Xavier Chaufour

Probucol Promotes Functional Reendothelialization in Balloon-Injured Rabbit Aortas

Background—Probucol remains the only conventional drug that reduces restenosis after coronary angioplasty. Apart from its weak cholesterol-lowering effect, probucol has antioxidant properties, but it remains unclear how this drug inhibits restenosis. Methods and Results—Aortic balloon-injured New Zealand White rabbits were fed 2% (wt/wt) cholesterol-enriched or normal chow, with 0.75% (wt/wt) probucol (P) or without (controls, C) for 6 weeks. Endothelial denudation of the abdominal aorta was performed at week 3 with a 3F Fogarty embolectomy catheter. The arteries were harvested after week 6 and analyzed for histology, lipids and antioxidants, and endothelial regeneration and function. Probucol significantly decreased aortic intima-to-media ratio (cholesterol-fed: C, 1.10±0.08 versus P, 0.70±0.10; normal: C, 0.89±0.02 versus P, 0.83±0.05;P <0.05) and the numbers of proliferating intimal smooth muscle cells and lowered serum cholesterol without altering the proportion of aortic lipids that was oxidized. Probucol promoted endothelial regeneration in the injured aorta in cholesterol-fed rabbits (25% increase in reendothelialization, P <0.05) and in those on normal chow (37% increase, P <0.01). This was associated with both improved endothelial function as assessed by enhanced aortic ring relaxation and cGMP production in response to acetylcholine and decreased intimal thickening. Conclusions—Probucol inhibits intimal thickening in balloon-damaged arteries of rabbits by promoting the regeneration of functional endothelium, without affecting the proportion of aortic lipids that was oxidized. This novel in vivo finding helps explain how probucol inhibits restenosis after coronary angioplasty and highlights potential new targets for therapeutic intervention.

Apoptosis of vascular smooth muscle cells induced by cholesterol and its oxides in vitro and in vivo

The ability of cholesterol and its oxides to induce apoptosis in vascular smooth muscle cells in tissue culture and in a rabbit model of atherosclerosis was evaluated. Apoptosis was detected using DNA laddering and in situ end-labelling of fragmented DNA. Cholesterol oxides, but not cholesterol, were found to inhibit proliferation and induce apoptosis of vascular smooth muscle cells in tissue culture. 7-ketocholesterol was found to be the most potent inhibitor of proliferation, while 25-hydroxycholesterol was found to be the most potent inducer of apoptosis. These data suggest that the inhibition of proliferation and the induction of apoptosis by cholesterol oxides within vascular smooth muscle cells use different pathways, suggesting a differential role for these cholesterol oxides within the arterial wall. Cholesterol feeding after balloon injury in a rabbit model of atherosclerosis is known to result in the accumulation of cholesterol oxides. However, we found that cholesterol feeding had no effect on the level of apoptosis in the rabbit aortic wall after balloon injury, suggesting that the major factor determining apoptosis in our model was the balloon injury.

Endovascular grafting for abdominal aortic aneurysms: Changing incidence and indications for conversion to open operation☆

The incidence and indications for conversion from endoluminal to open repair of abdominal aortic aneurysms are changing. This paper is based on a 5-year experience in which endoluminal repair of abdominal aortic aneurysms was undertaken in 156 patients. Primary conversion at the original operation was required in 14 patients and secondary conversion at a subsequent operation was required in 9 patients. The reasons for primary conversion were access problems (n = 2), balloon related problems (n = 2), endograft migration (n = 4), endograft thrombosis (n = 1) and failed deployment of a bifurcated endograft (n = 5). Twelve of 14 primary conversions occurred in the first half of the study period, in which 59 endoluminal abdominal aortic aneurysms repairs were undertaken. Improvements in technology and interventional techniques for overcoming obstacles, as well as increasing experience, has resulted in primary conversion being limited to two patients in the most recent 2.5-year period in which 97 endoluminal repairs were undertaken. The reasons for secondary conversion were renal arteries covered by the endograft (n = 2), increasing abdominal aortic aneurysm diameter in the absence of endoleak (n = 1) and persistent endoleak (n = 6). The latter group comprised three patients with intact aneurysms and three with known endoleaks who presented with ruptured aneurysms. The current indications for primary conversion include: (i) rupture of the aorta; (ii) complete migration of the endograft resulting in obstruction of the iliac arteries; and (iii) irreversible twisting of a non-modular bifurcated endograft. The current indications for secondary conversion include: (i) persistent endoleak; (ii) sealed endoleak with continued abdominal aortic aneurysms expansion; (iii) apparently successful endoluminal repair without evidence of endoleak but continued abdominal aortic aneurysms expansion; and (iv) infected endograft.

P2X (purinergic) receptor redistribution in rabbit aorta following injury to endothelial cells and cholesterol feeding

The redistribution of purinergic P2X receptor subunits (P2X1 to P2X7) within the rabbit aorta wall three weeks after endothelial balloon injury/cholesterol feeding was examined. P2X1 receptor cluster density was elevated in the media following balloon injury/cholesterol feeding by about 30% and these clusters appeared on smooth muscle cells throughout the greatly expanded neointima but they did not change significantly on the endothelial cells following balloon injury. P2X4 clusters were found in high density throughout the media and in very high density in the enlarged neointima following balloon injury, particularly on the endothelial cells where the density increased about 10-fold after balloon injury. P2X5 clusters were found in high density in the media of normal aorta but with little change following balloon injury. P2X3, P2X6 and P2X7 cluster density was low in normal aorta and remained unchanged following balloon injury. All receptor subunits were found on endothelial cells. It is suggested that the release of ATP from damaged endothelial cells and from smooth muscle cells sufficient to activate P2X4 receptors may contribute to neointimal proliferation.

