Restenosis Process Research Articles

Local delivery of c-myc neutrally charged antisense oligonucleotides with transport catheter inhibits myointimal hyperplasia and positively affects vascular remodeling in the rabbit balloon injury model.

Myointimal hyperplasia after percutaneous transluminal coronary angioplasty (PTCA) is a key component of the process of restenosis. The c-myc is a critical cell-cycle division protein involved in the formation of neointima. We evaluated the long-term impact of local delivery of c-myc neutrally charged antisense oligonucleotides (Resten-NG) on myointimal hyperplasia after PTCA in a rabbit model. PTCA was performed in the iliac arteries of 25 New Zealand white rabbits, using a Transport catheter at 8 atm for 30 sec, three times; 500 microg Resten-NG (n = 11) or saline (n = 14) was delivered to the PTCA site at 2 atm with the outer balloon for 2 min. The diet was supplemented with 0.25% cholesterol for 10 days before and 60 days after PTCA. Angiography was performed at harvest, and vessels were fixed in formalin, processed, and stained with hematoxylin and eosin (H&E) and Movat. Quantitative angiography showed that local delivery of antisense c-myc at PTCA reduced late luminal loss from 1.8 +/- 0.30 mm in control animals to 0.90 +/- 0.30 mm in the treatment group (P = 0.001). Histological analysis by planimetry showed that intimal areas were 1.67 +/- 0.44 mm(2) and 0.82 +/- 0.32 mm(2) in the control and antisense delivery groups, respectively (P < 0.05). We conclude that local delivery of Resten-NG inhibited myointimal hyperplasia after PTCA in cholesterol-fed rabbits for up to 60 days.

Handbook of Vascular Brachytherapy, 2nd ed

Ron Waksman, MD; Patrick Serruys, MD 238 pp. London, UK: Martin Dunitz; 2000. $69.95. ISBN 1-85317-803-9. Spencer B. King III, MD Atlanta, Ga. Endovascular brachytherapy has emerged as the most potent weapon to prevent restenosis after coronary interventions. Six clinical trials have now demonstrated that γ- and β-radiation are effective in blocking the restenosis process in patients who develop such proliferative lesions within previously placed stents. Depending on the extent of the restenotic material within the stents, repeat interventions may result in a re-restenosis ranging from 20% to 60%. When radiation therapy has been applied, this rate has been dramatically reduced. The 2 major shortcomings of radiation therapy have been identified …

Restenosis following coronary angioplasty: current status.

Restenosis following coronary angioplasty: current status.

Statin therapy is associated with reduced restenosis rates after coronary stent implantation in carriers of the Pl(A2)allele of the platelet glycoprotein IIIa gene.

Aims Platelets play a central role in the restenosis process by inducing neointimal proliferation after coronary interventions. Glycoprotein IIb/IIIa Pl(A2)polymorphism has been associated with the occurrence of acute coronary syndromes and increased restenosis rates. Statins have been shown to exert potent antiproliferative, antiinflammatory and antithrombotic properties, thereby potentially interfering with the major processes of in-stent restenosis. Therefore, we sought to find out whether statin therapy interferes with restenosis and clinical outcome at 6 months following successful coronary stent implantation in the presence or absence of the Pl(A2)allele. Methods and Results Six hundred and fifty consecutive patients were followed for 6 months after coronary stent insertion. Carriers of the Pl(A2)allele demonstrated a significantly increased restenosis rate, which was abrogated by statin therapy (50.9% vs 28.6%, P=0.01). Moreover, statin therapy was associated with a significant reduction (28.2% vs 49.3%, P<0.01) in the occurrence of major adverse coronary events (myocardial infarction, cardiac death, target vessel revascularization) in the 6 months after the intervention in patients with the Pl(A2)allele. Conclusion Statin therapy reduces increased stent restenosis rates and improves clinical outcome following coronary stent implantation in patients bearing the Pl(A2)allele, suggesting that statins interfere with the functional consequence of a genetically determined platelet-mediated risk factor associated with Pl(A2)polymorphism.

