Prevention Of Coronary Restenosis Research Articles

Une enquête de l’utilisation en Belgique de la radiothérapie pour des affections bénignes, non-tumorales

Two prior surveys were carried out in 1995 and 1999 to evaluate the use of radiotherapy in the treatment of non-malignant disease. In 2016, the same questionnaire was used and sent to the 24 centers of the country: 22 responded. A major decrease was observed in the number of patients treated: 360 in 2016 in contrast to 954 in 1999 and 1113 in 1995. The most frequent indications remain the prevention of heterotopic bone formation, keloids or gynecomastia. A new indication was observed: trigeminal nevralgia treated with radiosurgery. Two frequent indications in the past disappeared: the prevention of coronary restenosis and the macular degeneration. A great agreement was observed regarding the possible indications for radiotherapy but also to avoid it for inflammatory pathologies.

Indications non oncologiques de la radiothérapie : quelles indications en 2014 ?

This review updates the radiotherapy indications for non-malignant diseases, except those treated by radiosurgery. Since the last 2005 review, there have been no major changes in the indications: the prevention of heteropic bone formation and keloids remain classical indications, while the treatment of macular degeneration or the prevention of coronary restenosis are now past history. Nevertheless, the radiation treatment for benign diseases should have the same criteria as for malignant diseases: information of the patient on risks, benefits and treatment quality.

Systemic Immunosuppressive Therapy with Oral Sirolimus after Bare Metal Stent Implantation: The Missing Alternative in the Prevention of Coronary Restenosis after Percutaneous Coronary Interventions

In recent years, percutaneous coronary intervention (PCI) with drug eluting stents (DES) to treat de novo coronary lesions has been associated with a significant reduction of neointimal hyperplasia and in-stent restenosis. However, several publications raise concerns about long-term safety of DES, especially with the emerging anxiety with the problem of late stent thrombosis. Different registries with DES reported a growing incidence of stent thrombosis up to three years after stent implantation. In parallel with DES introduction in clinical practice in the last seven years, we identified six reported observational and randomized clinical experiences assessing the potential role of oral Sirolimus therapy in the prevention of coronary restenosis after bare metal stent implantation. Three observational and three randomized studies were performed during these years. Several implications were drawn: First, systemic therapy was given for only 14 days after PCI; minor transient side effects were observed in 25% of patients and were completely relieved after discontinuation of the drug. Secondly, angiographic restenosis and late loss are strongly related with Sirolimus blood concentration during the first week of treatment and were significantly reduced compared to non therapy. Finally, in the last randomized study, oral Sirolimus plus bare metal stent were cost saving compared to drug eluting stents with a trend to better clinical late outcome with the oral immunosuppressive therapy. The manuscript also reviews recent patents with new drugs, combination of drugs and DES designs which would improve safety and efficacy in the restenosis prevention after angioplasty.

The First Clinical Trial of Antioxidant, Carvedilol-Eluting Stent in Coronary Artery Diseases

Background and Objectives：Carvedilol is a beta- and alpha-receptor blocker, a direct inhibitor of smooth muscle cell proliferation and migration, and it produced a significant suppression of neointimal hyperplasia in our porcine experiment. The purpose of the study was to investigate the safety and efficacy of carvedilol-eluting BiodiVysio stent implantation for de novo lesions. Subjects and Methods：We performed a prospective randomized trial to compare two types of stents for revascularization in 39 patients [Group I (carvedilol-eluting stent): n=20, 58.311.1 years, and Group II (control stent): n=19, 59.98.5 years]. The primary effective end points were major adverse cardiac events (MACE): cardiac death, acute myocardial infarction, target lesion revascularization (TLR), in-stent restenosis and late lumen loss at the one-year clinical and angiographic follow-up. Results：All the stents were successfully deployed and the patients were discharged without experiencing any clinical events. The baseline clinical characteristics, baseline diameter stenosis and minimal luminal diameter were not different between the two groups. The follow-up diameter stenosis and late loss were significantly lower in the group I compared with group II (23.112.7% vs. 47.323.6%, p=0.012; and 0.520.26 mm vs. 1.120.67 mm; p=0.020, respectively). There were no TLR and MACE in group I; however the differences were not significant [0% (0/20) vs. 10.5% (2/19); p=0.231 and 0% (0/20) vs. 15.8% (3/19), p=0.106, respectively]. Conclusion：Carvediloleluting stents appear feasible to use and they may be effective in the prevention of coronary restenosis. These results warrant further confirmation with a large, randomized multi-center trial. (Korean Circulation J 2006; 36:115-120)

