| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Editorials |
1 From the Department of Radiology, University of North Carolina School of Medicine, CB 7510, UNC-CH, Chapel Hill, NC 27514. Received December 30, 2003; accepted January 2, 2004. Address correspondence to the author (e-mail: m_mauro@med.unc.edu).
Index terms: Arteries, radiation • Arteries, restenosis, 92.454, 92.458, 92.721 • Arteries, stenosis or obstruction, 92.721 • Arteries, transluminal angioplasty, 92.1281, 92.1282, 92.1286, 92.454 • Editorials
In this issue of Radiology, Krueger and colleagues (1), from the University of Cologne, Germany, report their 1- and 2-year angiographic and clinical follow-up findings in patients treated with endovascular gamma irradiation following femoropopliteal angioplasty as part of a prospective randomized controlled trial (1). Gamma irradiation is being used to control the development of neointimal hyperplasia following percutaneous transluminal angioplasty (PTA). The battle against intimal hyperplasia has become the "Holy Grail" for many endovascular therapies and critical in the war against femoropopliteal disease.
The development of intimal hyperplasia represents a usually healthy manner in which the body reacts against endoluminal trauma. Balloon angioplasty is a controlled traumatic event. Angioplasty causes rupture of the plaque, dissection of the plaque from the underlying vessel layer, partial dissection of the intima and media, and overstretching of the vessel wall (2). Endothelial cells, collagen fibrils in the subendothelial layer, and myocytes are damaged. It is the outer layers of the media and, more importantly, the tough fibrous tissue of the adventitia that prevent outright vessel rupture, as long as there is no massive overdilation or piercing from a calcified plaque.
On a microscopic level, there is activation of the intrinsic coagulation pathway. von Willebrand factor complex and fibronectin are released from the damaged endothelial cells. These substances, along with the collagen of the denuded subendothelial layer, cause prompt platelet adhesion. Factor VII, along with factor IXa, activates prothrombin (ie, factor Xa), encouraging thrombus formation. The activated platelets release a variety of substances, including thromboxane and platelet-derived growth factor. The platelet-derived growth factor causes smooth muscle cells in the media to begin replicating, forming fibroblasts, and migrating to form the neointima.
Monocytes and leukocytes are also activated and begin migrating into the vessel wall, further stimulating fibroblastic formation. After reendothelialization, the newly functional endothelium, as well as other unidentified factors, may cause apoptosis of the fibroblasts to control intimal hyperplasia. However, if fibroblasts continue to form intercellular matrices, intimal hyperplasia will continue (2).
One of the original hopes regarding endovascular stents is that they would prevent restenoses that develop from intimal hyperplasia. We now know that stents primarily improve the initial result of balloon angioplasty by preventing elastic recoil of the dilated vessel and fixating intimal flaps and dissections in the arterial wall. Soon after stent implantation, there is adhesion of platelets, plasma cells, and monocytes, followed by the development of a layer of thrombus covering the stent struts. Smooth muscle cells are again activated by the same mechanisms that are seen with PTA alone. This process ultimately results in an intimal covering and reendothelialization of the stent-treated area.
Giant cells often develop as a reaction to the foreign body—that is, the stent. Intimal hyperplasia is often more pronounced following stent implantation than following PTA alone and is responsible for the subsequent recurrent stenosis that is referred to as in-stent stenosis (2). The initial luminal gain and the reduced constrictive remodeling in stent placement procedures counter the intimal hyperplasia.
Depending on the severity of disease and the presence of concomitant disease in other vascular segments, patients with femoropopliteal disease present with either intermittent claudication or symptoms of critical limb ischemia. For patients with claudication, there is little doubt that walking capability can be improved with supervised exercise programs. Unsupervised programs are unlikely to facilitate substantially improved walking distances or qualities of life.
de Vries et al (3) performed a cost-effectiveness study in which they compared revascularization and exercise therapy in patients with intermittent claudication. Compared with an exercise program, revascularization (either with angioplasty or bypass surgery) improved effectiveness by 33–61 quality-adjusted life days in the patients with no coronary artery disease. Moreover, the incremental cost-effectiveness ratio was $38,000 per quality-adjusted life year gained with PTA and $311,000 per quality-adjusted life year gained with additional bypass surgery, as compared with the ratio calculated for exercise alone. The authors concluded that the expected gain in effectiveness achieved with bypass surgery for intermittent claudication is small compared with the costs. PTA performed whenever feasible was more effective than exercise alone, and the cost-effectiveness ratio was in the socially acceptable range.
There have been many studies in which the success or failure of PTA for femoropopliteal disease was reported. Such studies often have been limited owing to small patient numbers, poor follow-up protocols, the combining of patients who had claudication with those who had critical ischemia, and the use of simple clinical follow-up examinations rather than repeat imaging to evaluate the patency of treated arterial segments.
Muradin et al (4) performed a meta-analysis (involving 19 studies) of PTA and stent implantation in femoropopliteal arterial segments between 1999 and 2000 and adjusted for lesion type (ie, stenosis vs occlusion) and the indication for treatment (claudication vs critical limb ischemia). For balloon dilation, the combined 3-year patency rates were 61% for stenoses and claudication, 48% for occlusions and claudication, 43% for stenoses and critical ischemia, and 30% for occlusions and critical ischemia. The 3-year patency rates after stent implantation ranged from 63% to 66%, regardless of the clinical indication or lesion type. The authors did comment on the asymmetric distribution of data points, and the issue of possible publication bias was raised in the stent studies. In any event, PTA and stent implantation for treatment of claudication and stenosis yielded similar results, but stent placement appeared to be favored among the patients with more severe disease.
