Abstract: There is ongoing debate to identify the most effective, safe and cost-beneficial drug-eluting stent, between the two currently approved and used devices, i.e. sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES). To date, head-to-head comparison studies of SES vs PES have been however limited by relatively small sample sizes and the low number of events typically associated with these highly effective coronary devices. To overcome the drawbacks of single trials, direct and indirect comparison meta-analyses have been designed and conducted to thoroughly compare sirolimus- vs paclitaxel eluting-stents. This article provides results of a pooled analysis of such indirect and direct comparisons, definitively demonstrating across 5854 patients the superiority of SES in comparison to PES (odds ratio 0.62 [95% confidence interval 0.50-0.75], p<0.0001 for binary angiographic restenosis, and odds ratio 0.66 [0.52-0.84], p=0.0008 for target lesion revascularization). Indeed, such combination of direct and indirect comparisons should also be envisaged to soundly and timely appraise the next generation of drug-eluting stents.

Abstract: BACKGROUND: Clopidogrel is an established alternative to ticlopidine in addition to aspirin after coronary stenting because of its safety, but its optimal initial dosing is unclear. We performed a systematic review and meta-regression of randomized clinical trials comparing clopidogrel versus ticlopidine, focusing on clopidogrel front-loading. METHODS: PubMed was searched for pertinent studies (updated August 2006). Random-effect odds ratios (ORs) with 95% CIs were computed for death or nonfatal myocardial infarction, and weighted least squares random-effect meta-regression was performed to explore the impact of loading versus nonloading clopidogrel scheme. RESULTS: We retrieved 7 trials (3382 patients, average follow-up of 7 months). In 5 studies, both clopidogrel and ticlopidine were started with a loading dose, in 1 trial clopidogrel was administered without loading, and in 1 trial clopidogrel could be administered with or without loading. Overall analysis (P for heterogeneity = .02) showed similar results for clopidogrel and ticlopidine (OR 0.90, 95% CI 0.44-1.84, P = .77). In studies administering clopidogrel with loading, this treatment was, however, significantly better than ticlopidine (OR 0.60, 95% CI 0.36-0.99, P = .05). This significant interaction between clopidogrel loading and its superiority in comparison with ticlopidine was also formally confirmed by meta-regression (beta = -0.64, P = .012). CONCLUSIONS: This work supports the superiority of a clopidogrel regimen including an initial loading dose in comparison with ticlopidine in patients undergoing coronary stenting.

Abstract: Rupture of vulnerable plaques is the main cause of acute coronary syndromes and myocardial infarctions. Identification of these vulnerable plaques is therefore essential to enable the development of treatment modalities to stabilize them. Several intravascular technologies, investigating coronary areas that will be responsible for future events, are highlighted in this review. The ideal technique would provide morphological, mechanical and biochemical information. Although several imaging techniques are currently under development, none of them alone provides such an all-embracing assessment. Optical coherence tomography has the advantage of high resolution, thermography has the potential to measure metabolism, and Raman spectroscopy obtains information on chemical components. Intravascular coronary ultrasound (IVUS) and IVUS-palpography are easy to perform and assess morphology and mechanical instability. Shear stress is an important mechanical parameter deeply influencing vascular biology. Nevertheless, all these techniques are still under investigation and, at present, none of them can unequivocally and comprehensively identify a vulnerable plaque and, most importantly, predict its further development. From a clinical point of view, most techniques currently assess only one feature of the vulnerable plaque. Thus, a combination of several modalities will be important in the future to ensure a high sensitivity and specificity in detecting vulnerable plaques.

Abstract: Background Due to the recently published results of the MAGIC study there is confusion as to whether administration of granulocyte-colony stimulating factor (G-CSF) after acute myocardial infartion (MI) should be regarded as a potentially harmful treatment. This meta-analysis of appropriate clinical studies is intended to show the impact of G-CSF given after MI on aggravated incidence of coronary restenosis or progression of coronary lesions. Methods and Results We used a fixed effects model based on the Mantel-Haenszel method to combine results from the different trials. These studies provided the basis for the current analysis comprising 106 patients of whom 62 were subjected to G-CSF treatment. <BR> Minimum lumen diameter (MLD) measured immediately after percutaneous coronary intervention (PCI) was similar in both groups with a diameter stenosis of 12.3+/-9.5 percent in the G-CSF and 10.3+/-8.5 percent in the control group (p=0.32). At follow-up, both MLD and percent stenosis were not different between G-CSF-treated and control patients. Subsequently, averaged late lumen loss revealed similar results and no differences between groups (p=0.11), and neither stent thrombosis nor reinfarction in either group. Conclusions The current meta-analysis of clinical reports fails to justify an elevated risk for coronary restenosis after PCI in acute MI or adverse events following G-CSF in the setting of MI when used after state of the art treatment in carefully conducted clinical protocols.

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Abstract: BACKGROUND: The long-term effects of treatment with sirolimus-eluting stents, as compared with bare-metal stents, have not been established. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Abstract: OBJECTIVES: We sought to evaluate the impact of unstable coronary artery disease (CAD) on short- and mid-term outcomes in patients with multivessel disease treated by multiple sirolimus-eluting stents (SES) as part of ARTS II (Arterial Revascularization Therapies Study Part II). BACKGROUND: The differential safety/efficacy profile of SES when implanted in patients with unstable angina (UA) in comparison with stable angina (SA) undergoing multivessel intervention is largely unknown. METHODS: Between February 2003 and November 2003, 607 patients at 45 participating centers were treated; 221 of them (36%) presented with UA. RESULTS: At 30 days, the cumulative rate of death, myocardial infarction-defined as any creatine kinase (CK)/CK-myocardial band elevation beyond the upper limit of normal-cerebrovascular accident, and repeat revascularization (i.e., major adverse cardiac and cerebrovascular events [MACCEs]) was 19.9% in both groups. Angiographic subacute stent occlusion was documented in 1 (0.5%) and 4 (1%) patients in the UA and SA groups, respectively. At 1 year, the cumulative incidence of MACCEs was 27.1% in the UA and 24.9% in the SA group (p = 0.56). Two late occlusions occurred, both in the SA group. After adjustment for baseline and procedural characteristics, the presence of UA was not identified as an independent predictor of MACCE (hazard ratio 0.94; 95% confidence interval 0.41 to 2.12; p = 0.88). These findings remained consistent after increasing the CK/CK-myocardial band threshold to define periprocedural myocardial infarction up to at least 3 or 5 times the upper limit of normal. CONCLUSIONS: In ARTS II, an unstable clinical presentation did not exert a negative impact on short- and mid-term outcome after SES implantation for multivessel disease. (ARTS II Trial; ; NCT00235170).

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Abstract: Combined antiplatelet treatment with aspirin and clopidogrel is pivotal to minimize periprocedural adverse events in patients who undergo percutaneous coronary intervention. However, there is debate on the best clopidogrel loading dose. The investigators performed a systematic review and meta-analysis of the optimal clopidogrel loading dose. Pertinent trials comparing high (>300 mg) and standard (300 mg) clopidogrel loading doses in patients scheduled for catheterization and/or percutaneous coronary intervention were systematically searched in BioMedCentral, CENTRAL, Google Scholar, and PubMed (December 2006). The primary end point was the 1-month rate of death or myocardial infarction. Secondary end points included other ischemic and bleeding adverse effects. Peto odds ratios were computed. A total of 10 studies (7 randomized, 3 nonrandomized) were included, enrolling 1,567 patients (712 loaded with 300 mg, 11 with 450 mg, 790 with 600 mg, and 54 with 900 mg). Overall, a high loading dose proved significantly superior to a standard loading dose in preventing cardiac death or nonfatal myocardial infarction (odds ratio 0.54, 95% confidence interval 0.32 to 0.90, p = 0.02), without any statistically significant increase in major or minor bleedings (p = 0.55 and p = 0.98, respectively). Sensitivity analysis restricted to randomized trials confirmed the superiority of a high loading dose regimen (p = 0.0031). Meta-regression disclosed a significant interaction between event rate and the benefits of high loading doses (p = 0.005), suggesting that the greater the underlying risk, the greater the favorable impact of a high loading dose. In conclusion, a high clopidogrel loading dose (>300 mg) significantly reduces early ischemic events in patients scheduled for percutaneous coronary intervention.

Abstract: Aims To compare the efficacy and safety of drug-eluting stents vs. bare-metal stents in patients with acute ST-segment elevation myocardial infarction. Methods and results 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. Conclusion 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.

Abstract: BACKGROUND: Current treatment standards for patients undergoing primary percutaneous coronary intervention support early infusion of abciximab, followed by bare-metal stent (BMS) implantation. Whether the use of sirolimus-eluting stent (SES) would result in a further improvement of clinical outcomes remains to be proven. Similarly, whether tirofiban administered at high-bolus dose (HBD) followed by standard infusion is a valuable alternative to abciximab in the setting of ST-segment elevation myocardial infarction remains uncertain. STUDY DESIGN: Multicentre evaluation of single high-bolus dose tirofiban versus abciximab and sirolimus-eluting versus bare metal stent in acute myocardial infarction (MULTI-STRATEGY) is a phase III, open-label, multinational investigator-driven clinical trial evaluating, with a 2-by-2 factorial design, the safety/efficacy profile of 4 interventional strategies of reperfusion: tirofiban given at HBD (bolus of 25 microg/kg over 3 minutes), followed by an infusion of 0.15 microg/kg per minute for 18 to 24 hours versus abciximab and SES, as compared to BMS implantation in primary percutaneous coronary intervention. The coprimary objectives are (i) the evaluation of the effect of SES versus BMS on the incidence of major adverse cardiac events within 8 months of the index procedure and (ii) the degree of ST-segment resolution obtained after the mechanical intervention for the comparison of HBD tirofiban versus abciximab. The protocol mandates clinical follow-up for 5 years. CONCLUSIONS: MULTI-STRATEGY will evaluate the role of SES and HBD tirofiban versus BMS and abciximab in the acute management of patients presenting with ST-segment elevation myocardial infarction.

Abstract: BACKGROUND: The presence of a lumen narrowing at the ostium and the body of an unprotected left main coronary artery but does not require bifurcation treatment is a class I indication of surgical revascularization. METHODS AND RESULTS: A total of 147 consecutive patients who had a stenosis in the ostium and/or the midshaft of an unprotected left main coronary artery (treatment of the bifurcation not required) and were electively treated with percutaneous coronary intervention and sirolimus-eluting stents (n=107) or paclitaxel-eluting stents (n=40) in 5 centres were included in this registry. In 72 patients (almost 50%), intravascular ultrasound guidance was performed. Procedural success was achieved in 99% of the patients; in 1 patient with stenosis in the left main coronary artery ostium, a >30% residual stenosis persisted at the end of the procedure, and the patient was referred for coronary artery bypass graft surgery. During hospitalization, no patients experienced a Q-wave myocardial infarction or died. One patient died 19 days after the procedure because of pulmonary infection. At long-term clinical follow-up (886+/-308 days), 5 patients had died; 7 patients had target vessel revascularization (5 repeat percutaneous coronary interventions and 2 coronary artery bypass graft surgeries), and of these only 1 patient had a target lesion revascularization. Angiographic follow-up was performed in 106 patients (72%) with a late loss of -0.01 mm. Restenosis in the left main trunk occurred only in 1 patient (0.9%). CONCLUSIONS: Percutaneous coronary intervention with sirolimus-eluting stents or paclitaxel-eluting stents implantation in nonbifurcation left main coronary artery lesions appears safe with a long-term major adverse clinical event rate of 7.4% and a restenosis rate of 0.9%.

Abstract: It has been demonstrated recently that coagulation factor XIII (FXIII) plays an extraordinary role in myocardial healing after infarction, improving survival in a mouse model. Common FXIII gene variants (i.e. FXIIIA-V34L and FXIIIB-H95R) significantly influence the molecular activity. To evaluate whether there is a relationship between the two FXIII gene variants and survival in patients after myocardial infarction (MI), V34L and H95R were PCR-genotyped in a cohort of 560 MI cases and follow-up was monitored. Cases with ST-segment elevation MI (STEMI) were 416 (74.3%) and 374 of these were treated with primary percutaneous coronary intervention (PCI) (89.9%). The remaining 144 patients showed non-ST-segment elevation MI (NSTEMI) at enrollment. The combined endpoint was the occurrence of death, re-infarction, and heart failure. Kaplan-Meier analysis at one year yielded an overall rate for adverse events of 24.5% with a lower incidence in the L34-carriers (28.8% vs 17.1%; log-rank, P = 0.00025), similar to that of the 416 STEMI (23.8%) being (28.0% and 16.9%; VV34- and L34-carriers respectively; log-rank, P = 0.001). Primary PCI-group had a slight lower incidence (22.9%) of adverse events (26.8% and 17.1%; VV34- and L34-carriers respectively; log-rank, P = 0.009). During hospitalization, 506 patients received PCI (374 primary PCI and 132 elective PCI). Significance was conserved also in the overall PCI-group (28.6% and 17.8%; VV34- and L34-carriers respectively; log-rank, P = 0.001). Similar findings were observed at 30 days follow-up. Cases carrying both FXIII variants had improved survival rate (log-rank, P = 0.019). On the other hand, minor bleeding complications were found increased in L34-carriers (P = 0.0001) whereas major bleeding complications were not. Finally, more direct evidence on the role of FXIII molecule on survival might come from the fact that despite significant FXIII antigen reductions observed in cases after MI, regardless the FXIII genotype considered, L34-carriers kept almost normal FXIII activity (VV34- vs L34-carriers; P < 0.001). We conclude that FXIII L34-allele improves survival after MI in all the groups analyzed, possibly through its higher activity associated with assumable positive effects on myocardial healing and recovered functions. Genetically determined higher FXIII activity might influence post-MI outcome. This paves the way for using FXIII molecules to improve myocardial healing, recovery of functions, and survival after infarction.

Abstract: OBJECTIVES: We sought to investigate whether the previously reported midterm clinical benefit of planned sirolimus-eluting stent (SES) implantation in patients with ST-segment elevation myocardial infarction (STEMI) was maintained over a 24-month time period. Moreover, the distribution of clinical events in relation to thienopyridine discontinuation was thoroughly investigated. BACKGROUND: No randomized data are currently available on the safety/benefit profile of SES in this subset of patients beyond 12 months. METHODS: Between March 2003 and April 2004, 175 patients with STEMI were randomly allocated to tirofiban infusion followed by SES or abciximab plus bare-metal stent (BMS). Complete follow-up information up to 720 days was available for all patients. RESULTS: The cumulative incidence of death, myocardial infarction (MI), or target vessel revascularization (TVR) remained lower in the tirofiban-SES compared with the abciximab-BMS group at 2 years (24.2% vs. 38.6%, respectively; hazard ratio [HR] 0.56 [95% confidence interval (CI) 0.33 to 0.98]; p = 0.038). The composite of death/MI was similar in the tirofiban-SES (16.1%) and the abciximab-BMS groups (20.5%, HR 0.77 [95% CI 0.38 to 1.55]; p = 0.43) while the need for TVR was markedly reduced (9.8% vs. 25.5%, respectively; HR 0.34 [95% CI 0.16 to 0.77]; p = 0.01) in the tirofiban-SES arm. The rate of confirmed, probable, or possible stent thrombosis did not differ in the 2 groups, nor the incidence of death/MI after thienopyridine discontinuation. CONCLUSIONS: The midterm clinical benefit of planned SES implantation assisted by tirofiban infusion in STEMI patients was mainly carried over after 2 years with no overall excess of late adverse events after thienopyridine discontinuation.

Abstract: OBJECTIVE: To obtain a quantitative estimate of the overall costs and cost effectiveness ratio of sirolimus-eluting stents (SES) implantation and tirofiban infusion compared to abciximab and bare metal stent (BMS) in patients undergoing primary intervention for acute ST segment elevation myocardial infarction (STEMI). METHODS: In the attempt to make the unrestricted use of SES in STEMI patients affordable under the current European reimbursement system, between March 6, 2003, and April 23, 2004, 175 patients with STEMI were randomized to receive tirofiban infusion and SES versus abciximab and BMS as part of the STRATEGY trial. Costs and outcome were monitored for 2 years. RESULTS: The cost of the index procedure was euro9345+/-2573 and euro9657+/-2114 for the tirofiban+SES and abciximab+BMS group, respectively (P=0.048). At follow-up, the composite of death or myocardial infarction and the costs not related to target vessel revascularisation (TVR) did not differ in the two groups while the rate of TVR and the costs related to it were lower in the tirofiban+SES group. The overall 2-year cost of treating a patient in the tirofiban+SES group was euro10,971+/-4185 compared to euro12,066+/-4636 for the abciximab+BMS group (P=0.006). Halving the cost of abciximab resulted in higher initial hospital costs for the tirofiban+SES but overall cost neutrality over a 24-month time horizon. CONCLUSIONS: Compared to abciximab+BMS, tirofiban infusion+SES implantation in STEMI patients was an economically dominant strategy, with an improved composite outcome and lower overall costs.