Prevention of coronary restenosis with liquid-filled 188Re balloon: Preliminary results of an International Atomic Energy Agency (IAEA) multicenter study

Prevention of coronary restenosis with liquid-filled 188Re balloon: Preliminary results of an International Atomic Energy Agency (IAEA) multicenter study

The Long-term Clinical Results of a Platelet Glycoprotein IIb/IIIa Receptor Blocker Abciximab: ReoProR Coated Stent in Patients with Coronary Artery Disease

Background :Previously, the inhibition of coronary restenosis with Abciximab (ReoPro®)-coated stent in a porcine model was reported. ReoPro® inhibits platelet aggregation, the proliferation of vascular smooth muscle cells and the inflammatory reaction.Methods :A prospective randomized trial was performed to compare two types of stent for revascularization in the native coronary artery. The primary effective end points were major adverse coronary events (MACE): cardiac death, acute myocardial infarction, target vessel revascularization (TVR) and restenosis at the 6-month clinical and angiographic follow-ups.Results :One hundred and fifty-five patients were enrolled between August 2001 and June 2003. The mean ages (56.0±10.0 vs. 56.9±10.8 years), baseline diameter of stenosis and minimal luminal diameter were no different between the two groups. There was one myocardial infarction and revascularization during the hospital stay in control stent group. During the clinical follow-up there were two myocardial infarctions in control group. Follow-up coronary angiograms were performed in 62.3% (48/77) and 65.4% (51/78) of the coated and control groups, respectively. The diameter of stenosis and late loss were significantly less in the ReoPro®-coated stent group compared with the controls (16.4±5.8% vs. 34.3±6.1%, p=0.009; and 0.33±0.28 mm vs. 0.88±0.41 mm; p=0.002). The restenosis and TVR rates of the ReoPro®-coated stent were relatively lower compared with the control stent [14.6% (7/48) vs. 29.4% (15/51), p=0.062; and 9.2% (7/76) vs. 14.7% (11/75); p=0.327].Conclusion :A ReoPro®-coated stent is safe, and may be effective in the prevention of coronary restenosis.

Therapeutic potential of oral antiproliferative agents in the prevention of coronary restenosis.

The treatment of coronary artery disease has reached many milestones - from balloon angioplasty to drug-eluting stents. The last decade witnessed the revolution of bare metal stents with new designs, alloys and strut thicknesses. Yet restenosis, the aphorismic 'Achilles heel', remains to be conquered. The restenosis rates with balloon angioplasty alone are 30-40% and are reduced to 20-30% with stents. Although intravascular brachytherapy proved to be a durable and safely used technique to treat in-stent restenosis, clinical event rates were not reduced to single digits.Drug-eluting stents are showing positive results in this direction, but it is too early to predict their efficacy in various subsets of lesions. With the increased usage of these stents, there are reports of problems such as late stent malapposition, subacute and late thromboses, and aneurysm formations due to the vessel toxicity associated with this method of treatment. Furthermore, when multivessel stenting is considered, the cost of drug-eluting stents is a significant problem given the fact that these are no longer 'zero restenosis' devices. There is a definite need for a simple, safe and durable solution to restenosis. Oral agents are an alternative delivery strategy that can target multiple coronary lesions, which are targets for catheter-based revascularisation with any approved metal stent and with potentially lower cost. Although oral agents have been an interesting option to treat restenosis and several agents have been tested in trials since the 1980s, the results were disappointing. The development of devices such as intravascular ultrasound has led to a greater understanding of restenosis mechanisms, and the focus on pathophysiological mechanisms, which centred mainly on platelets, growth factors and lipids, has changed to inflammation, endothelium and smooth muscle cell proliferation.Accordingly, the targets of pharmaceutical agents have shifted from platelets to cell cycle inhibition, smooth muscle cell proliferation and migration, synthesis of extra cellular matrix, and inflammatory mediators. Initial encouraging results with oral drugs such as cilostazol, sirolimus (rapamycin) and thiazolidinediones indicate a definite place for this strategy to reduce restenosis. A desirable oral agent would be anti-inflammatory, inhibit smooth muscle cell migration and proliferation, promote endothelial growth, and be well tolerated and free from significant adverse effects. It may be useful to start with a high loading dose before stent implantation and then follow with a short-term lower maintenance dose. Future trials should be aimed at finding an ideal agent, effective loading dose, maintenance dose and optimum duration of therapy.

