Autologous Mesenchymal Stem Cells Show More Benefit on Systolic Function Compared to Bone Marrow Mononuclear Cells in a Porcine Model of Chronic Myocardial Infarction.

Cardiac cell therapy is a strategy to treat patients with chronic myocardial infarction (MI). No consensus exists regarding the optimal cell type. First, a comparison between autologous bone marrow-derived mononuclear cells (BMMNC) and mesenchymal stem cells (MSC) on therapeutic efficacy after MI was performed. Next, the effect of repetitive, NOGA-guided transendocardial injection was determined via a crossover design. Nineteen pigs were allocated in three groups: (1) placebo (at 4 and 8 weeks), (2) MSC (followed by placebo at 8 weeks), or (3) BMMNC (followed by MSC at 8 weeks) delivery including a priming strategy to enhance MSC effect. At 4 weeks, ejection fraction (EF) was significantly improved after MSC injection and not by BMMNC injection. After 8 weeks, no difference was observed in EF between cell-treated groups demonstrating the positive systolic effect of MSC. This study showed that MSC rather than BMMNC injection improves systolic function in chronic MI.

Long-term safety of intramuscular gene transfer of non-viral FGF1 for peripheral artery disease.

Peripheral artery disease is a progressive disease. Primary ischemic leg symptoms are muscle fatigue, discomfort or pain during ambulation, known as intermittent claudication. The most severe manifestation of peripheral artery disease is critical limb ischemia (CLI). The long-term safety of gene therapy in peripheral artery disease remains unclear. This four center peripheral artery disease registry was designed to evaluate the long-term safety of the intramuscular non-viral fibroblast growth factor-1 (NV1FGF), a plasmid-based angiogenic gene for local expression of fibroblast growth factor-1 versus placebo in patients with peripheral artery disease who had been included in five different phase I and II trials. Here we report a 3-year follow-up in patients suffering from CLI or intermittent claudication. There were 93 evaluable patients, 72 of them in Fontaine stage IV (47 NV1FGF versus 25 placebo) and 21 patients in Fontaine stage IIb peripheral artery disease (15 NV1FGF versus 6 placebo). Safety parameters included rates of non-fatal myocardial infarction (MI), stroke, death, cancer, retinopathy and renal dysfunction. At 3 years, in 93 patients included this registry, there was no increase in retinopathy or renal dysfunction associated with delivery of this angiogenic factor. There was also no difference in the number of strokes, MI or deaths, respectively, for NV1FGF versus placebo. In the CLI group, new cancer occurred in two patients in the NV1FGF group. Conclusions that can be drawn from this relatively small patient group are limited because of the number of patients followed and can only be restricted to safety. Yet, data presented may be valuable concerning rates in cancer, retinopathy, MI or strokes following angiogenesis gene therapy in the absence of any long-term data in angiogenesis gene therapy. It may take several years until data from larger patient populations will become available.

Insights on the role of diabetes and geographic variation in patients with critical limb ischaemia.

BACKGROUND: Patients with critical limb ischaemia (CLI) unsuitable for revascularisation have a high rate of amputation and mortality (30% and 25% at 1 year, respectively). Localised gene therapy using plasmid DNA encoding acidic fibroblast growth factor (NV1FGF, riferminogene pecaplasmid) has showed an increased amputation-free survival in a phase II trial. This article provides the rationale, design and baseline characteristics of CLI patients enrolled in the pivotal phase III trial (EFC6145/TAMARIS). METHODS: An international, double-blind, placebo-controlled, randomised study composed of 525 CLI patients recruited from 170 sites worldwide who were unsuitable for revascularisation and had non-healing skin lesions was carried out to evaluate the potential benefit of repeated intramuscular administration of NV1FGF. Randomisation was stratified by country and by diabetic status. RESULTS: The mean age of the study cohort was 70 ± 10 years, and included 70% males and 53% diabetic patients. Fifty-four percent of the patients had previous lower-extremity revascularisation and 22% had previous minor amputation of the index leg. In 94% of the patients, the index leg had distal occlusive disease affecting arteries below the knee. Statins were prescribed for 54% of the patients, and anti-platelet drugs for 80%. Variation in region of origin resulted in only minor demographic imbalance. Similarly, while diabetic status was associated with a frequent history of coronary artery disease, it had little impact on limb haemodynamics and vascular lesions. CONCLUSIONS: Clinical characteristics and vascular anatomy of CLI patients with ischaemic skin lesions who were unsuitable for revascularisation therapy show little variations by region of origin and diabetic status. The findings from this large CLI cohort will contribute to our understanding of this disease process. This study is registered with ClinicalTrials.gov, number NCT00566657.

