Atherosclerosis in Marek's disease virus infected hypercholesterolemic roosters is reduced by HMGCoA reductase and ACE inhibitor therapy

OBJECTIVES: Accelerated atherosclerosis is associated with herpesviral infection both in transplant patients and after balloon angioplasty. Marek's disease virus (MDV) is a herpesvirus that induces accelerated atherosclerosis associated with the development of an invasive lymphoma in hyperlipemic roosters. We have examined the effects of pravastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase inhibitor and quinapril, an angiotensin converting enzyme (ACE) inhibitor, on atherosclerosis development in MDV infected, cholesterol fed rooster chicks. METHODS: The effects of these drugs on plaque growth after MDV infection were examined in two studies. In Study 1, MDV infected White Leghorn rooster chicks were divided into 4 groups assigned to normal or high cholesterol diet, and treated at three months of age with either pravastatin or saline. In Study 2, cholesterol fed rooster chicks infected with MDV were divided into 3 groups for treatment with either pravastatin, quinapril, or saline control. RESULTS: A significant decrease in plaque area was detected after 60 days of treatment with both pravastatin and quinapril in cholesterol fed chicks (P < 0.001). Lymphocyte infiltration into the arterial wall or target organs was not inhibited by treatment with either drug. CONCLUSIONS: (1) HMGCoA reductase inhibitor and ACE inhibitor therapy reduce atherosclerosis induced by virus infection and cholesterol diet, but this decrease in plaque growth is not due to a reduction in lymphocyte invasion. (2) MDV infection in cholesterol fed roosters provides a model for virus-induced arterial injury in atherogenesis.     

The relation between de novo atherosclerosis remodeling and angioplasty-induced remodeling in an atherosclerotic Yucatan micropig model

Geometric remodeling in de novo atherosclerosis and in restenosis after balloon angioplasty constitutes a change in total arterial circumference that, together with plaque growth or neointima formation, determines the lumen of the artery. The heterogeneous nature of arterial obstructions raises the question of whether early and late outcomes (restenosis) of angioplasty are affected by the degree and direction of de novo atherosclerotic remodeling. This study was designed to assess the relationship between atherosclerotic remodeling and the degree and mechanism of restenosis after balloon angioplasty. Atherosclerosis was induced in 27 peripheral arteries of 18 Yucatan micropigs by a combination of denudation and atherogenic diet. Balloon angioplasty was performed, with serial intravascular ultrasound and quantitative angiography before and after intervention and at 42 days' follow-up. We used the relative media-bounded area (MBA), defined as the MBA of the treated site divided by the MBA of the reference, before angioplasty as a measure of remodeling in de novo atherosclerosis and late MBA loss as a measure of remodeling after balloon angioplasty. Relative MBA before angioplasty was not correlated with angiographic and echographic acute gain after balloon angioplasty (r=.22, P=.28 and r=.14, P=.48) or with late lumen loss (r=-.05, P=.81 and r=.19, P=.33). No correlation was found between relative MBA and late MBA loss (r=.14 and P=.48). In the atherosclerotic Yucatan micropig, remodeling during de novo atherosclerosis has no relevance for acute gain and late lumen loss after balloon angioplasty. Both the direction and the extent of remodeling after balloon angioplasty are not related to the direction and extent of remodeling during de novo atherosclerosis.     

Serial investigation of balloon angioplasty induced changes in the superficial femoral artery using colour duplex ultrasonography

Percutaneous transluminal balloon angioplasty (PTA) of superficial femoral artery lesions is associated with similar initial success rates in coronary and iliac artery angioplasty but its application is limited by a much higher incidence of restenosis. To improve understanding of the trauma caused to the vessel by balloon angioplasty and the mechanisms contributing to the subsequent processes of healing and restenosis requires serial investigations of the treated arteries in vivo. This paper describes a prospective study using colour duplex ultrasonic imaging to assess arterial changes in 51 patients with atherosclerotic disease undergoing PTA of superficial femoral artery stenoses and occlusions. Each patient was scanned prior to angioplasty and at intervals up to 6 months post-angioplasty. On each scan, measurements were made of the overall vessel and lumen diameters at each site of angioplasty. These measurements indicate that angioplasty improves vessel patency mainly by stretching of the vessel wall, with compression and/or redistribution of the atherosclerotic plaque contributing less than 25% to the improvement of lumen diameter. Serial measurements after angioplasty show complex patterns of change at the angioplasty sites indicating that several mechanisms may be contributing to the processes of vessel healing and subsequent restenosis. Possible mechanisms which could explain the measured changes in overall vessel and lumen diameters are discussed.     

