Patterns and Mechanisms of In-Stent Restenosis
A Serial Intravascular Ultrasound Study
Background Studies have suggested that restenosis within Palmaz-Schatz stents results from neointimal hyperplasia or chronic stent recoil and occurs more frequently at the articulation.
Methods and Results Serial intravascular ultrasound (IVUS) was performed after intervention and at follow-up in 142 stents in 115 lesions. IVUS measurements (external elastic membrane [EEM], stent, and lumen cross-sectional areas [CSAs] and diameters) were performed, and plaque CSA (EEM lumen in reference segments and stent lumen in stented segments), late lumen loss (Δlumen), remodeling (ΔEEM in reference segments and Δstent in stented segments), and tissue growth (Δplaque) were calculated. After intervention, the lumen tended to be smallest at the articulation because of tissue prolapse. At follow-up, tissue growth was uniformly distributed throughout the stent; the tendency for greater neointimal tissue accumulation at the central articulation reached statistical significance only when normalized for the smaller postintervention lumen CSA. In stented segments, late lumen area loss correlated strongly with tissue growth but only weakly with remodeling. Stents affected adjacent vessel segments; remodeling progressively increased and tissue growth progressively decreased at distances from the edge of the stent. These findings were similar in native arteries and saphenous vein grafts and in lesions treated with one or two stents. There was no difference in the postintervention or follow-up lumen (at the junction of the two stents) when overlapped were compared with nonoverlapped stents.
Conclusions Late lumen loss and in-stent restenosis were the result of neointimal tissue proliferation, which tended to be uniformly distributed over the length of the stent.
Although Palmaz-Schatz stent placement has been shown to reduce the rate of restenosis compared with balloon angioplasty,1 2 in-stent restenosis is a significant and (with increased stent implantation in intervention cardiology) a growing clinical problem. Recent histological and angiographic studies have suggested that stents trigger the development of neointimal hyperplasia, whereas other studies have indicated that inadequate stent expansion and chronic stent recoil may also contribute to restenosis.3 4 5 6 7 Angiographic studies have indicated that in-stent restenosis occurs more frequently at the central articulation; however, the reason for this is unclear.5 8 A reduction in the rate of in-stent restenosis will require a greater understanding of the pathogenesis of this problem.
IVUS permits detailed, high-quality, cross-sectional imaging of the coronary arteries in vivo. The normal coronary artery architecture, the major components of the atherosclerotic plaque, and the changes that occur in coronary arterial dimensions and anatomy with the atherosclerotic disease process, during transcatheter therapy, and on follow-up can be studied in vivo in a manner otherwise not possible. This includes the direct visualization of intensely echoreflective (but radiolucent) stainless steel stent struts.5 6 7 9 10
The purpose of the present study was to use serial IVUS (after stent implantation and at follow-up) to study the in-stent restenosis process to determine (1) the relative contribution of chronic stent recoil and neointimal hyperplasia to late lumen loss, (2) the relative distribution of neointimal hyperplasia over the axial length of the Palmaz-Schatz stent, and (3) the mechanism of exaggerated restenosis at the central articulation.
Patient and Lesion Population
With serial IVUS, 115 lesions in 103 patients were studied after implantation of Palmaz-Schatz stents and at follow-up after a mean interval of 5.4±3.8 months. Reasons for study exclusion were implantation of more than two stents per lesion and excision of the central articulation with overlap of the distal and proximal halves.
There were 82 men and 21 women in the study (mean age, 63±10 years). This represented an inclusive series of lesions treated with one or two Palmaz-Schatz stents and imaged both after intervention and at the time of follow-up angiography for recurrent symptoms or as part of clinical protocols. At the time of stent implantation, 15 patients presented with unstable angina and 7 with postinfarction angina. At the time of follow-up, 4 patients had experienced a myocardial infarction, and 12 presented with unstable angina.
Eighty-eight lesions were treated with placement of a single Palmaz-Schatz stent, and 27 lesions were treated with placement of two stents. Lesion location was saphenous vein graft in 53, left anterior descending in 21, left circumflex in 11, and right coronary artery in 30. Thirty-eight lesions (33%) were ostial in location, and 42 (37%) were restenotic. Forty-nine stents were articulated “biliary” stents (PS204), and 93 were “coronary” stents. Of the coronary stents, 39 were 3.0-mm, 35 were 3.5-mm, and 19 were 4.0-mm stents.