[Does diabetes affect therapy in coronary patients? Revascularisation]. / Le diabète influence-t-il les choix thérapeutiques chez le coronarien? La revascularisation.

Techniques of myocardial revascularisation are very commonly employed in diabetic patients. In unstable angina, the reported data suggests a very significant benefit of an invasive strategy for the diabetic patient. In stable angina, subgroups analysis of randomised clinical trials carried out over ten years ago showed a better outcome after surgery in cases of multivessel disease. What has been the impact of technical advances archived since then? Active stents and antiplatelet drugs have considerably improved the outcome of diabetics treated by angioplasty. Cardiac surgery has also made considerable progress with the systematic use of arterial grafts. New randomised clinical trials are underway to determine the modern options of myocardial revascularisation for diabetic patients.

[Coronary thrombosis imaging in humans]. / Imagerie de la thrombose coronaire chez l'homme.

The identification of coronary thrombosis in humans has important prognostic and therapeutic implications. Its recognition calls for invasive techniques: angioscopy, coronarography, and endocoronary ultrasound. Angioscopy allows visualisation of the arterial surface and the detection of thrombus with great sensitivity. Its presence is exclusive to the acute coronary syndromes: 67% in unstable angina, and 75% in myocardial infarction, although it is only present in 27% of cases of stable angina. The relative complexity of its use has led to the abandonment of this technique. Coronarography allows an indirect approach to coronary thrombosis. Certain aspects are evocative such as: intraluminal filling defect, complete occlusion with upstream convexity, ulceration and eccentric type 2 Ambrose classification plaques. As a function of the clinical presentation, the coronarographic views allow a good specificity for the diagnosis of thrombus. The sensitivity is weak, however, compared to angioscopy. Endocoronary ultrasound does not allow identification of fresh thrombus which is not echogenic and does not allow differentiation between older thrombus and lipid plaque. In the future, magnetic resonance imaging could prove interesting in the detection of recent thrombus.

Patency of percutaneous transluminal coronary angioplasty sites at 6-month angiographic follow-up: A key determinant of survival in diabetics after coronary balloon angioplasty.

BACKGROUND: Several reports have demonstrated a high mortality rate in diabetic patients treated by standard coronary balloon angioplasty. No clear explanation has been provided for this finding. METHODS AND RESULTS: Consecutive diabetic patients successfully treated by standard coronary balloon angioplasty (n=604) were enrolled in a follow-up program including repeated angiography at 6 months and long-term clinical follow-up. Clinical follow-up was available in 603 patients (99.8%). Twelve patients died, 2 underwent bypass surgery before scheduled repeated angiography, and 76 declined angiography. Determinants of long-term mortality were analyzed in the 513 patients with angiography at 6 months and long-term clinical follow-up (mean follow-up, 6.5+/-2.4 years). On the basis of the results of repeated angiography, 3 groups of patients were defined: group 1, 162 patients without restenosis (32%); group 2, 257 patients with nonocclusive restenosis (50%); and group 3, 94 patients with coronary occlusion (18%). Overall actuarial 10-year mortality rate was 36%. Actuarial 10-year mortality was 24% in group 1, 35% in group 2, and 59% in group 3 (P:<0.0001). Multivariate analysis demonstrated that coronary occlusion was a strong and independent correlate of long-term total mortality (hazard ratio, 2.16; 95% CI, 1.43 to 3.26; P:=0.0003) and cardiac mortality (hazard ratio, 2.38; 95% CI, 1.48 to 3.85; P:=0.0004). CONCLUSIONS: This study demonstrates that restenosis, especially in its occlusive form, is a major determinant of long-term mortality in diabetic patients after coronary balloon angioplasty.