The atherosclerotic Yucatan animal model to study the arterial response after balloon angioplasty: the natural history of remodeling

OBJECTIVE: Remodeling in de novo atherosclerosis and in restenosis after balloon angioplasty constitutes a change in total arterial circumference which, together with plaque growth or neointimal formation, determines the lumen of the artery. To better understand the fundamental biology of neointimal formation, remodeling and their interaction, animal studies are needed. In this study, we described in detail the methodology used and the natural history of neointimal formation and remodeling after balloon angioplasty in atherosclerotic Yucatan micropigs. METHODS AND RESULTS: Atherosclerosis was induced in 60 peripheral arteries of sixteen Yucatan micropigs by a combination of denudation and atherogenic diet. Balloon angioplasty was performed in 38 arteries, with serial intravascular ultrasound (IVUS) and quantitative angiography before and after intervention and at 2, 4, 7, 14 or 42 days follow-up. Remodeling, expressed as late media-bounded area (MBA) loss, increased progressively over time. At 42 days, late MBA loss after balloon angioplasty was significantly different compared to late MBA loss in control arteries, 2.2 +/- 1.0 versus -0.3 +/- 1.1 mm2 and p = 0.02. Late lumen loss increased over time and was highest at 42 days after balloon angioplasty (2.8 +/- 0.7 mm2). The contribution of neointimal formation to late lumen loss decreased over time and the contribution of late MBA loss to late lumen increased over time and was highest at 42 days (78%). Medial necrosis was 48% at two days after balloon angioplasty and the repopulation of the media was almost completed at seven days. CONCLUSION: Remodeling following balloon angioplasty has an early onset and progresses with neointimal formation to cause restenosis over the standard 42-day time course for Yucatan micropigs. This correlates to six months renarrowing in humans. In this model, atherosclerosis and the natural history of restenosis, both with respect to neointimal formation and remodeling, resemble the human disease quite closely.     

Propofol preserves the viability of isolated rat hepatocyte suspensions under an oxidant stress

OBJECTIVES: This study evaluated the long-term impact of endoluminal low power red laser light (LPRLL) on restenosis in an atherosclerotic rabbit model. BACKGROUND: Despite widespread application of balloon angioplasty for treatment of coronary artery disease, restenosis limits its clinical benefits. Restenosis is a complex process and may be partly attributed to the inability of the vascular endothelium to regenerate and cover the denuded area at the site of arterial injury. We previously demonstrated that LPRLL stimulates endothelial cell proliferation in vitro and contributes to rapid endothelial regeneration after balloon injury in nonatherosclerotic rabbits. METHODS: Rabbit abdominal aortas (n = 12) were treated in separate zones with balloon dilation and balloon dilation plus laser illumination. Endoluminal laser therapy was performed using a laser-balloon catheter delivering a single dose of 10 mW for 3 min from a helium-neon laser (632 nm). Angiography was performed before and after treatment and was repeated 8 weeks before harvesting the aortas. RESULTS: Quantitative angiographic analysis demonstrated no differences in the minimal lumen diameter (MLD) between the two zones before treatment; an increase in the MLD in both zones after balloon angioplasty and a significant versus slight reduction of the MLD in the balloon treatment versus balloon plus laser zones at 8 weeks. Histologic examination showed a very high level of myointimal hyperplasia in the balloon treatment zones but a minimal level in the LPRLL-treated zones. Morphometric analysis revealed a statistically significant difference in the lumen area, intimal area and intima/media ratio between the balloon versus balloon plus laser treatment sites. CONCLUSIONS: Our experimental data indicate that endoluminal irradiation with LPRLL prevents restenosis after balloon angioplasty in an atherosclerotic rabbit model.     

Anesthetic implications for implantation of a left ventricular assist device: a case study

Restenosis after coronary angioplasty is a major limitation of an otherwise highly effective and safe procedure for the treatment of atherosclerotic coronary artery disease. Although the advent of coronary stenting has reduced restenosis rates for selected patients, an overall restenosis rate of 20% to 25% remains. Despite numerous trials, no effective pharmacologic therapy has been found. Intracoronary irradiation is a new technique proposed to prevent restenosis after angioplasty. In animal models of restenosis after balloon injury, there is marked reduction of neointimal proliferation when the injured vessel is irradiated, using a variety of radiation sources and delivery systems. Early human trials have underscored the importance of careful source calibration and dosimetry. A small, randomized, double-blind, placebo-controlled study of intracoronary irradiation to prevent recurrent restenosis recently reported striking reductions in angiographic restenosis as well as clinical event rates. A number of important issues remain unresolved, such as defining which component of the arterial wall serves as the target tissue for radiation, the minimal effective dose, the maximum tolerable dose, and user-friendly radiation delivery systems. Further studies are needed to define the safety, efficacy and the ultimate usefulness of intracoronary irradiation as an adjunct to current procedures in interventional cardiology.     