Abstract: OBJECTIVES: This study was designed to investigate whether poor responders to thienopyridines after clopidogrel remain so even after ticlopidine administration (class effect) or whether a drug-specific effect exists between currently available thienopyridines. BACKGROUND: Whether clopidogrel poor responders also display inadequate platelet inhibition after ticlopidine administration remains undefined. METHODS: Platelet aggregation (PA) was measured in 143 patients, while they were taking aspirin, with light transmission aggregometry using adenosine diphosphate as an agonist at baseline (T0) and at clopidogrel steady state (T1). After T1) clopidogrel was stopped and substituted with ticlopidine. Then PA was assessed at ticlopidine steady state (T2). Resistance was defined as an absolute difference between T0 and after-treatment (T1 or T2) PA < or =10%. RESULTS: Clopidogrel and ticlopidine responsiveness was normally distributed; PA at T1 did not differ compared with T2. Thirty (21%) and 28 (19%) patients were clopidogrel and ticlopidine nonresponders, respectively. Only 5 patients (3.5%) were nonresponders to both clopidogrel and ticlopidine (class effect), whereas 25 patients (83%) who were clopidogrel nonresponders at T1 were responsive to ticlopidine, reaching a higher level of platelet inhibition at T2 (PA 69 +/- 15 vs. 44 +/- 18, p < 0.01) (drug-specific response). On the other hand, 23 patients who were responsive to clopidogrel showed resistance to ticlopidine at T2 (PA 46 +/- 15 vs. 70 +/- 15, p < 0.01) (drug-specific response). CONCLUSIONS: Poor responsiveness to either clopidogrel or ticlopidine at steady state was common, whereas nonresponders to both drugs were relatively infrequent (3.5%, 95% confidence interval 1.5% to 7.9%), suggesting that poor response to thienopyridines may frequently be a drug-specific mechanism.

Abstract: AIMS: This study sought to evaluate the effect of perindopril in coronary remodelling. METHODS AND RESULTS: In this sub-study of a double-blind, multicentre trial, patients without clinical evidence of heart failure were randomized to perindopril 8 mg/day or placebo for at least 3 years and IVUS investigation was performed at both time-points. Positive and negative remodelling were defined as a relative increase (positive remodelling) or decrease (negative remodelling) of the mean vessel cross-sectional area (CSA)>2 SD of the mean intra-observer difference. A total of 118 matched evaluable IVUS (711 matched 5 mm segments) were available at follow-up. After a median follow-up of 3.0 (inter-quartile range 1.9, 4.1) years, there was no significant difference in the change of plaque CSA between perindopril (360 segments) and placebo (351 segments) groups, P=0.27. Conversely, the change in vessel CSA was significantly different between groups (perindopril -0.18+/-2.4 mm2 vs. placebo 0.19+/-2.4, P = 0.04). Negative remodelling occurred more frequently in the perindopril than in the placebo group (34 vs. 25%, P=0.01). In addition, the placebo group showed a larger, although not significant, mean remodelling index (RI) than the perindopril group (1.03+/-0.2 vs. 1.00+/-0.2, P=0.06). The temporal change in vessel dimensions assessed by the RI was significantly correlated with the change in plaque dimensions (r=0.48, P<0.0001). CONCLUSION: In this sub-analysis of a multicentre, controlled study, long-term administration of perindopril was associated with a constrictive remodelling pattern without affecting the lumen.

Abstract: Background Due to the recently published results of the MAGIC study there is confusion as to whether administration of granulocyte-colony stimulating factor (G-CSF) after acute myocardial infartion (MI) should be regarded as a potentially harmful treatment. This meta-analysis of appropriate clinical studies is intended to show the impact of G-CSF given after MI on aggravated incidence of coronary restenosis or progression of coronary lesions. Methods and Results We used a fixed effects model based on the Mantel-Haenszel method to combine results from the different trials. These studies provided the basis for the current analysis comprising 106 patients of whom 62 were subjected to G-CSF treatment. <BR> Minimum lumen diameter (MLD) measured immediately after percutaneous coronary intervention (PCI) was similar in both groups with a diameter stenosis of 12.3+/-9.5 percent in the G-CSF and 10.3+/-8.5 percent in the control group (p=0.32). At follow-up, both MLD and percent stenosis were not different between G-CSF-treated and control patients. Subsequently, averaged late lumen loss revealed similar results and no differences between groups (p=0.11), and neither stent thrombosis nor reinfarction in either group. Conclusions The current meta-analysis of clinical reports fails to justify an elevated risk for coronary restenosis after PCI in acute MI or adverse events following G-CSF in the setting of MI when used after state of the art treatment in carefully conducted clinical protocols.

Abstract: BACKGROUND: Clopidogrel is an established alternative to ticlopidine in addition to aspirin after coronary stenting because of its safety, but its optimal initial dosing is unclear. We performed a systematic review and meta-regression of randomized clinical trials comparing clopidogrel versus ticlopidine, focusing on clopidogrel front-loading. METHODS: PubMed was searched for pertinent studies (updated August 2006). Random-effect odds ratios (ORs) with 95% CIs were computed for death or nonfatal myocardial infarction, and weighted least squares random-effect meta-regression was performed to explore the impact of loading versus nonloading clopidogrel scheme. RESULTS: We retrieved 7 trials (3382 patients, average follow-up of 7 months). In 5 studies, both clopidogrel and ticlopidine were started with a loading dose, in 1 trial clopidogrel was administered without loading, and in 1 trial clopidogrel could be administered with or without loading. Overall analysis (P for heterogeneity = .02) showed similar results for clopidogrel and ticlopidine (OR 0.90, 95% CI 0.44-1.84, P = .77). In studies administering clopidogrel with loading, this treatment was, however, significantly better than ticlopidine (OR 0.60, 95% CI 0.36-0.99, P = .05). This significant interaction between clopidogrel loading and its superiority in comparison with ticlopidine was also formally confirmed by meta-regression (beta = -0.64, P = .012). CONCLUSIONS: This work supports the superiority of a clopidogrel regimen including an initial loading dose in comparison with ticlopidine in patients undergoing coronary stenting.

Abstract: Rupture of vulnerable plaques is the main cause of acute coronary syndromes and myocardial infarctions. Identification of these vulnerable plaques is therefore essential to enable the development of treatment modalities to stabilize them. Several intravascular technologies, investigating coronary areas that will be responsible for future events, are highlighted in this review. The ideal technique would provide morphological, mechanical and biochemical information. Although several imaging techniques are currently under development, none of them alone provides such an all-embracing assessment. Optical coherence tomography has the advantage of high resolution, thermography has the potential to measure metabolism, and Raman spectroscopy obtains information on chemical components. Intravascular coronary ultrasound (IVUS) and IVUS-palpography are easy to perform and assess morphology and mechanical instability. Shear stress is an important mechanical parameter deeply influencing vascular biology. Nevertheless, all these techniques are still under investigation and, at present, none of them can unequivocally and comprehensively identify a vulnerable plaque and, most importantly, predict its further development. From a clinical point of view, most techniques currently assess only one feature of the vulnerable plaque. Thus, a combination of several modalities will be important in the future to ensure a high sensitivity and specificity in detecting vulnerable plaques.

Abstract: The Syntax score (SXscore) was recently developed as a comprehensive angiographic scoring system aiming to assist in patient selection and risk stratification of patients with extensive coronary artery disease undergoing contemporary revascularization. A validation of this angiographic classification scheme is lacking. We assessed its predictive value in patients who underwent percutaneous intervention (PCI) for 3-vessel disease and explored its performance in comparison with the modified lesion classification system of the American Heart Association/American College of Cardiology. The SXscore, applied to 1,292 lesions in 306 patients who underwent PCI for 3-vessel disease in the Arterial Revascularization Therapies Study Part II, was 4 to 54.5, and after a median of 370 days (range 274 to 400) predicted the rate of major adverse cardiac and cerebrovascular events (hazard ratio 1.08/U increase, 95% confidence interval 1.05 to 1.11, p <0.0001), with patients in the highest SXscore tertile having a significantly higher event rate (27.9%) than patients in the lowest tertile (8.7%, hazard ratio 3.5, 95% confidence interval 1.7 to 7.4, p = 0.001). By multivariable analyses, SXscore independently predicted outcome with an almost fourfold adjusted increase in the risk of major adverse cardiac and cerebrovascular events in patients with high versus low values based on the discrimination level provided by classification and regression tree analysis. Compared with the modified lesion classification scheme of the American Heart Association/American College of Cardiology, SXscore showed a greater discrimination ability (c-index 0.58 +/- 0.08 vs 0.67 +/- 0.08, respectively, p <0.001) and a better goodness of fit with the Hosmer-Lemeshow statistic. In conclusion, the SXscore is a promising tool to risk stratify outcome in patients with extensive coronary artery disease undergoing contemporary PCI.

Abstract: Combined antiplatelet treatment with aspirin and clopidogrel is pivotal to minimize periprocedural adverse events in patients who undergo percutaneous coronary intervention. However, there is debate on the best clopidogrel loading dose. The investigators performed a systematic review and meta-analysis of the optimal clopidogrel loading dose. Pertinent trials comparing high (>300 mg) and standard (300 mg) clopidogrel loading doses in patients scheduled for catheterization and/or percutaneous coronary intervention were systematically searched in BioMedCentral, CENTRAL, Google Scholar, and PubMed (December 2006). The primary end point was the 1-month rate of death or myocardial infarction. Secondary end points included other ischemic and bleeding adverse effects. Peto odds ratios were computed. A total of 10 studies (7 randomized, 3 nonrandomized) were included, enrolling 1,567 patients (712 loaded with 300 mg, 11 with 450 mg, 790 with 600 mg, and 54 with 900 mg). Overall, a high loading dose proved significantly superior to a standard loading dose in preventing cardiac death or nonfatal myocardial infarction (odds ratio 0.54, 95% confidence interval 0.32 to 0.90, p = 0.02), without any statistically significant increase in major or minor bleedings (p = 0.55 and p = 0.98, respectively). Sensitivity analysis restricted to randomized trials confirmed the superiority of a high loading dose regimen (p = 0.0031). Meta-regression disclosed a significant interaction between event rate and the benefits of high loading doses (p = 0.005), suggesting that the greater the underlying risk, the greater the favorable impact of a high loading dose. In conclusion, a high clopidogrel loading dose (>300 mg) significantly reduces early ischemic events in patients scheduled for percutaneous coronary intervention.

Abstract: BACKGROUND: Clopidogrel is an established alternative to ticlopidine in addition to aspirin after coronary stenting because of its safety, but its optimal initial dosing is unclear. We performed a systematic review and meta-regression of randomized clinical trials comparing clopidogrel versus ticlopidine, focusing on clopidogrel front-loading. METHODS: PubMed was searched for pertinent studies (updated August 2006). Random-effect odds ratios (ORs) with 95% CIs were computed for death or nonfatal myocardial infarction, and weighted least squares random-effect meta-regression was performed to explore the impact of loading versus nonloading clopidogrel scheme. RESULTS: We retrieved 7 trials (3382 patients, average follow-up of 7 months). In 5 studies, both clopidogrel and ticlopidine were started with a loading dose, in 1 trial clopidogrel was administered without loading, and in 1 trial clopidogrel could be administered with or without loading. Overall analysis (P for heterogeneity = .02) showed similar results for clopidogrel and ticlopidine (OR 0.90, 95% CI 0.44-1.84, P = .77). In studies administering clopidogrel with loading, this treatment was, however, significantly better than ticlopidine (OR 0.60, 95% CI 0.36-0.99, P = .05). This significant interaction between clopidogrel loading and its superiority in comparison with ticlopidine was also formally confirmed by meta-regression (beta = -0.64, P = .012). CONCLUSIONS: This work supports the superiority of a clopidogrel regimen including an initial loading dose in comparison with ticlopidine in patients undergoing coronary stenting.

Abstract: A 36-year-old man was admitted with reported short attacks of acute chest pain with small increment of troponin and CK-MB and normal ECG. The 64-slice CT coronary angiography revealed a large non-obstructing non-calcified plaque in the proximal left anterior descending artery with positive vessel remodeling. The conventional coronary angiogram was normal but the intravascular ultrasound confirmed the CT findings. A drug eluting stent was implanted to seal the plaque. During the procedure, myocardial damage had occurred. At 6-month follow-up, 64-slice CT revealed minimal in-stent hyperplasia, which was confirmed at conventional angiography.

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Abstract: There is ongoing debate to identify the most effective, safe and cost-beneficial drug-eluting stent, between the two currently approved and used devices, i.e. sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES). To date, head-to-head comparison studies of SES vs PES have been however limited by relatively small sample sizes and the low number of events typically associated with these highly effective coronary devices. To overcome the drawbacks of single trials, direct and indirect comparison meta-analyses have been designed and conducted to thoroughly compare sirolimus- vs paclitaxel eluting-stents. This article provides results of a pooled analysis of such indirect and direct comparisons, definitively demonstrating across 5854 patients the superiority of SES in comparison to PES (odds ratio 0.62 [95% confidence interval 0.50-0.75], p<0.0001 for binary angiographic restenosis, and odds ratio 0.66 [0.52-0.84], p=0.0008 for target lesion revascularization). Indeed, such combination of direct and indirect comparisons should also be envisaged to soundly and timely appraise the next generation of drug-eluting stents.

Abstract: There is ongoing debate to identify the most effective, safe and cost-beneficial drug-eluting stent, between the two currently approved and used devices, i.e. sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES). To date, head-to-head comparison studies of SES vs PES have been however limited by relatively small sample sizes and the low number of events typically associated with these highly effective coronary devices. To overcome the drawbacks of single trials, direct and indirect comparison meta-analyses have been designed and conducted to thoroughly compare sirolimus- vs paclitaxel eluting-stents. This article provides results of a pooled analysis of such indirect and direct comparisons, definitively demonstrating across 5854 patients the superiority of SES in comparison to PES (odds ratio 0.62 [95% confidence interval 0.50-0.75], p<0.0001 for binary angiographic restenosis, and odds ratio 0.66 [0.52-0.84], p=0.0008 for target lesion revascularization). Indeed, such combination of direct and indirect comparisons should also be envisaged to soundly and timely appraise the next generation of drug-eluting stents.

Abstract: There is ongoing debate to identify the most effective, safe and cost-beneficial drug-eluting stent, between the two currently approved and used devices, i.e. sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES). To date, head-to-head comparison studies of SES vs PES have been however limited by relatively small sample sizes and the low number of events typically associated with these highly effective coronary devices. To overcome the drawbacks of single trials, direct and indirect comparison meta-analyses have been designed and conducted to thoroughly compare sirolimus- vs paclitaxel eluting-stents. This article provides results of a pooled analysis of such indirect and direct comparisons, definitively demonstrating across 5854 patients the superiority of SES in comparison to PES (odds ratio 0.62 [95% confidence interval 0.50-0.75], p<0.0001 for binary angiographic restenosis, and odds ratio 0.66 [0.52-0.84], p=0.0008 for target lesion revascularization). Indeed, such combination of direct and indirect comparisons should also be envisaged to soundly and timely appraise the next generation of drug-eluting stents.