Stent Implantation Protocol
Palmaz-Schatz stents were implanted according to standard protocols. Operators were not blinded to the IVUS findings during stent implantation. Before October 1993, stents were implanted according to conventional techniques. In the last 95 lesions (83%), IVUS was used to guide routine high-pressure adjunct balloon inflations.11 12 The targeted stent expansion was a minimum CSA of ≥80% of the average of the proximal and distal reference lumen CSAs as well as complete stent/vessel wall apposition. When these criteria were met (in 88 of 95 lesions), patients were treated with aspirin (325 mg/d) and ticlopidine (250 mg BID). If not so treated, patients were systemically anticoagulated.
IVUS Imaging Protocol
IVUS imaging was performed after the administration of 0.2 mg intracoronary nitroglycerin. After intervention and at follow-up, the ultrasound catheter was advanced ≈10 mm beyond the target lesion, and a slow retrograde imaging run was performed from beyond the target lesion to the aorto-ostial junction.
Studies were performed with one of three commercially available systems. The first (CVIS/InterTherapy Inc) incorporated a 25-MHz transducer and angled mirror mounted on the tip of a flexible shaft that was rotated at 1800 rpm within a 3.9F short monorail imaging sheath and withdrawn automatically at 0.5 mm/s to perform the imaging sequence. The second (Hewlett Packard and Boston Scientific Corporation) incorporated a 30-MHz beveled transducer rotated at 1800 rpm within a 3.5F short monorail imaging catheter; with this system, the catheter was withdrawn manually under fluoroscopic guidance. The third (Cardiovascular Imaging Systems, Inc) involved a 30-MHz transducer mounted on the end of a flexible shaft that was rotated at 1800 rpm (within either a 2.9F long monorail/common distal lumen imaging sheath or within a 3.2F short monorail imaging sheath) and withdrawn automatically at 0.5 mm/s. Motorized transducer pullback through a stationary imaging sheath permitted the transducer to move at the same speed as the proximal end of the catheter. Ultrasound studies were recorded on 1/2-in high-resolution s-VHS tape for off-line analysis.
Patients were studied after giving written, informed consent as part of ongoing protocols approved by the Institutional Review Board of the Washington Hospital Center.
Quantitative Angiographic Analysis
All treatment and follow-up cineangiograms were analyzed by an independent core angiographic laboratory with a quantitative coronary angiographic automated edge-detection algorithm (ARTREK, Quantitative Cardiac Systems). The outer diameter of the contrast-filled catheter was used for calibration. Minimum lumen diameter, reference diameter, and percent diameter stenosis before and after intervention and at follow-up were measured from multiple projections, and the results from the “worst” view were recorded. Angiographic restenosis was defined as a diameter stenosis of ≥50%.
Quantitative IVUS Measurements
For lesions treated with a single stent, nine segments were identified and analyzed; five were within the stent, and four (two proximal and two distal) were in the reference segments proximal and distal to the stent (Fig 1⇓). The segments were as follows: (1) the most normal-looking cross section within a 10-mm segment proximal to the stent but distal to any major side branches, (2) a cross section midway between image slice 1 and the proximal edge of the stent, (3) the proximal edge of the stent, (4) the proximal body of the stent, (5) the central articulation, (6) the distal body of the stent, (7) the distal edge of the stent, (8) a segment midway between image slice 9 and the distal edge of the stent, and (9) the most normal-looking cross section within a 10-mm segment distal to the stent but proximal to any major side branches. If a stent was placed in an ostial location, proximal reference segments 8 and 9 were not analyzed.
In stented segments, the stent and lumen CSAs and maximum and minimum diameters were measured. In nonstented segments, EEM and lumen CSA and diameters were measured. Validation of measurements of EEM, lumen, P+M, and stent CSA by IVUS have been reported previously.12 13 14 15 16 17 Each border was routinely traced two to four times, and the results were averaged. The EEM (ie, the media/adventitia border) has been shown to be a reproducible measure of total arterial CSA. When the atherosclerotic plaque encompassed the catheter, the lumen was assumed to be the size of the imaging catheter. Because media thickness could not be measured accurately, P+M CSA was used as a measure of the atherosclerotic plaque.18 At the central articulation of the stent, the stent CSA was assumed to be the average of the edges of the stent on either side of the central articulation.