Conjugated equine estrogens inhibit progression of atherosclerosis but have no effect on intimal hyperplasia or arterial remodeling induced by balloon catheter injury in monkeys

OBJECTIVES: This study sought to determine the effects of estrogen treatment on atherosclerosis progression and the proliferative and structural responses of the atherosclerotic arteries to injury. BACKGROUND: Estrogen treatment suppresses the intimal response to arterial injury in nonatherosclerotic rodents and rabbits and inhibits the in vitro proliferation of smooth muscle cells. However, the effect of estrogen on the response of atherosclerotic arteries to transmural injury, as occurs in balloon catheter angioplasty in humans, is unknown. METHODS: Forty-six ovariectomized cynomolgus monkeys were fed an atherogenic diet for 30 months; 25 received 175 microg/day of conjugated equine estrogens, and 21 served as untreated control animals. All animals underwent balloon catheter injury of the left iliac artery. Subsets of animals underwent a necropsy study at 4, 7, 14 and 28 days after injury; injured and contralateral (uninjured) arteries were pressure-fixed and evaluated morphometrically. RESULTS: Estrogen treatment resulted in a 37% decrease (p < 0.05) in atherosclerosis (plaque area) in the uninjured artery. In response to injury, arterial cell proliferation increased at days 4 and 7, and intimal area was increased two- to threefold at day 28 (p < 0.05). Although estrogen treatment resulted in a trend toward decreased arterial cell proliferation at day 4, there was evidence of increased cell proliferation in both media and intima at day 7 (p < 0.05). However, there was no effect of estrogen treatment on intimal area or indexes of arterial remodeling in the injured artery at day 28 (p > 0.4). CONCLUSIONS. In contrast to previous studies of nonatherosclerotic animals, the results indicate that in the circumstance of transmural injury to arteries of primates with preexisting atherosclerosis, estrogen does not suppress arterial neointimal or structural responses to injury.     

Effect of the antioxidant Nicanartine on the proliferative and inflammatory response after experimental balloon angioplasty

BACKGROUND: Antioxidant treatment seems to reduce the development of restenosis after percutaneous transluminal angioplasty. In this study, the effect of Nicanartine, a new antioxidant drug with both antiproliferative and lipid-lowering properties, on the proliferative and inflammatory response after balloon angioplasty was investigated in a rabbit model of restenosis. METHODS: To induce pre-interventional plaques in the common carotid artery of 48 New Zealand White rabbits, electrostimulation was carried out for 28 days. After a break of 7 days, balloon angioplasty was performed in 36 animals, of which 18 received Nicanartine at a dose of 120 mg/kg body weight; the other 18 served as a control group. The vessels were excised by day 7 and 28 after balloon angioplasty and examined for intimal plaque size, macrophage content and proliferative activity. Bromodeoxyuridine labeling was used to determine proliferating cells in the dilated segment; macrophages were detected using the RAM-11 antibody. RESULTS: In the Nicanartine-treated group, immunohistological quantification 7 days after intervention showed a statistically significant (P< 0.05) reduction of both cells undergoing DNA synthesis (1.6+/-1.4% versus 3.7+/-2.2%) and intimal macrophages (0.7+/-1.2% versus 1.3+/-0.6%). Twenty-eight days after balloon angioplasty, proliferative activity in both groups was decreased to a level comparable to the non-dilated control groups. A clear trend towards smaller plaques could be seen in the Nicanartine group (0.146+/-0.077 mm2 versus 0.255+/-0.174 mm2). Total cholesterol levels did not differ significantly between the groups. CONCLUSION: Under treatment with Nicanartine a clear reduction in the proliferative and inflammatory response after balloon angioplasty was observed. Antioxidant treatment, especially with compounds having antiproliferative and lipid-lowering properties, appears to be an effective secondary preventive strategy after interventional treatment in patients with coronary artery disease.     