Effect of percutaneous adenovirus-mediated Gax gene delivery to the arterial wall in double-injured atheromatous stented rabbit iliac arteries.

Though the efficacy of intravascular gene transfer has been demonstrated in native vessels following acute injury, this methodology has not been validated in complex models of vascular injury that more closely mimic clinical angioplasty procedures. Previous studies have shown that Gax gene overexpression modulates the injury-induced remodeling of the vessel in rat carotid and normal rabbit iliac arteries. Here, we evaluated the effect of the Gax gene delivery in atheromatous stented vessels. Rabbits were fed 120 g daily of 1% cholesterol diet for 3 weeks. At 1 week they underwent initial injury on the external iliac artery, then balloon angioplasty was performed at 3 weeks at the same site with a 2.5 mm diameter channel balloon catheter (three times 1 min at 6 atm). Either saline (n = 4) or the control viral construct Ad-CMVluc (5 x 109 p.f.u.) (n = 5) or Ad-CMVGax (5 x 10(9) p.f.u.) (n = 4) was delivered with a poloxamer mixture via a channel balloon (6 atm, 30 min), and a 15 mm long Palmaz-Schatz stent (PS154) was then deployed at the site (1 min, 8 atm). Arteries were analyzed 1 month later. At 1 month, the Ad-CMVGax treated arteries exhibited a lower maximal intimal area (1. 15+/-0.1 mm2) than saline (1.87+/-0.15 mm2, P = 0.007) or Ad-CMVluc-treated vessels (1.98+/-0.31 mm2, P = 0.04). Likewise Ad-CMVGax-treated vessels displayed a lower maximal percentage cross-sectional area narrowing (35.1+/-3.5%) than saline (65.3+/-9.4%, P = 0.01) or Ad-CMVluc-treated vessels (62.7+/-6.7%, P = 0.02). Angiographic analysis revealed larger minimal lumen diameter in Ad-CMVGax treated arteries (2.0+/-0.1 mm) than saline (1.14+/-0.36 mm, P = 0.06) or Ad-CMVluc-treated vessels (1.23+/-0.25 mm, P = 0.02). Overexpression of the Gax gene inhibits neointimal hyperplasia and lumen loss in atheromatous stented rabbit iliac arteries.

[Coronary angioplasty in diabetic patients. Analysis of the problems to improve results]. / Angioplastie coronaire chez le patient diabétique. Analyser ses points faibles pour améliorer ses performances.

The object of this review is to update our knowledge of the results of revascularisation by angioplasty in diabetics. The authors discuss: 1. the clinical results in diabetic patients compared with non-diabetics and the results of coronary bypass surgery; 2. the factors influencing the prognosis of these patients after balloon angioplasty, especially with respect to restenosis; 3. the possibilities of improving the results by the use of modern techniques of revascularisation and prevention and 4. the strategies of revascularisation which may be proposed, based on available data.

Growth factors and endothelial dysfunction.

Endothelial dysfunction has been implicated in the pathogenesis of many cardiovascular diseases; experimental and clinical studies have shown that endothelial dysfunction may be a key factor in various processes, including abnormal arterial vasomotion, thrombosis or neointimal proliferation. Endothelial dysfunction has been shown to be a characteristic feature of atherosclerotic vessels, sites subject to mechanical injury or collateral vessels that develop in response to severe ischaemia. Fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) are important growth factors for endothelial cells in vitro. While VEGF is specific for endothelial cells, FGFs are also potent growth factors for other cell types such as smooth muscle cells. Recent studies have demonstrated the feasibility of using endothelial cell growth factors in vivo. Basic FGF (bFGF) and VEGF have been shown to increase the development of collateral vessels in ischaemic models and to enhance the extent of endothelial regrowth following arterial injury. The marked anatomical improvement associated with the administration of endothelial cell growth factors has promoted questions concerning a possible role for these factors in endothelial dysfunction. In vivo administration of endothelial cell growth factors is associated with significant improvement in endothelium-dependent responses. This effect is observed with bFGF and VEGF in various animal models of endothelial dysfunction such as the collateral circulation, the regenerated endothelium following arterial injury and experimental atherosclerosis. While the precise mechanisms underlying this ubiquitous beneficial effect of endothelial cell growth factors are still to be determined, these results do support the concept of using such factors as a new therapeutic strategy in patients with vascular diseases.

