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Circulation. 1996;94:35-43

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(Circulation. 1996;94:35-43.)
© 1996 American Heart Association, Inc.

Articles

Arterial Remodeling After Coronary Angioplasty

A Serial Intravascular Ultrasound Study

Gary S. Mintz, MD; Jeffrey J. Popma, MD; Augusto D. Pichard, MD; Kenneth M. Kent, MD, PhD; Lowell F. Satler, MD; S. Chiu Wong, MD; Mun K. Hong, MD; Julie A. Kovach, MD; Martin B. Leon, MD

From the Intravascular Ultrasound Imaging and Cardiac Catheterization Laboratories, the Washington Hospital Center, Washington, DC.

Correspondence to Martin B. Leon, MD, 110 Irving St NW (4B-1), Washington, DC 20010.


*    Abstract
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Background Restenosis occurs after 30% to 50% of transcatheter coronary procedures; however, the natural history and pathophysiology of restenosis are still incompletely understood.

Methods and Results Serial (postintervention and follow-up) intravascular ultrasound imaging was used to study 212 native coronary lesions in 209 patients after percutaneous transluminal coronary angioplasty, directional coronary atherectomy, rotational atherectomy, or excimer laser angioplasty. The external elastic membrane (EEM) and lumen cross-sectional areas (CSA) were measured; plaque plus media (P+M) CSA was calculated as EEM minus lumen CSA. The anatomic slice selected for serial analysis had an axial location within the target lesion at the smallest follow-up lumen CSA. At follow-up, 73% of the decrease in lumen (from 6.6±2.5 to 4.0±3.7 mm2, P<.0001) was due to a decrease in EEM (from 20.1±6.4 to 18.2±6.4 mm2, P<.0001); 27% was due to an increase in P+M (from 13.5±5.5 to 14.2±5.4 mm2, P<.0001). {Delta}Lumen CSA correlated more strongly with {Delta}EEM CSA (r=.751, P<.0001) than with {Delta}P+M CSA (r=.284, P<.0001). {Delta}EEM was bidirectional; 47 lesions (22%) showed an increase in EEM. Despite a greater increase in P+M (1.5±2.5 versus 0.5±2.0 mm2, P=.0009), lesions exhibiting an increase in EEM had (1) no change in lumen (-0.1±3.3 versus 3.6±2.3 mm2, P<.0001), (2) a reduced restenosis rate (26% versus 62%, P<.0001), and (3) a 49% frequency of late lumen gain (versus 1%, P<.0001) compared with lesions with no increase in EEM.

Conclusions Restenosis appears to be determined primarily by the direction and magnitude of vessel wall remodeling ({Delta}EEM). An increase in EEM is adaptive, whereas a decrease in EEM contributes to restenosis.


Key Words: angioplasty • restenosis • ultrasonics • remodeling


*    Introduction
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 *Introduction
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Restenosis occurs within the first 6 months after 30% to 50% of transcatheter procedures; it remains the major limitation to percutaneous coronary revascularization.1 2 3 4 5 Animal models,6 7 8 9 human necropsy studies,10 11 12 13 14 15 16 17 18 19 20 and analyses of retrieved atherectomy specimens21 22 23 24 25 26 27 originally suggested that an exaggeration of the normal reparative processes after angioplasty-induced local vessel trauma leads to uncontrolled smooth muscle cell proliferation and restenosis.28 29 30 However, no animal model completely simulates the vascular healing processes after catheter-induced trauma31 ; most animal models of restenosis occur in the absence of underlying chronic atherosclerosis with its associated pathobiology and flow abnormalities,31 and pharmacological strategies that prevent restenosis in animals have been strikingly ineffective in humans.31 32

One possible explanation for the failure of these treatment strategies is an incomplete understanding of the natural history and pathophysiology of restenosis.32 33 34 Recent animal and clinical studies have begun to question the predominant role of cellular proliferation, suggesting that remodeling with arterial constriction may result in lumen compromise and may be a major contributing factor to the development of restenosis.35 36 37 38 39 40 41 42 43 Furthermore, recent reexamination of original animal experiments (using different quantitative analyses) now indicate that arterial remodeling (which was once ignored) is, in fact, an important part of the restenosis process (D.P. Faxon, unpublished results, 1995, Los Angeles, Calif; with permission). In support of this hypothesis, endovascular stents, which merely scaffold the inner vascular lumen preventing recoil and remodeling without diminishing proliferative responses, have been shown to reduce restenosis in two randomized clinical trials.44 45

Importantly, arterial remodeling also represents an adaptive (or compensatory) response of blood vessels to hemodynamic stress, arterial injury, and cellular proliferation.6 31 46 47 48 49 50 51 52 53 Compensatory dilatation early in the coronary artery atherosclerotic disease process, as originally described by Glagov et al,54 55 delays the development of focal stenoses despite significant plaque accumulation.