Value of Transthoracic Echocardiography for the Detection of High-Grade Coronary Artery Stenosis: Prospective Evaluation in 50 Consecutive Patients Scheduled for Coronary Angiography

We prospectively evaluated the feasibility of direct, transthoracic evaluation of coronary arteries to diagnose flow-limiting lesions. Second harmonic mode in B-mode and fundamental mode for Doppler examinations was used. A stenosis was diagnosed when maximal flow velocity at least doubled in comparison with that of the adjacent segment or when local velocity was at least 2 m/s. Of the left anterior descending coronary artery segments assessed, 34 were proximal, 35 middle, and 34 distal segments. The corresponding figures for circumflex coronary artery segments were 17 proximal and 11 middle segments and for the right coronary artery, 14 proximal and 15 distal segments. No distal circumflex and only 1 mid right coronary artery segment was visualized. Twenty-eight stenoses were diagnosed. Specificity for stenosis detection was 96% to 100% and sensitivity was 62% to 66%. Echo-cardiography was unable to document occlusions. Transthoracic echocardiography allows for coronary artery assessment in a significant portion of patients scheduled for coronary angiography. It may be used to document the presence of coronary artery stenosis. With further technologic improvements, transthoracic echocardiography could enable the monitoring of the restenosis process after percutaneous transluminal coronary angioplasty/stent intervention and coronary artery luminal narrowing after heart transplantation. (J Am Soc Echocardiogr 2000;13:1091-9.)

Novel chimeric p16 and p27 molecules with increased antiproliferative activity for vascular disease gene therapy.

We describe the construction and characterization of a series of novel cyclin-dependent kinase inhibitors with increased antiproliferative activity for use in the genetic treatment of hyperproliferative cell disorders, such as angioplasty-induced restenosis. These inhibitors were generated through the fusion of truncated versions of the p27 gene to the full-length p16 gene. Biochemically, the p27-p16 chimeric molecules were of comparable potency to the parental p27 in inhibiting the activities of several cyclin-dependent kinases in vitro. Replication-deficient adenoviruses encoding the parental p16, p27 genes, or their derivatives were created to assess the potency of the novel cyclin-dependent kinase inhibitor chimeric molecules to inhibit vascular smooth muscle cell proliferation, which is the seminal event in the restenosis process. One of the p27-p16 chimeric molecules, W9, was observed to be the most potent inhibitor of human primary smooth muscle and endothelial cell proliferation when compared to the p16, p27, p27 derivatives or several alternative p27-p16 chimeric molecules. Overexpression of the W9 chimeric molecule in human coronary artery smooth muscle cells induced human coronary artery smooth muscle cell growth arrest in G1 but did not induce cell apoptosis. Recombinant adenoviral vectors that express this W9 chimeric cyclin-dependent kinase inhibitor molecule constitute a novel potent antiproliferative agent for the treatment of restenosis.

Peroxisome proliferator-activated receptor-gamma ligands inhibit nitric oxide synthesis in vascular smooth muscle cells.

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a key player in glucose metabolism. If PPARgamma ligands modulate nitric oxide (NO) synthesis in the vascular tissue, they may affect the process of plaque formation and postangioplasty restenosis. We investigated the effects of PPARgamma ligands on NO synthesis in vascular smooth muscle cells. Incubation of cultures with interleukin-1beta (10 ng/mL) for 24 hours caused a significant increase in the production of nitrite, a stable metabolite of NO, in cultured rat vascular smooth muscle cells. The PPARgamma agonists troglitazone and 15-deoxy-triangle up(12,14)-prostaglandin J(2) (15d-PG J(2)) dose-dependently inhibited nitrite production by interleukin-1beta-stimulated vascular smooth muscle cells. Decreased interleukin-1beta-induced nitrite production by the PPARgamma agonists was accompanied by decreased inducible NO synthase mRNA and protein accumulation. Interleukin-1beta induced nuclear factor-kappaB activation in vascular smooth muscle cells, and both troglitazone and 15d-PG J(2) markedly suppressed this nuclear factor-kappaB activation. PPARgamma ligands inhibit NO synthesis in cytokine-stimulated vascular smooth muscle cells, suggesting that these agonists may act directly on the vascular smooth muscle and influence the process of atherosclerosis and restenosis.