Growth factors and endothelial dysfunction.

Endothelial dysfunction has been implicated in the pathogenesis of many cardiovascular diseases: experimental and clinical studies have shown that endothelial dysfunction may be a key factor in various processes, including abnormal arterial vasomotion, thrombosis or neointimial proliferation. Endothelial dysfunction has been shown to be a characteristic feature of atherosclerotic vessels, sites subject to mechanical injury or collateral vessels that develop in response to severe ischaemia. Fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) are important growth factors for endothelial cells in vitro. While VEGF is specific for endothelial cells. FGFs are also potent growth factors for other cell types such as smooth muscle cells. Recent studies have demonstrated the feasibility of using endothelial cell growth factors in vivo. Basic FGF (bFGF) and VEGF have been shown to increase the development of collateral vessels in ischaemic models and to enhance the extent of endothelial regrowth following arterial injury. The marked anatomical improvement associated with the administration of endothelial cell growth factors has promoted questions concerning a possible role for these factors in endothelial dysfunction. In vivo administration of endothelial cell growth factors is associated with significant improvement in endothelium-dependent responses. This effect is observed with bFGF and VEGF in various animal models of endothelial dysfunction such as the collateral circulation, the regenerated endothelium following arterial injury and experimental atherosclerosis. While the precise mechanisms underlying this ubiquitous beneficial effect of endothelial cell growth factors are still to be determined, these results do support the concept of using such factors as a new therapeutic strategy in patients with vascular diseases.

[From the angiogenic response to ischemia to the validation of the concept of "therapeutic angiogenesis"]. / De la réponse angiogénique à l'ischémie et à la validation du concept "d'angiogenèse thérapeutique".

The object of this review is to assess the importance of angiogenesis in cardiovascular physiology and to review the new therapeutic approach which have opened up in this field. The authors report: 1) general information about growth factors implicated in angiotensin (fibroblast growth factor, vascular endothelial growth factor, scatter factor). 2) data obtained from embryo studies which have confirmed the relative rôle of certain intermediary molecules, especially vascular endothelial growth factor in vascular formation. 3) results of animal model experiments of chronic ischaemia and 4) the therapeutic possibilities that these studies suggest and the preliminary results of human applications.

Effects of poloxamer 407 on transfection time and percutaneous adenovirus-mediated gene transfer in native and stented vessels.

UNLABELLED: Reduction in transfection time and the ability to perform gene transfer in conjunction with endovascular stent implantation constitute two important challenges for percutaneous adenovirus-mediated gene transfer to vessel walls. Studies have suggested that the use of biocompatible polyol poloxamer 407 could be useful. We first evaluated the use of poloxamer 407 for percutaneous gene transfer in nonstented rabbit iliac arteries. A 200-microl mixture of Ad-RSVbetagal or Ad-CMVLuc in either phosphate-buffered saline (PBS) or 20% poloxamer was delivered. After 3 days, gene transfection was evaluated by X-Gal staining or measurement of luciferase activity. Poloxamer use resulted in a 3- to 15-fold increase in the percentage of transfected cells (X-Gal, p = 0.001) and a 16-fold increase in protein product (luciferase activity, p = 0.03), and allowed a decrease in transfection time from 30 to 5 min with minimal reduction in transfection efficiency. We then evaluated the feasibility of percutaneous gene transfer, using Ad-RSVbetagal diluted in pure PBS or 20% poloxamer, in conjunction with stent implantation. Gene delivery was performed either immediately before (pre-) or after (post-) stent implantation. When adenoviruses were diluted in PBS, gene transfer had a low efficiency (prestent, 0.3%; poststent, 0.2%; NS). With poloxamer, the efficacy was much higher (p = 0.0001) and similar "pre" (2.2%) or "post" (1.7%) stent delivery (NS). CONCLUSIONS: (1) The use of poloxamer, rather than PBS, as a vehicle increases the efficacy of percutaneous adenovirus-mediated gene transfer and reduces transfection time; (2) gene transfer performed during stent implantation with poloxamer is feasible and achieves a significant level of gene expression. Thus percutaneous gene delivery is applicable to conventional stents and could present an attractive method by which to achieve local biological effects in a stent environment.