Role of drugs in prevention of coronary restenosis

Role of drugs in prevention of coronary restenosis

Prevention of coronary restenosis with radiation therapy: a review.

The problem of restenosis after percutaneous transluminal coronary angioplasty remains the major limiting factor of the procedure. Over the last 10 years, investigators have been studying the use of radiation therapy for preventing restenosis after angioplasty or stent placement. Since radiotherapy has been proven in other cases to be effective in disrupting the cell cycle regulatory proteins and thereby slowing or stopping growth, it was decided to apply the same principle to neointimal hyperplasia. To review the data that have emerged regarding vascular radiation with an emphasis on irradiated stents, 65 articles were reviewed and both preclinical and clinical experiments were included. Overall, studies with gamma and beta radiation show promising results. Endovascular gamma radiation has been shown effective in randomized trials, even at 3-year follow-up. Beta radiation is preferred because of greater safety and localization, and because it has also shown encouraging results in initial clinical trials, as well as in larger randomized studies. Consequently, the Federal Drug Administration has approved the use of both. In both types of endovascular brachytherapy, it seems the greater the dose, the better the initial response. Safety concerns include an increased incidence of late thrombosis and greater restenosis at margins. With irradiated stents, however, the situation is not as clear. At times, animal models have presented confusing results. These have ranged from significant suppression of hyperplasia to outright adverse effects of radiation on the vessel wall. While some clinical trials have been encouraging, others have not. Follow-up of up to 1 year has been disappointing so far. Many issues, such as the "candy wrapper" effect and rebound hyperplasia, must be dealt with before this becomes a viable form of therapy. It has become clear that radiation therapy in this setting, while having potentially great benefits, can cause deleterious effects as well. However, the mixed bag of positive and negative results seen so far, and the attractiveness of stents or percutaneous transluminal coronary angioplasty being "restenosis-proofed," eventually is cause for cautious optimism.

Two-year follow-up after beta and gamma intracoronary radiation therapy for patients with diffuse in-stent restenosis

