Subbandage pressure measurements comparing a long-stretch with a short-stretch compression bandage

Although angioplasty has undergone considerable development, restenosis remains an unsolved problem. No drugs have been proved effective in the prevention of restenosis. Prophylactic stenting is the only treatment with some efficacy. The pathophysiology of restenosis involves both intimal hyperplasia with a major proliferative component at the dilated site and geometric constrictive remodeling of the artery. Stenting seems to prevent the remodeling but does not prevent and may even worsen the intimal hyperplasia. Gene therapy may be effective in preventing the proliferative component of the intimal hyperplasia: therapeutic genes can be delivered locally to the arterial wall cells at the dilated site during or immediately after angioplasty, using viral (e.g., adenoviruses) or nonviral vectors. The main candidate genes stimulate a variety of endogenous mechanisms whose effects consist in inhibition of smooth muscle cell proliferation (Rb gene); sensitization of proliferating cells to the effects of cytotoxic substances, thus allowing selective chemotherapy (HSV-tk gene); or stimulation of reendothelization (VEGF gene). Other genes have also yielded promising results (ecNOs, p21, Coxl, etc.). Clinical application of these techniques cannot be envisioned until studies are available proving that the delivery methods (transfer vectors or local delivery systems) are completely safe, and that the candidate genes are effective in "realistic" models. If these hurdles are cleared successfully, preventive gene therapy for gene restenosis may well become a clinical reality.     

Prospects of prevention of restenosis after coronary angioplasty

The prevention of restenosis after coronary angioplasty has been marked over recent years by the failure of trials of drug treatment based on inhibition of arterial smooth muscle cell proliferation. This failure could be due to an insufficient concentration of the orally or intravenously administered drug in the lesion to be treated. Another reason for this failure of drug treatment could be the nonexclusive role of intimal hyperplasia in the pathophysiology of restenosis, which also appears to be related to a education of the overall calibre of the artery at the site of dilatation. The pathogenesis of this phenomenon, called "remodelling", remains obecure and is only partly prevented by insertion of stents, which is currently the only treatment able to decrease the number of new revascularization procedures for restenosis. This benefit is related to optimization of the initial result (stents avoiding early "recoil", secondary to the elastic recoil forces of the arterial wall), and possibly to prevention of late remodelling of the vessel at the site of dilatation, either tonic (vasomotor) or trophic. On the other hand, the benefit related to the absence of "remodelling" of the stended lesions is partly limited by intimal hyperplasia, exacerbated by the presence of the stent. The future therapeutic strategy could combine insertion of stents and prevention of smooth muscle cell proliferation by new treatment strategies acting at the molecular level. Encouraging preliminary results have already been obtained in animals with chimeric toxins, antisense strategies and especially gene therapy using defective adenoviral vectors for replication.     

Mediators of restenosis

The multitude of actions and interacting components involved in inciting and sustaining myointimal hyperplasia and restenosis effectively precludes the use of a single type of intervention. No pharmacologic approach has been conclusively shown to prevent coronary restenosis after balloon angioplasty or graft restenosis after peripheral arterial bypass. Although no human studies have been performed to prevent restenosis with gene therapy, the animal data are compelling, and the local delivery of various inhibitory agents may represent a novel way of preventing restenosis in vascular beds subjected to endovascular or traditional open procedures. Until these modalities are proved effective, the treatment of vascular stenosis due to internal hyperplasia remains within the domain of the surgeon.     

Intervention and clinical aspects combined with endovascular irradiation of intimal hyperplasia of the vascular system

After implantation of stents in femoropopliteal arteries we found restenosis or occlusions by intimal hyperplasia in up to 40% especially in the hunter's channel. Repeated balloon angioplasty and prophylactic endovascular radiotherapy with a surface dose of 12 Gy in the vessel wall using an iridium 192 source in the same investigational session is a new technique to reduce or eliminate further recurrence. All 18 patients had developed recurrent stenoses or occlusions 6-8 months after original stent implantations. The patients have not redeveloped recurrent obstructions after this treatment, which up to date showed no short term or long term complications. We conclude that the encouraging results of this pilot study justify further randomized trials.     