In any case, there is clear room for substantial improvement in the current commonly used endovascular therapies. The clinically evident recurrence of symptoms is most often secondary to the progression of atherosclerotic disease in other vascular segments or to the development of recurrent stenoses in the treated segment due to intimal hyperplasia. Thus, intimal hyperplasia continues to be the major culprit that is limiting the success of durable endovascular treatments of all lesion types.
A variety of new techniques to improve the results of endovascular treatments of femoropopliteal disease are being studied. In addition to the standard treatments of PTA and stent placement, atherectomy (rotational and directional), excimer laser–assisted angioplasty, covered stents, and subintimal angioplasty are being used to treat complex femoropopliteal disease (5–7). Regardless of these new and innovative techniques, subsequent intimal hyperplasia continues to plague long-term results. The battle against intimal hyperplasia must be won if endovascular therapies are to be effective against any form of femoropopliteal disease in the long term.
This battle is being waged on a variety of fronts. Better understanding of the molecular pathways and mediators that lead to intimal hyperplasia has led to the use of a variety of substances aimed at interrupting or inhibiting the process. Heparin, low-molecular-weight heparin, aspirin, corticoids, angiotensin-converting enzyme inhibitors, vascular endothelial growth factor, cyclosporin, and other agents have been investigated (8). To date, however, none of these agents has been used with marked success at the clinical level. Perhaps drugs that are aimed at one or two of the growth factors or pathways leave other growth factors or pathways unaffected.
Systemic therapies have not been successful. The procedure of afterloading gamma irradiation causes the local inhibition of intimal hyperplasia formation at the treated site. It is, perhaps, the most studied and clinically established procedure that is performed locally in the peripheral arterial system (1,9). Afterloading gamma irradiation is not, however, without drawbacks: It is cumbersome and currently requires large (8–9-F) delivery systems. Patients are often transported to a secondary location with the brachytherapy-centering catheter in position. Edge effects remain problematic. The study results of Krueger et al (1) demonstrate the unquestionable benefits of endovascular irradiation, but in their study, these benefits were clearly more substantial early after PTA and were reduced at 24-month follow-up (1). The hope is for a more durable effect.
Many other locally directed techniques to inhibit neointimal hyperplasia are being evaluated. These include the use of drug-coated stents, local antiproliferative drug (eg, heparin, sirolimus, and ethanol) delivery at angioplasty, sonotherapy, photodynamic angioplasty, and cryoplasty. Use of the new drug-eluting stents has been shown to be promising in the coronary circulation and was approved by the Food and Drug Administration in 2003 (sirolimus-coated coronary stents specifically). Drug-eluting stents are already in widespread use, superseding the use of coronary brachytherapy in many laboratories. These results have not yet been duplicated at the periphery in large series, however. Potential problems include their expense; the need for multiple stents; and the potential late-developing sequelae of edge effects, aneurysm formation, vessel ulceration, and thrombotic occlusions. Many other drug coatings are being investigated in the coronary system.
Results of the Sirolimus-Coated Cordis SMART Nitinol Self-Expanding Stent for the Treatment of Obstructing Superficial Femoral Artery Disease, or SIROCCO, trial were presented at the 2003 Transcatheter Cardiovascular Therapeutics Meeting (10). Sirolimus is a naturally occurring antibiotic that inhibits growth factor and cytokine-stimulated cell proliferation. Thirty-six patients from six European and Canadian centers were examined in this prospective randomized feasibility trial. The end point was the in-stent percentage of mean diameter stenosis within 6 months. The coated-stent arm demonstrated a greater in-stent mean diameter, with a 0% restenosis rate, as compared with the bare-stent arm, which had a 23.5% restenosis rate. Stress fractures within the stent struts occurred in several cases in the coated-stent arm. Although no adverse clinical events occurred, the possibility of such complications needs to be addressed.
Photodynamic therapy is targeted at the inflammatory component of intimal hyperplasia. A photosensitizing agent that is selectively taken up by the diseased atherosclerotic plaque is administered systemically. The agent is then locally activated during angioplasty with a specific wavelength of light that generates cytotoxic biologic oxygen radicals that produce irreversible tissue damage. This tissue damage retards intimal hyperplasia (11). Sonotherapy was being studied in the coronary circulation as part of the Euro-SPAH trial (12). The trial results confirmed the feasibility of the procedure.
Cryoplasty is a technique involving the use of cryotherapy to locally inhibit intimal hyperplasia. The cryoplasty system simultaneously dilates and cools the plaque and vessel wall by inflating the balloon with nitrous oxide instead of saline and contrast material (13). Cryotherapy induces an acute phase change that triggers apoptosis in the smooth muscle cells. The theoretically beneficial effects include more controlled plaque fracture, reduced vessel wall recoil, and decreased neointimal hyperplasia. The Food and Drug Administration approved the use of the cryoplasty method in September 2002.
Intimal hyperplasia is a natural response to endovascular injury, whether this injury is induced by PTA, stent implantation, atherectomy, or laser-assisted angioplasty. Preventing recurrent stenoses secondary to intimal hyperplasia and prolonging patency remain the elusive goals that will allow endovascular techniques to become the therapies of choice for treatment of all forms of femoropopliteal disease, from focal stenoses to long-segment occlusions. The chosen technique should be not only clinically effective but also cost effective. Local gamma irradiation is but one of many techniques and approaches that are being evaluated. The battle against neointimal hyperplasia wages on, and more work is needed before we can declare a victory.
FOOTNOTES
See also the article by Krueger et al in this issue.
REFERENCES
Related Article
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| RADIOLOGY | RADIOGRAPHICS | RSNA JOURNALS ONLINE |