Abstract: OBJECTIVES: We sought to investigate whether plaques located in the left main stem (LMS) differ in terms of necrotic core content from those sited in the proximal tract of the left coronary artery. BACKGROUND: Plaque composition, favoring propensity to vulnerability, might be nonuniformly distributed along the vessel, which might explain the greater likelihood for plaque erosion or rupture to occur in the proximal but not in the distal tracts of the coronary artery or in LMS. METHODS: A total of 72 patients were included prospectively; 48 (32 men; mean age 57 +/- 11 years; 25 with stable angina and 23 affected by acute coronary syndromes) underwent a satisfactory nonculprit vessel investigation through spectral analysis of intravascular ultrasound radiofrequency data (IVUS-Virtual Histology, Volcano Corp., Rancho Cordova, California). The region of interest was subsequently divided into LMS and LMS carina, followed by 6 consecutive nonoverlapping 6-mm segments in left anterior descending artery in 34 patients or in circumflex artery in 14 patients. RESULTS: Necrotic core content (%): 1) was minimal in LMS (median [interquartile range]: 4.6 [2 to 7]), peaked in the first 6-mm coronary segment (11.8 [8 to 16]; p < 0.01), and then progressively decreased distally; 2) was overall greater in patients with acute coronary syndromes (11.4 [5.5 to 19.8]) than stable angina (7.3 [3.2 to 12.9]; p < 0.001); 3) was largely independent from plaque size; and 4) did not correlate to systemic levels of C-reactive protein or lipid profile. CONCLUSIONS: Plaques located in the LMS carry minimal necrotic content. Thus, they mimic the distal but not the proximal tract of the left coronary artery, where plaque rupture or vessel occlusion occurs more frequently.

Abstract: BACKGROUND: Current treatment standards for patients undergoing primary percutaneous coronary intervention support early infusion of abciximab, followed by bare-metal stent (BMS) implantation. Whether the use of sirolimus-eluting stent (SES) would result in a further improvement of clinical outcomes remains to be proven. Similarly, whether tirofiban administered at high-bolus dose (HBD) followed by standard infusion is a valuable alternative to abciximab in the setting of ST-segment elevation myocardial infarction remains uncertain. STUDY DESIGN: Multicentre evaluation of single high-bolus dose tirofiban versus abciximab and sirolimus-eluting versus bare metal stent in acute myocardial infarction (MULTI-STRATEGY) is a phase III, open-label, multinational investigator-driven clinical trial evaluating, with a 2-by-2 factorial design, the safety/efficacy profile of 4 interventional strategies of reperfusion: tirofiban given at HBD (bolus of 25 microg/kg over 3 minutes), followed by an infusion of 0.15 microg/kg per minute for 18 to 24 hours versus abciximab and SES, as compared to BMS implantation in primary percutaneous coronary intervention. The coprimary objectives are (i) the evaluation of the effect of SES versus BMS on the incidence of major adverse cardiac events within 8 months of the index procedure and (ii) the degree of ST-segment resolution obtained after the mechanical intervention for the comparison of HBD tirofiban versus abciximab. The protocol mandates clinical follow-up for 5 years. CONCLUSIONS: MULTI-STRATEGY will evaluate the role of SES and HBD tirofiban versus BMS and abciximab in the acute management of patients presenting with ST-segment elevation myocardial infarction.

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Abstract: Combined antiplatelet treatment with aspirin and clopidogrel is pivotal to minimize periprocedural adverse events in patients who undergo percutaneous coronary intervention. However, there is debate on the best clopidogrel loading dose. The investigators performed a systematic review and meta-analysis of the optimal clopidogrel loading dose. Pertinent trials comparing high (>300 mg) and standard (300 mg) clopidogrel loading doses in patients scheduled for catheterization and/or percutaneous coronary intervention were systematically searched in BioMedCentral, CENTRAL, Google Scholar, and PubMed (December 2006). The primary end point was the 1-month rate of death or myocardial infarction. Secondary end points included other ischemic and bleeding adverse effects. Peto odds ratios were computed. A total of 10 studies (7 randomized, 3 nonrandomized) were included, enrolling 1,567 patients (712 loaded with 300 mg, 11 with 450 mg, 790 with 600 mg, and 54 with 900 mg). Overall, a high loading dose proved significantly superior to a standard loading dose in preventing cardiac death or nonfatal myocardial infarction (odds ratio 0.54, 95% confidence interval 0.32 to 0.90, p = 0.02), without any statistically significant increase in major or minor bleedings (p = 0.55 and p = 0.98, respectively). Sensitivity analysis restricted to randomized trials confirmed the superiority of a high loading dose regimen (p = 0.0031). Meta-regression disclosed a significant interaction between event rate and the benefits of high loading doses (p = 0.005), suggesting that the greater the underlying risk, the greater the favorable impact of a high loading dose. In conclusion, a high clopidogrel loading dose (>300 mg) significantly reduces early ischemic events in patients scheduled for percutaneous coronary intervention.

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Abstract: OBJECTIVE: We sought to explore in vivo the relation between mechanical and compositional properties of matched cross sections (CSs) using novel catheter-based techniques. BACKGROUND: Intravascular ultrasound (IVUS) palpography allows the assessment of local mechanical tissue properties. Spectral analysis of IVUS radiofrequency data (IVUS-VH) is a tool to assess plaque morphology and composition. METHODS AND RESULTS: Palpography analysis defined high- and low-strain regions. One hundred twenty-three CSs (27 vessels) were colocalized. The mean strain value was higher in CSs with necrotic core (NC) in contact with the lumen than in CSs with no NC contact with the lumen (1.03 +/- 0.5 vs 0.86 +/- 0.4, P = .06). Mean relative calcium (1.61 +/- 2.5% vs 0.25 +/- 0.7%, P = .001) and NC (15.64 +/- 10.6% vs 2.8 +/- 3.9%, P < .001) content were significantly higher in the CSs with NC in contact with the lumen, whereas the inverse was seen for the fibrotic component of the plaque (64.16 +/- 11.6% vs 75.75 +/- 13.7, P < .001). The sensitivity, specificity, positive predictive value, and negative predictive value of IVUS-VH to detect high strain were 75.0%, 44.4%, 56.3%, and 65.1%, respectively. A significant inverse relationship was present between calcium and strain levels (r = -0.20, P = .03). After adjusting for univariate predictors, the contact of NC with the lumen was identified as the only independent predictor of high strain (OR 5.0, 95% CI 1.7-14.1, P = .003). CONCLUSION: In the present study, IVUS-VH showed an acceptable sensitivity to detect high strain. In turn, the specificity was low. Of interest, a significant inverse relationship was present between calcium and strain levels.

Abstract: OBJECTIVES: This study sought to investigate whether the anatomical location of the disease carries prognostic implications in patients undergoing drug-eluting stent (DES) implantation for the left main coronary artery (LMCA) stenosis. BACKGROUND: Liberal use of DES, compared with a bare metal stent (BMS), has resulted in an improved outcome in patients undergoing LMCA intervention. However, the overall event rate in this subset of patients remains high, and alternative tools to risk-stratify this population beyond conventional surgical risk status would be desirable. METHODS: From April 2002 to June 2004, 130 patients received DES as part of the percutaneous intervention for LMCA stenoses in our institution. Distal LMCA disease (DLMD) was present in 94 patients. They were at higher surgical risk and presented with a greater coronary disease extent compared with patients without DLMD. RESULTS: After a median of 587 days (range 368 to 1,179 days), the cumulative incidence of major adverse cardiac events (MACE) was significantly higher in patients with DLMD at 30% versus 11% in those without DLMD (hazard ratio [HR] 3.42, 95% confidence interval [CI] 1.34 to 9.7; p = 0.007), mainly driven by the different rate of target vessel revascularization (13% and 3%; HR 6, 95% CI 1.2 to 29; p = 0.02). After adjustment for confounders, DLMD (HR 2.79,95% CI 1.17 to 8.9; p = 0.032) and surgical risk status (HR 2.18,95% CI 1.06 to 4.5; p = 0.038) remained independent and complementary predictors of MACE. CONCLUSIONS: Distal LMCA disease carries independent prognostic implications, and it may help in selecting the most appropriate patient subset for LMCA intervention beyond the conventional surgical risk status in the DES era.

Abstract: BACKGROUND: Identification of subclinical high-risk plaques is potentially important because they may have greater likelihood of rupture and subsequent thrombosis. The purpose of this study was to assess the relationship between plaque composition determined by intravascular ultrasound (IVUS) radio frequency (RF) data analysis and clinical presentation. METHODS: In 55 patients, a nonculprit vessel with < 50% diameter stenosis was studied with IVUS. Tissue maps were reconstructed from RF data using IVUS-Virtual Histology software. RESULTS: Mean percentage of the different plaque components were 0.99% +/- 0.9%, calcium; 68.04% +/- 9.8%, fibrous; 19.31% +/- 7.3%, fibrolipidic; and 9.43% +/- 6.6%, lipid core. Mean lipid core percentage was significantly larger in patients with acute coronary syndrome (ACS) when compared with stable patients (12.26% +/- 7.0% vs 7.40% +/- 5.5%, P = .006). In addition, stable patients showed more fibrotic vessels (70.97% +/- 9.3% vs 63.96% +/- 9.1%, P = .007). There was no significant difference for either mean calcium (1.20% +/- 1.1% vs 0.83% +/- 0.7%, P = .124) or fibrolipidic (20.57% +/- 6.9% vs 18.40% +/- 7.6%, P = .281) percentages in ACS and stable patients, respectively. Vessel area obstruction did not differ between groups (46.49% +/- 10.9% vs 42.83% +/- 11.8%, P = .221). There was a significant, albeit weak, positive correlation between lipid core percentage and stenosis severity as determined by vessel area obstruction (r = 0.34, P = .015). CONCLUSIONS: In this study, plaque characterization of nonculprit vessels using spectral analysis of IVUS RF data analysis was significantly related to clinical presentation. Percentage of lipid core, a feature related to acute coronary events and worse prognosis, was significantly larger in patients with ACS. Conversely, stable patients showed more fibrotic content.

Abstract: OBJECTIVE: To appraise multiple systematic reviews on the same clinical topic, focusing on predictors and correlates of quality of reporting of meta-analysis (QUOROM) scores. DESIGN: Case study. SETTING: Reviews providing at least individual quantitative estimates on role of acetylcysteine in the prevention of contrast associated nephropathy. DATA SOURCES: PubMed, the database of abstracts of reviews of effects, and the Cochrane database of systematic reviews (updated March 2005). MAIN OUTCOME MEASURES: Funding, compliance with the QUOROM checklist, scores on the Oxman and Guyatt quality index, and authors' recommendations. RESULTS: 10 systematic reviews, published August 2003 to March 2005, were included. Nine pooled events despite heterogeneity and five recommended routine use of acetylcysteine, whereas the remaining studies called for further research. Compliance with the 18 items on the QUOROM checklist was relatively high (median 16, range 11 to 17), although shorter manuscripts had significantly lower scores (R = 0.73; P = 0.016). Reviewers who reported previous not for profit funding were more likely to score higher on the Oxman and Guyatt quality index. No association was found between QUOROM and Oxman and Guyatt scores (R = -0.06; P = 0.86), mainly because of greater emphasis of the Oxman and Guyatt scores on the appraisal of bias in selection and validity assessment (inadequate in five reviews). CONCLUSIONS: Multiple systematic reviews on the same clinical topic varied in quality of reporting and recommendations. Longer manuscripts and previous not for profit funding were associated with higher quality.

Abstract: AIMS: To compare the global characteristics of patients with and without evidence of plaque rupture (PR) in their coronary tree and to evaluate the phenotype of ruptured plaques using intravascular ultrasound (IVUS) radiofrequency data analysis (IVUS-VH). METHODS AND RESULTS: Forty patients underwent three-vessel IVUS-VH interrogation. Twenty-eight PRs were diagnosed in 26 vessels (25.7% of the vessels studied) of 20 patients (50% of the population). Ruptures located in the left anterior descending were clustered in the proximal part of the vessel, whereas ruptures located in the right coronary artery were more distally located (P=0.02). Patients with at least one PR presented larger body mass index (BMI) (28.4+/-3.7 vs. 25.8+/-2.6 kg/m(2), P=0.01) and plaque burden (40.7+/-7.6 vs. 33.7+/-8.4%, P=0.01) than patients without rupture, despite showing similar lumen cross-sectional area (9.6+/-3.3 vs. 9.2+/-2.3 mm(2), P=0.60). Among current smokers, 66.7% presented a PR in their coronary tree. Finally, PR sites showed a higher content of necrotic core compared with minimum lumen area sites (17.48+/-10.8 vs. 13.10+/-6.5%, P=0.03) and a trend towards higher calcified component. CONCLUSION: Patients with at least one PR in their coronary tree presented larger BMI and worse IVUS-derived characteristics compared with patients without PR.

Abstract: OBJECTIVES: The purpose of this study was to assess in vivo the reproducibility of tissue characterization using spectral analysis of intravascular ultrasound (IVUS) radiofrequency data (IVUS-VH). BACKGROUND: Despite the need for reproducibility data to design longitudinal studies, such information remains unexplored. METHODS AND RESULTS: IVUS-VH (Volcano Corp., Rancho Cordova, USA) was performed in patients referred for elective percutaneous intervention and in whom a non-intervened vessel was judged suitable for a safe IVUS interrogation. The IVUS catheters used were commercially available catheters (20 MHz, Volcano Corp., Rancho Cordova, USA). Following IVUS-VH acquisition, and after the disengagement and re-engagement of the guiding catheter, an additional acquisition was performed using a new IVUS catheter. Fifteen patients with 16 non-significant lesions were assessed by 2 independent observers. The relative inter-catheter differences regarding geometrical measurements were negligible for both observers. The inter-catheter relative difference in plaque cross-sectional area (CSA) was 3.2% for observer 1 and 0.5% for observer 2. The limits of agreement for (observer 1 measurements) lumen, vessel, plaque and plaque burden measurements were 0.82, -1.10 mm(2); 0.80, -0.66 mm(2); 1.08, -0.66 mm(2); and 5.83, -3.89%; respectively. Limits of agreement for calcium, fibrous, fibrolipidic and necrotic core CSA measurements were 0.22, -0.25 mm(2); 1.02, -0.71 mm(2); 0.61, -0.65 mm(2); and 0.43, -0.38 mm(2) respectively. Regarding the inter-observer agreement, the limits of agreement for lumen, vessel, plaque and plaque burden measurements were 2.61, -2.09 mm(2); 2.20-3.03 mm(2); 1.70, -3.04 mm(2); and 9.16, -16.41%; respectively, and for calcium, fibrous, fibrolipidic and necrotic core measurements of 0.08, -0.09 mm(2); 0.89, -1.28 mm(2); 0.74, -1.06 mm(2); and 0.16, -0.20 mm(2); respectively. CONCLUSIONS: The present study demonstrates that the geometrical and compositional output of IVUS-VH is acceptably reproducible.

Abstract: OBJECTIVE: To appraise multiple systematic reviews on the same clinical topic, focusing on predictors and correlates of quality of reporting of meta-analysis (QUOROM) scores. DESIGN: Case study. SETTING: Reviews providing at least individual quantitative estimates on role of acetylcysteine in the prevention of contrast associated nephropathy. DATA SOURCES: PubMed, the database of abstracts of reviews of effects, and the Cochrane database of systematic reviews (updated March 2005). MAIN OUTCOME MEASURES: Funding, compliance with the QUOROM checklist, scores on the Oxman and Guyatt quality index, and authors' recommendations. RESULTS: 10 systematic reviews, published August 2003 to March 2005, were included. Nine pooled events despite heterogeneity and five recommended routine use of acetylcysteine, whereas the remaining studies called for further research. Compliance with the 18 items on the QUOROM checklist was relatively high (median 16, range 11 to 17), although shorter manuscripts had significantly lower scores (R = 0.73; P = 0.016). Reviewers who reported previous not for profit funding were more likely to score higher on the Oxman and Guyatt quality index. No association was found between QUOROM and Oxman and Guyatt scores (R = -0.06; P = 0.86), mainly because of greater emphasis of the Oxman and Guyatt scores on the appraisal of bias in selection and validity assessment (inadequate in five reviews). CONCLUSIONS: Multiple systematic reviews on the same clinical topic varied in quality of reporting and recommendations. Longer manuscripts and previous not for profit funding were associated with higher quality.

Abstract: OBJECTIVES: The purpose of this study was to investigate the long-term clinical and angiographic profile of sirolimus-eluting stent (SES) versus paclitaxel-eluting stent (PES) in patients undergoing percutaneous intervention for left main (LM) coronary disease. BACKGROUND: The long-term clinical and angiographic impact of SES as opposed to PES implantation in this subset of patients is unknown. METHODS: From April 2002 to March 2004, 110 patients underwent percutaneous intervention for LM stenosis at our institution; 55 patients were treated with SES and 55 with PES. The two groups were well balanced for all baseline characteristics. RESULTS: At a median follow-up of 660 days (range 428 to 885), the cumulative incidence of major adverse cardiovascular events was similar (25% in the SES group vs. 29%, in the PES group; hazard ratio 0.88 [95% confidence interval 0.43 to 1.82]; p = 0.74), reflecting similarities in both the composite death/myocardial infarction (16% in the SES group and 18% in the PES group) and target vessel revascularization (9% in the SES group and 11% in the PES group). Angiographic in-stent late loss (mm), evaluated in 73% of the SES group and in 77% of the PES group, was 0.32 +/- 74 in the main and 0.36 +/- 0.59 in the side branch in the SES group vs. 0.46 +/- 0.57 (p = 0.36) and 0.52 +/- 0.42 (p = 0.41) in the PES group, respectively. CONCLUSIONS: In consecutive patients undergoing percutaneous LM intervention, PES may perform closely to SES both in terms of angiographic and long-term clinical outcome.