Lesion-to-lesion relationship of the restenosis process after placement of coronary stents.

The interrelation between multiple stented lesions within one patient in the restenosis process is only partially understood. From 492 patients with follow-up angiograms after coronary stent placement, 115 patients underwent multilesion procedures involving 233 lesions. In randomly chosen 39 patients with 79 lesions, additional intravascular ultrasound (IVUS) studies were performed to measure intimal hyperplasia cross-sectional area (CSA) and thickness. A general linear model with intraclass correlation was used to calculate the coefficient of correlation rho (rho = 1.0 indicates perfect correlation; rho = 0.0 indicates no correlation) of late loss, late loss index, intimal hyperplasia CSA, and intimal hyperplasia thickness. Multivariate analysis showed restenosis in the companion lesion (odds ratio 4.68, 95% confidence interval 1. 68-12.92, P = 0.003) and small minimal lumen diameter preintervention (odds ratio 0.28, 95% confidence interval 0.11-0.73, P = 0.009) to be predictors of restenosis. There was a weak correlation between multiple lesions within the same patient for late lumen loss rho = 0.28 (95% confidence interval 0.10-0.46, P < 0. 001) and late loss index. IVUS analysis demonstrated correlation of intimal hyperplasia CSA rho = 0.40 (95% confidence interval 0.06-0. 74, P = 0.009) and of intimal hyperplasia thickness. In conclusion, late loss and intimal hyperplasia demonstrate a correlation between multiple stented lesions within one patient. In addition to known lesion related factors, restenosis in a companion lesion is a predictor for restenosis. Cathet. Cardiovasc. Intervent. 51:266-272, 2000.

Pathology of in-stent restenosis.

The process of in-stent restenosis parallels wound healing responses. Stent deployment results in early thrombus deposition and acute inflammation, granulation tissue development, and ultimately smooth muscle cell proliferation and extracellular matrix synthesis. The severity of arterial injury during stent placement correlates with increased inflammation and late neointimal growth. These pathological findings provide useful targets for therapies aimed at reducing the incidence of in-stent restenosis.

Prognostic value of the modified american college of Cardiology/American heart association stenosis morphology classification for long-term angiographic and clinical outcome after coronary stent placement.

Background-The modified American College of Cardiology/American Heart Association (ACC/AHA) lesion morphology criteria are predictive of early outcome after various coronary catheter interventions. Their potential prognostic value after stent implantation and, in particular, for restenosis and long-term clinical outcome has not been studied. We assessed the prognostic value of the modified ACC/AHA criteria for the long-term angiographic and clinical outcome of patients after coronary stenting. Methods and Results-This study includes 2944 consecutive patients with symptomatic coronary artery disease treated with coronary stent placement. Modified ACC/AHA lesion morphology criteria were used to qualitatively assess the angiograms; type A and B1 lesions were categorized as simple, and type B2 and C lesions were designated complex. Primary end points were angiographic restenosis and 1-year event-free survival. Restenosis rate was 33.2% in complex lesions and 24.9% in simple lesions (P<0.001). It was 21. 7% for type A, 26.3% for type B1, 33.7% for type B2, and 32.6% for type C lesions. One-year event-free survival was 75.6% for patients with complex lesions and 81.1% for patients with simple lesions (P<0. 001). It was 85.2% for patients with type A, 79.4% for type B1, 75. 9% for type B2, and 75.2% type C lesions. The higher risk for restenosis and an adverse outcome associated with complex lesions was also maintained after multivariate adjustment for other clinical and angiographic characteristics. Conclusions-The modified ACC/AHA lesion morphology scheme has significant prognostic value for the outcome of patients after coronary stent placement. Lesion morphology is able to influence the restenosis process and thus the entire 1-year clinical course of these patients.

Monte Carlo calculations of dose distributions around 32P and 198Au stents for intravascular brachytherapy.