Reduction of restenosis after angioplasty in an atheromatous rabbit model by suicide gene therapy

BACKGROUND: Gene delivery of the thymidine kinase (tk) gene combined with ganciclovir (GCV) limits intimal hyperplasia after abrasion of normal arteries. However, the low efficiency of adenoviral-mediated gene transfer to atherosclerotic arteries has raised concerns about the applicability of this strategy to the prevention of restenosis. METHODS AND RESULTS: A replication-defective adenoviral vector expressing tk (Ad-RSVtk) demonstrated selective toxicity toward GCV-treated arterial smooth muscle cells, with oligonucleolytic cleavage suggesting apoptosis. In vivo, after demonstration of tk expression after Ad-RSVtk delivery, the combination of Ad-RSVtk followed by GCV was tested in a rabbit model of angioplasty of atheromatous iliac arteries. Angioplasty (8 atm, 20 minutes) was performed by use of a hydrogel balloon coated with Ad-RSVtk (4x10(9) plaque forming units). GCV was infused (25 mg.kg(-1) I.V. BID) from days 2 through 7 after angioplasty in 8 of 12 rabbits. Four weeks later, morphometric analysis demonstrated a reduced intima-to-media ratio in the group receiving combination therapy compared with Ad-RSVtk alone (3.0+/-1.2 versus 5.2+/-0.5, P<.018). GCV per se had no effect on intimal hyperplasia after arterial injury. CONCLUSIONS: In vitro, Ad-RSVtk demonstrates selective toxicity toward GCV-treated arterial smooth muscle cells involving apoptosis. In vivo, GCV conditions reduction of neointimal formation after percutaneous delivery of Ad-RSVtk during angioplasty of atheromatous arteries.     

Percutaneous transluminal angioplasty in atherosclerosis

Percutaneous transluminal balloon angioplasty has achieved a dominant role in the interventional treatments of atherosclerotic peripheral, renal, and coronary artery disease. Improved operator's technique and equipment design have increased the primary success rate. Despite improved success rate and safety, acute closure, late restenosis and difficulty in treating chronic total occlusions or diffuse lesions remain as serious limitations of this procedure. To overcome these limitations of balloon angioplasty, new devices such as stenting, atherectomy or laser ablation have been developed. Although there are many problems for each device, these techniques appear to reduce the limitations in angioplasty.     

Coronary artery restenosis after balloon angioplasty in humans is associated with circumferential coronary constriction

Therapies that inhibit intimal hyperplasia do not prevent restenosis after coronary artery balloon angioplasty, suggesting that additional mechanisms may be responsible for restenosis in humans. Using an intravascular ultrasound (Hewlett-Packard Sonos Intravascular Imaging System). 3.5F, 30-MHz (Boston Scientific) monorail imaging catheter, we studied 17 patients with clinical and angiographic restenosis at an average (mean +/- SD) of 7 +/- 6 months after balloon angioplasty (13 men age, 71 +/- 10 years; 12 left anterior descending coronary arteries, 4 right coronary arteries, and 1 left circumflex coronary artery) The lumen area (L.A), vessel wall area (VWA), and total cross-sectional area (CSA) within the external elastic lamina were measured at the restenosis site and at proximal and distal reference sites, which were defined as adjacent segments with the least amount of plaque. Consistent with coronary angiography findings, decreased LA at the restenotic site was detected in all 17 patients. The unique finding was that total CSA at the restenotic site was significantly decreased compared with both proximal and distal reference sites (10.1 +/- 2.4 versus 14.8 +/- 3.2 mm2 and 10.1 +/- 2.4 versus 13.8 +/- 3.1 mm2, respectively, P < .001), whereas VWA (intima plus media) was slightly increased at the angioplasty site compared with both proximal and distal reference sites (8.0 +/- 2.3 versus 7.6 +/- 2.3 mm2 and 8.0 +/- 2.3 versus 6.7 +/- 2.3 mm2, respectively, P = NS). Eighty-three percent of the loss in LA at the restenotic site was due to constriction of the total CSA, while the increase in VWA at the restenotic site accounted for only a 17% loss in LA. We then compared these results with the morphology of coronary artery segments in 14 patients without restenosis. These coronary artery segments had been previously treated with balloon angioplasty (7 +/- 5 months). Unlike that in restenotic lesions, the total CSA within the external elastic lamina at the sites of previous angioplasty was similar to that in distal and proximal reference sites (P = NS). Significant and consistent reduction in arterial CSA, with a minor increase in VWA, characterizes human coronary lesions that cause angiographic restenosis. These data suggest that in humans, "recoil" and/or vascular contraction with healing in response to balloon injury is a major contributor to restenosis after balloon angioplasty.     