Mechanisms and prevention of restenosis after coronary angioplasty]

The success of PTCA is limited by late restenosis, which occurs in 30-50% of all cases, chiefly within the first six months after the intervention. Restenosis is due to the proliferation of smooth muscle cells and especially to overproduction of extracellular matrix in the arterial wall. The coronary intervention is followed by a not fully defined constrictive process of wound healing, so-called remodeling. Various alternative intervention techniques were investigated but did not show any clear advantage concerning restenosis compared to PTCA. Although the rate of restenosis is reduced by stent implantation, which hinders remodeling, the remaining intimal hyperplasia often leads to restenosis. In spite of promising results in animal models, to date no effective human pharmacological therapy has been found to prevent restenosis. To determine whether antioxidants, endovascular radiation or gene therapy show any benefit will require further, larger trials.     

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.     

Histological evaluation of coronary plaque in patients with variant angina: relationship between vasospasm and neointimal hyperplasia in primary coronary lesions

OBJECTIVES: This study was designed to determine whether coronary vasospasm in patients with variant angina pectoris (VAP) may produce focal organic lesions at the site of vasospasm that would contribute to disease progression. BACKGROUND: Recent clinical angiographic and experimental studies have demonstrated the potential role of vasospasm in the worsening of organic coronary stenosis. METHODS: We studied histologically the coronary plaques obtained at atherectomy in 202 patients with moderate to severe coronary stenosis. This population included 22 patients with VAP, 100 patients with chronic stable angina and 80 patients with restenosis following angioplasty or atherectomy. Diagnosis of VAP was based on both the clinical feature of angina at rest associated with ST elevation and a positive response to acetylcholine provocation test. RESULTS: The most common histological appearance in 92% of patients with stable angina was hypocellular fibroatheromatous plaques, whereas neointimal hyperplasia was the characteristic feature of the plaque observed in 90% of patients with restenosis. The coronary specimens at the site of spasm in 15 of the 22 patients (68%) with VAP demonstrated intimal injuries such as neointimal hyperplasia (15), thrombus formation (2), and intimal hemorrhage (3). Neointimal hyperplasia was significantly more common in the patients with VAP as compared with those with stable angina (68% vs. 8%; p < 0.0001). A rapid progression of organic stenosis within three years was angiographically found in 5 of the 22 patients with variant angina. In all five cases, neointimal hyperplasia was the main contributor to the worsening of the organic lesion at the site of spasm. These histological findings in patients with VAP extremely resembled those in restenosis. Except for vasospasm, no factors significantly predicted the presence of neointimal formations in primary coronary lesions. CONCLUSIONS: Coronary vasospasm may provoke vascular injury that leads to the formation of neointima in VAP patients similar to that seen with restenosis. Coronary spasm may thus play a key role in the rapid coronary stenosis progression in certain patients with VAP.     

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.     

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.     

Probucol decreases neointimal formation in a swine model of coronary artery balloon injury. A possible role for antioxidants in restenosis

BACKGROUND: Restenosis after percutaneous transluminal coronary angioplasty is the major limitation of the long-term success of this procedure. The process of restenosis is similar to an accelerated form of atherosclerosis. Thus, therapeutic interventions that limit the progression and initiation of atherosclerosis may be beneficial in the treatment of restenosis. One such intervention is the antioxidant drug probucol, which has demonstrated benefit in animal models of atherosclerosis. METHODS AND RESULTS: Twenty-six female domestic swine were divided into three study groups (control, n = 9; low-dose probucol, n = 9; high-dose probucol, n = 8) before oversized balloon injury of the left anterior descending and left circumflex coronary arteries. Probucol (1 g/d, low-dose group; 2 g/d, high-dose group) was administered 2 days before balloon injury and was continued until the swine were killed 2 weeks after balloon injury. Morphometric analysis of the injured arteries included the intimal area (square millimeters), maximal intimal thickness (millimeters), and residual lumen (ratio of luminal to intimal plus luminal area). Treatment with high-dose probucol significantly reduced neointimal formation compared with control animals (decreases of 36% in intimal area, P = .007; 20% in maximal intimal thickness, P = NS; and an increase of 15% in residual lumen, P = .02). CONCLUSIONS: The major finding of this study is that the antioxidant drug probucol reduces neointimal formation after oversized balloon injury in a swine model of restenosis. This suggests that active oxygen species may play a role in restenosis.     