Abstract: AIMS: Relative plaque composition, more than its morphology alone, is thought to play a pivotal role in determining propensity to vulnerability. Thus, we investigated in vivo whether the distance from coronary ostium to plaque location independently affects plaque composition in humans. This may help explaining the recently reported non-uniform distribution of culprit lesions along the vessel in acute coronary syndromes. METHODS AND RESULTS: In 51 consecutive patients (45 men), aged 38-76 years (mean age: 58+/-10), a non-culprit vessel was investigated through spectral analysis of IVUS radiofrequency data (IVUS-Virtual Histology). The study vessel was the left anterior descending artery in 23 (45%) patients; the circumflex artery in nine (18%), and right coronary artery in 19 (37%). The overall length of the region of interest, subsequently divided into 10 mm segments, was 41.5+/-13 mm long (range: 30.2-78.4). No significant change was observed in terms of relative plaque composition along the vessel with respect to fibrous, fibrolipidic, and calcified tissue, whereas the percentage of lipid core resulted to be increased in the first (median: 8.75%; IQR: 5.7-18) vs. the third (median: 6.1%; IQR: 3.2-12) (P=0.036) and fourth (median: 4.5%; IQR: 2.4-7.9) (P=0.006) segment. At multivariable regression analysis, distance from the ostium resulted to be an independent predictor of relative lipid content [beta=-0.28 (95%CI: -0.15, -0.41)], together with older age, unstable presentation, no use of statin, and presence of diabetes mellitus. CONCLUSION: Plaque distance from the coronary ostium, as an independent determinant of relative lipid content, is potentially associated to plaque vulnerability in humans.

Abstract: This study was conducted to reevaluate the significance of angiographic late loss and to assess the agreement between new proposed neointimal volumetric measurements derived from quantitative coronary angiography (QCA) and standard intravascular ultrasound (IVUS)-based parameters. Neointimal volumetric measurements may better estimate the magnitude of neointimal growth after stenting than late loss. In 56 in-stent segments (27, everolimus; 29, bare metal) in the SPIRIT FIRST study, we compared QCA measures with the corresponding IVUS parameters. Two IVUS-late loss models were derived from minimal luminal diameter (MLD) using either a circular model or a so-called projected MLD. QCA-neointimal volume was calculated as follows: stent volume (mean area of the stented segment x stent length) at post procedure - lumen volume (mean area of the stented segment x stent length) at follow-up (the stent length either from nominal stent length or the length measured by QCA). Videodensitometric neointimal volume was also evaluated. Each of the three neointimal volume and percentage volume obstruction by QCA showed significant correlation with the corresponding IVUS parameters (r = 0.557-0.594, P < 0.0001), albeit with a broad range of limits of agreement. Late loss and volumetric measurements by QCA had a broader range of standard deviation than those by IVUS. QCA-volumetric measurements successfully confirmed the efficacy of everolimus-eluting stents over bare metal stents (P < 0.05). Our proposed QCA volumetric measurements may be a practical surrogate for IVUS measurements and a discriminant methodological approach for assessment of treatment effects of drug-eluting stents.

Abstract: OBJECTIVE: To assess the potential relation between plaque composition and vascular remodelling by using spectral analysis of intravascular ultrasound (IVUS) radiofrequency data. METHODS AND RESULTS: 41 coronary vessels with non-significant (< 50% diameter stenosis by angiography), < or = 20 mm, non-ostial lesions located in non-culprit vessels underwent IVUS interrogation. IVUS radiofrequency data obtained with a 30 MHz catheter, were analysed with IVUS virtual histology software. A remodelling index (RI) was calculated and divided into three groups. Lesions with RI > or = 1.05 were considered to have positive remodelling and lesions with RI < or = 0.95 were considered to have negative remodelling. Lesions with RI > or = 1.05 had a significantly larger lipid core than lesions with RI 0.96-1.04 and RI < or = 0.95 (22.1 (6.3) v 15.1 (7.6) v 6.6 (6.9), p < 0.0001). A positive correlation between lipid core and RI (r = 0.83, p < 0.0001) and an inverse correlation between fibrous tissue and RI (r = -0.45, p = 0.003) were also significant. All of the positively remodelled lesions were thin cap fibroatheroma or fibroatheromatous lesions, whereas negatively remodelled lesions had a more stable phenotype, with 64% having pathological intimal thickening, 29% being fibrocalcific lesions, and only 7% fibroatheromatous lesions (p < 0.0001). CONCLUSIONS: In this study, in vivo plaque composition and morphology assessed by spectral analysis of IVUS radiofrequency data were related to coronary artery remodelling.

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Abstract: Late luminal loss after percutaneous coronary intervention, although not normally distributed, has been shown to be monotonically correlated with the probability of binary angiographic restenosis after drug-eluting stent implantation. A recently proposed method has been shown to predict the restenosis rate after sirolimus-eluting stent and paclitaxel-eluting stent implantation using a power transformation of the value of late loss obtained after implantation of the 2 stent types. We used the same method to compute and compare restenosis rates from late loss values observed in the "head-to-head" randomized sirolimus-eluting stent versus paclitaxel-eluting stent comparisons available thus far. Our results showed that the model proposed has a poor overall ability to predict the real incidence and relative risk of restenosis because the use of late loss as an end point tended to overestimate the difference in restenosis, and the derived effect estimate of 1 stent compared with that of the other seemed to be overemphasized with respect to the real risk. We thus believe that further investigations are needed to appraise the real clinical effect of late loss and its reliability as an end point in direct comparative drug-eluting stent trials before its use can be recommended as a clinical surrogate.

Abstract: OBJECTIVES: Our purpose was to assess noninvasive imaging in detection of subclinical atherosclerosis and to examine novel invasive modalities to describe prevalence and temporal changes in putative characteristics of "high-risk" plaques. BACKGROUND: Conventional coronary imaging cannot identify "high-risk" lesions. METHODS: Conventional (quantitative angiography and intravascular ultrasound [IVUS]) and novel imaging (IVUS-based palpography and gray scale echogenicity) were performed at baseline and 6 months later in 67 patients with diverse clinical presentations. Different imaging techniques were compared within a common segment defined by multislice computed tomography (MSCT). RESULTS: Compared with IVUS, the sensitivity, specificity, and positive and negative predictive value of MSCT for detecting significant plaque was 86%, 69%, 90%, and 61%, respectively. In coronary arteries with <50% stenosis, there were no temporal changes in luminal and plaque dimensions measured by quantitative coronary angiography or IVUS; however, a significant reduction in abnormal strain pattern was detected on palpography (density high strain spots/cm: 1.6 +/- 1.5 vs. 1.2 +/- 1.4, p = 0.0123. These changes were mainly related to significant changes in patients who presented with ST-segment elevation myocardial infarction. The assessment of plaque echogenicity showed no temporal changes. There were no correlations between circulating biomarkers and quantifiable imaging parameters. CONCLUSIONS: Mild angiographic disease is associated with large atherosclerotic plaques on MSCT. Conventional invasive coronary imaging reveals static luminal and plaque dimensions on standard medical therapy with plaque hypoechogenicity remaining unchanged over the 6-month period. By contrast, palpography measurements of strain correlate with clinical presentation and significantly decrease on standard medical therapy. Novel imaging modalities, such as palpography, might provide insights into plaque biology and might eventually serve as intermediate end points in interventional trials.

Abstract: BACKGROUND: Surveillance conventional coronary angiography (CCA) is recommended 2 to 6 months after stent-supported left main coronary artery (LMCA) percutaneous coronary intervention due to the unpredictable occurrence of in-stent restenosis (ISR), with its attendant risks. Multislice computed tomography (MSCT) is a promising technique for noninvasive coronary evaluation. We evaluated the diagnostic performance of high-resolution MSCT to detect ISR after stenting of the LMCA. METHODS AND RESULTS: Seventy-four patients were prospectively identified from a consecutive patient population scheduled for follow-up CCA after LMCA stenting and underwent MSCT before CCA. Until August 2004, a 16-slice scanner was used (n = 27), but we switched to the 64-slice scanner after that period (n = 43). Patients with initial heart rates > 65 bpm received beta-blockers, which resulted in a mean periscan heart rate of 57 +/- 7 bpm. Among patients with technically adequate scans (n = 70), MSCT correctly identified all patients with ISR (10 of 70) but misclassified 5 patients without ISR (false-positives). Overall, the accuracy of MSCT for detection of angiographic ISR was 93%. The sensitivity, specificity, and positive and negative predictive values were 100%, 91%, 67%, and 100%, respectively. When analysis was restricted to patients with stenting of the LMCA with or without extension into a single major side branch, accuracy was 98%. When both branches of the LMCA bifurcation were stented, accuracy was 83%. For the assessment of stent diameter and area, MSCT showed good correlation with intravascular ultrasound (r = 0.78 and 0.73, respectively). An intravascular ultrasound threshold value > or = 1 mm was identified to reliably detect in-stent neointima hyperplasia with MSCT. CONCLUSIONS: Current MSCT technology, in combination with optimal heart rate control, allows reliable noninvasive evaluation of selected patients after LMCA stenting. MSCT is safe to exclude left main ISR and may therefore be an acceptable first-line alternative to CCA.

Abstract: BACKGROUND: There is experimental evidence that transplanting skeletal myoblasts (SM) into the post-infarction myocardial scar improves regional and global left ventricular (LV) function. AIMS: To evaluate short- and long-term regional and global LV functional effects of percutaneously transplanted SM in patients with ischaemic heart failure. METHODS AND RESULTS: Ten patients (mean age 60+/-10 years, 8 males) with dilated ischaemic cardiomyopathy underwent percutaneous injection of autologous myoblasts. Regional and global LV function was evaluated by 2-dimensional echocardiography and tissue Doppler imaging (TDI) at rest and during low-dose dobutamine infusion to assess contractile reserve. After a baseline examination, sequential follow-ups were performed at 1, 3, and 6 months and 1 year. NYHA functional class decreased from 2.7+/-0.5 to 1.9+/-0.5 (p<0.01) at one year. LV function and volumes at rest remained unchanged while contractile reserve significantly improved during follow-up. At low-dose dobutamine infusion, the peak systolic velocity in the regions of myoblasts injection significantly increased at TDI examination (from 7.7+/-2.1 to 8.6+/-1.8 cm/s, p=0.02); LV ejection fraction improved (from 40+/-9% to 46+/-8%, p<0.0001) and end-systolic volumes decreased (from 56+/-28 to 50+/-25 ml/m(2), p=0.001) at 1 year. CONCLUSION: In patients with ischaemic heart failure, percutaneous injection of autologous myoblasts may improve regional and global LV systolic function during dobutamine infusion, at 1-year follow-up.

Abstract: BACKGROUND: We sought to compare, using meta-analytic techniques, bare-metal stent versus balloon angioplasty in the percutaneous treatment of total coronary occlusions by means of a quantitative systematic review and to indicate new avenues for future treatments. METHODS: MEDLINE and CENTRAL were searched. Inclusion criteria were random allocation, prospective comparison, and intention to treat. Random-effect odds ratios (ORs) with 95% confidence intervals (CIs) for death, myocardial infarction (MI), repeated revascularization, major adverse cardiac events (MACE), and angiographic restenosis and reocclusion were computed. RESULTS: Nine trials (1409 patients) were included. Death rate was not different in the 2 groups, 0.4% after stenting versus 0.7% after balloon angioplasty (OR 0.72, 95% CI 0.21-2.50). MI rate was significantly increased after stenting (6.7% vs 3.4%, OR 2.06, 95% CI 1.22-3.46), mainly because of a higher rate of periprocedural non-Q-wave MI. By contrast, the risk of repeated revascularization was significantly reduced by stenting (17% vs 32%, OR 0.41, 95% CI 0.31-0.53). This yielded to an overall reduction in the rate of MACE after stenting (23.2% vs 35.4%, OR 0.49, 95% CI 0.36-0.68). Angiographic restenosis and reocclusion were also decreased by stent (41.1% vs 60.9%, OR 0.36, 95% CI 0.23-0.57; 6.8% vs 16%, OR 0.36, 95% CI 0.22-0.59, respectively). CONCLUSIONS: In total coronary occlusions, stenting yields an important benefit over balloon angioplasty in reduction of MACE, repeated revascularizations, and angiographic restenosis and reocclusion. However, these events remain frequent. Moreover, the finding of an increased rate of periprocedural minor myocardial damage after stenting casts caution. New strategies aimed to reduce the need of repeated revascularizations and periprocedural MIs should be further investigated.

Abstract: The human heart has a limited capacity for self-repair because, unlike most other cells, cardiomyocytes do not regenerate. Therefore, if a substantial number of myocytes is lost after a myocardial infarction, the performance of the heart may become severely limited, leading to a condition of heart failure. Recently, cell transplantation has emerged as a potential therapy for patients with end-stage heart failure. Of the various cell types being investigated for this purpose, skeletal myoblasts are an attractive option, because they are readily available from muscle biopsies and, if autologous cells are used, immunosuppression is not required and ethical issues are avoided. Several studies have shown that the cells can survive and differentiate after transplantation, and promising clinical results have been reported. However, effects of this therapy on left ventricular function remain largely unknown. In the present study, we investigated the long-term hemodynamic effects of intramyocardial injection of autologous skeletal myoblasts in patients with ischemic heart failure. Our findings indicate hemodynamic improvement after follow-up for up to 1 year, which is especially promising in view of the expected decline in left ventricular function in these patients.

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Abstract: OBJECTIVES: The purpose of this study was to evaluate predictors of an adverse outcome after "crush" bifurcation stenting. BACKGROUND: The "crush" technique is a recently introduced strategy with limited data regarding long-term outcomes. METHODS: We identified 231 consecutive patients treated with drug-eluting stent implantation with the "crush" technique for 241 de novo bifurcation lesions. Clinical follow-up was obtained in 99.6%. RESULTS: The in-hospital major adverse cardiac event (MACE) rate was 5.2%. At 9 months, 10 (4.3%) patients had an event consistent with possible post-procedural stent thrombosis. Survival free of target lesion revascularization (TLR) was 90.3%; the only independent predictor of TLR was left main stem (LMS) therapy (odds ratio [OR] 4.97; 95% confidence interval [CI] 2.00 to 12.37, p = 0.001). Survival free of MACE was 83.5% and independent predictors of MACE were LMS therapy (OR 3.79; 95% CI 1.76 to 8.14, p = 0.001) and treatment of patients with multivessel disease (OR 4.21; 95% CI 0.95 to 18.56, p = 0.058). Angiographic follow-up was obtained in 77% of lesions at 8.3 +/- 3.7 months. The mean late loss of the main vessel and side branch were 0.30 +/- 0.64 mm and 0.41 +/- 0.67 mm, respectively, with binary restenosis rates of 9.1% and 25.3%. Kissing balloon post-dilation significantly reduced the side branch late lumen loss (0.24 +/- 0.50 mm vs. 0.58 +/- 0.77 mm, p < 0.001). CONCLUSIONS: The crush technique of bifurcation stenting with drug-eluting stents is associated with favorable outcomes for most lesions; however, efficacy appears significantly reduced in LMS bifurcations, and further research is needed before the technique can be routinely recommended in this group. Furthermore, the incidence of possible stent thrombosis is of concern and requires further investigation. Kissing balloon post-dilatation is mandatory to reduce side branch restenosis.