Ultrasound coronary angioplasty: state of the art and new clinical aspects

Therapeutic ultrasound was shown to ablate thrombi and to disrupt atherosclerotic plaques in vitro and recently to recanalize occluded coronary arteries in acute myocardial infarction (AMI). The goal of this article is to update collective experience and to weigh the promising and unresolved aspects of this newly developed technology and its clinical results. As therapeutic ultrasound was for long known a synonym for lithotripsy of calculi diseases, it lastly received high attention as a catheter-based ultrasound method to ablate thrombi and disrupt atherosclerotic plaques in interventional cardiology (Figure 1). The effect of therapeutic ultrasound to ablate selectively pathological tissue depends on its bioselectivity for elastic fibers: After ultrasound sonication, healthy tissue-rich in elastin and collagen-including arterial wall remains intact whereas thrombus and plaque with their minimal elastic support are found to be highly susceptible to ablation. Our catheter for coronary ultrasound thrombolysis (Figure 2) consists of a solid metal probe and is connected to a piezo-electric transducer at its proximal end. The distal part ends in a three-wire flexible segment with a 1.6 mm tip ball to guarantee maximal wire flexibility and optimal transmission of ultrasound energy. The initial in vitro studies resulted in a fundamental understanding of the destructive effect of ultrasound on tissue based on 4 factors: mechanical vibration, thermal effects, microcurrents, and cavitation. The first studies on human peripheral vessels were published in 1991 being performed during femoral bypass surgery on occluded and partially obstructed arteries. The procedure was performed without perforation, no adverse side effects emerged, restenosis rate was 20%. The clinical application of coronary ultrasound angioplasty was initiated in 1991; Siegel published his data on 44 patients. In his study, 30 patients with chronic atherosclerotic occlusive lesions and 14 with unstable or stable angina or AMI were treated by ultrasound angioplasty. Residual stenosis after ultrasound treatment was 71%, after balloon dilation reduced to 34%. In the 6-month follow-up angiograms showed no major adverse effect or restenosis. Our experience with coronary ultrasound thrombolysis (CUT) is based on the analysis of 33 patients' data in the feasibility (Table 1) plus multicenter phase of the ACUTE trial (Analysis of Coronary Ultrasound Thrombolysis Endpoints) (Figure 3). Our patients were exclusively treated for AMI by ultrasound angioplasty and afterwards by PTCA if required (Figure 4). The average final percent stenosis was 20% (Figure 5). The main efficacy parameters, device success and angiographic success rates were 100%, clinical success rate was 91.7% (Figure 6 and Table 2). The adverse clinical events of CUT are limited--at least in our studies--to reocclusion of infarct-related artery and ischemia and could be reversed by additional PTCA. No adverse clinical side effects were observed during sonication of the coronary tree. Final angiography revealed residual stenosis of 20% without morphological signs. These excellent results suggest that bioselectivity of ultrasound together with the developed skills of the catheter system induces rapid and selective thrombolysis with no need to cross the target lesion before sonication. But what is the better solution for thrombosis and which for plaque disruption? The development of transluminal balloon catheter really modified therapeutic approach to obstructive coronary and peripheral arterial disease but it is still accompanied by a high rate of abrupt closure, AMI and death. Although the use of intravenous thrombolytic agents is well established in the treatment of AMI and these agents are widely used, a large patient collective remains (up to 33% and more) in whom their use is inadvisable due to recent stroke, surgery, trauma or other contraindications. (ABSTRACT TRUNCATED)     

Antioxidant enzymes and atherosclerosis in Japanese quail: heritability and genetic correlation estimates

OBJECTIVES: To estimate, in male quail susceptible to atherosclerotic plaque formation (SUS) fed a regular diet and an atherogenic diet, the genetic and phenotypic parameters associated with antioxidant enzymes and atherogenesis. DESIGN: Genetic parameters were estimated from variance components of the analysis of variance on 70 males from 13 full-sib families. MAIN RESULTS: Under the regular diet, seven of 35 males developed mild atherosclerosis. Heritability was zero for atherosclerotic plaque score and plasma cholesterol level. Plaque score was highly correlated to plasma triglyceride level (rp = 0.96) and liver fattiness (rp = 0.97), but only moderately to plasma cholesterol level (rp = 0.39). With the high cholesterol diet, plasma cholesterol level increased sixfold and became heritable (h2 = 0.4). Many males developed severe atherosclerosis. Plaque score became associated more with plasma and aortic cholesterol levels (rp = 0.56) and 0.76, respectively) than with plasma triglyceride level (rp = 0.54). Aortic glutathione reductase activity was negatively correlated with plaque score (rp = -0.42; rg = -0.51) and aortic cholesterol level (rp = -0.39; rg = -0.62). CONCLUSIONS: Plasma triglyceride level was an important factor affecting the development of fatty streaks and the early progression of atherosclerotic plaques. Without high levels of dietary cholesterol in the plasma and aorta, any early atherosclerotic plaques that developed did not progress further within the time-frame of the experiment. Aortic cholesterol concentration and glutathione reductase activity were important factors in the advancement of severe plaque formation. Heritability of plaque score was high in the SUS line, and further selective breeding should increase the susceptibility of these quail to cholesterol-induced atherosclerosis.     

