Laurent Leborgne

Predictors of subacute stent thrombosis: results of a systematic intravascular ultrasound study.

Background Factors leading to subacute stent thrombosis after percutaneous coronary intervention (PCI) have not been well established. We assessed the pre‐ and post‐PCI intravascular ultrasound (IVUS) characteristics of subacute stent thrombosis. Methods and Results We analyzed 7484 consecutive patients without acute myocardial infarction who were treated with PCI and stenting and underwent IVUS imaging during the intervention. Twenty‐seven (0.4%) had angiographically documented subacute closure <1 week after PCI (median time to subacute closure, 24 hours). Subacute closure lesions were compared with a control group (selected to be 3 times the abrupt closer group) matched by procedure date (within 6 months), age, gender, stable or unstable angina, lesion location, and additional treatment (balloon angioplasty or atherectomy). Postintervention IVUS did not identify a cause in 22% and did identify at least 1 cause for abrupt closure in 78% of patients (versus 33% in matched lesions, P=0.0002). In 48% of the patients, there were multiple causes in 48% (versus 3% in matched lesions, P<0.0001). Causes included dissection (17%), thrombus (4%), and tissue protrusion within the stent struts leading to lumen compromise lumen (4%). A total of 83% of patients with >1 of these abnormal morphologies also had reduced lumen dimensions post‐PCI (final lumen <80% reference lumen). Preprocedural lesion characteristics were not different from matched lesions. Conclusions Subacute stent thrombosis is infrequently related to the preintervention lesion characteristics. Inadequate postprocedure lumen dimensions, alone or in combination with other procedurally related abnormal lesion morphologies (dissection, thrombus, or tissue prolapse), contribute to this phenomenon. (Circulation. 2003;108:43‐47.)

Patent Foramen Ovale Closure or Anticoagulation vs. Antiplatelets after Stroke

BACKGROUND Trials of patent foramen ovale (PFO) closure to prevent recurrent stroke have been inconclusive. We investigated whether patients with cryptogenic stroke and echocardiographic features representing risk of stroke would benefit from PFO closure or anticoagulation, as compared with antiplatelet therapy. METHODS In a multicenter, randomized, open‐label trial, we assigned, in a 1:1:1 ratio, patients 16 to 60 years of age who had had a recent stroke attributed to PFO, with an associated atrial septal aneurysm or large interatrial shunt, to transcatheter PFO closure plus long‐term antiplatelet therapy (PFO closure group), antiplatelet therapy alone (antiplatelet‐only group), or oral anticoagulation (anticoagulation group) (randomization group 1). Patients with contraindications to anticoagulants or to PFO closure were randomly assigned to the alternative noncontraindicated treatment or to antiplatelet therapy (randomization groups 2 and 3). The primary outcome was occurrence of stroke. The comparison of PFO closure plus antiplatelet therapy with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 2, and the comparison of oral anticoagulation with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 3. RESULTS A total of 663 patients underwent randomization and were followed for a mean (±SD) of 5.3±2.0 years. In the analysis of randomization groups 1 and 2, no stroke occurred among the 238 patients in the PFO closure group, whereas stroke occurred in 14 of the 235 patients in the antiplatelet‐only group (hazard ratio, 0.03; 95% confidence interval, 0 to 0.26; P<0.001). Procedural complications from PFO closure occurred in 14 patients (5.9%). The rate of atrial fibrillation was higher in the PFO closure group than in the antiplatelet‐only group (4.6% vs. 0.9%, P=0.02). The number of serious adverse events did not differ significantly between the treatment groups (P=0.56). In the analysis of randomization groups 1 and 3, stroke occurred in 3 of 187 patients assigned to oral anticoagulants and in 7 of 174 patients assigned to antiplatelet therapy alone. CONCLUSIONS Among patients who had had a recent cryptogenic stroke attributed to PFO with an associated atrial septal aneurysm or large interatrial shunt, the rate of stroke recurrence was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone. PFO closure was associated with an increased risk of atrial fibrillation. (Funded by the French Ministry of Health; CLOSE ClinicalTrials.gov number, NCT00562289.)