For lesions treated with two stents, similar measurements were made, except 15 segments were analyzed. In 14 of 27 lesions treated with two stents, there was overlap of the two stents. Minimum stent and lumen CSAs were measured within the segment of stent overlap. In 13 of 27 lesions treated with two stents, the stents were not overlapped. The gap between the nonoverlapped stents was analyzed in a manner similar to the analysis of the central articulation.
In lesions studied with the use of motorized transducer pullback, the length of the gap between nonoverlapped stents was measured on the basis of the number of seconds of videotape in which the gap appeared. At a pullback speed of 0.5 mm/s, 2 seconds of videotape equal 1 mm of axial length.
The following calculations were then made for all segments in all lesions: (1) stent symmetry index=(minimum stent diameter/maximum stent diameter), (2) late lumen loss=(postintervention lumen CSA−follow-up lumen CSA), (3) plaque area (in nonstented segments)=(EEM CSA−lumen CSA), (4) plaque prolapse (in stented segments)=(stent CSA−lumen CSA), (5) remodeling (in nonstented segments)=(postintervention EEM CSA−follow-up EEM CSA), (6) remodeling (in stented segments)=(postintervention stent CSA−follow-up stent CSA), and (7) tissue growth=(follow-up plaque CSA−postintervention plaque CSA). A stent symmetry index of 1.0 would indicate a perfectly circular stent. In stented segments, remodeling was equivalent to chronic stent recoil, and tissue growth was equivalent to in-stent neointimal hyperplasia. Tissue growth was also normalized for the postintervention lumen CSA.
The impact of stent symmetry was assessed by comparing the symmetry of each stent segment with (1) the subsequent amount of neointimal tissue accumulation within that stent segment (eg, effect of proximal stent body symmetry on proximal stent body neointimal tissue accumulation) and (2) the subsequent amount of downstream neointimal tissue accumulation (eg, effect of proximal stent body symmetry on central articulation neointimal tissue accumulation).
Volumetric IVUS Analysis
Serial (after intervention and follow-up) volumetric IVUS analysis was performed on a subset of 52 stents in 41 lesions (32 native coronary and 9 saphenous vein grafts). Volumetric analysis was performed by an observer blinded to the planar IVUS results. Motorized transducer pullback through a stationary imaging sheath (as was incorporated into two of the IVUS systems used in this study) permitted measurements of stent, lumen, and plaque CSA at 2-mm axial increments throughout the length of each lesion. Postintervention and follow-up stent, lumen, and plaque volumes were calculated using Simpson's rule; these methods have been reported previously.5 Late lumen volume loss was calculated as postintervention lumen volume minus follow-up lumen volume. Stent volume remodeling was calculated as postintervention stent volume minus follow-up stent volume. Intimal hyperplasia (tissue growth) volume was calculated as follow-up plaque volume minus postintervention plaque volume.
Reproducibility of IVUS Measurements
When the same lesions were studied at least 3 months apart, the intraclass correlation coefficient for each of these cross-sectional measurements was >.90. The intraclass correlation coefficient considered both between-lesion variability and within-lesion variability and has been widely used as a measure of interrater variability. Specifically, in nonstented segments, the intraclass correlation coefficient for repeated measurement of the EEM CSA was .99, of the lumen CSA was .98, and of the P+M CSA was .99; in stented segments, the intraclass correlation coefficient of the minimum stent CSA was .98. This indicated almost perfect agreement. These results have been reported previously.19 20
Statistical analysis was performed with StatView 4.02. Quantitative data were presented as mean±1 SD. Qualitative data were presented as frequencies. Comparisons between groups were performed using the χ2 statistic and Fisher's exact test for categorical variables, paired and unpaired t tests for continuous variables or factorial ANOVA with post hoc analysis using Fisher's protected least significant difference, and Pearson's correlation coefficient as appropriate. Significance was a value of P≤.05.
Quantitative Angiographic Results
The minimum lumen diameter increased from 1.13±0.65 mm before intervention to 3.19±0.51 mm after intervention. At follow-up, the minimum lumen diameter decreased to 2.13±0.82 mm.
Serial IVUS Results in Lesions Treated With One Stent
Twenty-three lesions were restenotic at follow-up (Fig 2⇓). After stent implantation, IVUS imaging showed that the smallest lumen CSA tended to be located at the central articulation (Table 1⇓ and Fig 3⇓). (After intervention, the location of the minimum lumen CSA was at the central articulation in 41% of stents, P<.0001.) This was the result of tissue prolapsing through the stent (which averaged 0.7±1.1 mm2) and not the result of a smaller stent CSA (Table 1⇓).