3D dose distributions are calculated for a 32P impregnated stent and a 198Au stent for intravascular brachytherapy with the EGS4 Monte Carlo simulation code. The stents were modeled as a combination of eight helicoidal struts. This allowed investigation of the effect of the stent geometry and the electron absorption in the strut material on the dose distributions. Absorbed dose to water was calculated at radial distances ranging from 50 microm to 5 mm from the stent surface. The dose distributions around the stents are compared to the dose distribution around an intravascular brachy-therapy 192Ir source, also calculated with the EGS4 Monte Carlo code. The dose profiles near the struts show hot spots. At 50 microm distance a peak to valley ratio of 3 for 32P and 6 for 198Au in the dose distribution is obtained. For both the isotopes the inhomogeneities decrease with distance and at a radial depth of 350 microm the effect becomes negligible. The calculations showed the importance of the effect of the absorption in the stent material as this leads to a dose decrease to 67% for the 198Au stent and to 77% for 32P near the stent at a distance of 2 mm from the stent axis. It is concluded that from the dosimetric point of view, the 198Au stent is inferior to the 32P stent and the 192Ir source. Application of the 198Au stent in clinical practice requires further investigation of the importance of the adventitia in the restenosis process, and the tolerance dose of the intima.

Endovascular brachytherapy for peripheral vascular disease

The most common cause of morbidity and mortality in the United States is vascular disease, which afflicts a wide spectrum of organs such as the heart (cardiovascular system), brain (cerebrovascular system), kidney (renal system), liver (hepatic system), and extremities (peripheral vascular system). The most common pathology of vascular diseases is occlusion. Percutaneous Transluminal Angioplasty (PTA) is currently the most common nonsurgical treatment for obstructive arteries. Unfortunately, the long-term effectiveness of PTA is limited by a high restenosis rate. Efforts to reduce post-PTA restenosis, including laser, mechanical atherectomy, intravascular stenting, and pharmacologic agents, have not been successful. With recent advances in the pathogenesis of restenosis, we have learned that the major problem is the intimal hyperplastic reaction in response to vessel injury. Encouraging animal data in the use of various radiotherapeutic approaches to prevent restenosis has led to a large number of multi-national, multicenter, randomized trials on coronary vascular systems. Because early results have been in favor of radiation therapy, and because the basic process of restenosis is similar for coronary and noncoronary vascular systems, many investigators extend the application of radiotherapy to the prevention of restenosis in peripheral vascular systems. However, the clinical scenarios are much different for peripheral vascular systems than for the coronary vascular system. This article discusses the current views of the pathophysiology of restenosis, major clinical trials, and perspectives on future studies. Experimental studies on animal models have documented the profound effects of endovascular brachytherapy in reducing restenosis caused by angioplasty and stenting. Early results of clinical trials are encouraging and confirm these positive results. Long-term follow-up data are needed to show that radiation does prevent, not merely delay, restenosis; Several areas of opportunity exist for both basic science research and clinical studies to enhance our knowledge of the pathophysiology. This would optimize the treatment strategy, maximizing the benefits and minimizing late complications.

Prevention of Restenosis after Percutaneous Coronary Interventions: The Medical Approach

Restenosis following successful percutaneous coronary revascularization continues to represent a major problem limiting the clinical efficacy of this procedure. The underlying mechanisms of restenosis are comprised of a combination of effects from vessel recoil, negative vascular remodeling, thrombus formation and neointimal hyperplasia. Indeed, there are important interactions among all of these mechanisms. For example, neointimal hyperplasia is stimulated by growth factors, which are released by local thrombi and the injured arterial segment itself, and act to enhance the expression of other growth-regulating proteins, in particular "second messengers", proto-oncogenes and other cell cycle controlling proteins. This results in an inflammatory and myofibroproliferative response, which may worsen vessel narrowing caused by recoil and result in the formation of a clinically significant restenotic lesion. A multitude of pharmacologic trials have been conducted in an attempt to prevent restenosis, but most have demonstrated little benefit. Studies in smaller numbers of patients have suggested a potential benefit for several classes of agents, including: 1) the antiproliferatives, angiopeptin, trapidil and tranilast; 2) selective elimination or alteration of proliferating cells; 3) enhancement of natural growth inhibitors; and 4) signal transduction blockade or inhibition of the gene expression for various growth-stimulating proteins. Finally, there have been advances in related areas, including development of antithrombotic catheters, novel polymers, and more efficient methods for transferring genes into the vessel wall. All of these offer the possibility of delivering agents (drugs, genes, or antisense oligonucleotides) locally at the site of intervention in a way that may optimize antiproliferative effects while minimizing systemic effects--ultimately leading to a more specific inhibition of the restenosis process.