In-stent restenosis (ISR) has become a major challenge as the use of stents has increased. 1 Casterella P.J. Teirstein P.S. Prevention of coronary restenosis. Cardiol Rev. 1999; 7: 219-231 Crossref PubMed Scopus (63) Google Scholar The recurrence rate after treatment for ISR remains high (>30%), and is not influenced by the device used in the interventional procedure. 2 Hoffmann R. Mintz G.S. Dussaillant G.R. Popma J.J. Pichard A.D. Satler L.F. Kent K.M. Griffin J. Leon M.B. Patterns and mechanisms of in-stent restenosis. A serial intravascular ultrasound study. Circulation. 1996; 94: 1247-1254 Crossref PubMed Scopus (1230) Google Scholar , 3 Reimers B. Moussa I. Akiyama T. Tucci G. Ferraro M. Martini G. Blengino S. Di Mario C. Colombo A. Long-term clinical follow-up after successful repeat percutaneous intervention for stent restenosis. J Am Coll Cardiol. 1997; 30: 186-192 Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar , 4 Mehran R. Mintz G.S. Satler L.F. Pichard A.D. Kent K.M. Bucher T.A. Popma J.J. Leon M.B. Treatment of in-stent restenosis with excimer laser coronary angioplasty mechanisms and results compared with PTCA alone. Circulation. 1997; 96: 2183-2189 Crossref PubMed Scopus (238) Google Scholar , 5 Baim D.S. Levine M.J. Leon M.B. Levine S. Ellis S.G. Schatz R.A. Management of restenosis within the Palmaz-Schatz coronary stent (the U.S. multicenter experience). The U.S. Palmaz-Schatz Stent Investigators. Am J Cardiol. 1993; 71: 364-366 Abstract Full Text PDF PubMed Scopus (185) Google Scholar The predominant mechanism of ISR is neointimal tissue proliferation. 6 Gordon P.C. Gibson C.M. Cohen D.J. Carrozza J.P. Kuntz R.E. Baim D.S. Mechanisms of restenosis and redilation within coronary stents-quantitative angiographic assessment. J Am Coll Cardiol. 1993; 21: 1166-1174 Abstract Full Text PDF PubMed Scopus (224) Google Scholar Preclinical and clinical studies have shown efficacy of intracoronary radiation delivered by catheter-based systems after intervention in reducing ISR using beta and gamma emitters. 7 Wiedermann J.G. Marboe C. Amols H. Schwartz A. Weinberger J. Intracoronary irradiation markedly reduces restenosis after balloon angioplasty in a porcine model. J Am Coll Cardiol. 1994; 23: 1491-1498 Abstract Full Text PDF PubMed Scopus (297) Google Scholar , 8 Waksman R. Robinson K.A. Crocker I.R. Gravanis M.B. Cipolla G.D. King III, S.B. Endovascular low-dose irradiation inhibits neointima formation after coronary artery balloon injury in swine. A possible role for radiation therapy in restenosis prevention. Circulation. 1995; 91: 1533-1539 Crossref PubMed Scopus (361) Google Scholar , 9 Waksman R. Robinson K.A. Crocker I.R. Wang C. Gravanis M.B. Cipolla G.D. Hillstead R.A. King III, S.B. Intracoronary low-dose β-irradiation inhibits neointima formation after coronary artery balloon injury in the swine restenosis model. Circulation. 1995; 92: 3025-3031 Crossref PubMed Scopus (265) Google Scholar The Beta Washington Radiation for In-Stent restenosis Trial (WRIST) using 90-yttrium (90Y) showed inhibition of angiographic and clinical restenosis compared with placebo at 6 months follow-up with similar outcomes in the gamma radiation arm (iridium-192 [192Ir]) of WRIST. 10 Waksman R. Bhargava B. White L. Chan R.C. Mehran R. Lansky A.J. Mintz G.S. Satler L.F. Pichard A.D. Leon M.B. Kent K.M. Intracoronary β-radiation therapy inhibits recurrence of in-stent restenosis. Circulation. 2000; 101: 1895-1898 Crossref PubMed Scopus (312) Google Scholar The long-term impact and safety of this technology is unknown, with concerns of late thrombosis, aneurysm formation, accelerated vascular disease, and perforation. 11 Teirstein P.S. Massullo V. Jani S. Popma J.J. Russo R.J. Schatz R.A. Guarneri E.M. Steuterman S. Sirkin K. Cloutier D.A. Leon M.B. Tripuraneni P. Three-year clinical and angiographic follow-up after intracoronary radiation results of a randomized clinical trial. Circulation. 2000; 101: 360-365 Crossref PubMed Scopus (333) Google Scholar In this study, we report a 2-year clinical follow-up of the beta and gamma WRIST cohorts.

153 Technique and preliminary results of IND/American trial of “intracoronary irradiation (de-novo) in the prevention of coronary restenosis” (INDIRA)

153 Technique and preliminary results of IND/American trial of “intracoronary irradiation (de-novo) in the prevention of coronary restenosis” (INDIRA)

Prevention of coronary restenosis.

Percutaneous transluminal coronary angioplasty (PTCA) was introduced 22 years ago as a nonsurgical catheter-based treatment for obstructive coronary artery disease. Over the following 2 decades, major advances in equipment and techniques led to tremendous growth in the use of PTCA to treat coronary artery disease and angina. Restenosis persists as the limiting factor in the maintenance of vessel patency after PTCA, occurring in 30% to 50% of patients and accounting for significant morbidity and health care expenditures. Plaque persistence and vessel recoil, thrombus formation, constrictive remodeling, and neointimal proliferation are the primary contributors to the development of restenosis after PTCA. Early clinical trials in restenosis prevention using various revascularization devices, antiplatelet drugs, antithrombotic drugs, and antiinflammatory drugs were uniformly negative. Coronary stents are the only devices that have shown a reduction in the incidence of restenosis. Recently, novel therapies, such as intracoronary radiation, antioxidant drugs, and platelet-derived growth factor antagonists, have shown reductions in the incidence of restenosis in small randomized trials. This review focuses on the etiology and pathophysiology of restenosis and discusses current and future therapies that may reduce the incidence of restenosis.