Growth arrest-specific gene 6 expression in proliferating rabbit vascular smooth muscle cells in vitro and in vivo.

Proliferation and migration of vascular smooth muscle cells (VSMCs) are involved in the processes of atherosclerosis and restenosis. The protein product of the growth arrest‐specific gene 6 (Gas‐6) has recently been identified as a ligand for the Axl/Rse/Mer tyrosine kinase receptor family, which may be involved in proliferation and migration of VSMCs. Here we show that Gas‐6 gene expression is increased in proliferating VSMCs in tissue culture (2.5‐fold increase by Northern blot) and following neointimal proliferation in a rabbit balloon‐injury model (3‐fold increase by Western blot). Neither platelet‐derived growth factor (PDGF) nor thrombin stimulate the expression of Gas‐6 in cultured VSMCs despite the ability of the PDGF, but not thrombin, to stimulate proliferation in growth‐arrested cells. These data suggest a role for the Gas‐6 regulatory system in VSMC proliferation, which may be a target for therapeutic interventions in the atherosclerotic process and restenosis after angioplasty.

Evaluation of the risks of using an oversized balloon catheter in the human infrarenal abdominal aorta

OBJECTIVESnTo evaluate the effects on the aortic wall of balloon dilatation as utilised in deployment of stent-graft devices during endoluminal repair of infrarenal abdominal aortic aneurysm.nnnMETHODSnLarge dilatation balloons were expanded within the aorta of 41 cadavers. Testing was done to evaluate the effect of differing degrees of balloon oversizing, at pressures in the range of 0.15-2.5 atm. The aorta was then open for macroscopic inspection.nnnRESULTSnIn group 1 (mild atherosclerosis) no macroscopic abnormalities were detected with up to 6 mm oversized balloon. In group 2 (moderate atherosclerosis) fracture of atherosclerotic plaque occurred in seven of 14 aortas (50%) with 2.5 mm-4mm oversized balloon. In group 3 (severe atherosclerosis) fracture of atherosclerotic plaque occurred in six of seven (85%) with 2.5 mm to 4 mm oversized balloon and rupture of the aorta occurred at 6 mm oversizing.nnnCONCLUSIONSnThis study suggests that balloon overdilatation of the aorta by 2 mm, at pressures less than 2 atmospheres, allows safe deployment even in the presence of severe atheroma. Larger amounts of overdilatation are relatively safe in mildly atherosclerotic aorta. Aortic rupture is unlikely with overdilatation up to 6 mm, especially in less calcified vessels.

Protective effects of probucol in two animal models of atherosclerosis.

Abstract Lipid oxidation is widely accepted to be critical in the initiation of atherosclerosis,1 the major cause of death in industrialized countries. The use of antioxidants to improve health in non-deficient individuals, however, remains contentious as randomized trials of antioxidant supplementation in patients with established coronary disease have shown conflicting results.2–4 The potential role for antioxidants in earlier stages of atherosclerosis remains untested. Probucol, a cholesterol-lowering antioxidant, has generated much interest as it decreases restenosis after coronary angioplasty.5 Studies using probucol in animal models of atherosclerosis have, however, shown conflicting results, including inhibitory,6 neutral7 or promoting8 effects. Furthermore, the mechanisms of action of probucol in vivo remain unclear.

Delay in opening the infarct related coronary artery increases plasma atrial natriuretic peptide levels.

Plasma atrial natriuretic peptide (ANP) levels were measured in rabbits during the late healing phase of myocardial infarcts. Significant differences in plasma ANP levels (P < 0.02) were found between rabbits that had undergone very late (6 h) or early reperfusion (20 and 45 min of ischemia) of the infarct related coronary artery. Differences in ANP levels were independent of infarct size, ventricular remodeling and infarct expansion. We conclude late reperfusion of infarct related artery, independent of myocardial salvage, is associated with increased circulating ANP plasma levels.

Diameter of large balloons used in endoluminal graft deployment varies with inflation pressure.

Purpose: To evaluate the characteristics of large-diameter balloon catheters used during endoluminal repair of aortic aneurysms. Methods: Thirty-three large balloon dilatation catheters in the diameter range of 15 to 30 mm were measured at controlled pressures from 1 to 4 atm. The balloons were inflated with water using an inflation syringe connected to a pressure transducer. Diameters at stable pressure and pressure changes against time were recorded for each balloon. Results: Dilation catheters in the range of 15 to 20 mm in diameter were significantly smaller (p < 0.005) than their nominal diameter at 1 and 2 atm; they reached nominal diameter only at the relatively high pressure of 4 atm. Most larger diameter balloons (25 and 30 mm) did not attain their nominal diameter even with pressures up to 4 atm. All sizes of balloon catheters tested became relatively compliant at pressures > 3 atm. Conclusions: The large balloon catheters tested in this study were designed for arterial angioplasty or valvuloplasty. They attained a significantly smaller size than their nominal diameter at pressures < 3 atm and became compliant at pressures exceeding 3 atm. Interventionists should be aware of these characteristics when using balloon catheters such as these during endoluminal graft deployment. Large balloons that reach predictable diameter at lower pressures should be designed specifically for use in endoluminal graft procedures.