Restenosis, the Achilles' heel of coronary angioplasty.

Coronary angioplasty is widely performed for the management of symptomatic coronary artery disease. With improvements in technique, operator experience, and tools, more complex lesions are being treated. Unfortunately, luminal renarrowing continues to limit the long-term success of the procedure, resulting in the need for repeat revascularization in approximately 30% of patients within 6 months. As the pathophysiologic process of restenosis is better defined, various pharmacologic and mechanical interventions have been tried to attenuate the process. Some agents are antithrombotics, antiplatelets, angiotensin-converting enzyme inhibitors, lipid-lowering drugs, and calcium channel blockers. Improvement has been noted with the newer glycoprotein IIb- and IIIa-blocking agents, mechanical stents, and radioactive materials. Whether these new compounds will withstand the test of time is unknown.

Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators.

Peroxisome proliferator-activated receptors (PPARs) are key players in lipid and glucose metabolism and are implicated in metabolic disorders predisposing to atherosclerosis, such as dyslipidaemia and diabetes. Whereas PPARgamma promotes lipid storage by regulating adipocyte differentiation, PPARalpha stimulates the beta-oxidative degradation of fatty acids. PPARalpha-deficient mice show a prolonged response to inflammatory stimuli, suggesting that PPARalpha is also a modulator of inflammation. Hypolipidaemic fibrate drugs are PPARalpha ligands that inhibit the progressive formation of atherosclerotic lesions, which involves chronic inflammatory processes, even in the absence of their atherogenic lipoprotein-lowering effect. Here we show that PPARalpha is expressed in human aortic smooth-muscle cells, which participate in plaque formation and post-angioplasty re-stenosis. In these smooth-muscle cells, we find that PPARalpha ligands, and not PPARgamma ligands, inhibit interleukin-1-induced production of interleukin-6 and prostaglandin and expression of cyclooxygenase-2. This inhibition of cyclooxygenase-2 induction occurs transcriptionally as a result of PPARalpha repression of NF-kappaB signalling. In hyperlipidaemic patients, fenofibrate treatment decreases the plasma concentrations of interleukin-6, fibrinogen and C-reactive protein. We conclude that activators of PPARalpha inhibit the inflammatory response of aortic smooth-muscle cells and decrease the concentration of plasma acute-phase proteins, indicating that PPARalpha in the vascular wall may influence the process of atherosclerosis and re-stenosis.

Abciximab: platelet IIb/IIIa receptor blockade in the management of patients with acute coronary syndromes

Summary Complications of percutaneous transluminal coronary angioplasty (PTCA) include abrupt vessel closure in 5% of patients, and restenosis, which can occur in up to 45% of patients. Abciximab is a chimeric monoclonal antibody to the platelet glycoprotein IIb/IIa receptor and inhibits platelet aggregation. It also binds to the vitronectin receptor in the vessel wall, which is involved in the process of smooth muscle cell migration and proliferation, components of the restenosis process. Abciximab is licensed for use in high-risk PTCA (due to the presenting clinical syndrome and/or lesion morphology) with the aim of reducing peri-procedural complications and improving long-term outcomes. Several multi-centre randomized trials have proven the efficacy of abciximab in various clinical situations and have also shown that using lower doses of heparin with abciximab not only minimizes bleeding complications but also optimizes clinical outcomes. Abciximab can be administered in high-risk clinical situations from primary PTCA to sub-acute stent thrombosis, and recent experience is discussed. Although this drug is an expensive addition to an already formidable cardiology budget, pharmaco-economic data have shown that, when used appropriately, it is cost effective.