Potentiated angiogenic effect of scatter factor/hepatocyte growth factor via induction of vascular endothelial growth factor: the case for paracrine amplification of angiogenesis.

BACKGROUND: Scatter factor/hepatocyte growth factor (SF/HGF) is a pleiotropic growth factor that stimulates proliferation and migration of endothelial cells (ECs) via the c-Met receptor, present on ECs as well as other cell types, including smooth muscle cells (SMCs). We studied the effects of recombinant human (rh) SF/HGF in vitro and in vivo in a rabbit model of hindlimb ischemia. We further compared these effects with those of recombinant human vascular endothelial growth factor (rhVEGF165), an EC-specific mitogen. METHODS AND RESULTS: In vitro, rhSF/HGF and rhVEGF165 exhibited similar effects on proliferation and migration of ECs. When both cytokines were administered together, the result was an additive effect on EC proliferation and a synergistic effect on EC migration. Application of rhSF/HGF to cultures of human SMCs resulted in the induction of VEGF mRNA and protein. In vivo, administration of rhSF/HGF (500 microg x 3) was associated with significant improvements in collateral formation (P<.001) and regional blood flow (P<.0005) and with a significant reduction in muscle atrophy (P<.0001). These effects were significantly more pronounced than those of rhVEGF165 administered according to the same protocol (P<.05). Neither remote angiogenesis nor other pathological sequelae were observed with either rhSF/HGF or rhVEGF165. CONCLUSIONS: The pleiotropic effects of certain growth factors may potentiate angiogenesis via a combination of direct effects on EC proliferation and migration and indirect effects that result in the generation of other potent EC mitogens from non-EC populations. The synergistic effects demonstrated when SF/HGF and VEGF are administered together in vitro may be reproduced in vivo by SF/HGF-induced upregulation of VEGF in vascular SMCs.

Coronary angioscopic findings in the infarct-related vessel within 1 month of acute myocardial infarction: natural history and the effect of thrombolysis.

BACKGROUND: Limited angioscopic information is available on the natural history of infarct-related plaque after myocardial infarction (MI), in particular the effect of thrombolysis. METHODS AND RESULTS: We studied with angioscopy the morphological characteristics of the infarct-related lesion in 56 patients between 24 hours and 4 weeks after MI. Forty of these patients were initially treated with a thrombolytic agent. Most lesions were complex (complex + ulcerated shape = 54%). The predominant color of the plaque was yellow in 79% of cases; only 6% were uniformly white. Angioscopically visible thrombus was found in 77% of cases. Despite angioscopic evidence of instability, only 7% of the patients had post-MI angina. During the 1-month time window since the occurrence of MI, there was no significant difference in the angioscopic appearance of the plaque except for a slight increase in uniformly white plaques (P=.07). The use of a thrombolytic agent at the onset of MI was associated with a reduction in thrombus size and less protruding thrombi (P=.02) but not with a decreased frequency of plaque containing thrombi. Furthermore, a trend for more frequently ulcerated plaques (45% versus 16%, P=.06) was associated with the use of a thrombolytic agent. CONCLUSIONS: These results suggest that healing of the infarct-related lesion requires more than 1 month and that an "unstable" yellow plaque with adherent thrombus is common during that period. This finding may partly explain the unique behavior of recent infarct-related lesions, which are more prone to occlude than other lesions.