At follow-up, lumen (but not stent) dimensions also tended to be smallest at the central articulation (Table 2⇓ and Fig 3⇑). (At follow-up, the location of the minimum lumen CSA was at the central articulation in 39% of stents, P<.0001.) This was because of a greater plaque mass at the central articulation, resulting in a smaller minimum lumen diameter (P=.0034) and in a trend toward a statistically smaller lumen CSA (P=.0660). Although there appeared to be a tendency for greater neointimal tissue accumulation at the central articulation, this reached statistical significance only when normalized for the smaller postintervention lumen CSA at the central articulation (Table 1⇑). Thus, the smaller lumen within the central articulation at follow-up was the result of the greater tissue mass within the central articulation at follow-up; this, in turn, was the result of a combination of initial tissue prolapse and superimposed neointimal tissue accumulation.
After implantation, the stent symmetry index was 0.85±0.06; only eight stent segments (2%) had a symmetry index of <0.7, and stent symmetry did not vary among stent segments. Symmetrically expanded stents tended to be larger than less symmetrically expanded stents (Table 2⇑). However, even when neointimal tissue accumulation was normalized for the postintervention lumen CSA, stent symmetry did not correlate with follow-up neointimal tissue accumulation either within or downstream from any individual stent segment (Table 2⇑). In addition, the worst asymmetry index within an individual stent did not correlate with overall neointimal tissue accumulation.
Results in Native Coronary Arteries Versus Saphenous Vein Grafts
These findings held true when native vessel and saphenous vein graft lesions were analyzed separately, although postintervention and follow-up stent and lumen dimensions were larger in saphenous vein graft lesions. When normalized for postintervention stent CSA, mean neointimal tissue accumulation was similar in native coronary arteries and in saphenous vein grafts (Table 3⇓). In addition, (1) lumen CSA tended to be smallest at the central articulation both after intervention and at follow-up, (2) when normalized for the final lumen dimensions, neointimal tissue accumulation was greatest at the central articulation, and (3) neointimal tissue accumulation was not influenced by stent symmetry.
Results in Coronary Versus Biliary Stents
When coronary stents were compared with biliary stents, mean stent recoil (Δstent CSA) was similar (0.1±0.3 versus 0.2±0.5 mm2, respectively; P=.1045). Mean late lumen area loss (2.8±1.7 versus 3.2±1.8 mm2, P=.3603) and mean neointimal tissue accumulation (2.7±1.7 versus 2.9±1.7 mm2, P=.6062) were also similar.
Impact of Stents on Adjacent Reference Segments
Serial IVUS analysis showed the impact of single Palmaz-Schatz stents on adjacent arterial segments (Fig 4⇓). The more distal reference segment showed a greater degree of remodeling (decrease in EEM CSA from 18.2±7.2 to 17.0±6.8 mm2) than of tissue growth (7.1±3.6 to 7.5±3.6 mm2); however, this segment was still within 5 to 10 mm of the edge of the stent. Late lumen loss correlated more with remodeling (r=.809, P<.0001) than with tissue growth (r=.283, P=.0014). Anatomic sections sampled at a point closer to the edge of the stent showed a similar amount of remodeling (decrease in EEM CSA from 18.5±6.8 to 17.3±6.4 mm2, P=NS versus more distant reference segments) and a greater degree of cellular proliferation (increase in P+M CSA from 7.8±3.7 to 9.1±4.1 mm2, P=.02 versus more distant reference segments). Within this intermediate segment, late lumen loss correlated less with remodeling (r=.283, P=.0014) than with tissue growth (r=.636, P<.0001).
Serial IVUS Results in Lesions Treated With Two Stents
Thirteen lesions were restenotic at follow-up. Overall, lesions treated with two stents showed the same patterns of final and follow-up lumen dimensions (Fig 5⇓), late lumen loss, remodeling, and tissue proliferation as did lesions treated with one stent. In the lesions treated with nonoverlapping Palmaz-Schatz stents, the gap was 2.4±1.6 mm (range, 0.5 to 5 mm). When this gap was compared with the region of overlap (in lesions treated with two overlapping stents), there was no significant difference in final or follow-up lumen dimensions, late lumen loss, remodeling, or tissue proliferation (Table 4⇓).