Frontiers in interventional cardiology.

n more than 20 years since the first percutaneous coronary revascularization procedures, the field of interventional cardiology has proliferated beyond all expectations. Now more than 1 million procedures are performed worldwide each year. Stenting has revolutionized the field, which previously relied on balloon dilatation in the majority of patients. With 50% of patients now undergoing stent implantation, the groundwork is laid for further important advances. In this article, we discuss the 4 most important new advances in the field of interventional cardiology: platelet inhibition, prevention of restenosis, stent evolution, and angiogenesis.

Local drug delivery systems and prevention of restenosis.

Time for primary review 38 days. It is somewhat incongruous that the successful performance of percutaneous transluminal coronary revascularization, a technically challenging and somewhat delicate endeavour, is predicated on the delivery of a traumatic insult to the vascular wall. This injury incites a cascade of compensatory responses, involving thrombosis and inflammation, vascular smooth muscle proliferation and migration, and matrix production and deposition. Although this reparative process usually stabilizes the site of injury and ensures a successful long term result, in 30 to 50% of cases it is excessive [1], resulting in compromise of the lumen with the potential for recurrent ischemia. Our understanding of the process of restenosis, although not yet complete, has evolved considerably in recent years. There is a complex interplay of vessel wall remodeling and neointimal proliferation. Remodeling refers to a contracture or ‘shrinkage’ of the vessel, primarily related to the inflammatory process in the vessel wall which involves the media and adventitia. The neointimal proliferative process appears to be linked to vascular smooth muscle cell activation, proliferation and migration [2, 3]. The deployment of an intracoronary stent at the site of injury, by providing a scaffold within the vessel wall, can reduce the impact of vascular remodeling, but may be accompanied by an exhuberant intimal hyperplastic response [4]with consequent restenosis in a persistent 20–30% of cases [5, 6]. Thus, over recent years there has been a widespread intensive research effort directed towards identifying pharmacotherepeutic regimens targeting primarily (but not exclusively) the smooth muscle cell, to prevent the neointimal restenotic process. These have involved conventional pharmacological agents, as well as novel gene therapies, and many of these have been found to be effective in preventing restenosis in animal models of vascular injury following systemic administration. However, when these agents have progressed to clinical … * Corresponding author. Tel.: +1 216 4459490; Fax: +1 216 4459595; E-mail: topole@cesmtp.ccf.org

INTRAVASCULAR ULTRASOUND IN THE SETTING OF DIRECTIONAL CORONARY ATHERECTOMY AND PERCUTANEOUS TRANSLUMINAL CORONARY ROTATIONAL ATHERECTOMY

The first section of this article reviews how intracoronary ultrasound (ICUS) has been used to identify the mechanisms of action of directional coronary atherectomy (DCA) and examines the influence of plaque composition and morphology on DCA outcomes. The process of restenosis is then described. Results from trial using ICUS-guided DCA are evaluated, demonstrating how the information obtained from ICUS is being used to improve the angiographic and clinical outcomes of directional atherectomy. Finally, data are incorporated to provide practical applications for the use of DCA.

Association between pre-PTCA blood haemoglobin concentration and the risk of symptomatic restenosis after successful PTCA of primary coronary stenoses.

Thrombus formation at the dilation site has been suggested to initiate the restenosis process after percutaneous transluminal coronary angioplasty (PTCA). High haemoglobin concentrations may predispose to thrombus formation by increasing blood viscosity, slowing coronary blood flow and increasing thrombocyte adhesion. Pre-PTCA blood haemoglobin concentrations (Hb) in 44 patients with symptomatic restenosis > or = 50% of the vessel diameter (Group A) were compared with Hb in the remaining 215 patients in a consecutive study population (Group B). Median Hb (range) was 149 (119-164) g/l in Group A and 142 (117-164) g/l in Group B, P = 0.004. Odds ratio (95% CI) for symptomatic restenosis was 3.22 (1.62-6.42) when Hb was dichotomised according to the median in the entire material. Hb, but not sex was a significant risk factor in multivariate analysis. Hb is a hitherto not recognized factor associated with the risk of symptomatic restenosis after PTCA and may be a link coupling male sex with increased risk of restenosis.