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Abstract: BACKGROUND: We sought to compare, using meta-analytic techniques, bare-metal stent versus balloon angioplasty in the percutaneous treatment of total coronary occlusions by means of a quantitative systematic review and to indicate new avenues for future treatments. METHODS: MEDLINE and CENTRAL were searched. Inclusion criteria were random allocation, prospective comparison, and intention to treat. Random-effect odds ratios (ORs) with 95% confidence intervals (CIs) for death, myocardial infarction (MI), repeated revascularization, major adverse cardiac events (MACE), and angiographic restenosis and reocclusion were computed. RESULTS: Nine trials (1409 patients) were included. Death rate was not different in the 2 groups, 0.4% after stenting versus 0.7% after balloon angioplasty (OR 0.72, 95% CI 0.21-2.50). MI rate was significantly increased after stenting (6.7% vs 3.4%, OR 2.06, 95% CI 1.22-3.46), mainly because of a higher rate of periprocedural non-Q-wave MI. By contrast, the risk of repeated revascularization was significantly reduced by stenting (17% vs 32%, OR 0.41, 95% CI 0.31-0.53). This yielded to an overall reduction in the rate of MACE after stenting (23.2% vs 35.4%, OR 0.49, 95% CI 0.36-0.68). Angiographic restenosis and reocclusion were also decreased by stent (41.1% vs 60.9%, OR 0.36, 95% CI 0.23-0.57; 6.8% vs 16%, OR 0.36, 95% CI 0.22-0.59, respectively). CONCLUSIONS: In total coronary occlusions, stenting yields an important benefit over balloon angioplasty in reduction of MACE, repeated revascularizations, and angiographic restenosis and reocclusion. However, these events remain frequent. Moreover, the finding of an increased rate of periprocedural minor myocardial damage after stenting casts caution. New strategies aimed to reduce the need of repeated revascularizations and periprocedural MIs should be further investigated.

Abstract: OBJECTIVE: To appraise multiple systematic reviews on the same clinical topic, focusing on predictors and correlates of quality of reporting of meta-analysis (QUOROM) scores. DESIGN: Case study. SETTING: Reviews providing at least individual quantitative estimates on role of acetylcysteine in the prevention of contrast associated nephropathy. DATA SOURCES: PubMed, the database of abstracts of reviews of effects, and the Cochrane database of systematic reviews (updated March 2005). MAIN OUTCOME MEASURES: Funding, compliance with the QUOROM checklist, scores on the Oxman and Guyatt quality index, and authors' recommendations. RESULTS: 10 systematic reviews, published August 2003 to March 2005, were included. Nine pooled events despite heterogeneity and five recommended routine use of acetylcysteine, whereas the remaining studies called for further research. Compliance with the 18 items on the QUOROM checklist was relatively high (median 16, range 11 to 17), although shorter manuscripts had significantly lower scores (R = 0.73; P = 0.016). Reviewers who reported previous not for profit funding were more likely to score higher on the Oxman and Guyatt quality index. No association was found between QUOROM and Oxman and Guyatt scores (R = -0.06; P = 0.86), mainly because of greater emphasis of the Oxman and Guyatt scores on the appraisal of bias in selection and validity assessment (inadequate in five reviews). CONCLUSIONS: Multiple systematic reviews on the same clinical topic varied in quality of reporting and recommendations. Longer manuscripts and previous not for profit funding were associated with higher quality.

Abstract: Late luminal loss after percutaneous coronary intervention, although not normally distributed, has been shown to be monotonically correlated with the probability of binary angiographic restenosis after drug-eluting stent implantation. A recently proposed method has been shown to predict the restenosis rate after sirolimus-eluting stent and paclitaxel-eluting stent implantation using a power transformation of the value of late loss obtained after implantation of the 2 stent types. We used the same method to compute and compare restenosis rates from late loss values observed in the "head-to-head" randomized sirolimus-eluting stent versus paclitaxel-eluting stent comparisons available thus far. Our results showed that the model proposed has a poor overall ability to predict the real incidence and relative risk of restenosis because the use of late loss as an end point tended to overestimate the difference in restenosis, and the derived effect estimate of 1 stent compared with that of the other seemed to be overemphasized with respect to the real risk. We thus believe that further investigations are needed to appraise the real clinical effect of late loss and its reliability as an end point in direct comparative drug-eluting stent trials before its use can be recommended as a clinical surrogate.

Abstract: OBJECTIVES: This study was designed to define the current role of multislice spiral computed tomography (MSCT) for the diagnosis of coronary artery disease (CAD) using a meta-analytic process. BACKGROUND: Multislice spiral computed tomography has recently been proposed as an alternative to conventional coronary angiography (CA) for the diagnosis of CAD. METHODS: Using Medline, we identified 29 studies (2,024 patients) evaluating CAD by means of both MSCT (> or =16 slices) and conventional CA before July 2006. After data extraction the analysis was performed according to a random-effects model. RESULTS: The per-segment analysis pooled the results from 27 studies corresponding to a cumulative number of 22,798 segments. Among unassessable segments, 4.2% were excluded from the analysis and 6.4% were classified at the discretion of the investigators, underscoring the shortcomings of MSCT. With this major limitation, the per-segment sensitivity and specificity were 81% (95% confidence interval [CI] 72% to 89%) and 93% (95% CI 90% to 97%), respectively, with positive and negative likelihood ratios of 21.5 (95% CI 13.1 to 35.5) and 0.11 (95% CI 0.06 to 0.21), respectively, and positive and negative predictive values of 67.8% (95% CI 57.6% to 78.0%) and 96.5% (95% CI 94.7% to 98.3%), respectively. As expected, the per-patient analysis has shown an increased sensitivity of 96% (95% CI 94% to 98%) but a decreased specificity of 74% (95% CI 65% to 84%). CONCLUSIONS: Multislice spiral computed tomography has shortcomings difficult to overcome in daily practice and, at the more clinically relevant per-patient analysis, continues to have moderate specificity in patients with high prevalence of CAD. Studies evaluating the diagnostic performance of the newest generation of MSCT, including patients with low to moderate CAD prevalence, will be critical in establishing the clinical role of this emerging technology as an alternative to CA.

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Abstract: BACKGROUND: We sought to compare, using meta-analytic techniques, bare-metal stent versus balloon angioplasty in the percutaneous treatment of total coronary occlusions by means of a quantitative systematic review and to indicate new avenues for future treatments. METHODS: MEDLINE and CENTRAL were searched. Inclusion criteria were random allocation, prospective comparison, and intention to treat. Random-effect odds ratios (ORs) with 95% confidence intervals (CIs) for death, myocardial infarction (MI), repeated revascularization, major adverse cardiac events (MACE), and angiographic restenosis and reocclusion were computed. RESULTS: Nine trials (1409 patients) were included. Death rate was not different in the 2 groups, 0.4% after stenting versus 0.7% after balloon angioplasty (OR 0.72, 95% CI 0.21-2.50). MI rate was significantly increased after stenting (6.7% vs 3.4%, OR 2.06, 95% CI 1.22-3.46), mainly because of a higher rate of periprocedural non-Q-wave MI. By contrast, the risk of repeated revascularization was significantly reduced by stenting (17% vs 32%, OR 0.41, 95% CI 0.31-0.53). This yielded to an overall reduction in the rate of MACE after stenting (23.2% vs 35.4%, OR 0.49, 95% CI 0.36-0.68). Angiographic restenosis and reocclusion were also decreased by stent (41.1% vs 60.9%, OR 0.36, 95% CI 0.23-0.57; 6.8% vs 16%, OR 0.36, 95% CI 0.22-0.59, respectively). CONCLUSIONS: In total coronary occlusions, stenting yields an important benefit over balloon angioplasty in reduction of MACE, repeated revascularizations, and angiographic restenosis and reocclusion. However, these events remain frequent. Moreover, the finding of an increased rate of periprocedural minor myocardial damage after stenting casts caution. New strategies aimed to reduce the need of repeated revascularizations and periprocedural MIs should be further investigated.

Abstract: Late luminal loss after percutaneous coronary intervention, although not normally distributed, has been shown to be monotonically correlated with the probability of binary angiographic restenosis after drug-eluting stent implantation. A recently proposed method has been shown to predict the restenosis rate after sirolimus-eluting stent and paclitaxel-eluting stent implantation using a power transformation of the value of late loss obtained after implantation of the 2 stent types. We used the same method to compute and compare restenosis rates from late loss values observed in the "head-to-head" randomized sirolimus-eluting stent versus paclitaxel-eluting stent comparisons available thus far. Our results showed that the model proposed has a poor overall ability to predict the real incidence and relative risk of restenosis because the use of late loss as an end point tended to overestimate the difference in restenosis, and the derived effect estimate of 1 stent compared with that of the other seemed to be overemphasized with respect to the real risk. We thus believe that further investigations are needed to appraise the real clinical effect of late loss and its reliability as an end point in direct comparative drug-eluting stent trials before its use can be recommended as a clinical surrogate.

Abstract: OBJECTIVES: This study was designed to define the current role of multislice spiral computed tomography (MSCT) for the diagnosis of coronary artery disease (CAD) using a meta-analytic process. BACKGROUND: Multislice spiral computed tomography has recently been proposed as an alternative to conventional coronary angiography (CA) for the diagnosis of CAD. METHODS: Using Medline, we identified 29 studies (2,024 patients) evaluating CAD by means of both MSCT (> or =16 slices) and conventional CA before July 2006. After data extraction the analysis was performed according to a random-effects model. RESULTS: The per-segment analysis pooled the results from 27 studies corresponding to a cumulative number of 22,798 segments. Among unassessable segments, 4.2% were excluded from the analysis and 6.4% were classified at the discretion of the investigators, underscoring the shortcomings of MSCT. With this major limitation, the per-segment sensitivity and specificity were 81% (95% confidence interval [CI] 72% to 89%) and 93% (95% CI 90% to 97%), respectively, with positive and negative likelihood ratios of 21.5 (95% CI 13.1 to 35.5) and 0.11 (95% CI 0.06 to 0.21), respectively, and positive and negative predictive values of 67.8% (95% CI 57.6% to 78.0%) and 96.5% (95% CI 94.7% to 98.3%), respectively. As expected, the per-patient analysis has shown an increased sensitivity of 96% (95% CI 94% to 98%) but a decreased specificity of 74% (95% CI 65% to 84%). CONCLUSIONS: Multislice spiral computed tomography has shortcomings difficult to overcome in daily practice and, at the more clinically relevant per-patient analysis, continues to have moderate specificity in patients with high prevalence of CAD. Studies evaluating the diagnostic performance of the newest generation of MSCT, including patients with low to moderate CAD prevalence, will be critical in establishing the clinical role of this emerging technology as an alternative to CA.

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Abstract: OBJECTIVE: To appraise multiple systematic reviews on the same clinical topic, focusing on predictors and correlates of quality of reporting of meta-analysis (QUOROM) scores. DESIGN: Case study. SETTING: Reviews providing at least individual quantitative estimates on role of acetylcysteine in the prevention of contrast associated nephropathy. DATA SOURCES: PubMed, the database of abstracts of reviews of effects, and the Cochrane database of systematic reviews (updated March 2005). MAIN OUTCOME MEASURES: Funding, compliance with the QUOROM checklist, scores on the Oxman and Guyatt quality index, and authors' recommendations. RESULTS: 10 systematic reviews, published August 2003 to March 2005, were included. Nine pooled events despite heterogeneity and five recommended routine use of acetylcysteine, whereas the remaining studies called for further research. Compliance with the 18 items on the QUOROM checklist was relatively high (median 16, range 11 to 17), although shorter manuscripts had significantly lower scores (R = 0.73; P = 0.016). Reviewers who reported previous not for profit funding were more likely to score higher on the Oxman and Guyatt quality index. No association was found between QUOROM and Oxman and Guyatt scores (R = -0.06; P = 0.86), mainly because of greater emphasis of the Oxman and Guyatt scores on the appraisal of bias in selection and validity assessment (inadequate in five reviews). CONCLUSIONS: Multiple systematic reviews on the same clinical topic varied in quality of reporting and recommendations. Longer manuscripts and previous not for profit funding were associated with higher quality.

Abstract: OBJECTIVES: This study was designed to define the current role of multislice spiral computed tomography (MSCT) for the diagnosis of coronary artery disease (CAD) using a meta-analytic process. BACKGROUND: Multislice spiral computed tomography has recently been proposed as an alternative to conventional coronary angiography (CA) for the diagnosis of CAD. METHODS: Using Medline, we identified 29 studies (2,024 patients) evaluating CAD by means of both MSCT (> or =16 slices) and conventional CA before July 2006. After data extraction the analysis was performed according to a random-effects model. RESULTS: The per-segment analysis pooled the results from 27 studies corresponding to a cumulative number of 22,798 segments. Among unassessable segments, 4.2% were excluded from the analysis and 6.4% were classified at the discretion of the investigators, underscoring the shortcomings of MSCT. With this major limitation, the per-segment sensitivity and specificity were 81% (95% confidence interval [CI] 72% to 89%) and 93% (95% CI 90% to 97%), respectively, with positive and negative likelihood ratios of 21.5 (95% CI 13.1 to 35.5) and 0.11 (95% CI 0.06 to 0.21), respectively, and positive and negative predictive values of 67.8% (95% CI 57.6% to 78.0%) and 96.5% (95% CI 94.7% to 98.3%), respectively. As expected, the per-patient analysis has shown an increased sensitivity of 96% (95% CI 94% to 98%) but a decreased specificity of 74% (95% CI 65% to 84%). CONCLUSIONS: Multislice spiral computed tomography has shortcomings difficult to overcome in daily practice and, at the more clinically relevant per-patient analysis, continues to have moderate specificity in patients with high prevalence of CAD. Studies evaluating the diagnostic performance of the newest generation of MSCT, including patients with low to moderate CAD prevalence, will be critical in establishing the clinical role of this emerging technology as an alternative to CA.

Abstract: BACKGROUND: Routine drug-eluting stent (DES) implantation has recently improved outcome in patients undergoing percutaneous treatment of left main (LM) coronary artery. However, even in the DES era, distal LM treatment remains an independent predictor of poor outcome. Whether single-vessel stenting (SVS) or bifurcation stenting (BS) should be performed to optimize treatment of such a lesion is unclear. METHODS: From April 2002 to June 2004, 94 patients affected by distal LM disease underwent percutaneous intervention at our institution either with SVS (n = 48) or BS (n = 46). The 2 groups were well balanced for all baseline characteristics but the extension of disease in the LM carina. RESULTS: After a median follow-up of 587 days (range, 328-1179), the cumulative incidence of MACE was similar between the 2 groups (31% in the BS vs 28% in SVS group, HR 0.96, 95% CI 0.46-1.49, P = .92), with no difference for the composite death/myocardial infarction or target vessel revascularization. After adjustment for confounders, the technique of stenting was not a predictor of either major adverse cardiac events or target vessel revascularization. Angiographic analysis--performed in 81% of eligible patients in SVS and 87% in the BS group--confirmed the equivalency between SVS versus BS. CONCLUSIONS: In consecutive patients undergoing catheter-based distal LM intervention, SVS or BS may perform equally under both clinical and angiographic perspective in current DES era.

Abstract: OBJECTIVES: The purpose of this study was to evaluate the value of platelet reactivity (PR) in predicting the response to treatment and outcome in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention assisted by glycoprotein (GP) IIb/IIIa inhibition. BACKGROUND: There is limited prognostic information on the role of spontaneous or drug-modulated PR in STEMI patients. METHODS: The PR was measured with Platelet Function Analyzer (PFA)-100 and light transmission aggregometry (LTA) using adenosine diphosphate as agonist in 70 consecutive STEMI patients at entry (PR-T0), 10 min after GP IIb/IIIa bolus (PR-T1), and discharge (PR-T2) and in 30 stable angina (SA) patients (PR-SA). Complete platelet inhibition (CPI) was based on closure time >300 s by PFA-100 and percentage inhibition of platelet aggregation >95% by LTA. Clinical, electrocardiographic, and angiographic responses to treatment during 1-year follow-up were collected. RESULTS: According to both techniques, PR-T0 was higher than: 1) PR-T2 and PR-SA; 2) in those without CPI at T1; and 3) in patients with final Thrombolysis In Myocardial Infarction (TIMI) flow grade <3. The PR-T0 assessed with PFA-100 correlated with: 1) corrected TIMI frame count (r = -0.6, p < 0.001); 2) ST-segment resolution (r = 45, p < 0.001); and 3) creatine kinase-MB (r = -0.47, p < 0.001). At 1 year, patients with high PR-T0 showed an adjusted 5- to 11-fold increase in the risk of death, reinfarction, and target vessel revascularization (hazard ratio [HR] 11, 95% confidence interval [CI] 1.5 to 78 [p = 0.02] in PFA-100; HR 5.2, 95% CI 1.1 to 23 [p = 0.03] in LTA). CONCLUSIONS: The PR at entry affects response to GP IIb/IIIa inhibition, mechanical treatment, and long-term outcome in STEMI patients undergoing primary intervention.