Outcome Impact of Coronary Revascularization Strategy Reclassification With Fractional Flow Reserve at Time of Diagnostic Angiography Insights From a Large French Multicenter Fractional Flow Reserve Registry

Background— There is no large report of the impact of fractional flow reserve (FFR) on the reclassification of the coronary revascularization strategy on individual patients referred for diagnostic angiography. Methods and Results— The Registre Français de la FFR (R3F) investigated 1075 consecutive patients undergoing diagnostic angiography including an FFR investigation at 20 French centers. Investigators were asked to define prospectively their revascularization strategy a priori based on angiography before performing the FFR. The final revascularization strategy, reclassification of the strategy by FFR, and 1-year clinical follow-up were prospectively recorded. The strategy a priori based on angiography was medical therapy in 55% and revascularization in 45% (percutaneous coronary intervention, 38%; coronary artery bypass surgery, 7%). Patients were treated according to FFR in 1028/1075 (95.7%). The applied strategy after FFR was medical therapy in 58% and revascularization in 42% (percutaneous coronary intervention, 32%; coronary artery bypass surgery, 10%). The final strategy applied differed from the strategy a priori in 43% of cases: in 33% of a priori medical patients, in 56% of patients undergoing a priori percutaneous coronary intervention, and in 51% of patients undergoing a priori coronary artery bypass surgery. In reclassified patients treated based on FFR and in disagreement with the angiography-based a priori decision (n=464), the 1-year outcome (major cardiac event, 11.2%) was as good as in patients in whom final applied strategy concurred with the angiography-based a priori decision (n=611; major cardiac event, 11.9%; log-rank, P=0.78). At 1 year, >93% patients were asymptomatic without difference between reclassified and nonreclassified patients (Generalized Linear Mixed Model, P=0.75). Reclassification safety was preserved in high-risk patients. Conclusion— This study shows that performing FFR during diagnostic angiography is associated with reclassification of the revascularization decision in about half of the patients. It further demonstrates that it is safe to pursue a revascularization strategy divergent from that suggested by angiography but guided by FFR.

Outcome Impact of Coronary Revascularization Strategy Reclassification With Fractional Flow Reserve at Time of Diagnostic Angiography

Background— There is no large report of the impact of fractional flow reserve (FFR) on the reclassification of the coronary revascularization strategy on individual patients referred for diagnostic angiography. Methods and Results— The Registre Français de la FFR (R3F) investigated 1075 consecutive patients undergoing diagnostic angiography including an FFR investigation at 20 French centers. Investigators were asked to define prospectively their revascularization strategy a priori based on angiography before performing the FFR. The final revascularization strategy, reclassification of the strategy by FFR, and 1-year clinical follow-up were prospectively recorded. The strategy a priori based on angiography was medical therapy in 55% and revascularization in 45% (percutaneous coronary intervention, 38%; coronary artery bypass surgery, 7%). Patients were treated according to FFR in 1028/1075 (95.7%). The applied strategy after FFR was medical therapy in 58% and revascularization in 42% (percutaneous coronary intervention, 32%; coronary artery bypass surgery, 10%). The final strategy applied differed from the strategy a priori in 43% of cases: in 33% of a priori medical patients, in 56% of patients undergoing a priori percutaneous coronary intervention, and in 51% of patients undergoing a priori coronary artery bypass surgery. In reclassified patients treated based on FFR and in disagreement with the angiography-based a priori decision (n=464), the 1-year outcome (major cardiac event, 11.2%) was as good as in patients in whom final applied strategy concurred with the angiography-based a priori decision (n=611; major cardiac event, 11.9%; log-rank, P=0.78). At 1 year, >93% patients were asymptomatic without difference between reclassified and nonreclassified patients (Generalized Linear Mixed Model, P=0.75). Reclassification safety was preserved in high-risk patients. Conclusion— This study shows that performing FFR during diagnostic angiography is associated with reclassification of the revascularization decision in about half of the patients. It further demonstrates that it is safe to pursue a revascularization strategy divergent from that suggested by angiography but guided by FFR.

Effect of direct stenting on clinical outcome in patients treated with percutaneous coronary intervention on saphenous vein graft

BACKGROUND Percutaneous coronary intervention (PCI) of saphenous vein graft (SVG) is associated with frequent postprocedural enzyme elevation and late cardiac events. New strategies are proposed to minimize distal embolization and to improve the outcome of patients treated with stenting for SVG lesions. The objectives of the current study were to examine direct stenting (DS) strategy of PCI in SVG lesions and its effects on creatine-kinase (CK) release, major adverse cardiac events (MACE), and late outcome when compared to conventional stenting (CS). METHODS A consecutive series of 527 patients treated with stent implantation for SVG stenosis was analyzed. In this cohort, 170 patients with 229 lesions were treated with DS and 357 patients with 443 lesions were treated with CS. The inhospital and 12-month follow-up events were recorded and reported. RESULTS Baseline clinical and postprocedural angiographic characteristics were similar between the 2 groups except for higher preprocedural prevalence of thrombus-containing lesions in the DS group. Patients in the DS group had less CK-MB release (P <.001), and less non-Q-wave myocardial infarction (P =.024). Multivariate analysis detected unstable angina (odds ratio [OR] = 1.8, P =.03) as a correlate for non-Q-wave MI; DS was inversely associated with non-Q-wave myocardial infarction (OR = 0.65, P =.04). At 1 year, the target lesion revascularization-MACE was significantly lower in the DS group (P =.021). Multivariate analysis showed that DS (OR = 0.47, P =.007) was associated with reduction of the target lesion revascularization-MACE. CONCLUSIONS When feasible, DS may be the best approach for treating SVG stenosis.