Pathology of radiation-induced coronary artery disease in human and pig

Purpose. External beam mediastinal radiation-induced accelerated coronary atherosclerotic heart disease in humans has been recognized, especially when the condition occurs in young persons. The purpose of the present study was to compare external beam radiation-induced accelerated coronary atherosclerosis in humans with that seen in the pig coronary arteries following radioactive stent placement. Methods. A literature review of radiation-induced coronary artery disease was performed. In addition, clinical records and coronary histology from the Armed Forces Institute of Pathology Registry were reviewed from patients who had received external beam radiation for mediastinal malignancies. Coronary arteries from pigs that had radioactive coronary stent placement were evaluated from our stent pathology laboratory and analyzed for comparison with the human disease. Results. In humans, the characteristics of the intimal plaque in accelerated atherosclerosis postradiation therapy were similar to that seen in typical atherosclerotic coronary disease in the absence of radiation therapy. However, medial thinning and adventitial fibrosis were the distinguishing pathologic arterial changes secondary to radiation seen in humans. Radioactive stent placement in pig coronary arteries produced similar changes to that observed in humans post-external beam radiation, consisting of medial injury and adventitial thickening accompanied by intimal foam cell collections, calcification, and necrotic core formation containing cholesterol clefts resulting in severe luminal narrowing. Conclusions. Radiation, delivered via external beam or radioactive stent, induces changes of intimal atherosclerosis with medial thinning and adventitial scarring in human and pig. Therefore, pending completion of long-term clinical studies, caution should be exercised before the widespread use of brachytherapy is advocated for the treatment and prevention of coronary restenosis.

Mithramycin inhibits myointimal proliferation after balloon injury of the rat carotid artery in vivo.

Smooth muscle proliferation and extracellular matrix formation in the subintimal region of blood vessels that have been subjected to intimal injury are responsible for restenosis following balloon angioplasty of the coronary arteries and for accelerated atherosclerosis in a variety of other pathophysiological states. The immediate early-response gene c-myc is overexpressed in proliferating vascular smooth muscle cells in vitro, and c-myc antisense oligomers have been shown to reduce c-myc expression and to inhibit proliferation of vascular smooth muscle cells in culture. Mithramycin is a commercially available G-C-specific DNA binding drug that selectively inhibits transcription of genes, such as c-myc, that have G-C-rich promoter sequences. This study tested the hypothesis that mithramycin inhibits transcription of the c-myc proto-oncogene and prevents myointimal proliferation after balloon injury of the rat carotid artery in vivo. Ten-week-old male Sprague-Dawley rats received mithramycin (150 micrograms/kg IP) or distilled H2O 1 hour before and 1 hour after balloon injury of the right common carotid artery. After 2 weeks, the rats were killed by overdose of pentobarbital, and the injured right and uninjured control left arteries were pressure-fixed and subjected to morphological analysis for evaluation of the degree of myointimal thickening. Separate groups of rats were killed at 2 and 6 hours after vascular injury, and total RNA from injured and control vessels of mithramycin- and vehicle-treated rats was subjected to Northern analysis for assessment of steady-state c-myc mRNA levels. The areas of neointima and the ratios of neointimal to medial area were significantly less in mithramycin-treated than in control rats (0.6 +/- 0.1 versus 1.2 +/- 0.1 mm2, P < .01 and 95 +/- 16% versus 190 +/- 14%, P < .01). Lumen size was significantly greater in mithramycin-treated than in control rats (1.5 +/- 0.1 versus 0.8 +/- 0.1 mm2, P < .01). Steady-state c-myc mRNA levels were increased 10-fold and 2-fold (compared with undamaged carotid arteries) at 2 and 6 hours after balloon injury, respectively; mithramycin treatment reduced c-myc mRNA levels at 2 and 6 hours by 66% and 53%, respectively. These results support the hypothesis that systemic administration of mithramycin immediately (1 hour before and after intervention effectively inhibits transcription of the c-myc proto-oncogene and prevents myointimal proliferation after balloon injury of the rat carotid artery in vivo. Because mithramycin has been shown to be well tolerated by humans and to effectively inhibit transcription of c-myc in proliferating human cells, this agent may be useful in the prevention of coronary restenosis.