Abstract: OBJECTIVE: We investigated in patients with ongoing myocardial infarction (MI) whether coagulation factor VII (FVII) and tissue factor (TF) levels are affected at admission by genetic components and whether they may predict subsequent cardiovascular events. METHODS AND RESULTS: 256 patients admitted for MI were evaluated for FVII and TF antigen levels before any treatment at entry, and were genotyped for FVII and TF polymorphisms. FVII gene insertions at -323, 11293 and the -402G/A change predicted FVII levels and explained 14% of variance. The -603 TF gene polymorphism failed to affect significantly TF levels (P=0.07). These variables were correlated with the incidence of death (36 patients) and reinfarction (9 patients) after a median follow-up of 397 days. Events were independently predicted by FVII (HR 2.1, 95% CI 1.2 to 5.7) and TF (HR 4.1, 95% CI 2 to 11) levels. Composite end point was significantly worse when both parameters were above the receiver-operating characteristics (ROC) values (HR 8.3, 95% CI 5 to 18, compared with FVII and TF below), and above the ROC value of TF (>630 pg/mL) it differed among FVII genotype groups. CONCLUSIONS: Admission FVII and TF antigen levels, partially predicted by polymorphisms, are independent predictors of mortality and reinfarction in patients with acute MI.

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Abstract: Grey scale intravascular ultrasound (IVUS) is a valuable clinical tool to assess the extent and severity of coronary atheroma. However, it cannot reliably identify plaques with a high-risk of future clinical events. Serial IVUS studies to assess the progression and/or regression of atherosclerotic plaques demonstrated only modest effects, of pharmacological intervention on plaque burden, even when clinical efficacy is documented. Spectral analysis of radiofrequency ultrasound data (IVUS-virtual histology (IVUS-VH), Volcano Therapeutics, Rancho Cordova, CA) has the potential to characterize accurately plaque composition. The Integrated Biomarker and Imaging Study (IBIS) evaluated both invasive and non-invasive imaging techniques along with the assessment of novel biomarkers to characterize sub-clinical atherosclerosis. IVUS-VH was not included at the start of the IBIS protocol. The purpose of this paper is to describe the methodology we used to obtain and analyse IVUS-VH images and the approach to cross-correlations with the other techniques.

Abstract: A number of techniques have been proposed for circulatory support during high-risk percutaneous coronary interventions (PCI), but no single approach has achieved wide acceptance so far. We report on a patient with severe left ventricular (LV) impairment who underwent a PCI with the use of a new left ventricular assist device, the Impella Recover LP 2.5 system. The effects on global cardiac output were determined by thermodilution (TD) and LV pressure-volume loops obtained by conductance catheter. The activation of the pump resulted in a rapid and sustained unloading effect of the LV. At the same time, the continuous expulsion of blood into ascending aorta throughout the cardiac cycle produced by the pump resulted in an increase of systemic overall CO, measured by the TD technique, of 1.43 L/min. The procedure was uncomplicated and the patient remained uneventful at follow-up. Our single experience gives new input for future trials to assess the effect of the Impella Recover LP 2.5 assist device on outcome in this subset of patients.

Abstract: INTRODUCTION: The most effective strategy for bifurcation stenting is currently undefined. The Culotte technique was developed as a method that ensures complete bifurcation lesion coverage. However, it went out of favour due to a high rate of restenosis when utilizing bare metal stents. Drug-eluting stents reduce the rate of restenosis and need for repeat lesion revascularization compared with bare metal stents; we re-evaluated this technique with drug-eluting stent implantation. METHODS: Between April 2002 and October 2003, 207 patients were treated for at least one bifurcation lesion with drug-eluting stent implantation to both the main vessel and side branch. Of these, 23 were treated with the Culotte technique (11.1%) for 24 lesions. Sirolimus-eluting stents were used in 8.3%, and paclitaxel-eluting stents in the remaining 92.7%. RESULTS: Clinical follow-up was obtained in 100%. One patient had a myocardial infarction at 14 days (maximum rise in creatine kinase 872 IU/L) related to thrombosis occurring in another lesion, and underwent repeat revascularization. There were no episodes of stent thrombosis in the Culotte lesions. At eight months follow-up, there were no deaths and no further myocardial infarction. One patient required target lesion revascularization (TLR), and a second underwent target vessel revascularization. The cumulative rates of survival-free of TLR and major adverse cardiac events were 94.7% and 84.6% respectively. Angiographic follow-up was obtained in 16 patients (69.6%) at a mean period of 8.3+/-4.3 months. The late lumen loss for the main vessel and side branch were 0.48+/-0.56 mm and 0.53+/-0.33 mm respectively, with binary restenosis rates of 18.8% and 12.5%. CONCLUSIONS: In this small study of bifurcation stenting utilizing the Culotte technique with drug-eluting stent implantation, there was a low rate of major adverse events and need for target lesion revascularization at eight months, when compared with historical data of bifurcation stenting with bare metal stents. Further re-evaluation of this technique utilizing drug-eluting stents, is warranted in the setting of larger randomized studies.

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Abstract: OBJECTIVE: To compare clinical outcome of paclitaxel eluting stents (PES) versus sirolimus eluting stents (SES) for the treatment of acute ST elevation myocardial infarction. DESIGN AND PATIENTS: The first 136 consecutive patients treated exclusively with PES in the setting of primary percutaneous coronary intervention for acute myocardial infarction in this single centre registry were prospectively clinically assessed at 30 days and one year. They were compared with 186 consecutive patients treated exclusively with SES in the preceding period. SETTING: Academic tertiary referral centre. RESULTS: At 30 days, the rate of all cause mortality and reinfarction was similar between groups (6.5% v 6.6% for SES and PES, respectively, p = 1.0). A significant difference in target vessel revascularisation (TVR) was seen in favour of SES (1.1% v 5.1% for PES, p = 0.04). This was driven by stent thrombosis (n = 4), especially in the bifurcation stenting (n = 2). At one year, no significant differences were seen between groups, with no late thrombosis and 1.5% in-stent restenosis (needing TVR) in PES versus no reinterventions in SES (p = 0.2). One year survival free of major adverse cardiac events (MACE) was 90.2% for SES and 85% for PES (p = 0.16). CONCLUSIONS: No significant differences were seen in MACE-free survival at one year between SES and PES for the treatment of acute myocardial infarction with very low rates of reintervention for restenosis. Bifurcation stenting in acute myocardial infarction should, if possible, be avoided because of the increased risk of stent thrombosis.

Abstract: AIMS: There is increasing evidence that stem cell (SC) mobilization to the heart and their differentiation into cardiac cells is a naturally occurring process. We sought to assess the safety and feasibility of granulocyte-colony stimulating factor (G-CSF) administration in humans to enhance SC mobilization and left ventricle (LV) injury repair during myocardial infarction (MI). METHODS AND RESULTS: Twenty patients with STEMI (mean age, 61+/-10 years), of whom 14 were submitted to primary percutaneous coronary intervention, were randomized to G-CSF (5 microg/kg/day s.c. for 4 consecutive days) or placebo. At entry and then at months 3 and 6, (99m)Tc-sestamibi gated-SPECT was performed to estimate extension of perfusion defect (PD) and LV function. The study drug was well tolerated and induced a significant increase of white blood count, CD34(+) cells, and CD34(+) cells coexpressing AC133 and VEGFR-2. At follow-up, treated and placebo groups did not differ for the angiographic coronary late loss and showed a similar pattern of PD recovery, whereas in the former at 6 months LVEF and especially LVEDV tended to be relatively higher (P=0.068) and lower (P=0.054), respectively. CONCLUSION: G-CSF administration in acute MI patients was feasible and did not lead to any clinical or angiographic adverse events and resulted in CD34(+) and CD34(+)AC133(+)VEGFR2(+) cell mobilization.

Abstract: BACKGROUND: The impact of drug-eluting stent (DES) implantation on the incidence of major adverse cardiovascular events in patients undergoing percutaneous intervention for left main (LM) coronary disease is largely unknown. METHODS AND RESULTS: From April 2001 to December 2003, 181 patients underwent percutaneous coronary intervention for LM stenosis at our institution. The first cohort consisted of 86 patients (19 protected LM) treated with bare metal stents (pre-DES group); the second cohort comprised 95 patients (15 protected LM) treated exclusively with DES. The 2 cohorts were well balanced for all baseline characteristics. At a median follow-up of 503 days (range, 331 to 873 days), the cumulative incidence of major adverse cardiovascular events was lower in the DES cohort than in patients in the pre-DES group (24% versus 45%, respectively; hazard ratio [HR], 0.52 [95% CI, 0.31 to 0.88]; P=0.01). Total mortality did not differ between cohorts; however, there were significantly lower rates of both myocardial infarction (4% versus 12%, respectively; HR, 0.22 [95% CI, 0.07 to 0.65]; P=0.006) and target vessel revascularization (6% versus 23%, respectively; HR, 0.26 [95% CI, 0.10 to 0.65]; P=0.004) in the DES group. On multivariate analysis, use of DES, Parsonnet classification, troponin elevation at entry, distal LM location, and reference vessel diameter were independent predictors of major adverse cardiovascular events. CONCLUSIONS: When percutaneous coronary intervention is undertaken at LM lesions, routine DES implantation, which reduces the cumulative incidence of myocardial infarction and the need for target vessel revascularization compared with bare metal stents, should currently be the preferred strategy.

Abstract: The aim of this study was to assess the short- and mid-term clinical impact of intravascular ultrasound guidance in 58 patients referred for elective percutaneous treatment of unprotected left main coronary artery disease with drug-eluting stents. The use of intravascular ultrasound, used in 41% of the procedures, was not associated with additional clinical benefit with respect to angiographic-assisted stent deployment.

Abstract: OBJECTIVES: We investigated the efficacy of paclitaxel-eluting stents (PES) compared to sirolimus-eluting stents (SES) when used without restriction in unselected patients. BACKGROUND: Both SES and PES have been separately shown to be efficacious when compared to bare stents. In unselected patients, no direct comparison between the two devices has been performed. METHODS: Paclitaxel-eluting stents have been used as the stent of choice for all percutaneous coronary interventions in the prospective Taxus-Stent Evaluated At Rotterdam Cardiology Hospital (T-SEARCH) registry. A total of 576 consecutive patients with de novo coronary artery disease exclusively treated with PES were compared with 508 patients treated with SES from the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry. RESULTS: The PES patients were more frequently male, more frequently treated for acute myocardial infarction, had longer total stent lengths, and more frequently received glycoprotein IIb/IIIa inhibitors. At one year, the raw cumulative incidence of major adverse cardiac events was 13.9% in the PES group and 10.5% in the SES group (unadjusted hazard ratio [HR] 1.33, 95% confidence interval [CI] 0.95 to 1.88, p = 0.1). Correction for differences in the two groups resulted in an adjusted HR of 1.16 (95% CI 0.81 to 1.64, p = 0.4, using significant univariate variables) and an adjusted HR of 1.20 (95% CI 0.85 to 1.70, p = 0.3, using independent predictors). The one-year cumulative incidence of clinically driven target vessel revascularization was 5.4% versus 3.7%, respectively (HR 1.38, 95% CI 0.79 to 2.43, p = 0.3). CONCLUSIONS: The universal use of PES in an unrestricted setting is safe and is associated with a similar adjusted outcome compared to SES. The inferior trend in crude outcome seen in PES was due to its higher-risk population. A larger, randomized study enrolling an unselected population may assist in determining the relative superiority of either device.

Abstract: BACKGROUND: Tumor necrosis factor alpha-alpha (TNF-alpha) activation is an independent prognostic indicator of mortality in patients with heart failure (HF). Despite the recognition that several TNF family cytokines are elevated during myocardial infarction, their role in predicting subsequent prognosis in these setting remains poorly understood. METHODS AND RESULTS: We performed a systematic evaluation of TNF-alpha and its type 1 and 2 soluble receptors, together with interleukin (IL)-6, IL-1 receptor antagonist, and IL-10, in 184 patients (132 men; mean age, 64+/-12) consecutively admitted for myocardial infarction. We correlated their values to short- and long-term incidence of death and HF (primary outcome). In 10 patients, we also studied the presence of transcardiac gradients for TNF-alpha and its soluble receptors. The control group comprised 45 healthy subjects who were sex and age matched (33 men; mean age, 65+/-6 years) to the patients. All tested cytokines were increased in patients, and no transcardiac or systemic AV difference was found. After a median follow-up of 406 days (range, 346 to 696 days), 24 patients died and 32 developed HF. Univariate analysis showed that all cytokines were related to outcome, whereas after adjustment for baseline and clinical characteristics, sTNFR-1 remained the only independent predictor of death and HF (hazard ratio, 2.9; 95% CI, 1.9 to 3.8, tertile 1 versus 3), together with left ventricular ejection fraction, Killip class, and creatine kinase-MB at peak. CONCLUSIONS: sTNFR-1 is a major short- and long-term predictor of mortality and HF in patients with acute myocardial infarction.

Abstract: CONTEXT: Bare-metal stenting with abciximab pretreatment is currently considered a reasonable reperfusion strategy for acute ST-segment elevation myocardial infarction (STEMI). Sirolimus-eluting stents significantly reduce the need for target-vessel revascularization (TVR) vs bare-metal stents but substantially increase procedural costs. At current European list prices, the use of tirofiban instead of abciximab would absorb the difference in cost between stenting with sirolimus-eluting vs bare-metal stents. OBJECTIVE: To evaluate the clinical and angiographic impact of single high-dose bolus tirofiban plus sirolimus-eluting stenting vs abciximab plus bare-metal stenting in patients with STEMI. DESIGN, SETTING, AND PATIENTS: Prospective, single-blind, randomized controlled study (Single High Dose Bolus Tirofiban and Sirolimus Eluting Stent vs Abciximab and Bare Metal Stent in Myocardial Infarction [STRATEGY]) of 175 patients (median age, 63 [interquartile range, 55-72] years) presenting to a single referral center in Italy with STEMI or presumed new left bundle-branch block and randomized between March 6, 2003, and April 23, 2004. INTERVENTION: Single high-dose bolus tirofiban regimen plus sirolimus-eluting stenting (n = 87) vs standard-dose abciximab plus bare-metal stenting (n = 88). MAIN OUTCOME MEASURES: The primary end point was a composite of death, nonfatal myocardial infarction, stroke, or binary restenosis at 8 months. Secondary outcomes included freedom, at day 30 and month 8, from major cardiac or cerebrovascular adverse events (composite of death, reinfarction, stroke, and repeat TVR). RESULTS: Cumulatively, 14 of 74 patients (19%; 95% confidence interval [CI], 10%-28%) in the tirofiban plus sirolimus-eluting stent group and 37 of 74 patients (50%; 95% CI, 44%-56%) in the abciximab plus bare-metal stent group reached the primary end point (hazard ratio, 0.33; 95% CI, 0.18-0.60; P<.001 [P<.001 by Fischer exact test]). The cumulative incidence of death, reinfarction, stroke, or TVR was significantly lower in the tirofiban plus sirolimus-eluting stent group (18%) vs the abciximab plus bare-metal stent group (32%) (hazard ratio, 0.53; 95% CI, 0.28-0.92; P = .04), predominantly reflecting a reduction in the need for TVR. Binary restenosis was present in 6 of 67 (9%; 95% CI, 2%-16%) and 24 of 66 (36%; 95% CI, 26%-46%) patients in the tirofiban plus sirolimus-eluting stent and abciximab plus bare-metal stent groups, respectively (P = .002). CONCLUSION: Tirofiban-supported sirolimus-eluting stenting of infarcted arteries holds promise for improving outcomes while limiting health care expenditure in patients with myocardial infarction undergoing primary intervention.

