| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Editorial |
1 From the Department of Radiology, Duke University Medical Center, Box 3808, Rm 1502, Erwin Rd, Durham, NC 27710. Received June 21, 2002; accepted June 24. Address correspondence to the author (e-mail: smith146@mc.duke.edu).
Index terms: Arteries, femoral, 928.1286 • Arteries, transluminal angioplasty, 548.1286, 928.1286 • Editorial
The 59-year-old vice president–elect of the United States awoke on the morning of November 22, 2000, with chest discomfort. By that evening, a stent had been placed in a large diagonal branch of his left coronary artery (1). The vice president was forced to return to the hospital on March 5, 2001, because of recurrent chest pains. Findings at cardiac catheterization demonstrated restenosis of the coronary artery stent placed less than 4 months earlier.
This scenario is well known to most physicians in the United States. Sadly, for those of us who deal with percutaneous revascularization, restenosis is not at all surprising, even in someone who is obviously receiving the best possible medical care. Despite the best technical and medical therapy, restenosis occurs in approximately 30% of patients who undergo coronary angioplasty with stent placement (2). In the peripheral circulation, this percentage is lower in some areas, such as the iliac and renal arteries, but it is worse in cases of femoropopliteal angioplasty, where even conventional stent placement offers little assistance in long-term patency.
Traditional angioplasty, regardless of the vascular bed, presents two main temporally related patency concerns: abrupt closure and delayed restenosis. A great deal of advancement has been achieved in dealing with abrupt closure. Restenosis, however, remains the curse of the interventionalist. Interestingly, prevention of restenosis has for the most part depended on the same two treatments that are used for abrupt vessel closure: stent placement and postprocedural treatment with antithrombotic and antiplatelet agents. With stent placement, one eliminates the problems of elastic recoil and provides a more uniform surface area for normal healing to occur.
Efforts to decrease platelet adhesion to the angioplasty surface serve not only to decrease abrupt closure but also to increase long-term patency. Rates of restenosis correlate with anatomic factors following treatment, including residual stenosis, irregularity of the lumen surface (particularly, presence of a dissection), and relative rates of blood flow, including quality and quantity of outflow. Unfortunately, all of these predictors can only be assessed following treatment, and they have a relatively low predictive value for restenosis. However, what would the effect be if one could have an accurate prospective predictor of restenosis, or more precisely, a reliable prospective predictor of the long-term success of angioplasty?
In this issue of Radiology, Schillinger and colleagues (3) discuss the association of blood serum inflammatory markers with restenosis of femoropopliteal arteries after angioplasty. Their study is predicated on the concept that vessel response to percutaneous transluminal angioplasty is an inflammatory process. Although serum markers exist in the presence of many inflammatory processes, the three most commonly studied serum markers relative to atherosclerosis and its response to treatment are C-reactive protein, serum amyloid A, and fibrinogen. These three markers are easily measured and were the ones evaluated in the study of Schillinger et al (3).
Over the past few years, it has become evident that atherosclerosis itself represents a form of chronic inflammation (4). The best evidence for this probably lies in the aforementioned inflammatory markers. It has been known for some time that elevations of serum C-reactive protein and serum amyloid A protein at the time of hospital admission are predictors of poor outcomes in patients with unstable angina (5). However, do these inflammatory markers correlate with angioplasty of atherosclerotic plaque, and do these markers have any relevance to outcomes—particularly, the chance of restenosis?
Pathologically, restenosis has a different appearance than atherosclerosis (6) and has always been considered a developmentally different process altogether. A complex process of lipid accumulation forms atherosclerotic plaque, whereas restenosis consists of an equally complex fibroproliferative process that results in an exuberant neointima consisting mostly of smooth-muscle cells. Throughout my training, I have been taught to diagnose one disease in a patient and try to make the pieces of the puzzle fit, rather than to assign a different cause to each of a patient’s problems. The same concept should apply here—maybe the missing piece of the puzzle is inflammation. If atherosclerosis has an inflammatory process at its core, then is it not logical that restenosis is also an inflammatory process?
It is obvious that angioplasty is a form of trauma—hopefully controlled and well executed, but trauma nonetheless. More recent theories now hold that the triggering process for the formation of atherosclerosis may in fact be "trauma" to the endothelium and that atherosclerosis itself may in fact be a "response to injury" (4). The trauma, however, is more likely to be endothelial dysfunction rather than denudation. Some of the probable causes of endothelial dysfunction are most certainly related to the known risk factors for atherosclerosis, including elevated low-density lipoprotein levels and free radicals induced by cigarette smoking, hypertension, and diabetes, among other causes, including of course many that are yet to be discovered.
Although atherosclerosis and restenosis share an inflammatory cause in response to trauma, endothelial dysfunction versus mechanical dilation appears to result in a different pathologic response, probably based on the response of a normal artery versus a diseased one. After angioplasty, monocytes and macrophages appear within the atheromatous plaque along with circulating leukocytes and platelets, which adhere to the angioplasty site and produce cytokines (particularly interleukin-1 and -6), which in turn trigger the liver to produce inflammatory proteins. However, pure mechanical trauma from the angioplasty balloon that results in plaque rupture may not necessarily be the culprit for the enhanced inflammatory response but rather may be related to the existing degree of inflammation.