Prevention and treatment of restenosis after percutaneous transluminal coronary angioplasty

Restenosis is a clinical problem after coronary angioplasty associated with major ischemic events or repeat interventions in 20-50% of the patients undergoing this procedure. Major efforts have been undertaken in the past decade to successfully prevent or treat restenosis but no pharmacologic approach to the problem has as yet been identified to be effective enough in clinical conditions. New strategies to cope with restenosis are targeted by local application of ionizing radiation which markedly reduces cell proliferation after angioplasty in animal experiments. Preliminary clinical trials indicate that endovascular radiation therapy is a safe and effective means to treat restenosis. Randomized, multicenter studies with long follow-up periods are needed to support these early results.     

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.     

A brief survey of the current sexual practices of a population admitted for inpatient treatment of drug dependence

Restenosis remains the main limitation of interventional cardiology. Restenosis occurs when angioplasty-induced intimal hyperplasia as well as arterial remodelling result in flow-limiting renarrowing of the arterial lumen at the angioplasty site. Intimal hyperplasia is an important candidate for gene therapy since it is related to smooth muscle cell proliferation, which is an inviting target for molecular antiproliferative strategies. To date, adenoviral vectors are, by far, the most efficient vectors to perform in vivo arterial gene transfer. These vectors, as well as others, have been recently used to demonstrate that therapeutic genes encoding cytotoxic (herpes virus thymidine kinase) or cytostatic (hypophosphorylatable Rb, Gax, endothelial nitric oxide synthase) products successfully inhibit smooth muscle cell proliferation and related intimal hyperplasia. Despite substantial progress, major technical issues, including the toxicity of first-generation adenoviral vectors, inefficient transduction of atherosclerotic arteries, and the risk of extra-arterial transfection remain to be addressed before gene therapy is applied to clinical restenosis.     

Short- and long-term clinical and quantitative angiographic results with the new, less shortening Wallstent for vessel reconstruction in chronic total occlusion: a quantitative angiographic study

OBJECTIVES: This study was designed to examine whether oversized implantation of the new, less shortening Wallstent provides a more favorable long-term clinical and angiographic outcome in chronic total occlusions than does conventional coronary balloon angioplasty. BACKGROUND: Restenosis and reocclusion remain major limitations of balloon angioplasty for chronic total occlusions. Enforced mechanical remodeling by implantation of the oversized Wallstent may prevent elastic recoil and improve accommodation of intimal hyperplasia. METHODS: Lumen dimension was measured by a computer-based quantitative coronary angiography system (CAAS II). These measurements (before and after intervention and at 6-month follow-up) were compared between the groups with Wallstent implantation (20 lesions, 20 patients) and conventional balloon angioplasty (266 lesions, 249 patients) for treatment of chronic total occlusion. Acute gain (minimal lumen diameter after intervention minus that before intervention), late loss (minimal lumen diameter after intervention minus that at follow-up) and net gain (acute gain minus late loss) were examined. RESULTS: Wallstent deployment was successful in all patients. High pressure intra-Wallstent balloon inflation (mean +/- SD 14 +/- 3 atm) was performed in all lesions. Although vessel size did not differ between the Wallstent and balloon angioplasty groups, acute gain was significantly greater in the Wallstent group (2.96 +/- 0.55 vs. 1.61 +/- 0.34 mm, p < 0.0001). Although late loss was also significantly larger in the Wallstent group (0.81 +/- 0.95 vs. 0.43 +/- 0.68 mm, p < 0.05), net gain was still significantly greater in this group (2.27 +/- 1.00 vs. 1.18 +/- 0.69 mm, p < 0.0001). Angiographic restenosis (> or = 50% diameter stenosis) occurred at 6 months in 29% of lesions in the Wallstent group and in 45% of those in the balloon angioplasty group (p = 0.5150). CONCLUSIONS: Implantation of the oversized Wallstent, with full coverage of the lesion length, ensures resetting of the vessel size to its original caliber before disease and allows greater accommodation of intimal hyperplasia and chronic vessel recoil. Wallstent implantation provides a more favorable short- and long-term clinical and angiographic outcome than does conventional balloon angioplasty for chronic total occlusions.     