Determinants of Late Lumen Loss
When all of the individual stent segments were considered together (5 per single stent and 11 per double stent, for a total of 715 stent segments analyzed), late lumen loss within stents correlated strongly with tissue growth (neointimal tissue accumulation, r=.975, P<.0001; Fig 6A⇓) and only weakly with stent recoil (r=.200, P<.0001; Fig 6B⇓). This was also true when the individual stent segments (Table 5⇓), native coronary and vein graft lesions, and coronary and biliary stents were analyzed separately.
Independent volumetric analysis showed no chronic change in stent volume (164±104 to 164±104 mm3). The decrease in lumen volume (from 161±102 to 110±87 mm3, P<.0001) was equaled by the growth in neointimal tissue volume (54±38 mm3). Late lumen volume loss correlated with the growth in neointimal tissue volume (r=.990, P<.0001).
Comparison of Quantitative Angiography and IVUS
IVUS late lumen diameter loss (0.85±0.51 mm) correlated with but was consistently smaller than the angiographic late lumen loss (1.04±0.78 mm, r=.81, P<.0001). The regression line was IVUS=0.55*angiography+0.18.
With the use of serial IVUS analysis (poststent implantation and at follow-up), in the present study we demonstrated that (1) chronic stent recoil was minimal, (2) late lumen loss and in-stent restenosis were the result of neointimal tissue proliferation, (3) late lumen diameter loss by IVUS was less than late lumen diameter loss by quantitative angiography, (4) neointimal tissue accumulation was uniformly distributed over the length of the stent except for a tendency for exaggerated neointimal tissue accumulation at the central articulation, (5) there was a similar pattern of in-stent restenosis in native coronary arteries compared with saphenous vein grafts and in coronary compared with biliary stents, and (6) stents appeared to affect the adjacent vessel segments, causing a combination of arterial remodeling and tissue proliferation.
Impact of Stents on Restenosis
The beneficial effects of stent implantation on restenosis have been attributed to the larger acute lumen dimensions achieved compared with other interventions as well as to the elimination of acute recoil after intervention.21 22 Recent studies of restenosis after balloon angioplasty and other nonstent interventional procedures have begun to focus on pathological arterial remodeling (the late decrease in arterial CSA) as an important mechanism of restenosis.20 23 24 25 The results of the present study demonstrated that stents were able to withstand the remodeling forces that otherwise may have contributed to restenosis. There was no late decrease in focal stent CSA or overall stent volume. This was true for lesions treated with single or double stents, for native artery lesions and saphenous vein grafts, and for both coronary and biliary Palmaz-Schatz stents. Thus, in addition to achieving larger postprocedural lumen dimensions and withstanding acute recoil, stents appear to reduce restenosis by resisting arterial remodeling.26
Mechanism of In-Stent Restenosis
This study also confirmed previous observations that intimal hyperplasia is the major mechanism of late lumen loss after stent implantation.3 4 5 8 Late lumen loss correlated with neointimal tissue proliferation both overall (through the use of volumetric analysis) and at individual stent segments. Furthermore, because stents have been shown to achieve larger acute lumen dimensions compared with other devices, stents appear to withstand arterial remodeling (the dominant mechanism of late lumen loss in nonstented lesions), and late lumen loss is proportionate to acute lumen gain, there must have been a stent-related exaggeration in neointimal tissue proliferation. Thus, the major limitation to stent implantation is the initiation of neointimal tissue proliferation within and adjacent to the stent.
There is a potential downside to stent-related inhibition of arterial remodeling. In nonstented lesions, arterial remodeling has been shown to be bidirectional. In some nonstented lesions, a chronic increase in EEM CSA will accommodate cellular proliferation to limit late lumen loss and restenosis and even occasionally result in late lumen gain.20 23 24 The present study shows that rigid, slotted-tubular stents neither recoil nor expand over time; thus, lesions treated with Palmaz-Schatz stents are unable to adapt to in-stent tissue proliferation.
Using angiography, both Penn et al8 and Ikari et al27 found that 75% to 90% of restenoses involved the central articulation; at follow-up, there was a smaller luminal diameter at the articulation than at the edges and bodies of the stent. This was confirmed by Dussaillant et al5 through the use of IVUS. These three studies suggested an increased proliferative response at the central articulation. However, these studies used only serial angiography or follow-up ultrasound. An important report by Nakamura et al6 showed that angiography overestimated the adequacy of acute stent expansion and the size of poststent implantation lumen dimensions. The present study supports these findings. Postintervention minimum lumen diameter by IVUS was consistently smaller than that by quantitative angiography; as a result, late lumen diameter loss by IVUS was also consistently smaller than by quantitative angiography. These findings were explained, in part, by the radiolucency and porosity of the tubular-slotted stainless-steel Palmaz-Schatz stents that allow contrast to flow outside of the stent. (However, IVUS could not be used to measure lumen dimensions smaller than the imaging catheter, which minimized late lumen loss in severely restenotic lesions.)
