nervous system and release of AVP contribute to the central pressor action of ANG II to a similar extent and independently of each other. In contrast, the central pressor responses to SP appear to be exclusively mediated by the sympathetic nervous system without participation of AVP.

The objective of this meta-analysis was to evaluate the effect of stem cell mobilization by granulocyte colony-stimulating factor (G-CSF) on myocardial regeneration on the basis of a synthesis of the data generated by randomized, controlled clinical trials of G-CSF after acute myocardial infarction (AMI).Experimental studies and early-phase clinical trials suggest that stem cell mobilization by G-CSF may have a positive impact on cardiac regeneration after AMI. The role of G-CSF in patients with AMI remains unclear considering the inconsistent results of several clinical trials.For our analysis, PubMed, the Cochrane Central Register of Controlled Trials, conference proceedings from major cardiology meetings, and Internet-based sources of information on clinical trials in cardiology from January 2003 to August 2007 served as sources. Two reviewers independently identified studies and abstracted data on sample size, baseline characteristics, and outcomes of interest. Eligible studies were randomized trials with stem cell mobilization by G-CSF after reperfused AMI that reported data regarding the change in left ventricular ejection fraction (LVEF) at follow-up.Ten trials using stem cell mobilization by G-CSF, including 445 patients, met the inclusion criteria. Significant improvement in LVEF at follow-up was observed in both the G-CSF and placebo groups. Compared with placebo, stem cell mobilization by G-CSF did not enhance the improvement of LVEF at follow-up (mean difference 1.32% [95% confidence interval -1.52 to 4.16; p = 0.36]). Moreover, the mean difference of reduction of infarct size between the treatment and placebo groups was -0.15 (95% confidence interval -0.38 to 0.07, p = 0.17).Cumulatively, available evidence does not support a beneficial effect of G-CSF in patients with AMI after reperfusion.

This study sought to evaluate the diagnostic value of contrast-enhanced magnetic resonance imaging (CMR) and single-photon emission computed tomography (SPECT) for detection of myocardial necrosis after acute myocardial infarction (AMI).Single-photon emission computed tomography is widely accepted in the clinical setting for detection and estimation of myocardial infarction. Contrast-enhanced magnetic resonance imaging offers technical advantages and is therefore a promising new method for identification of infarcted tissue.Seventy-eight patients with AMI were examined by CMR and SPECT 7 days after percutaneous coronary intervention. Contrast-enhanced magnetic resonance imaging and SPECT images were scored for presence and location of infarction using a 17-segment model. Results were compared with the peak troponin T level, electrocardiographic, and angiographic findings.Acute myocardial infarction was detected significantly more often by CMR than SPECT (overall sensitivity: 97% vs. 87%; p = 0.008). Sensitivity of CMR was superior to SPECT in detecting small infarction as assessed by the peak troponin T level <3.0 ng/ml (92 vs. 69%; p = 0.03), and infarction in non-anterior location (98% vs. 84%; p = 0.03). Non-Q-wave infarctions were more likely to be detected by CMR (sensitivity 85% vs. 46%; p = 0.06). While CMR offered high sensitivity for detection of AMI irrespective of the infarct-related artery, SPECT was less sensitive, particularly within the left circumflex artery territory.Contrast-enhanced magnetic resonance imaging is superior to SPECT in detecting myocardial necrosis after reperfused AMI because CMR detects small infarcts that were missed by SPECT independent of the infarct location. Thus, CMR is attractive for accurate detection and assessment of the myocardial infarct region in patients early after AMI.

In atherosclerosis, circulating platelets interact with endothelial cells and monocytes, leading to cell activation and enhanced recruitment of leukocytes into the vascular wall. The invasion of monocytes is accompanied by overexpression of matrix metalloproteinases (MMPs), which are thought to promote atherosclerosis and trigger plaque rupture. Following interaction with itself, the extracellular matrix metalloproteinase inducer (EMMPRIN) induces MMP synthesis via a little-known intracellular pathway. Recently, we showed upregulation of EMMPRIN on monocytes during acute myocardial infarction. EMMPRIN also stimulates secretion of MMP-9 by monocytes and of MMP-2 by smooth muscle cells, indicating that it may be an important regulator of MMP activity. Expression of EMMPRIN on platelets has not been described until now. Here, we demonstrate that resting platelets show low surface expression of EMMPRIN, which is upregulated by various platelet stimulators (flow cytometry). EMMPRIN is located in the open canalicular system and in alpha granules of platelets (according to electron microscopy and sucrose gradient ultracentrifugation). Platelet stimulation with recombinant EMMPRIN-Fc induced surface expression of CD40L and P-selectin (according to flow cytometry), suggesting that EMMPRIN-EMMPRIN interaction activates platelets. Coincubation of platelets with monocytes induced EMMPRIN-mediated nuclear factor kappaB activation (according to Western blot) in monocytes with increased MMP-9 (zymography), interleukin-6, and tumor necrosis factor-alpha secretion (according to ELISA) by monocytes. In conclusion, EMMPRIN displays a new platelet receptor that is upregulated on activated platelets. Binding of EMMPRIN to platelets fosters platelet degranulation. Platelet-monocyte interactions via EMMPRIN stimulate nuclear factor kappaB-driven inflammatory pathways in monocytes, such as MMP and cytokine induction. Thus, EMMPRIN may represent a novel target to diminish the burden of protease activity and inflammation in atherosclerosis.

The aim of this study was to compare the 3-year efficacy and safety of biodegradable polymer with permanent polymer stents and of everolimus-eluting stents (EES) with sirolimus-eluting stents (SES). Biodegradable polymer drug-eluting stents (DES) offer potential for enhanced late outcomes in comparison with permanent polymer stents. In addition, there is increasing interest in the comparison of EES (Xience, Abbott Vascular, Abbott Park, Illinois) versus SES (Cypher, Cordis Corporation, Miami Lakes, Florida). The ISAR-TEST 4 (Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents-4) was a randomized clinical trial with broad inclusion criteria, enrolling 2,603 patients at 2 clinics in Munich, Germany. Patients were randomized to either biodegradable polymer (n = 1,299) or permanent polymer stents (n = 1,304); patients treated with permanent polymer stents were randomly allocated to EES (n = 652) or SES (n = 652). The primary endpoint was the composite of cardiac death, target vessel-related myocardial infarction, or target lesion revascularization. Clinical events continued to accrue at a low rate out to 3 years in all groups. Overall, there was no significant difference between biodegradable polymer and permanent polymer DES with regard to the primary endpoint (20.1% vs. 20.9%, hazard ratio [HR]: 0.95, 95% confidence interval [CI]: 0.80 to 1.13; p = 0.59). Rates of definite/probable stent thrombosis were also similar in both groups (1.2% vs. 1.7%, respectively; HR: 0.71, 95% CI: 0.37 to 1.39; p = 0.32). In patients treated with permanent polymer stents, EES were comparable to SES with regard to the primary endpoint (19.6% vs. 22.2%, respectively; HR: 0.87, 95% CI: 0.68 to 1.11; p = 0.26) as well as definite/probable stent thrombosis (1.4% vs. 1.9%, HR: 0.75, 95% CI: 0.32 to 1.78; p = 0.51). Biodegradable polymer and permanent polymer DES are associated with similar clinical outcomes at 3 years. In addition, EES are comparable to SES in terms of overall clinical efficacy and safety. (Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting STents [ISAR-TEST 4]: Prospective, Randomized Trial of 3-limus Agent-eluting Stents With Different Polymer Coatings; NCT00598676)