IVUS allows transmural, tomographic imaging of coronary arteries in humans in vivo, providing unique insights into the pathology of coronary artery disease by defining vessel wall geometry and the major components of the atherosclerotic plaque. Sequential IVUS studies have been used to study mechanisms of angioplasty devices.56 57 58 59 The purpose of this study was to use serial IVUS imaging in human coronary arteries after successful angioplasty and at the time of late angiographic follow-up to define the relative contributions of the changes in plaque and arterial cross-sectional areas to late lumen loss.


*    Methods
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Patient Population
From July 1, 1991, to April 30, 1995, serial IVUS imaging was used to study 212 native coronary target lesions in 209 patients. This represents a consecutive series of patients imaged after intervention and at the time of follow-up angiography for recurrent symptoms or as part of clinical protocols. Reasons for study exclusion were stent implantation at the lesion site, ostial left main or ostial right coronary artery lesion location, target lesion calcification extensive enough to preclude accurate cross-sectional vessel quantification, and the inability to perform follow-up IVUS imaging because of clinical instability, patient refusal, or follow-up angiography performed at another institution.

There were 171 men and 38 women, ages 58±11 years. Lesion location was left main in 5, left anterior descending in 99, left circumflex in 31, and right coronary artery in 77. Interventional procedures performed included balloon angioplasty (n=29), DCA (n=114), high-speed rotational atherectomy (n=45), and excimer laser angioplasty (n=24). Adjunct balloon angioplasty was used in 138 lesions (65%) and adjunct DCA (after excimer laser angioplasty or rotational atherectomy) in 22 lesions (10%). Fifty-nine lesions (28%) were restenotic lesions.

Angiographic Analysis
All treatment and follow-up cineangiograms were analyzed by an independent core angiographic laboratory using a quantitative coronary angiographic automated edge detection algorithm (ARTREK, Quantitative Cardiac Systems). The outer diameter of the contrast-filled catheter was used for calibration. MLD, reference diameter, and percent DS before and after intervention and on follow-up were measured from multiple projections, and the results from the "worst" view were recorded. Angiographic restenosis was defined as a DS >=50%.60

IVUS Imaging Systems
IVUS studies were performed using one of two systems. The first (InterTherapy Inc) incorporated a single-element, 25-MHz transducer coupled to an angled mirror, mounted on the tip of a flexible shaft, and rotated at 1800 rpm within a 3.9F short monorail polyethylene imaging sheath to form cross-sectional images in real time. The second (Cardiovascular Imaging Systems Inc) incorporated a single-element, 30-MHz beveled transducer within either a 2.9F long monorail imaging catheter having a common distal lumen design (the distal lumen alternatively accommodated the imaging core or the guidewire, but not both) or a 3.2F short monorail imaging catheter. In all studies the transducer was withdrawn at 0.5 mm/s within the stationary imaging sheath using a motorized pullback device. At 0.5 mm/s, contiguous tomographic image slices were 16.7 µm apart. This systematic approach facilitated comparative image analysis of the serial ultrasound studies. Studies were recorded on 1/2-inch, high-resolution s-VHS taped for off-line analysis.

Before angioplasty (as the first step in the procedure), after angioplasty (as the last step in the procedure), and on follow-up (before any subsequent intervention), 0.2 mg intracoronary nitroglycerin was administered and a complete ultrasound imaging run was performed from beyond the target lesion to the aortoostial junction.

Quantitative IVUS Measurements
Validation of cross-sectional measurements by IVUS has been reported previously.61 62 63 64 65 66 67 By use of computerized planimetry, the EEM and lumen CSA were measured at the lesion site; P+M CSA was calculated as EEM CSA minus lumen CSA (Fig 1Down). The EEM CSA (which represents the area within the border between the hypoechoic media and the echoreflective adventitia) has been shown to be a reproducible measure of total arterial CSA. Because ultrasound cannot measure media thickness accurately, P+M CSA was used as a measure of plaque mass.68 When the atherosclerotic plaque encompassed the catheter, the lumen was assumed to be the physical size of the imaging catheter.