Coronary Restenosis: Prospects for Solution and New Perspectives From a Porcine Model

Coronary restenosis, a major unresolved problem for percutaneous coronary revascularization procedures, has thus far been resistant to all therapeutic strategies. In part, ineffective treatment or prevention of coronary restenosis may be due to reliance on a conceptualization of the restenosis process that incompletely reflects the pathophysiologic factors associated with neointimal formation after arterial injury. In a porcine coronary restenosis model, three stages of neointimal growth after arterial injury have been identified: an early thrombotic stage, with platelets, fibrin, and erythrocytes; a cellular recruitment stage, with endothelialization and an infiltration by lymphocytes and monocytes; and a proliferative stage, in which smooth muscle cells migrate into and proliferate within the fibrin-rich degenerating thrombus. Evaluation of basic mechanisms responsible for neointimal formation has been possible with this model. In particular, a direct relationship exists between the depth of arterial injury and subsequent neointimal thickness. This relationship can be used for investigating the efficacy of new therapies. Treatment strategies for restenosis should be directed toward interference with the cellular or humoral events that lead to neointimal formation, with the specific goal of decreasing the neointimal volume. These strategies may include delivery of drugs to the site of arterial injury to limit the amount of early mural thrombus or decreasing subsequent cellular recruitment and proliferation as well as synthesis of extracellular matrix.

Inhibition of smooth muscle cell proliferation by an antisense oligodeoxynucleotide targeting the messenger RNA encoding proliferating cell nuclear antigen.

The process by which normally quiescent vascular smooth muscle cells (SMCs) change into proliferating cells, which express and respond to multiple growth factors, plays a major role in restenosis after coronary angioplasty. We are attempting to inhibit SMC proliferation by interventions that inhibit specific factors involved in signal transduction pathways leading to cell division. To date, all studies taking this approach have attempted to block the effects of mitogens acting on the cell surface. In contrast, we have focused on a strategy that bypasses cell surface-mediated events by directly inhibiting the expression of proliferating cell nuclear antigen (PCNA), an intranuclear protein that functions in a final common pathway shared by diverse mitogen-induced signals. In the present investigation, we determined whether antisense oligodeoxynucleotides (ODNs) complementary to the messenger RNA of PCNA will inhibit PCNA expression and thereby reduce SMC proliferation. When antisense ODNs (15- or 18-mer), modified to inhibit their degradation, are introduced into the medium of rat aortic SMCs in concentrations ranging from 10 to 100 microM, the 18-mer ODN, in a concentration-related manner, decreases SMC growth (as assessed by cell counting) by more than 50%. This effect persists for at least 9 days. An ODN with the same nucleotides but a scrambled sequence has little effect. Western blots and immunocytochemistry indicate that the antisense ODN reduces expression of PCNA protein. Our results demonstrate that an antisense ODN directed at the messenger RNA of PCNA decreases expression of the PCNA gene product and reduces SMC proliferation. In addition, these results provide an important impetus to initiating in vivo studies to determine the feasibility of antisense strategies in the prevention of coronary restenosis.

Prevention of coronary restenosis by stenting.

Balloon angioplasty fails to provide acceptable long-term results for a significant proportion of patients. An intravascular mechanical support, developed with the aim of preventing restenosis and acute closure of diseased arteries after transluminal angioplasty, was implanted in 44 patients (39 male and five female), aged from 35 to 70 years (mean 56 years) with documented restenosis of native coronary artery (41 stents) and bypass grafts (12 stents). In the group of bypass graft patients there was no local restenosis and no major complication. In patients in whom stents were placed in native coronary arteries, the complication rate was higher (two patients died after coronary bypass surgery). One patient died suddenly at home. Except for one patient, in whom a new lesion developed proximally with extension into the stent, no case of restenosis could be observed. Despite the still relatively high complication rate, we feel that stenting may present a rational approach to the unresolved problem of restenosis after coronary angioplasty.