Effects of beta3-integrin blockade (c7E3) on the response to angioplasty and intra-arterial stenting in atherosclerotic nonhuman primates

Because the beta3-antagonist abciximab (c7E3 Fab) has significantly improved late outcomes after coronary angioplasty, the beta3 integrins have been implicated in the arterial response to injury. However, the mechanisms underlying this benefit are unknown. The observation that c7E3 binds beta3 integrins on vascular cells (alphavbeta3) with affinity equal to that for the platelet glycoprotein IIb/IIIa integrin has led to the hypothesis that c7E3 may act directly on the artery wall to prevent restenosis after angioplasty. To test this hypothesis, we studied the effects of c7E3 on structural changes within the artery wall after angioplasty or stent angioplasty in 23 male cynomolgus monkeys with established atherosclerosis. Animals were randomly assigned to receive either a bolus of c7E3 (0.4 mg/kg IV, n=11) followed by a 48-hour infusion (0. 2 microg. kg-1. min-1) or an equal volume of vehicle (n=12). Animals received weight-adjusted aspirin and heparin and then underwent unilateral iliac artery experimental angioplasty and subclavian artery stent angioplasty (Palmaz). Iliac artery lumen diameter (LD) was determined by angiography at baseline (LDPre), after angioplasty (LDPost), and 35 days later (LDDay35). Arteries were then fixed by perfusion and removed for analysis. Lumen, intima, media, and external elastic lamina (EEL) areas were measured in iliac artery cross sections. Values from each injured iliac artery were normalized to the contralateral uninjured iliac artery to control for interanimal variability in baseline artery size and atherosclerosis extent. Intimal area was also measured in subclavian stent cross sections. c7E3 blocked platelet aggregation and prolonged the bleeding time from 2.8+/-1.1 to 19.8+/-2.5 minutes, P<0.001. Experimental angioplasty increased LDPost an average of 28%, and the initial gain was similar in both groups (P=NS). Despite an anti-platelet effect, c7E3 did not inhibit iliac lumen narrowing (LDDay35-LDPost: c7E3, -0.69+/-0.17 versus vehicle, -0.99+/-.17 mm, P=0.35); intimal hyperplasia (neointima area: c7E3, 1.12+/-.28 versus vehicle, 1.22+/-.20 mm2, P=0.77); or decrease in artery wall size (EEL area [percent of uninjured control]: c7E3, 101+/-7% versus vehicle, 121+/-7%). Stent intimal hyperplasia was also unaltered by c7E3 treatment (neointimal area: c7E3, 1.09+/-0.16 versus vehicle, 1. 28+/-0.11 mm2, P=0.36). These results suggest that the benefits of c7E3 treatment in coronary angioplasty were not from inhibition of intimal hyperplasia or improved artery wall remodeling. Alternative mechanisms should be explored to explain improved late outcomes after angioplasty in patients treated with c7E3.     

Significance of ST segment elevations in posterior chest leads (V7 to V9) in patients with acute inferior myocardial infarction: application for thrombolytic therapy

Thrombus formation and neointimal growth are the critical events in restenosis after balloon angioplasty. However, the responses of diseased vessels to injuries caused by balloon angioplasty have not been well examined. We investigated the thrombus formation and neointimal development following the balloon injury to the previously induced neointima in the rabbit aorta and the effects of recombinant tissue factor pathway inhibitor (rTFPI) on these responses. Rabbit thoracic aortas were subjected to injury with a Fogarty 4F balloon catheter at 1.75 atm (first injury), and 4 weeks later the same vessels were subjected to the second injury with a Swan-Ganz 5F balloon catheter at 1.4 atm (mild-injury group) or 1.8 atm (severe-injury group), and immediately after that a retrograde bolus injection of rTFPI (100 microg/kg body weight) or saline was performed into the injured segments via the central tube of the Swan-Ganz catheter. Twenty minutes after the second injury, the injured surfaces were covered with platelet-rich thrombi in the mild-injury group and with fibrin-rich thrombi in the severe-injury group. Damaged intimal smooth muscle cells, which were immunohistochemically positive for tissue factor (TF), were observed beneath the fibrin-rich thrombi. The neointima 4 weeks after the second injury was significantly thicker in the severe-injury group than in the mild-injury group. The bolus infusion of rTFPI markedly inhibited fibrin formation on the injured surfaces, and significantly reduced the neointimal development in the severe-injury group at 4 weeks after the second injury. These results indicate that TF-dependent coagulation pathway is primarily responsible for fibrin-rich thrombus formation and may play an important role in neointimal development following the balloon injury to the rabbit aortic neointima. Additionally the bolus administration of rTFPI to the injured vessels could prevent mural thrombus formation and neointimal growth after balloon angioplasty.     