Hypercholesterolemia attenuates angiogenesis but does not preclude augmentation by angiogenic cytokines.

BACKGROUND: The impact of hyperlipidemia on collateral vessel development in vivo remains enigmatic. We sought to determine the anatomic extent and functional capacity of the collateral bed that develops in response to limb ischemia in a well characterized animal model of spontaneous hypercholesterolemia, the Watanabe heritable hyperlipidemic (WHHL) rabbit. We further characterized the impact of exogenous angiogenic cytokine administration on collateral vessel development and function in the same animal model. METHODS AND RESULTS: Weight-matched 6-month-old male homozygous WHHL (n=9) and normal New Zealand White (NZW) (n=9) rabbits underwent surgical resection of one femoral artery. Ten days later, the ischemic hindlimb was evaluated for collateral vessel formation, blood flow, and tissue damage. Collateral vasculature was less extensive among WHHL than NZW, as indicated by a significant reduction in angiographic score (0.19+/-0.02 versus 0.35+/-0.03, P<.001) and capillary density (46.4+/-4.1 versus 78.9+/-4.6/mm2, P<.0002). This was associated with a reduction in calf blood pressure index (9.5+/-3.5% versus 32.8+/-2.8%, P<.0001), arterial blood flow (7.5+/-0.6 versus 13.6+/-0.7 mL/min, P<.0001), and muscle perfusion index (40.1+/-3.2% versus 65.9+/-2.0%, P<.0001) and an increase in muscle necrosis (48.16+/-5.41% versus 25.90+/-3.83% negative 2,3,5-triphenyltetrazolium chloride staining, P<.004). Treatment of WHHL rabbits (n=9) with recombinant human vascular endothelial growth factor produced a statistically significant improvement in all functional as well as anatomic indices of collateral development. CONCLUSIONS: Collateral vessel development associated with hindlimb ischemia in vivo is severely attenuated in an animal model of spontaneous hypercholesterolemia but nevertheless may be augmented by administration of angiogenic cytokines.

Accelerated endothelialization by local delivery of recombinant human vascular endothelial growth factor reduces in-stent intimal formation.

Endothelium plays an important role in vascular smooth muscle cell proliferation and thrombus deposition. We thus hypothesized that local delivery of recombinant human vascular endothelial growth factor (rhVEGF) might reduce in-stent intimal formation. Balloon injury followed by Palmaz-Schatz stent implantation was performed in the external iliac artery of 30 New Zealand rabbits. Animals were then randomized to: 1) no local delivery (Control group, n=10); 2) local delivery via a channel balloon catheter of 100 microg rhVEGF165 (VEGF group, n=10); or 3) local delivery of the vehicle solution (Vehicle group, n=10). Animals were sacrificed 28 days later and morphometric analysis was performed. Maximal intimal area was reduced from 1.47+/-0.12 mm2 and 1.44+/-0.10 mm2 in the Control and Vehicle groups, respectively, to 0.87+/-0.06 mm2 in the VEGF group (p<.001). Accelerated endothelialization by local delivery of an endothelial-specific growth factor, rhVEGF, significantly reduces in-stent intimal formation and could constitute an attractive alternative to direct antiproliferative strategies.

Passivation of metallic stents after arterial gene transfer of phVEGF165 inhibits thrombus formation and intimal thickening.