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  		Figure 1. An example of the IVUS cross-sectional measurements is shown. On the left, the EEM (representing the border between the hypoechoic media and the hyperechoic adventitia) and the lumen are indicated by white arrows. On the right, the EEM has been traced (white line) and the lumen has been traced (black line). The CSAs within these borders were then measured; the P+M CSA was calculated as EEM CSA minus lumen CSA.

The same anatomic image slice was analyzed before intervention, after intervention, and on follow-up, and the differences were compared. By using one or more reproducible axial landmarks (for example, the aortoostial junction, large proximal and/or distal side branches, or unusually shaped calcium deposits) and a known pullback speed, identical cross-sectional slices on serial studies could be identified for comparison. The anatomic slice selected for serial analysis had an axial location within the target lesion at the smallest follow-up lumen CSA (rather than at the smallest preintervention or postintervention lumen CSA).

In practice, the follow-up study was analyzed first to identify the anatomic slice with the smallest lumen; then, the distance from this anatomic slice to the closest identifiable axial landmark was measured (using seconds or frames of videotape); finally, this distance was used to identify the corresponding anatomic slice on the preintervention and postintervention studies. Vascular and perivascular markings (eg, small side branches, venous structures, calcific and fibrotic deposits) were used to confirm image slice identification. If necessary, the postintervention and follow-up studies were analyzed side by side and the imaging runs studied frame by frame to ensure that the same anatomic cross section was measured.

Assessment of Reproducibility
All cross-sectional measurements were made by the same individual, who was blinded to the angiographic results. To assess reproducibility and intraobserver variability of sequential IVUS measurements, a consecutive series of 40 postintervention and follow-up ultrasound studies were analyzed at least 3 months apart. This reanalysis began with the original videotapes and therefore included the error involved in repeatedly selecting the same image slice as well as the error involved in performing the cross-sectional measurements. The differences in the postintervention measurements were as follows: EEM CSA (0.05±1.01 mm2), lumen CSA (0.01±1.06 mm2), and P+M CSA (0.03±1.05 mm2). The intraclass correlation coefficient69 for repeated postintervention measurement of the EEM CSA was 0.99, of lumen CSA was 0.92, and of P+M CSA was 0.98. The differences in the follow-up measurements were as follows: EEM CSA (0.04±0.80 mm2), lumen CSA (0.13±0.36 mm2), and P+M CSA (0.17±0.63 mm2). The intraclass correlation coefficient69 for repeated follow-up measurement of the EEM CSA was 0.99, of the lumen CSA was 0.96, and of the P+M CSA was 0.99.

Statistics
Statistical analysis was performed using StatView 4.02 or BMDP.70 Quantitative data are presented as mean±1 SD. Qualitative data are presented as frequencies. The intraclass correlation coefficient, which considers both between-lesion variability and within-lesion variability and is widely used as a measure of interrater variability, was used to assess reproducibility of repeated measures.69 An intraclass correlation coefficient of 0.80 to 1.00 indicates almost perfect agreement. Comparisons between groups were performed using Mann-Whitney U test or Wilcoxon test for continuous variables or {chi}2 statistics and Fisher's exact test for categorical variables.


*    Results
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Serial Angiographic Results
Overall, the preintervention MLD measured 0.90±0.48 mm and the DS measured 68±16%. The postintervention MLD increased to 2.42±0.59 mm, and the DS decreased to 17±13%. The follow-up interval was 5.6±3.4 months (range, 1 to 22). At follow-up, there was attrition in MLD to 1.44±0.88 mm, with an associated increase in DS to 49±28%; 99 target lesions (47%) were classified as restenotic lesions. See Table 1Down.


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  		Table 1. Serial Quantitative Angiographic and Intravascular Ultrasound Results

Serial IVUS Measurements
After intervention, the improvement in lesion site lumen CSA (1.7±0.9 to 6.6±2.5 mm2, P<.0001) was due to a combination of vessel expansion (increase in EEM CSA from 18.5±6.3 to 20.1±6.4 mm2, P<.0001) and tissue ablation (decrease in P+M CSA from 16.8±6.2 to 13.5±5.5 mm2, P<.0001). At follow-up, the decrease in lumen CSA (to 4.0±3.7 mm2, P<.0001) was due more to a decrease in EEM CSA (to 18.2±6.4 mm2, P<.0001) than to an increase in P+M CSA (to 14.2±5.4 mm2, P<.0001) (Fig 2Down). Thus, 73% of late lumen loss was explained by the decrease in EEM CSA (Figs 3Down and 4Down; also see Table 1Up).