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.     

New insights for dinucleotide backbone binding in conserved C5''-H . . . O hydrogen bonds

OBJECTIVE: Although a number of pharmacologic agents have been shown to reduce intimal hyperplasia in animal models of restenosis, to date no systemic agent has conclusively been shown to be effective in humans. Recently, considerable attention has been directed towards endothelin (ET), a potent vasoconstrictor and a powerful mitogen for vascular smooth muscle cells, as a mediator of intimal hyperplasia. Endothelin-1 has been shown to be mitogenic for human saphenous vein smooth muscle cells, and expression also is elevated in human vein graft stenosis. The aim of this study was the investigation of whether ET receptor antagonists can attenuate neointima formation in a laboratory model of vein graft intimal hyperplasia and the determination of whether the effects are mediated by a specific ET receptor subtype. METHODS: We used an organ culture of human saphenous vein, a well-validated model of vein graft intimal hyperplasia. Paired segments of human long saphenous vein were cultured with and without the following antagonists: bosentan, a nonselective ET receptor antagonist; BQ 123, a specific endothelin-A antagonist; or BQ 788, a specific endothelin-B (ETB) antagonist. After 14 days in the culture, the segments were fixed and processed and the sections were immunostained to facilitate the measurements of neointimal thickness with a computerized image analysis system. RESULTS: The nonselective antagonist bosentan and the ETB selective antagonist BQ 788 significantly reduced neointima formation by 70% (P = .001) and 50% (P = .03), respectively, but the ETA antagonist BQ 123 had no significant effect on the reduction of neointima formation (P = 1.0). CONCLUSION: The results of this study imply an important role for ET as a mediator of human vein graft intimal hyperplasia and imply further that a specific ETB antagonist may have a therapeutic potential for the prevention of vein graft stenosis.     

Treating gastro-oesophageal reflux disease during pregnancy and lactation: what are the safest therapy options?

About 30% of patients who underwent percutaneous transluminal coronary angioplasty show evidence of restenosis, which appears to be independent of the angioplasty method used. The restenosis is due of two factors, firstly migration of smooth vascular muscle cells of the vascular media to the intima and multiplication which lead to the formation of a neo-intima. Irradiation limits the proliferation by acting of the cells in the mitotic stage. The vascular target volume is not very thick and is difficult to define it, that why brachytherapy seems to be the best procedure to prevent restenosis. However, the development of this treatment present many difficulties. Different irradiation techniques have been studied. Such techniques include catheter containing radioactive sealed source, radioactive stent, or balloon containing radioactive liquid inside. Each of these methods have their own advantages, inconveniences, problems and risks. Radioisotope may be either beta or gamma emitters. Gamma emitter presents problems for radioprotection but the satisfactory dose distribution may be difficult to obtain using beta emitter. Choice of dose, dose rate and delay between the end of angioplasty and the beginning of brachytherapy is subject to some discuss. Animal experiments using radioisotope have shown reduction in cell proliferation. Human trials showed feasibility, safety of the method and real impact on restenosis prevention. However, long-term efficacy has not been proved because the follow-up of the patients is too short. A randomized trial of 192Ir brachytherapy for prevention of restenosis has recently shown the efficacy in short and median term. However, long term efficiency and secondary effects have not yet been established as the follow up time of this study is still too short. That is why, collaboration between cardiologists and radiotherapists and physicists is indispensable to enable the development of an optimal technique.     

Flow input waveform effects on the temporal and spatial wall shear stress gradients in a femoral graft-artery connector

Employing a validated finite volume code, a computer-aided design of the distal end of a femoral graft-artery junction has been considered to simulate transient three-dimensional blood flow for various flow input waveforms. The study relies on the hypothesis that large sustained wall shear stress gradients play a major role in the rapid recurrence of intimal hyperplasia plus atheroma after bypass surgery, leading to early graft failure. Two new dimensionless parameters have been introduced to correlate flow waveform characteristics with the severity of nonuniform hemodynamics and hence the potential risk for restenosis. The transient and, more importantly, the time-averaged wall shear stress gradient distributions shown, map out the junction areas which are still susceptible to restenosis, especially the toe region. Future geometric modifications will further reduce disturbed flow patterns and hence the probability of graft failure.