Compensatory enlargement versus chronic constriction. The two features of vascular remodelling after experimental angioplasty

Considerable efforts have been made to prevent post-angioplasty restenosis targeted mainly against a pathogenesis suggesting a dominant role of hyperplasia. We and others have already shown that constrictive remodelling plays a major role in restenosis. This article evaluates not only the constrictive remodeling theory but also compensatory enlargement associated with prevention of restenosis. The present study on 33 rabbits used the following protocol. Four weeks after inducing an atherosclerotic lesion by air-dessication of a femoral artery segment and a high cholesterol diet, angioplasty was performed. The angiographic minimal luminal diameter significantly increased after angioplasty. Three to four weeks later, initial gain was significantly lost. Restenosis was quantified histologically as well as a remodelling index and a hyperplasia index. No correlations were observed between degree of stenosis and hyperplasia present at the same degree in animals with and without restenosis. On the other hand, there was a strong correlation between restenosis and constrictive remodelling, and with absence of restenosis and compensatory enlargement. Moreover, there was significant a correlation between the degree of hyperplasia and the compensatory remodelling. These data point to the double nature of remodelling: compensatory enlargement observed in animals without restenosis, and constrictive remodelling, the principal mechanism observed in animals with restenosis.     

Vitamin E supplementation attenuates myointimal proliferation of the abdominal aorta after balloon injury in diet-induced hypercholesterolemic rabbits

The effects of vitamin E supplementation in a dose of 450 mg/1000 g chow on the myointimal proliferation of the abdominal aorta after balloon injury were studied in 4 groups of rabbits (24 each). The animals were fed regular diet, regular diet plus vitamin E, 1% cholesterol-enriched diet, and 1% cholesterol-enriched diet plus vitamin E. Each animal underwent a balloon injury of the abdominal aorta and left common iliac artery after 2 weeks of feeding. The animals remained on their respective diets thereafter. In 8 balloon-injured and 8 sham-operated animals of each group, the abdominal aortas were harvested 3 days after the procedure for the analysis of prostacyclin and thromboxane A2 synthesis, thiobarbituric acid reactive substances (TBARS) levels, enzyme activities of glutathione reductase (GR) and glutathione peroxidase (GP) as well as reduced (GSH) and oxidized (GSSG) glutathione levels, 3H-thymidine uptake, cholesterol as well as vitamin E contents. In the other 8 balloon-injured rabbits of each group, the tissue was harvested 3 weeks later for the morphometric study. In dependent of high cholesterol feeding, the vitamin E-treated rabbits had lower aortic production of thromboxane B2, higher 6-keto-PGF1 alpha and higher 6-keto-PGF1 alpha/thromboxane B2 ratios in both procedures. The aortic TBARS levels of the rabbits treated high cholesterol alone were significantly higher than the other three groups in both procedures. Balloon injury had a trend to increase TBARS levels and had significantly higher 3H-thymidine uptake (each p < 0.001) than sham operation in each group. Vitamin E supplement to high cholesterol diet or regular chow reduced aortic TBARS levels (p < 0.005 and 0.01, respectively) and 3H-thymidine uptake (p < 0.05 and 0.01, respectively), as well as attenuated myointimal proliferation of the abdominal aorta and left common iliac artery after balloon injury; but only supplement to high cholesterol diet reached statistical significances (both p < 0.05 compared to rabbits fed high cholesterol alone). These results suggest that vitamin E supplement changes prostanoid metabolism to a favorable pattern and reduces lipid peroxidation of the abdominal aortic wall, thus attenuates myointimal proliferation after balloon injury; these presentations are particularly obvious in diet-induced hypercholesterolemic rabbits.     