Time Course of Stent Endothelialization After Intravascular Radiation Therapy in Rabbit Iliac Arteries

Background—Late total occlusion after vascular brachytherapy (VBT) continues to be a serious complication. Delayed reendothelialization was suggested as a pivotal cause, but the time course for complete healing is unknown. Methods and Results—Seventy-two rabbit iliac arteries underwent stent implantation and were treated with &ggr;-radiation using 192Ir. The prescribed doses were 0 Gy (controls, n=24 arteries), 15 Gy (n=24), or 30 Gy (n=24) at 2 mm. Animals were killed at 1 month (n=24), 3 months (n=24), or 6 months (n=24) and were analyzed for histomorphometry or scanning electron microscopy. Intimal area was reduced after VBT at 3 months with 15 and 30 Gy (0.66±0.07 and 0.66±0.04 mm2, respectively) compared with controls (1.01±0.11 mm2, P <0.05) and at 6 months with 30 Gy (0.75±0.09 versus 1.28±0.26 mm2 in controls, P <0.01). Intimal area was similar at 6 months between 15 Gy and controls. At 1 month, 92±4% of the control stented segment was covered with endothelial cells, whereas only 37±4% and 37±8% was covered in the 15- and 30-Gy arteries, respectively. Similarly, at 3 and 6 months, there was a difference in the extent of reendothelialized areas (at 3 months, 95±2%, 32±12%, and 29±13%; and at 6 months, 98±2%, 40±8%, and 35±12% in control, 15-Gy, and 30-Gy arteries, respectively). Excess platelets and leukocytes were seen in irradiated arteries without complete coverage of endothelium. Conclusions—Reendothelialization after VBT is not completed at 6 months after VBT. Special care with prolonged antiplatelet therapy should be considered beyond that time point.

Oral rapamycin inhibits growth of atherosclerotic plaque in apoE knock-out mice

INTRODUCTION Inflammatory and immunological responses of vascular cells are known to play significant roles in atherosclerotic plaque development. Rapamycin with antiinflammatory, immunosuppressive and antiproliferative properties has been shown to reduce neointima formation when coated on stents. This study is designed to test the potential of oral rapamycin to inhibit atherosclerotic plaque development. METHODS Eight-week-old apoE knock-out mice were fed with 0.25% cholesterol supplemented diet (control diet), control diet containing 50 microg/kg rapamycin (low-dose rapamycin) or 100 microg/kg rapamycin (high-dose rapamycin) for 4 or 8 weeks. Subsets of mice from each group (n=10) were weighed and euthanized. Whole blood rapamycin levels were determined using HPLC-MS/MS, and histological analyses of atherosclerotic lesions in the aortic root were performed. RESULTS Mice fed with high-dose rapamycin did not gain weight (18.5+/-1.5 vs. 20.6+/-0.9 g, P=.01). Blood levels of rapamycin 117+/-7 pg/ml were detected in the blood of mice fed with high-dose rapamycin for 8 weeks. The plaque area in mice fed with high dose oral rapamycin is significantly less as compared to control (0.168+/-0.008 vs. 0.326+/-0.013 mm2, P=.001 at 4 weeks; 0.234+/-0.013 vs. 0.447+/-0.011 mm2, P=.001 at 8 weeks). Lumen area was inversely proportional to the plaque area. CONCLUSIONS The results indicate that oral rapamycin is effective in attenuating the progression of atherosclerotic plaque in the mice.

Radiation-induced atherosclerotic plaque progression in a hypercholesterolemic rabbit: a prospective vulnerable plaque model?