OBJECTIVES: This study sought to test the hypothesis that direct gene transfer of an endothelial cell mitogen could passivate metallic stents by accelerating endothelialization of the prosthesis. BACKGROUND: Thrombosis and restenosis comprise the principal clinical manifestations of compromised biocompatibility of endovascular stents. Previous studies have demonstrated that endothelial recovery at sites of balloon injury is a critical determinant of consequent intimal thickening and mural thrombus. We therefore investigated the potential for an endothelial cell mitogen delivered as plasmid DNA to optimize stent biocompatibility. METHODS: Naked plasmid DNA encoding vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF) (phVEGF165) was delivered locally using a hydrogel-coated balloon angioplasty catheter to 16 rabbit iliac arteries in which metallic stents had been placed at the site of balloon injury; the contralateral iliac artery of each rabbit was balloon injured and stented but not transfected. RESULTS: Stent endothelialization was accelerated by phVEGF165 gene transfer (87.38 +/- 5.06% vs. 33.13 +/- 9.73% [mean +/- SEM] of the planimetered stent surface in the treated vs. contralateral limb, p = 0.005). This was associated with a significant reduction in mural thrombus (3.7 +/- 2.4% vs. 32.7 +/- 9.7%, p = 0.01) at day 7 and intimal thickening (maximal intimal area 0.61 +/- 0.09 vs. 1.44 +/- 0.12 mm2, p < 0.0001) at day 28. No benefit was observed from pCMV-luciferase in 14 similarly instrumented control rabbits. CONCLUSIONS: These findings indicate that arterial gene transfer of naked plasmid DNA encoding for an endothelial cell mitogen may successfully passivate endovascular stents by accelerating stent endothelialization, thereby reducing in-stent thrombus and obstruction due to intimal thickening.

[Coronary angioscopy]. / Angioscopie coronaire.

Coronary angioscopy evaluates the composition of the atherosclerotic plaque by direct examination of the arterial wall. The angioscope is fitted with a balloon which prevents assessment of the proximal segment of the vessels. The fibre optic system provides and excellent view of the mid and distal segments of the coronary arteries. The coronary arteries appear smooth and white on angioscopy. The atherosclerotic plaque is a white or yellowish incursion. Unstable plaques are characterised by the presence of thrombus. In unstable angina, thrombus is observed in 64% of cases and in 75% of cases during the first month after myocardial infarction. The colour of the plaque seems to be related to its fragility: the yellow plaque is much more common during myocardial infarction than in unstable angina (75% versus 47% of cases). Finally, after coronary angioplasty restenosis is more commonly white, covered by neo-intimal proliferation. Angioscopy has been shown to be feasible and safe and it is a better method of identifying thrombus. At present, it is a tool for clinical research in coronary thrombosis and interventional cardiology.

Stent endothelialization. Time course, impact of local catheter delivery, feasibility of recombinant protein administration, and response to cytokine expedition.

BACKGROUND: Because prior studies have established the critical role of the endothelium in preventing vascular thrombosis and intimal thickening, we designed a series of experiments to determine the feasibility of percutaneous local catheter delivery of recombinant protein to accelerate development of an intact endothelial monolayer after stent implantation. METHODS AND RESULTS: Balloon injury followed by percutaneous delivery of a 15-mm-long, balloon-expandable metallic stent was performed in 64 rabbit external iliac arteries (baseline diameter, 2.67 +/- 0.07 mm). Planimetric time-course analysis disclosed < 20% stent endothelialization at 4 days, < 40% at 7 days, and near-complete endothelialization at 28 days. The reporter protein horseradish peroxidase and the endothelial cell-specific recombinant protein vascular endothelial growth factor (VEGF) were each effectively delivered from a local delivery catheter (channel balloon catheter, ChB) after stent implantation. Although local catheter delivery (of vehicle control) itself mildly retarded the extent of stent endothelialization (10.6 +/- 2.9%) versus no local delivery (25.5 +/- 6.6%, P = .045), local ChB delivery of 100 micrograms VEGF overcame this catheter effect: By day 7, stent endothelialization was nearly complete (91.8 +/- 3.8%) (P < .0001 versus no local delivery). Consequently, stent thrombus was reduced in the VEGF-treated group (mural thrombus, 5.3 +/- 3.7%) versus no local delivery (29.3 +/- 6.8%, P = .006). Occlusive thrombus was seen only in the absence of local VEGF administration. CONCLUSIONS: (1) Local delivery of recombinant protein to the arterial wall is feasible after stent implantation, and (2) local delivery of the endothelial cell mitogen VEGF accelerates stent endothelialization, reducing stent thrombosis. These results thus establish a novel means by which the safety and/or bioactivity of endovascular stents may be further enhanced.