(Circulation. 1997;95:2244-2246.)
© 1997 American Heart Association, Inc.
Articles |
Identifying the Predictors of Restenosis
Do We Need New Glasses?
the Division of Cardiology, University of Southern California, Los Angeles.
Correspondence to David P. Faxon, MD, Professor of Medicine, Chief, Division of Cardiology, University of Southern California, School of Medicine, 1355 San Pablo St, Suite 117, Los Angeles, CA 90003. E-mail dfaxon{at}hsc.usc.edu
Key Words: Editorials • ultrasonics • restenosis
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Introduction |
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 Top Introduction References |
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The ability to predict restenosis after coronary interventional procedures has remained remarkably difficult. A number of clinical, procedural, and angiographic factors have been reported to be related to subsequent risk of restenosis.1 2 3 4 5 These include sex, prior history of restenosis, diabetes, hyperlipidemia, hypertension, unstable angina, vasospastic angina, renal disease, and smoking. Procedural factors include balloon-to-artery ratio, presence of significant residual gradient, significant residual stenosis, and the extent of dissection. In addition, angiographic factors such as the size of the reference vessel, severity of the stenosis, presence of calcium, eccentric lesions, saphenous vein graft location, ostial or proximal lesion location, and left anterior descending lesion location, as well as chronic total occlusion and long lesions, have all been associated with a higher rate of restenosis on follow-up. However, when evaluated in large studies in which multivariate analyses were performed and complete angiographic follow-up was available, the predictive power of these variables was remarkably poor.1 2 3 4 5 In one recent study,5 only 30% of restenosis could be predicted from clinical, procedural, and angiographic variables. Of all the factors that have been analyzed, the most potent appears to be a large postprocedural lumen diameter. The consistency of this finding, regardless of the device used, has led to the current widely embraced strategy of angioplasty, namely that "bigger is better."4 It has been the principal explanation for the improved long-term outcome seen with coronary stenting and directional atherectomy and is responsible for the improved outcomes of angioplasty.6 7
Nevertheless, further refinement in our ability to define those at risk for short-term and long-term complications would be of enormous value. Intravascular ultrasound (IVUS) would appear to offer significant advantages over angiographic evaluation.8 IVUS can more accurately define the lumen diameter than angioplasty. This is particularly true after interventional procedures in which focal dissection creates a hazy lumen due to contrast interdigitating around the dissection flaps. IVUS can more accurately define the absolute lumen diameter in this setting. In addition, ultrasound is a more sensitive method for determining the presence, location, and extent of coronary calcification, a factor that has also been related to the short-term outcome of angioplasty. As mentioned, IVUS can determine the presence and extent of coronary dissections or fracture after interventional procedures. Along with these attributes, it also can quantify total vessel area and the amount of atherosclerotic plaque as well as the type of plaque present, parameters not measurable by angiography. Because IVUS can measure the degree of vascular damage more accurately and estimate the amount of atherosclerosis present, it should prove to be highly effective in determining the risk of restenosis.
In the PICTURE study, reported by Peters et al in this issue of Circulation,9 the authors evaluated the ability of IVUS parameters to predict restenosis in 200 patients undergoing balloon angioplasty.9 Although the study found a strong relationship between the lumen area immediately after angioplasty and the minimal lumen diameter at follow-up, only a weak relationship was found between total vessel area, plaque area, and the percent of obstruction (plaque area/vessel area). Also, somewhat unexpectedly, plaque morphology and rupture or dissection after angioplasty did not relate to long-term risk of restenosis. There have been a number of conflicting reports concerning IVUS findings and the risk of restenosis. Jain et al10 and Tenaglia et al11 reported that dissections or fracture after interventional procedures was associated with a greater incidence of restenosis on follow-up. On the other hand, Honye et al12 reported that the absence of dissection was associated with a higher incidence of restenosis. These conflicting IVUS studies add to a number of conflicting angiographic studies. One of the earliest studies of angiographic prediction of restenosis reported a decreased incidence of restenosis in the presence of coronary dissection on angiography.13 However, a number of subsequent reports found no effect on long-term outcome.3 5 Given the greater accuracy of IVUS in determining the presence of postprocedural dissection, it seems reasonable to conclude that coronary dissection and plaque fracture are not major predictors of restenosis. Although this may appear to be contrary to the idea that the greater the degree of vascular damage, the greater the incidence of restenosis, coronary dissection may occur more often in lesions that are composed of inelastic components. Thus, it may be more a reflection of the underlying atheroma than of the degree of vascular damage. The lack of a strong relationship between plaque morphology and restenosis is also of some concern because it might be hypothesized that soft plaques composed of more active cellular elements would be more prone to the vascular injury of balloon angioplasty. However, the accuracy and specificity of IVUS determination of these plaque constituents are currently quite poor.