PURPOSE Human observations provide rich soil for making hypotheses, but good animal models are essential for understanding the disease and to test treatment modalities. Currently, there is no standard animal model of vulnerable plaque; therefore, the purpose of this study is to develop a pathophysiologically relevant vulnerable plaque model. METHODS New Zealand White rabbits were fed with 1% hypercholesterolemic (HC) diet for 7 days, followed by balloon denudation of both the iliac arteries, and continued on 1% HC diet. Four weeks later, in 12 rabbits one of the iliac arteries was radiated (192-Ir, 15 Gy), and in five rabbits both the iliac arteries were sham treated. Following that, rabbits were fed with 0.15% HC diet. Four weeks later, arteries were processed for histomorphometry or immunohistochemistry. RESULTS Serum cholesterol levels were similar in all the groups. In radiated arteries, plaque area was significantly larger (32% larger then in sham). Macrophage-positive area in radiated arteries was 2.4 times greater than the macrophage-positive area in the nonradiated arteries. The area positive for macrophages is also positive for metalloproteinases (MMP)-1. The extent of alpha-actin positive area was significantly less (2.3-fold) in radiated arteries. CONCLUSION The atherosclerotic plaque developed in the current model is predominantly composed of macrophages expressing metalloproteinases with few smooth muscle cells (SMC)--a characteristic of vulnerable plaque. The animal model presented in this study can elucidate at least part of the mechanism of plaque vulnerability and could be used to test treatment modalities to test plaque stability.

How to Fix the Edge Effect of Catheter-Based Radiation Therapy in Stented Arteries

Background—Edge stenosis remains a serious limitation of catheter-based vascular brachytherapy (VBT). This study aims to identify the mechanisms and evaluate strategies to minimize edge restenosis in patients treated with VBT. Methods and Results—Thirty-four porcine stented coronary arteries were irradiated (doses of 15 or 22 Gy) with 192Ir trains of either 6 seeds (23 mm) with 0 mm coverage at the distal stent edge and 10 mm at the proximal stent edge or 14 seeds (55 mm) centered at the distal edge of the stent with 27.5 and 14.5 mm coverage at the distal and proximal edges, respectively. After VBT, an additional 13-mm stent was positioned overlapping the distal margin of the first stent. Animals were killed at 28 days, and arteries were analyzed. Longer radiation margins were associated with reduced intimal area (IA) at the stent edge: 2.3±0.9, 3.6±2.0, and 5.3±2.2 mm2 with 15 Gy for a radiation margin of 14.5, 10, and −13 mm (−13 versus 10, P =0.06; 10 versus 14.5, P =0.06). Additional stenting was associated with an increase of IA: 4.0±2.3 mm2 at the overlapped segment. Increasing the dose to 22 Gy resulted in a reduction of the IA at the overlap segment to 1.31±0.57 mm2 with 14 seeds (27.5 mm coverage) but was not helpful with 6 seeds (0 mm coverage): IA, 5.56±2.28 mm2. Conclusions—Extending the radiation margins to 14.5 mm from each end of the stent minimized the edge-effect phenomenon. A higher dose is essential to eliminate further increases in IA at the overlapped segment with additional stents.

Effect of antioxidants on atherosclerotic plaque formation in balloon-denuded and irradiated hypercholesterolemic rabbits.

The oxidative modification of low-density lipoprotein (LDL) hypothesis implies that antioxidants should be effective in suppressing atherosclerosis. This study is designed to test the potential of antioxidants to inhibit atherosclerotic plaque progression in balloon-denuded and irradiated hypercholesterolemic rabbits. Rabbits were fed with a 1% cholesterol diet supplemented with or without a mixture of antioxidants (vitamin E, vitamin C, selenium, zinc, copper, manganese, N-acetylcysteine, glutamine). At 7 days both iliac arteries were balloon denuded, and 4 weeks later, 1 iliac artery underwent endovascular irradiation (n = 12), while the contralateral was sham treated (n = 12). Four weeks after irradiation, animals were euthanized, and arteries were fixed and processed for histo- or immunohistochemistry for determining the plaque area, macrophage count, and oxidized LDL-positive areas. Plasma antioxidant levels were significantly higher in the animals fed with antioxidant diet. Plasma (thiobarbituric acid-reactive substances) and arterial tissue oxidized LDL (immunoreactive to specific oxidized LDL antibody) levels were significantly higher in the irradiated as compared with nonirradiated animals (0.69 ± 0.09 and 31.05 ± 4.21 versus 0.24 ± 0.04 and 18.42 ± 4.62, P < 0.001 and 0.05), and antioxidants partially lowered the oxidized LDL levels (0.35 ± 0.14 and 25.41 ± 4.82, P < 0.001 and 0.01). Plaque area in the irradiated animals was 175% greater than in nonirradiated animals (P < 0.05). Antioxidant supplementation resulted in a 50% decrease in plaque area of both control and irradiated animals. Antioxidants reduced both the cholesterol-induced and radiation-enhanced circulating and tissue oxidized LDL levels, resulting in reduced plaque.