Effects of locally administered argatroban on restenosis after balloon angioplasty: experimental and clinical study

1. This study was undertaken to evaluate the preventive effects of locally administered argatroban, a competitive inhibitor of thrombin-induced platelet activation, on restenosis after balloon angioplasty. 2. A hydrogel-coated balloon catheter was immersed three times in argatroban/saline solution (1 mg/mL) for 60 s, inflated to a pressure of 606 kPa and left in the rabbit common carotid artery for 1 min. The same procedure was performed, without drug, as a control. The pharmacokinetics of delivered argatroban in the arterial wall were assessed using [14C]-argatroban. Platelet deposition 2 h after balloon injury was quantified by fluorescence studies using antiplatelet antibody. Vascular smooth muscle cell (VSMC) proliferation 3 days after balloon injury was assessed by immunohistochemical staining for proliferative cell nuclear antigen (PCNA). In a clinical study, we divided 50 elective patients into two groups: argatroban and control. 3. In the experimental study, the mean quantities of argatroban at 0, 2 and 6 h after deflation were 24.63, 0.49 and 0.11 nmol/g wet weight of artery, respectively. Argatroban was undetected 24 h after deflation. Two hours after deflation, argatroban-treated arteries showed less platelet adhesion than saline-treated controls. The mean number of PCNA-positive cells was 16.9 and 43.8% in the argatroban and control groups, respectively (P < 0.01). In the clinical study, the mean late gain loss was 8.2 and 27.3% in the argatroban and control groups, respectively (P < 0.05). The mean late restenosis rate was 11.1 and 41.4% in the argatroban and control groups, respectively (P < 0.05). 4. These data suggest that blood coagulation plays a significant role in VSMC proliferation after balloon injury and that locally administered argatroban using hydrogel-coated balloon catheter may prevent post-percutaneous transluminal coronary angioplasty restenosis.     

Laser angioplasty and recanalization

Percutaneous transluminal coronary balloon angioplasty (PTCA) still is the most frequently applied interventional technique for treatment of coronary artery disease. Plastic deformation of the obstructive plaque with creation of splits, intimal tears and dissections is the main mechanism of PTCA for lumen widening. As a result, acute complications due to flow limiting dissections and acute vessel closure can unpredictably occur resulting in myocardial infarction, urgent bypass surgery and death. Furthermore, long-term success of PTCA is limited by restenosis. In order to overcome these limitations of PTCA, alternative interventional techniques were developed, which instead of deforming the obstructive plaque ablate this tissue. These techniques include high and low speed rotational angioplasty, directional atherectomy, the transluminal extraction catheter, ultrasound angioplasty and laser (Light Amplification by Stimulated Emission of Radiation) angioplasty. 308 nm XeCl excimer laser angioplasty today is the laser technique of choice for clinical application. This pulsed laser requires direct contact to the obstructive plaque. It creates fast (< 200 microseconds) expanding gas bubbles which induce plaque ablation. Main indications for 308 nm XeCl excimer laser angioplasty are diffuse and long coronary lesions and total coronary occlusions. Despite promising initial results this technique showed no better acute and long-term results in comparison to PTCA for the treatment of these types of lesions ("Amsterdam-Rotterdam" Study, "Excimer Rotational Balloon Angioplasty Comparison" Study). As a result, this interventional technique was rarely applied for patient treatment. More recently, the concept of plaque ablation by 308 nm XeCl excimer laser angioplasty was renewed for the treatment of in-stent restenosis. This indication is being investigated in the "Laser Angioplasty of Restenosed Stents" trial. First results document the practicability and safety of this approach. Long-term results are awaited. With ongoing miniaturization, laser guidewires were developed for the recanalization of chronic total occlusions. The randomized multicenter "Total Occlusion Trial with Angioplasty assisted by Laser guidewire "Study documented a success rate of laser wire recanalization in up to 66% in contrast to 47.5% for mechanical wires only. Long-term results are still awaited. Technical and procedural progress including saline flush during laser application, homogeneous light distribution and the concept of smooth laser ablation is pushed foreward to make excimer laser angioplasty safer, more predictable and more effective.     

Enhanced monocyte tissue factor response after experimental balloon angioplasty in hypercholesterolemic rabbit: inhibition with dietary L-arginine