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  		Figure 2. During the follow-up period (averaging 5.6 months), lumen CSA in the total cohort of 212 lesions decreased from 6.6±2.5 to 4.0±3.7 mm2 (P<.0001); 73% of the decrease in lumen CSA was the result of a decrease in EEM CSA (from 20.1±6.4 to 18.2±6.4 mm2, P<.0001) and the rest was the result of an increase in P+M CSA (from 13.5±5.5 to 14.2±5.4 mm2, P<.0001).



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  		Figure 3. This ostial left anterior descending lesion was treated with DCA. By quantitative angiographic analysis, the DS measured 7% after intervention and 55% at follow-up 7 months later. By IVUS analysis, 84% of late lumen area loss was the result of a decrease in EEM CSA. The EEM CSA decreased from 14.5 mm2 after intervention (double black arrows) to 8.8 mm2 at follow-up (double black arrows). The lumen CSA decreased from 10.8 mm2 after intervention (double white arrows) to 4.0 mm2 at follow-up (double white arrows). The P+M CSA increased from 3.7 mm2 after intervention to 4.8 mm2 at follow-up.



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  		Figure 4. This mid left anterior descending lesion was treated with DCA. At follow-up, there was restenosis presenting as a total occlusion (large white arrow). By IVUS analysis, all of the late lumen loss was the result of a decrease in EEM CSA. The lumen CSA (double white arrows) decreased from 10.3 to 1.0 mm2 as a result of a decrease in EEM CSA from 14.7 to 5.5 mm2 (double black arrows). The P+M CSA did not change.

Restenotic lesions had a greater decrease in EEM CSA (3.1±3.0 mm2) and lumen CSA (4.1±2.1 mm2) than nonrestenotic lesions (0.8±2.9 and 1.2±2.8 mm2, respectively, both P<.0001). Compared with nonrestenotic lesions, restenotic lesions showed a trend toward an increase in P+M CSA (1.0±2.3 versus 0.4±2.0 mm2, P=.0784; Table 2Down).


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  		Table 2. Comparison of Restenotic Versus Nonrestenotic Lesions

The change in lumen CSA correlated more strongly with the change in EEM CSA (r=.751, P<.0001; Fig 5ADown) than with the change in P+M CSA (r=.284, P<.0001; Fig 5BDown). The changes in EEM CSA and in P+M CSA also were significantly correlated (r=.452, P<.0001; Fig 6Down).



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  		Figure 5. Change in lumen CSA correlated better with the change in EEM CSA (r=.751, P<.0001; A) than with the change in P+M CSA (r=.284, P<.0001; B).



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  		Figure 6. Change in EEM CSA correlated with the change in P+M CSA ({Delta}EEM CSA=0.6*{Delta}P+M CSA-2.5).

The change in EEM CSA was bidirectional. Forty-seven lesions (22%) showed an increase in EEM CSA (Figs 7Down and 8Down). Despite a greater increase in P+M CSA (1.5±2.5 versus 0.5±2.0 mm2, P=.0009), lesions exhibiting an increase in EEM CSA had (1) no change in lumen CSA (-0.1±3.3 mm2 versus a decrease in lumen CSA of 3.6±2.3 mm2 for lesions with a decrease in EEM CSA, P<.0001), (2) a reduced restenosis rate (26% versus 62% for lesions with a decrease in EEM CSA, P<.0001), and (3) a 49% incidence of late lumen gain (versus 1% for lesions with no increase in EEM CSA, P<.0001).



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  		Figure 7. During the follow-up period, 47 lesions (22%) showed an increase in EEM CSA (3.1±2.6 mm2); 165 lesions had a decrease in EEM CSA (1.6±2.0 mm2). Lesions exhibiting an increase in EEM CSA had (1) no change in lumen CSA ({Delta}lumen CSA=-0.1±3.3 mm2 vs 3.6±2.3, P<.0001), (2) a greater increase in P+M CSA ({Delta}P+M CSA=1.5±2.5 mm2 vs 0.5±2.0 mm2, P=.0009), (3) a reduced restenosis rate (26% vs 62% for lesions with a decrease in EEM CSA, P<.0001), and (4) a 49% frequency of late lumen gain (vs 1% for lesions with a decrease in EEM CSA, P<.0001).