Abstract: Death or myocardial infarction, the most serious clinical consequences of atherosclerosis, often result from plaque rupture at non-flow limiting lesions. Current diagnostic imaging with coronary angiography only detects large plaques that already impinge on the lumen and cannot accurately identify those that have a propensity to cause unheralded events. Accurate evaluation of the composition or of the biomechanical characteristics of plaques with invasive or non-invasive methods, alone or in conjunction with assessment of circulating biomarkers, could help identify high-risk patients, thus providing the rationale for aggressive treatments in order to reduce future clinical events. The IBIS (Integrated Biomarker and Imaging Study) study is a prospective, single-center, non-randomized, observational study conducted in Rotterdam. The aim of the IBIS study is to evaluate both invasive (quantitative coronary angiography, intravascular ultrasound (IVUS) and palpography) and non-invasive (multislice spiral computed tomography) imaging techniques to characterize non-flow limiting coronary lesions. In addition, multiple classical and novel biomarkers will be measured and their levels correlated with the results of the different imaging techniques. A minimum of 85 patients up to a maximum of 120 patients will be included. This paper describes the study protocol and methodological solutions that have been devised for the purpose of comparisons among several imaging modalities. It outlines the analyses that will be performed to compare invasive and non-invasive imaging techniques in conjunction with multiple biomarkers to characterize non-flow limiting subclinical coronary lesions.

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Abstract: Cardiovascular disease is a major public health problem. Rapid and accurate diagnosis in the emergency department is essential for timely initiation of treatment, thus any means for improving the speed and accuracy of acute coronary syndrome (ACS) diagnosis can contribute to better clinical and economic outcomes. Measurement of circulating level of troponin has proven to be a sensitive and specific test for cardiac damage detection but they do not discriminate between ischemic and not ischemic etiologies of myocardial injury. Combining troponin with other cardiac biomarkers may offer complimentary information on the underlying pathobiology and prognosis in an individual patient, may increase the analytic sensitivity for myocardial damage and offer insights into the timing and mechanism of myocardial injury. Several prospective epidemiological studies have documented an association between inflammatory markers and cardiovascular disease and their role in primary and secondary prevention and as predictor of mortality. OBJECTIVE: We sought to report a selected but representative evidence on some new biological markers of cardiac damage, including inflammatory cytokines in patients with cardiovascular disease. DATA SOURCES: We searched in Medline from January 1998 to March 2005 for all studies focusing on the diagnostic and prognostic value of new markers of cardiac damage in patients with ACS and heart failure. CONCLUSION: The use of necrotic markers to risk stratify patients with chest pain has become an established practice in the clinical setting while the role of other inflammatory biomarkers, despite being still undefined, seems promising under both pathophysiologic and prognostic perspective.

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Abstract: The aim of this study was to assess the short- and mid-term clinical impact of intravascular ultrasound guidance in 58 patients referred for elective percutaneous treatment of unprotected left main coronary artery disease with drug-eluting stents. The use of intravascular ultrasound, used in 41% of the procedures, was not associated with additional clinical benefit with respect to angiographic-assisted stent deployment.

Abstract: OBJECTIVES: The purpose of this study was to assess the prevalence of intravascular ultrasound (IVUS)-derived thin-cap fibroatheroma (IDTCFA) and its relationship with the clinical presentation using spectral analysis of IVUS radiofrequency data (IVUS-Virtual Histology [IVUS-VH]). BACKGROUND: Thin-cap fibroatheroma lesions are the most prevalent substrate of plaque rupture. METHODS: In 55 patients, a non-culprit, non-obstructive (<50%) lesion was investigated with IVUS-VH. We classified IDTCFA lesions as focal, necrotic core-rich (> or =10% of the cross-sectional area) plaques being in contact with the lumen; IDTCFA definition required a percent atheroma volume (PAV) > or =40%. RESULTS: Acute coronary syndrome (ACS) (n = 23) patients presented a significantly higher prevalence of IDTCFA than stable (n = 32) patients (3.0 [interquartile range (IQR) 0.0 to 5.0] vs. 1.0 [IQR 0.0 to 2.8], p = 0.018). No relation was found between patient's characteristics such as gender (p = 0.917), diabetes (p = 0.217), smoking (p = 0.904), hypercholesterolemia (p = 0.663), hypertension (p = 0.251), or family history of coronary heart disease (p = 0.136) and the presence of IDTCFA. A clear clustering pattern was seen along the coronaries, with 35 (35.4%), 31 (31.3%), 19 (19.2%), and 14 (14.1%) IDTCFAs in the first 10 mm, 11 to 20 mm, 21 to 30 mm, and > or =31 mm segments, respectively, p = 0.008. Finally, we compared the severity (mean PAV 56.9 +/- 7.4 vs. 54.8 +/- 6.0, p = 0.343) and the composition (mean percent necrotic core 19.7 +/- 4.1 vs. 18.1 +/- 3.0, p = 0.205) of IDTCFAs between stable and ACS patients, and no significant differences were found. CONCLUSIONS: In this in vivo study, IVUS-VH identified IDTCFA as a more prevalent finding in ACS than in stable angina patients.

Abstract: BACKGROUND: Stented segment length was a predictive factor for restenosis in the bare metal stent era. The objective of the study was to evaluate the medium-term clinical outcome and the potential for adverse effects when very long segments (ie, > or =64 mm of stented length) are treated by drug-eluting stent (DES) implantation, an approach colloquially referred to as a "full metal jacket." METHODS: Since April 2002, we have used DES as the default stent for all percutaneous coronary interventions. From our prospective institutional database we identified 122 consecutive patients, with de novo coronary lesions, in whom a coronary artery was treated with at least 64 mm of overlapping DES: 81 patients were treated with sirolimus-eluting stents and 41 with paclitaxel-eluting stents. RESULTS: The mean number of stents per lesion was 3.3 +/- 1.1, and the median stented length was 79 mm (range 64-168 mm). Periprocedural Q-wave myocardial infarction (MI) occurred in 2 patients (1.6%) and subacute stent thrombosis in 1 patient (0.8%). During 1-year follow-up, 5 patients (4.1%), including 3 patients treated for acute MI with cardiogenic shock, died and 10 patients (8.2%) had nonfatal MI (creatine kinase-MB >3 times). The 1-year target vessel revascularization rate was 7.5% and the overall incidence of major adverse cardiac events was 18%. Outcomes in sirolimus-eluting stents and paclitaxel-eluting stents groups did not differ statistically. CONCLUSIONS: The use of DES for the treatment of diffuse lesions was associated with a low rate of repeat revascularization, irrespective of stent type. No safety concerns were raised at medium-term follow-up.

Abstract: BACKGROUND: The efficacy of sirolimus-eluting stents (SES) compared to paclitaxel-eluting stents (PES) remains unknown. We evaluated the clinical outcomes after implantation of 2.25 mm diameter SES and PES. METHODS AND RESULTS: PES have been used as the stent of choice for all percutaneous coronary interventions as part of the prospective Taxus-Stent Evaluated At Rotterdam Cardiology Hospital (T-SEARCH) Registry. Ninety consecutive patients received at least one 2.25 mm PES (PES group), and were compared with 107 patients who received at least one 2.25 mm SES as part of the RESEARCH registry. The overall population presented high-risk characteristics commonly excluded from most studies. Populations were well-matched. There were 2 (2.2%) incidents of subacute stent thrombosis in the PES group (in a 2.25 mm stent), and none in the SES group. At one year, the cumulative incidence of major adverse cardiac events was 5.6% in the SES group, and 17.8% in the PES group (p = 0.007). After adjustments for other significant univariate variables, presentation with acute coronary syndrome (ACS) (adjusted OR 5.2 [95% CI 1.8-15.0], p = 0.002) and PES utilization (adjusted OR 3.7 [95% CI 1.3-10.5], p = 0.013) were found to be significant independent predictors of major adverse cardiac events (MACE). CONCLUSIONS: In an unselected population treated for very small vessel disease, SES were associated with better 12-month clinical outcomes and the use of PES was identified as an independent predictor of adverse events.

Abstract: The aim of this study was to evaluate the outcome after paclitaxel-eluting stent implantation in 40 patients with 52 saphenous vein graft lesions. By Kaplan-Meier estimates, the probability of major adverse cardiac event-free survival for 1 year was 92.5%. A paclitaxel-eluting stent for saphenous vein graft disease appears to be feasible and safe, with a low rate of reintervention at 1 year, but late follow-up is needed to confirm these observations.

Abstract: This study evaluated and compared the efficacy of sirolimus-eluting stents (n = 145 patients) with that of paclitaxel-eluting stents (n = 148 patients) in 293 consecutive unselected patients who had diabetes mellitus. Baseline clinical characteristics and presentations were similar: mean age of 64 years, 50% presented with unstable angina or myocardial infarction, and 66% had multivessel disease. Angiographic and procedural characteristics differed, with more complex lesions and more vein grafts managed in the paclitaxel-eluting stent group. Overall mean stented length was 46 +/- 32 mm. There were no differences in unadjusted outcomes by stent type (1-year major adverse cardiac event rates of 20.4% for sirolimus-eluting stents vs 15.6% for paclitaxel-eluting stents, p = 0.12) or when adjusted for multivariate predictors (adjusted hazard ratio 0.68, 95% confidence interval 0.37 to 1.24, p = 0.21). Independent predictors of outcome in patients who had diabetes mellitus were stenting of the left main artery, stenting of the left anterior descending artery, creatinine clearance, and female gender. Patients who required insulin had a significantly higher, crude major adverse cardiac event rate at 1 year compared with those who used oral agents, but this rate became nonsignificant when adjusted for independent predictors of outcome.

Abstract: OBJECTIVE: To assess the safety and efficacy of the implantation of Paclitaxel Eluting Stents (PES) for de novo, non-flow limiting lesions. METHODS AND RESULTS: We assessed the 12-month occurrence of major adverse cardiac events (MACE) in 21 patients (4% of the total population treated in a 'real world' registry) with 22 non-significant coronary narrowings treated with PES. The following criteria had to be met: (1) the lesion was de novo; (2) the location was non-ostial, and not a bifurcation lesion; (3) the diameter stenosis by quantitative coronary angiography (QCA) was <50%; (4) there was no visible thrombus and (5) the lesion was not located in an angiographically diffusely diseased segment. Procedural success rate was 100% without any periprocedural myocardial infarction. After a mean follow-up of 407.33+/-53 (range: 344-498) days the overall MACE-free survival was 95.2%. Freedom from target revascularization was 95.2%. CONCLUSIONS: The result of this non-randomized observational study suggests that the implantation of PES for de novo, non-significant lesions appears most probably safe and effective.

Abstract: BACKGROUND: Percutaneous transluminal septal myocardial ablation (PTSMA) recently emerged as an alternative to myectomy for hypertrophic obstructive cardiomyopathy (HOCM) patients with drug-refractory symptoms. The target septal branch selection is a main point to achieve the therapeutic result. METHODS AND RESULTS: We report about PTSMA performed using intracardiac echocardiography (ICE) to guide the procedure in 9 symptomatic HOCM patients. The target septal branch was chosen on the basis of the risk-area visualized using ICE after injection of a contrast agent. During alcohol administration a backscattered signal enhancement of the infarcted area was detected. The procedures were uncomplicated and effective to reduce the gradient from 78.9+/-20.4 mmHg to 7.8+/-7.9 mmHg (p<0.0001). CONCLUSIONS: In this initial experience ICE monitoring during PTSMA was safe and provided high quality and continuous imaging of the treated segment of the septum during the whole procedure.

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Abstract: OBJECTIVES: We used acetylsalicylic acid (ASA) as a probing agent to quantify hydroxyl radical ((*)OH) in Controls and patients with coronary artery disease and to prospectively investigate (*)OH production in patients with myocardial infarction (MI) complicated by heart failure (HF). BACKGROUND: Oxidative stress status (OSS) is a mechanism for transition to HF in experimental heart injury models, but evidence for its causal role in humans is still limited. METHODS: Thirty healthy subjects (Controls), 12 patients with stable angina (Group 1), and 74 patients with ST-segment elevation MI (Group 2) were enrolled. A dose of 250 mg Flectadol was given intravenously before each blood collection to determine the 2,3-dihydroxybenzoic acid/salicylic acid (DHBA/SA) ratio. We also quantified vitamin E and coenzyme Q(10) to monitor antioxidant reserve, as well as tumor necrosis factor (TNF)-alpha, TNF-soluble receptors, interleukin (IL)-6, and IL-1ra to assess inflammatory status. All measurements were repeated at month 6 in Group 2. RESULTS: There were no differences between Controls and Group 1. Group 2 showed increased (*)OH production, peaking at 24 h, whereas vitamin E and coenzyme Q(10) progressively declined. Group 2 patients developing HF during hospitalization (Group 2Bi) presented with an increase of both (*)OH production at discharge and inflammatory status, as compared with patients without HF (Group 2Ai), persisting at month 6 in post-MI patients with HF (Group 2Bii). CONCLUSIONS: We found a distinct pattern of (*)OH generation in post-MI patients who show progression to HF. The interplay between OSS and inflammatory status should be targeted as a possible mechanism of progression to post-MI left ventricular dysfunction.

Abstract: BACKGROUND: Primary bare metal stenting and abciximab infusion are currently considered the best available reperfusion strategy for acute ST-segment elevation myocardial infarction (STEMI). Sirolimus eluting stents (SES), compared to bare metal stent (BMS), greatly reduce the incidence of binary restenosis and target vessel revascularisation (TVR), but their use on a routine basis results in a significant increase in medical costs. With current European list prices, the use of tirofiban instead of abciximab would save enough money to absorb the difference between SES and BMS. AIM: To assess whether in patients with STEMI the combination of SES with high dose bolus (HDB) tirofiban results in a similar incidence of major cardiovascular events (MACE) but in a lower binary restenosis rate after six months compared to BMS and abciximab. METHODS AND RESULTS: 160 patients are required to satisfy the primary composite end-point, including MACE and binary restenosis. The study is ongoing: the current paper focuses on the methodology and demography of the first 100 patients so far enrolled. Patients randomised to HDB tirofiban (n = 50, mean age: 62 +/- 12, 40 males) and abciximab (n = 50, mean age: 63 +/- 12, 38 males) do not differ for medical history, presentation profile, medications at discharge, angiographic profile and creatine-kinase MB-fraction at peak. CONCLUSIONS: The results of the trial will be available by the end of 2004: they will be crucial for the cardiologists to know whether the gold standard for AMI treatment should be reconsidered after the introduction of SES into the clinical practice.

Abstract: BACKGROUND: Peripheral blood CD34(+) cells and circulating endothelial progenitor cells (EPCs) increase in myocardial infarction and vascular injuries as a reflection of endothelial damage. Despite the occurrence of endothelial dysfunction in heart failure (HF), no data are available on EPC mobilization in this setting. We investigated the pattern of CD34(+) cells and EPC mobilization during HF and their correlation with the severity and origin of the disease. METHODS AND RESULTS: Peripheral blood CD34(+) cells (n=91) and EPCs (n=41), assessed both as CD34(+) cells coexpressing AC133 and vascular endothelial growth factor (VEGF) receptor-2 and as endothelial colony-forming units, were studied in HF patients (mean age 67+/-11 years) and 45 gender- and age-matched controls. Tumor necrosis factor-alpha (TNF-alpha) and its receptors (sTNFR-1 and sTNFR-2), VEGF, stromal derived factor-1 (SDF-1), granulocyte-colony stimulating factor (G-CSF), and B-type natriuretic peptide were also measured. CD34(+) cells, EPCs, TNF-alpha and receptors, VEGF, SDF-1, and B-type natriuretic peptide were increased in HF. CD34(+) cells and EPCs were inversely related to functional class and to TNF-alpha, being decreased in New York Heart Association class IV compared with class I and II and controls. No role was found for the origin of the disease. CONCLUSIONS: CD34(+) cells and EPC mobilization occurs in HF and shows a biphasic response, with elevation and depression in the early and advanced phases, respectively. This could be related to the myelosuppressive role of TNF-alpha.

Abstract: OBJECTIVES: We sought to determine the safety and efficacy of high-dose bolus (HDB) tirofiban in high-risk patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: The use of HDB tirofiban in the catheterization laboratory is controversial. In particular, in patients with acute coronary syndromes undergoing PCI, there is no evidence that tirofiban administered in the catheterization laboratory is superior to heparin alone. This finding probably reflects the suboptimal platelet inhibition when tirofiban is employed at RESTORE (Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis) regimen. METHODS: A total of 202 patients (mean age 69 +/- 8 years; 137 males [68%]) undergoing high-risk PCI, pretreated with thienopyridines, were consecutively randomized to HDB tirofiban (25 microg/kg/3 min, and infusion of 0.15 microg/kg/min for 24 to 48 h) or placebo immediately before the procedure and then followed for a median time of 185 days (range 45 to 324 days) for the occurrence of the primary composite end point of death, myocardial infarction, target vessel revascularization (TVR), and bailout use of glycoprotein (GP) IIb/IIIa inhibitors. RESULTS: The cumulative incidence of the primary end point was 35% and 20% in placebo and HDB tirofiban groups, respectively (hazard ratio 0.51, 95% confidence interval 0.29 to 0.88; p = 0.01). This difference was mainly due to the reduction of myocardial infarction and bailout use of GP IIb/IIIa inhibitors, with no significant effect on TVR or death. The safety profile did not differ between tirofiban and placebo. CONCLUSIONS: The use of tirofiban, when administered at HDB, is safe and significantly reduces the incidence of ischemic/thrombotic complications during high-risk PCI.