BACKGROUND: There is evidence that tissue factor (TF) is a major contributor to the thrombogenicity of a ruptured atherosclerotic plaque. Nitric oxide (NO) has antiatherogenic and antithrombotic properties. We investigated whether L-arginine (L-arg), the endogenous precursor of NO, might affect the ability of monocytes to produce TF. METHODS AND RESULTS: We studied TF expression in 18 rabbits with atherosclerosis induced by bilateral iliac damage and 10 weeks of a 2% cholesterol diet. Six weeks after the initiation of the diet, an angioplasty was performed. After angioplasty, the surviving rabbits (n=15) were randomized to receive L-arg (2.25%) supplementation in drinking water (L-arg group, n=8) or no treatment (untreated group, n=7). TF expression was evaluated in mononuclear cells from arterial blood in the presence and absence of endotoxin stimulation. Monocyte TF expression, as assessed with an amidolytic assay, did not differ significantly before or after the induction of atherosclerotic lesions (87+/-15 versus 70+/-12 mU of TF/1000 monocytes, P=NS). Endotoxin-stimulated TF activity increased significantly 4 weeks after angioplasty (138+/-22 versus 70+/-12 mU of TF/1000 monocytes, P=0.02). This increase was blunted by L-arg (43+/-16 mU of TF/1000 monocytes, P=0.01). CONCLUSIONS: This study demonstrates that angioplasty-induced plaque rupture is associated with a marked increase in monocyte TF response that is blunted by the oral administration of L-arg. This suggests that the documented antithrombotic properties of NO may be related in part to an inhibitory effect on monocyte TF response.     

The relation between multiple sleep latency test findings and the frequency of apneic events in REM and non-REM sleep

OBJECTIVES: The purpose of this prospective study was to evaluate the immediate results and the 6-month angiographic recurrent restenosis rate after balloon angioplasty for in-stent restenosis. BACKGROUND: Despite excellent immediate and mid-term results, 20% to 30% of patients with coronary stent implantation will present an angiographic restenosis and may require additional treatment. The optimal treatment for in-stent restenosis is still unclear. METHODS: Quantitative coronary angiography (QCA) analyses were performed before and after stent implantation, before and after balloon angioplasty for in-stent restenosis and on a 6-month systematic coronary angiogram to assess the recurrent angiographic restenosis rate. RESULTS: Balloon angioplasty was performed in 52 patients presenting in-stent restenosis. In-stent restenosis was either diffuse (> or =10 mm) inside the stent (71%) or focal (29%). Mean stent length was 16+/-7 mm. Balloon diameter of 2.98+/-0.37 mm and maximal inflation pressure of 10+/-3 atm were used for balloon angioplasty. Angiographic success rate was 100% without any complication. Acute gain was lower after balloon angioplasty for in-stent restenosis than after stent implantation: 1.19+/-0.60 mm vs. 1.75+/-0.68 mm (p=0.0002). At 6-month follow-up, 60% of patients were asymptomatic and no patient died. Eighteen patients (35%) had repeat target vessel revascularization. Angiographic restenosis rate was 54%. Recurrent restenosis rate was higher when in-stent restenosis was diffuse: 63% vs. 31% when focal, p=0.046. CONCLUSIONS: Although balloon angioplasty for in-stent restenosis can be safely and successfully performed, it leads to less immediate stenosis improvement than at time of stent implantation and carries a high recurrent angiographic restenosis rate at 6 months, in particular in diffuse in-stent restenosis lesions.     

Effect of nadroparin, a low-molecular-weight heparin, on clinical and angiographic restenosis after coronary balloon angioplasty: the FACT study. Fraxiparine Angioplastie Coronaire Transluminale

BACKGROUND: Experimental studies suggest that the antiproliferative effect of heparin after arterial injury is maximized by pretreatment. No previous studies of restenosis have used a pretreatment strategy. We designed this study to determine whether treatment with nadroparin, a low-molecular-weight heparin, started 3 days before the procedure and continued for 3 months, affected angiographic restenosis or clinical outcome after coronary angioplasty. METHODS AND RESULTS: In a prospective multicenter, double-blind, randomized trial, elective coronary angioplasty was performed on 354 patients who were treated with daily subcutaneous nadroparin (0.6 mL of 10,250 anti-Xa IU/mL) or placebo injections started 3 days before angioplasty and continued for 3 months. Angiography was performed just before and immediately after angioplasty and at follow-up. The primary study end point was angiographic restenosis, assessed by quantitative coronary angiography 3 months after balloon angioplasty. Clinical follow-up was continued up to 6 months. Clinical and procedural variables and the occurrence of periprocedural complications did not differ between groups. At angiographic follow-up, the mean minimal lumen diameter and the mean residual stenosis in the nadroparin group (1.37+/-0.66 mm, 51.9+/-21.0%) did not differ from the corresponding values in the control group (1.48+/-0.59 mm, 48.8+/-18.9%). Combined major cardiac-related clinical events (death, myocardial infarction, target lesion revascularization) did not differ between groups (30.3% versus 29.6%). CONCLUSIONS: Pretreatment with the low-molecular-weight heparin nadroparin continued for 3 months after balloon angioplasty had no beneficial effect on angiographic restenosis or on adverse clinical outcomes.