Clearly, the response is greater in hypersensitive individuals, as evidenced by already increased baseline levels of circulating inflammatory markers (7). The increase in inflammatory markers following angioplasty may therefore result from the traumatic triggering of an already ongoing atherosclerotic inflammatory response, coupled with the exposure of preexisting plaque inflammation to circulating triggering factors, probably in the form of cytokines (8). This response varies among patients, however, but appears to be based mostly on baseline serum levels of the inflammatory markers, as evidenced by observations of C-reactive protein levels in the study of Schillinger et al (3).
Each of the three serum proteins studied by Schillinger et al (3) have been evaluated in the coronary system and have predictive values for restenosis. As noted above, C-reactive protein appears to have the strongest correlation with atherosclerosis and restenosis, as was shown in their study. In the coronary circulation, serum amyloid A and fibrinogen have shown some predictive value, but the correlation does not appear to be as strong (5,9,10). This is borne out in the study of Schillinger et al (3), and the reasons are unclear. It may be that the response as indicated by the markers is different for the femoropopliteal versus coronary arterial systems.
Still, as an interventional radiologist, I believe that fibrinogen is the most interesting of the serum proteins measured, as it presents a possible marker for both inflammation and thrombosis and may hint at a link between the two. Clearly, platelet adhesion to the angioplasty site is intimately involved with long-term patency. It has been shown that activation of inflammatory cells and cytokines can aggravate local thrombotic complications by increasing procoagulant or platelet activity or by promoting thrombin generation (9).
Furthermore, there appears to be a correlation between the more popular antiplatelet agents and the ability to control inflammation, as evidenced by the effects of these agents on inflammatory markers. Interestingly, it appears that aspirin has a greater protective effect in those patients with elevated inflammatory markers (11). It is likely that the positive effects of aspirin in preventing restenosis are a combination of anti-inflammatory and antithrombotic properties. Abciximab blocks platelet glycoprotein IIb/IIIa receptors and is often used as a potent antiplatelet agent following angioplasty. Interestingly, abciximab also decreases inflammatory markers, including C-reactive protein at 24–48 hours and at 4 weeks following coronary revascularization (12). The mechanism is unknown, but it may be a decrease in the platelet-leukocyte interaction.
Schillinger et al (3) and a number of others (13–15) have attempted to correlate restenosis with inflammatory markers in the femoropopliteal systems. Arteries of the lower limb present different problems than do those of the coronary arterial system, on which most data have been published. Stent placement is routine in coronary arteries but is generally regarded as a poor long-term treatment for arteries below the inguinal ligament. Lower-limb arterial disease often occurs with tissue loss, which has an inflammatory component itself. Schillinger et al (3) therefore had to eliminate from their study population any patients who required stent placement and those with chronic limb ischemia and ischemic ulceration.
The potential uses for inflammatory markers fall into three categories: prevention techniques, new types of treatment, and response to conventional therapies. Certainly, if atherosclerosis is in some way an inflammatory process, then determination of who is at high risk and development of altered approaches to prevention are the best overall forms of therapy. The current approach of making lifestyle adjustments aimed at reducing risk factors will probably always be central to the issue. Newer therapies aimed at the inflammatory process or at triggers for this process on the basis of a patient’s baseline markers may have a bright future but may unmistakably require a more thorough understanding. For now, surgery or transluminal balloon angioplasty and stent placement are the conventional and accepted therapies and are undoubtedly only as good as the rate of restenosis.
Attempts to control restenosis following transluminal balloon angioplasty have been focused on a number of areas, including systemic therapy, temperature alterations (either cooling or heating), and local irradiation. Systemic therapy aimed at decreasing the inflammatory measures following angioplasty have not been successful thus far. The greatest attention is currently being focused on drug-eluting stents. Early data regarding anti-inflammatory drug-eluting stents are available. Results in the coronary circulation from the Study of Antirestenosis with Biodivysio Dexamethasone Eluting Stent (STRIDE registry) (16) have recently been published in abstract form. Restenosis occurred in 13% of patients, although there was less late lumen loss in patients with unstable versus stable angina, suggesting, as the markers have predicted, that inflammation may be a greater component of acute coronary syndromes when compared with stable atherosclerotic plaque.
Although these results suggest a substantial improvement over conventional stents, they pale in comparison to early data from drug-eluting stents aimed at preventing the replication of smooth-muscle cells (17). These drug-eluting stents are not as theoretically attractive because they contain chemotherapeutic agents aimed at controlling the mitotic response of smooth-muscle cells rather than the triggering events for restenosis or even atherosclerosis. However, they mark an exciting step forward. Where these new stents will fit in peripheral vascular intervention is unknown. Drug-eluting stent placement may become a viable option for lesions in areas where conventional stent placement has thus far been futile because of rapid and severe restenosis. Prime among these locations is the lower limb.
Atherosclerosis and problems with its therapy, including restenosis, are baffling and complex processes that remain largely enigmatic. Fortunately, this subject continues to be one of the most frequently studied, and new theories and possible treatments are surfacing at a rapid rate. Clearly, inflammation plays a role, but further research must be supported at all levels. We should applaud and encourage the work of Schillinger, his co-authors, and others who are attempting to pick apart the disease process or processes we call atherosclerosis and the nemesis of its percutaneous treatment: restenosis.
FOOTNOTES
See also the article by Schillinger et al in this issue.
REFERENCES
Related Article
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| RADIOLOGY | RADIOGRAPHICS | RSNA JOURNALS ONLINE |