Abstract: BACKGROUND: Endothelial apoptosis of atherosclerotic lesions is a possible determinant for the stable-to-vulnerable plaque transition. Recent data support the notion that plaque activation may be a pan-coronary process, advocating the existence of circulating triggers. METHODS AND RESULTS: Serum from 40 healthy subjects (group 1) and 73 patients with stable angina (n=32; group 2) or acute coronary syndromes (n=41; group 3) was incubated with human umbilical vein endothelial cells. The percentage of apoptosis by flow cytometry and Fas, Bax, and Bcl-2 protein expression by immunoblotting were evaluated at entry in patients and control subjects and repeated after 12 months in group 3. At baseline, apoptotic nuclei were higher in group 3 (14+/-6%) than in group 2 (3.3+/-1.8%) and group 1 (1.35+/-0.8%) (P<0.001). Fas and Bcl-2 were increased in group 3 with respect to groups 1 and 2 (P<0.01). Coincubation of group 3 serum with anti-tumor necrosis factor-alpha and anti-interleukin-6 monoclonal antibodies did not affect the human umbilical vein endothelial cell apoptotic process, whereas addition of Trolox decreased apoptosis to <50%. The percentage of apoptosis in group 3 significantly correlated to the numbers of coronary complex lesions at angiography (r=0.58, P<0.0005). In group 3, apoptosis and the Bax/Bcl-2 ratio decreased at 1 year (P<0.0001, P<0.05 respectively). CONCLUSIONS: Serum from patients with acute coronary syndromes displays a proapoptotic effect on human endothelial cells, supporting the theory of the existence of circulating triggers potentially able to activate atherosclerotic lesions.

Abstract: The past two decades have highlighted the pivotal role of the endothelium in preserving vascular homeostasis. Among others, nitric oxide (NO) is currently believed to be the main component responsible for endothelium dependent vasorelaxation and therefore for endothelial function integrity. Reduced NO bioavailability causes the so-called "endothelial dysfunction," which seems to be the common molecular disorder comprising stable atherosclerotic narrowing lesions or acute plaque rupture causing unstable angina or myocardial infarction. Compelling evidence is accumulating, stressing the role of oxidative stress in causing reduced NO bioavailability and subsequently endothelial dysfunction (ED). More recently, the role of endothelial cell (EC) apoptosis as a possible final stage of ED and plaque activation has been suggested. In vitro and in vivo evidence suggests a role of oxidative stress also as a putative mechanism finally leading to plaque denudation and activation through increased EC apoptosis. Thus, oxidative stress, irrespective of atherosclerotic disease stages, seems to represent a key phenomenon in vascular disease progression and possible prevention.

Abstract: Excessive biohumoral activation participates in the pathophysiology and progression of congestive heart failure (CHF). Pharmacological inhibition of the renin-angiotensin-aldosterone and beta-adrenergic systems improves the mortality and morbidity of this disease. Among other detrimental molecules, two local factors, tumor necrosis factor (TNF)-alpha and endothelin (ET) both contribute to the worsening of CHF. TNF-alpha can induce many of the cellular modifications typically associated with CHF, such as myocyte death, interstitial tissue derangement and negative inotropism. On the other hand ET promotes vasoconstriction, and cell growth and proliferation. On the premise of some favorable experimental studies, selective antagonism of TNF-alpha or ET has been tested in clinical trials in order to control the progression of or even reverse CHF. However, contrasting results have been obtained so far with either approach, in accordance with other unfavorable data from animal models of heart failure. Etanercept (Enbrel, a recombinant dimer of two p75sTNFR molecules fused to the Fc fragment of human IgG1) has proved to be useful and effective in basic and animal experiments, while contrasting data have been reported on humans. The Randomized EtaNErcept Worldwide evALuation (RENEWAL) trial has recently been prematurely stopped due to impossibility of showing statistically significant results with the pre-specified sample size. Results of phase II to III clinical trials on different ET receptor antagonists in CHF have yielded conflicting results, so that none of the agents of this class have been labeled for CHF. The mechanisms by which TNF-alpha and ET might exert their negative biological actions are discussed together with an analysis of the possible reasons why they have failed so far in human CHF.

Abstract: The role of reactive oxygen species (ROS) in liver disease is controversial. This mostly reflects the difficulties to quantify ROS in vivo, particularly in humans. We aimed to measure the presence of ROS in diseased human liver and identify possible relations between ROS levels and etiology, histology and hepatocyte proliferation. Liver biopsy specimens from 102 individuals: 18 healthy controls and 84 patients (42 HCV chronic hepatitis (CHC), 19 HBV chronic hepatitis (CHB), 7 PBC, 4 PSC, 4 HCV relapsing hepatitis after liver transplantation, 3 autoimmune hepatitis, 3 hepatocellular carcinoma, 2 alcoholic hepatitis) underwent analysis by radical-probe electron paramagnetic resonance (EPR). ROS in patients (median = 5 x 10(-6) mmol/mg) were higher than in controls (median = 3 x 10(-11) mmol/mg) (p < 0.001). Progressively increasing levels of ROS were recorded passing from control values to CHB (median = 4 x 10(-7) mmol/mg), CHC (median = 3 x 10(-6) mmol/mg) and PBC (median = 2 x 10(-5) mmol/mg), the differences being significant (p < 0.001). ROS in CHC positively correlated with histological disease activity (r = 0.92; p < 0.001). No correlation was found between ROS and hepatocyte proliferation rate, presence/degree of steatosis, serum ferritin levels and aminotransferases. ROS overproduction in liver appears to be a common thread linking different pathologic conditions and seems to be influenced by diseases' etiologies.

Abstract: A 65-year-old man was submitted to coronary angioplasty and stent implantation for stable angina. The treatment included a 30-day therapy with ticlopidine (in addition to aspirin, metoprolol, ramipril, amlodipine and nitrates). One month after ticlopidine withdrawal a progressive cholestatic jaundice took place. Viral, immunogenic as well as nutritional causes were ruled out. The abdominal echography disclosed a normal biliary tree and the liver biopsy showed a centrolobular cholestasis pattern. Drug-induced cholestatic reaction was diagnosed and attributed to ticlopidine. There was a progressive improvement in clinical and laboratory findings 4 months after steroid treatment. The clinical picture was normalized after 6 months. When considering the option ticlopidine, even for a short time after coronary angioplasty, the possibility of drug-induced hepatotoxicity should be kept in mind. Consequently, markers of liver toxicity should be monitored carefully.

Abstract: OBJECTIVES: High concentrations of serum xanthine oxidase (XO) have been reported during human liver disease and hepatocyte injury in experimental settings. However, it is unclear whether this elevation reflects hepatocyte necrosis or has a different meaning. METHODS: The serum level of XO in 64 patients with chronic liver disease (17 patients with cirrhosis, 30 with chronic hepatitis, and 17 with cholestatic disorders) and in 12 control subjects was determined by a competitive ELISA. Conventional serum markers of liver damage were assessed in all patients, and grading and staging were scored in the chronic hepatitis group according to Knodell. RESULTS: The XO serum levels were significantly higher in the patients than in the controls. The differences were also significant when controls were compared to patients with chronic hepatitis and cholestatic disorders separately, but not when compared to the cirrhosis group. Patients with cholestatic disorders had XO values higher than those of patients with cirrhosis or chronic hepatitis. XO levels did not correlate with stage and grade in chronic hepatitis group. We found a weak but significant positive correlation in patients between XO serum level and gamma-glutamyl transpeptidase (r = 0.37). This correlation was stronger when chronic hepatitis (r = 0.42) and, especially cholestatic disorders (r = 0.71), were separately tested, but was absent in the cirrhosis group. The XO values positively correlated with alkaline phosphatase in patients with cholestatic disorders. A level of serum XO >32 microg/ml specifically identified cholestatic disorders in our study population. CONCLUSIONS: A marked elevation of serum XO in patients with chronic liver disease seems to reflect the presence of cholestasis. No correlation between XO levels and histological or serum evidence of hepatocyte necrosis was found in these patients.

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Abstract: Variceal bleeding, whose triggering mechanisms are largely unknown, occurs with a circadian rhythmicity, with 2 peaks, one greater, in the evening, and one smaller, in the early morning. We assessed some clotting and hemodynamic parameters, possibly involved in variceal hemorrhage, over a 24-hour period, at 4-hour intervals, in 16 patients with cirrhosis and esophageal varices and in 9 controls. At each time interval, tissue plasminogen activator (tPA) and tPA inhibitor-1 (PAI-1) antigens and activities and total euglobulin fibrinolytic activity were determined and portal-vein flow velocity, volume, and congestion index were measured by duplex-Doppler. Significant circadian rhythms were searched for by least-squares and cosinor methods. tPA activity showed a circadian rhythm in cirrhosis, with a peak of 2.85 times the trough value, calculated at 18:42, and remained over 2.5-fold until shortly after 22:00. Total fibrinolytic activity showed a similar pattern, which was statistically significant also in controls. tPA and PAI antigens also showed significant circadian rhythm both in controls and cirrhotics, with higher values in the morning. Among the portal hemodynamic parameters only the congestion index showed significant rhythmic changes and only in cirrhosis, with the highest values in the late evening, but with limited diurnal excursion (+/- 5.5%). In conclusion, we showed the existence of a circadian rhythm of fibrinolysis in cirrhosis, whose temporal distribution might suggest a role of fibrinolysis in variceal hemorrhage on the basis of the comparison to the known chronorisk of variceal bleeding.

Abstract: A method for the measurement of reactive oxygen species (ROS) in human hepatic tissue has been developed. The method is based on the EPR detection of the nitroxide radical produced by reaction of the hydroxylamine spin-probe bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)decandioate with ROS generated under pseudo-physiologic conditions in fine needle biopsies of healthy (10 controls) and diseased (22 patients) human liver. Measures of malonaldehyde in 9 liver biopsies (3 controls and 6 patients) have also been obtained by high pressure liquid chromatography and values parallel those obtained by the spin-probe technique. The amount of ROS found in healthy human liver (median = 1.8 x 10(-11) mol/mg) was significantly lower than values found in liver affected by hepatitis B (median=5.8 x 10(-10) mol/mg; p < 0.02) or by hepatitis C (median = 2.7 x 10(-9) mol/mg; p < 0.003) as well as compared to some other non-viral liver diseases (NVLD): autoimmune hepatitis, primary biliary cirrhosis, primary schlerosing cholangitis (median = 9.8 x 10(-9) mol/mg; p < 0.005). NVLD also showed significantly higher ROS levels compared to hepatitis B (p < 0.04) and hepatitis C (p < 0.04). The mechanism, potentiality and limitations of our method are discussed.

Abstract: BACKGROUND: Patients with alcoholic cirrhosis have left ventricular dimensions similar to controls. Few data have been reported in patients with cirrhosis of viral origin. AIM: To assess left ventricular dimensions in patients with pure viral cirrhosis. PATIENTS AND METHODS: Thirty patients with virus-related cirrhosis, 23 patients with alcoholic cirrhosis and 12 healthy controls were submitted to measurement of left ventricular volumes, cardiac output, mean arterial pressure and total peripheral resistance. RESULTS: Patients with cirrhosis showed a similar increase in cardiac index and heart rate and reduction of mean arterial pressure and peripheral vascular resistance in comparison to controls, irrespective of the aetiology. Left ventricular end systolic volume index was lower (p<0.01) and ejection fraction higher (p<0.01) in virus-related cirrhotic patients [mean +/- SD, respectively 12.4+/-4.1 ml/sqm and 77.9%) in comparison both to controls (21.5+/-6.3 ml/sqm and 66.8%) and alcoholics (20.6+/-7.0 ml/sqm and 68.8%). End diastolic volume index was not significantly different between the three groups. CONCLUSIONS: Our findings indicate smaller left ventricular volumes and higher ejection fraction in pure virus-related cirrhosis than in alcoholic cirrhosis and controls. Since peripheral haemodynamics proved similar in virus- and alcohol-related cirrhosis, a subclinical alcohol cardiomyopathy may be hypothesised to account for the absence of such left ventricular pattern in alcoholic patients.

Abstract:

Abstract: To determine whether transcriptional alterations of the fragile histidine triad (FHIT) gene play a role in the development and progression of human hepatocellular carcinoma (HCC) we used reverse transcription-PCR to examine mRNA FHIT expression in 28 paired samples of HCC (24 in cirrhotic and 4 in noncirrhotic livers) and matched noncancerous tissue and in 10 normal livers. We also assessed loss of heterozygosity of the polymorphic D3S1300 microsatellite marker in the intron between exons 5 and 6 of the FHIT gene. Abnormal FHIT transcripts were detected in 13 cases (46.4%): 10 in the cancerous tissue only, 1 with the same pattern in both cancerous and matched noncancerous tissue, and 2 in the noncancerous tissue only. The four HCCs that arose in noncirrhotic liver all showed abnormal FHIT transcripts. No alterations were found in normal livers. Sequence analysis of abnormally sized transcripts revealed that they were generated by the fusion of exons 3 or 4 with exons 8 or 9. Among the cancerous specimens, one case showed only an abnormal sized transcript derived from the fusion of exons 4 and 9 in the absence of any normal-sized transcript, and another case showed deletion of a sequence comprised between nucleotides -35 and 399 resulting in an exon 4-9 fusion not respecting the exons' bounds. Loss of heterozygosity was found in two cases with abnormal FHIT transcripts and in only one case with normal transcript. Patients with aberrant FHIT transcripts showed a significantly higher relapse rate and shorter recurrence time (P = 0.001). This could be related to a primary genomic instability affecting particularly susceptible regions like FRA3B and could be associated with an increasing risk of recurrence without involving a causative role.

Abstract: The effect of orthotopic liver transplantation (OLT) on the systemic and splanchnic hemodynamic alterations of cirrhosis is still largely unknown. The aim of this study was to prospectively investigate the long-term changes induced by OLT on several hemodynamic parameters. In 28 patients undergoing OLT for cirrhosis, the following parameters were measured before surgery and subsequently at 6-month intervals (mean follow-up period, 17 months): cardiac index, mean arterial pressure (MAP), heart rate, total peripheral resistance (TPR), portal vein flow velocity and flow volume, spleen size, and Doppler ultrasound resistance or pulsatility indexes (RI or PI) in the: 1) interlobular renal, 2) superior mesenteric, 3) splenic, and 4) hepatic arteries. The same parameters were measured in 10 healthy controls. After OLT, cardiac index and heart rate significantly decreased (P <.01), while MAP and TPR increased (P <.001), so that any significant difference from controls disappeared. Renal RI progressively decreased, achieving a significant reduction (P <.05) to normal values at the 12th month of follow-up. Portal flow velocity and hepatic and splenic RI returned to values not significantly different from controls. Portal flow volume increased over normal values after OLT (P <.001), and SMA PI, lower than normal before OLT, did not show any statistically significant increase thereafter. Spleen size decreased significantly, but persisted to be larger than in controls. In conclusion, systemic, renal, and most, but interestingly not all, splanchnic circulatory alterations of cirrhosis are restored to normal after OLT.

Abstract: Splenic arteriovenous fistula (AVF) is a rare cause of portal hypertension. An early diagnosis is crucial because lethal complications may occur if the disease is not treated. We report a case of AVF in a noncirrhotic patient in whom the diagnosis was made by duplex sonography. This technique can differentiate between AVF and other, more common vascular abnormalities in the left upper quadrant in patients with portal hypertension. Duplex sonography can therefore be recommended as the first imaging approach in this population.

Abstract: A 47-year-old women developed an acute vestibular syndrome with a peripheral facial palsy not associated with any trauma. Magnetic resonance imaging showed an ischemic lesion in the territory of the posterior inferior cerebellar artery. Color Doppler ultrasonography detected an occlusion of the right vertebral artery and dissection of the artery was confirmed by a subsequent angiography. During follow-up Duplex-Doppler allowed a non-invasive monitoring of recanalization of the occluded artery. Copyright 1997 Elsevier Science Ireland Ltd.