Using serial IVUS analysis, we found that lumen dimensions were significantly smaller at the central articulation both acutely and at follow-up. Several factors contributed to this finding. First, there was a small but statistically significant amount of acute tissue prolapse through the central articulation that caused the smaller lumen dimensions after intervention. Second, when superimposed on the acute tissue prolapse through the central articulation, chronic neointimal tissue accumulation (which also tended to be greater at the central articulation) resulted in the increased tissue mass at follow-up. However, the acute tissue prolapse (0.7 mm2) and the tendency for increased neointimal tissue accumulation at the central articulation (0.5 mm2) were modest in comparison to the otherwise uniform neointimal tissue accumulation over the length of the stent (2.5 mm2).
Using serial IVUS analysis, we found that stent asymmetry had little impact on subsequent neointimal tissue accumulation either locally or downstream. However, most of the stents studied were symmetrically expanded; only 8 stent segments of a total of 440 segments in lesions treated with a single stent fit the previously published definition of stent asymmetry (minimum/maximum stent diameter <0.7).6 Thus, in this study, the impact of marked stent asymmetry might not have been able to be detected.
Lesions Treated With Two Stents
Previous studies have suggested that restenosis is more common with multiple stents.28 29 At the junction of the two stents, acute lumen dimensions, tissue growth, late lumen loss, and chronic lumen dimensions were similar regardless of whether the stents overlapped; this indicated that it was the acute stent and lumen dimensions that were important, not the technique of achieving them. Because lesions with more than two stents were excluded from analysis, these findings may not be extendable to lesions treated with three or more devices.
Impact of Stents on Adjacent Vascular Segments
In this study, dissections at the stent/vessel wall margins were uncommon. However, even in the absence of postprocedural dissections, stents had an important impact on adjacent vascular segments. There appeared to be a continuum of changes beginning at the stent/vessel margin and continuing out to the reference segments proximally and distally for at least 5 to 10 mm. At the stent/vessel wall margins, the tissue proliferation and remodeling (chronic stent recoil) were similar to the body and central articulation of the stents. Remodeling appeared to progressively increase and tissue proliferation appeared to progressively decrease at axial distances farther from the edge of the stent.
First, although this was an inclusive series of lesions and patients studied after stent implantation and at follow-up, there was the potential for bias because of the reason for and nature of the angiographic and IVUS follow-up. Furthermore, follow-up angiography and IVUS imaging were available in only a minority (115 of 736) of previously stented lesions. Second, only 36 of the lesions were restenotic at follow-up. This number may be too small to detect the predisposition of neointimal tissue proliferation at any one segment within the stent. Third, the operators were not blinded to the acute IVUS images, which were often used to optimize the acute procedural results. Fourth, most of the lesions in this study were treated with one stent. The number of lesions treated with two stents was relatively small.
Conclusions and Implications
Recent studies have shown that in nonstented lesions, restenosis appears to be determined primarily by the direction and magnitude of arterial remodeling. This may explain the failure of treatment strategies designed to prevent restenosis by limiting cellular proliferation in nonstented lesions. Conversely, the present study showed that in stented lesions late lumen loss and restenosis were the result of neointimal tissue proliferation and that overall neointimal tissue proliferation was the Achilles' heel of stent implantation. Treatment strategies designed to limit cellular proliferation that were ineffective in nonstented lesions (because they were aimed at the wrong target) may be efficacious in reducing in-stent restenosis. This supports the concept of an interventional strategy combining an endovascular prosthesis (to withstand remodeling forces) and a pharmacological agent (to inhibit cellular proliferation).
Selected Abbreviations and Acronyms
|EEM||=||external elastic membrane|
This study was supported in part by the Cardiology Research Foundation, Washington, DC, and the Heinrich-Hertz Stiftung, Dusseldorf, Germany.
- Received January 25, 1996.
- Revision received April 15, 1996.
- Accepted May 6, 1996.
- Copyright © 1996 by American Heart Association
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