The lack of a strong relationship between plaque morphology and restenosis suggests that either new IVUS parameters need to be developed or that IVUS cannot "see" what the most important predictors of restenosis are. There is evidence to suggest that both of these limitations are likely. The prevailing theory of restenosis has been that the late loss in lumen diameter is due to lumen obstruction from intimal hyperplasia. More recently, a number of experimental and clinical studies have strongly suggested that the dominant pathophysiological process is geometric remodeling.14 15 16 17 18 Remodeling is a ubiquitous process that involves structural and geometric changes to the vessel wall. Pathological studies have clearly demonstrated that compensatory dilation of coronary and peripheral vessels occurs during the development of atherosclerosis.19 Not until 40% of the vessel area is occupied by plaque does the lumen begin to narrow. Thus, during the early development of atherosclerosis, compensatory enlargement of the vessel preserves lumen area. Other IVUS studies have demonstrated that atherosclerotic remodeling can occur not only as a failure of compensatory dilation but from vessel constriction as well. Therefore, vascular remodeling is a bidirectional process.
The importance of vascular remodeling in restenosis has been demonstrated by a number of experimental and clinical IVUS studies.14 15 16 The most compelling clinical data demonstrate that 60% to 80% of the late lumen loss is due to vessel constriction rather than to an increase in plaque volume.17 18 A recent longitudinal study18 demonstrated that vessel enlargement occurs early and that vessel constriction is a late phenomenon.
The biological factors responsible for remodeling are poorly defined. Whereas intimal thickening is largely due to an increase in smooth muscle cell migration, proliferation, and matrix production, the occurrence of remodeling during the late phases of wound healing suggests that other processes may be more important. It is well known that matrix components undergo considerable metabolism during the late healing phases. The factors that influence matrix production and degradation are only now being carefully studied. Some of the factors that appear to be important include the degree of inflammatory response and oxidant stress. Although smooth muscle cell proliferation and matrix production are closely related, it is likely that different stimuli are important for each of these separate smooth muscle cell functions. Experimental studies have also suggested that adventitial changes may be important in remodeling.20 Thus, the factors that are responsible for intimal hyperplasia may not be the same factors that are responsible for geometric remodeling. Accordingly, IVUS parameters that relate to intimal hyperplasia are not likely to be the same parameters that relate to subsequent favorable remodeling.
A number of studies do suggest that vessel size, plaque burden, and percent obstruction relate to late loss.10 21 22 These factors may also be important in remodeling. Other studies suggest that the type of remodeling present before angioplasty (dilation or constriction) influences short-term and long-term outcomes. In a preliminary report by Kimura et al,18 the change in external elastic lamina over a 6-month period (remodeling) correlated not only with the final late loss but also with short-term gain. In addition, plaque burden may contribute to remodeling not only because of a larger plaque mass predisposed to more damage in the process of balloon angioplasty but also because of its impact on remodeling. Because of geometric considerations, a small change in total vessel area creates an enormously large change in vessel lumen in the presence of a large amount of plaque burden. Experimental studies have shown that a change in vessel area of 10% can cause as much as a 100% change in lumen area.16
Another problem with measuring these parameters is a matter of definition. Geometric remodeling has been variously defined. Most commonly, it is defined as the change in total vessel area over time. It has also been defined as the ratio of the dilated-segment total vessel area to the adjacent reference-segment total vessel area. However, just as in measuring the percent of stenosis, the reference vessel areas may also remodel. Thus, a similar directional change in the reference- and dilated-segment total vessel areas might result in no apparent change in remodeling, when in fact a true change in vessel size has actually occurred. Consistency in definition is needed to assist in determining which IVUS parameters are most likely to predict remodeling and therefore restenosis.
IVUS also has a number of limitations. It is recognized that at present it defines plaque characteristics (eg, calcium, eccentricity, soft versus hard) only crudely. It is likely that when a more complete definition of plaque constituents can be obtained by IVUS, better prediction of response to injury can occur. Highly cellular plaques have been shown experimentally to respond to vascular injury in a different manner than more fibrotic, lipid-laden plaques. In addition, IVUS poorly identifies thrombus. Angioscopic studies have suggested that thrombus is an important predictor of late outcome.23 In support of this, therapy with the potent platelet glycoprotein IIb/IIIa receptor antagonist 7E3 (ReoPro) in both the EPIC and EPILOG trials showed a reduced incidence of clinical restenosis.24
Other unseen factors may also be important in predicting restenosis. Oxidant stress has been shown experimentally to relate to restenosis. The recent report of the MVP study25 suggests that antioxidant therapy with probucol was highly effective in the prevention of restenosis. IVUS is not capable of identifying these factors, and other means, such as serum markers, may prove to be more useful.
The prediction of restenosis remains an elusive goal. Despite remarkable advances in IVUS technology, we seem no closer to being able to predict those patients at high risk for developing restenosis. Because restenosis is a complex biological process, structural features of the vessel wall may not be the most important factors to examine. Although thus far we have failed to see the factors responsible for restenosis, we haven't stopped looking, nor should we. As we gain understanding of the pathophysiology of restenosis and develop improved imaging methods combined with estimation of thrombotic, inflammatory, or other biological predictors, we will be able to more accurately define the risk of restenosis.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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17.
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