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  		Figure 8. This mid right coronary artery lesion was treated with DCA and adjunct balloon angioplasty (PTCA). By quantitative angiographic analysis, MLD measured 4.39 mm after intervention and 4.54 mm at follow-up 9 months later; the DS measured 13% after intervention and 10% at follow-up. The IVUS study demonstrated that this late lumen gain was the result of adaptive arterial remodeling. The EEM CSA increased from 44.2 mm2 after intervention (double black arrows) to 48.6 mm2 at follow-up (double black arrows). The lumen CSA increased from 20.2 mm2 after intervention (double white arrows) to 24.0 mm2 at follow-up (double white arrows). There was little change in P+M CSA (from 24.0 mm2 after intervention to 24.6 mm2 at follow-up).

There were no consistent clinical (eg, history of diabetes), lesion-related (eg, calcification or eccentricity), or procedural (eg, vessel expansion versus tissue ablation) predictors of the direction or magnitude of the change in EEM or P+M CSA.


*    Discussion
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 up arrowMethods
 up arrowResults
 *Discussion
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The pathophysiology of restenosis is complex and incompletely understood.28 30 71 Catheter-induced vascular injury causes immediate and progressive release of thrombogenic, vasoactive, and mitogenic factors leading to platelet aggregation, thrombus formation, and inflammatory changes, with activation of macrophages and smooth muscle cells.72 73 74 75 These events induce the production and release of growth factors and cytokines, which in turn may promote their own synthesis and release from target cells.7 9 27 73 76 77 78 79 80 81 Thus, a self-perpetuating cascade82 is initiated that results in the migration of smooth muscle cells from their usual location in the media to the intima, where they undergo a phenotype change, produce extracellular matrix, and proliferate.29 72 76 77 78 83 84 85 The restenotic lesion is therefore thought to be a proliferative lesion, with both cellular and matrix components causing an increased tissue mass.9 16 17 20 22 28 30 79 83 84 86 87 As the understanding of this process has advanced, attempts have been made to attack restenosis by interfering with this cascade.88 Although the results in animal models have been impressive, pharmacological trials using antiproliferative agents in humans have been disappointing.5 32 89 90 91

Recently, data from various sources have begun to challenge the traditional injury-proliferation restenosis hypothesis.35 37 38 92 New studies of retrieved atherectomy specimens have shown only a low level of active cellular proliferation in restenotic coronary lesions.35 In addition, animal studies have suggested that cellular proliferation may be a universal response to the trauma of transcatheter therapy regardless of the development of restenosis; the presence or absence of compensatory arterial dilatation (accommodating the increase in tissue mass) was the greater determinant of restenosis.37 38 42 Furthermore, late arterial contraction has now been shown to cause restenosis in the absence of extensive cellular proliferation.38

In this study, IVUS data from human coronary arteries support the emerging new animal model data.35 37 38 42 92 93 The impact of a change in EEM CSA on lumen dimensions could be differentiated from the change in P+M CSA. Serial ultrasound imaging indicated that (1) a decrease in total arterial (EEM) CSA accounted for 70% to 75% of late lumen loss and (2) late lumen loss correlated better with a decrease in EEM CSA than with an increase in P+M CSA.

This study does not seek to address the reasons for a decrease in EEM CSA. However, several mechanisms have been postulated including (1) fibrosis of the vessel wall, especially of the adventitia in response to deep wall injury,39 94 (2) programmed cell death (apoptosis),95 (3) changes in the extracellular matrix composition and structure,96 and (4) responses to shear stress–induced changes in vasomotor tone.31 The ultrasound data can be used to support any or all of these theories; for example, the decrease in EEM CSA was often associated with a decrease in P+M CSA (Fig 6Up), suggesting the presence of apoptosis with subsequent plaque retraction. Importantly, these findings cannot exclude a possible relationship between early cellular proliferation and a disproportionate late decrease in EEM CSA resulting in exaggerated late lumen loss and restenosis in some patients.

The change in EEM CSA was, in fact, bidirectional. Approximately 20% of lesions showed a compensatory increase in EEM CSA. This resulted in a decreased incidence of restenosis and an increased incidence of late lumen gain despite an increase in plaque mass analogous to adaptive arterial remodeling and vasodilatation early in the atherosclerotic disease process.49 50 51 52 54 55 Adaptive arterial remodeling (an increase in EEM CSA) in noninstrumented arteries prevents the reduction in lumen dimensions until plaque occupies 40% to 50% of the CSA within the internal elastic membrane (40% to 50% cross-sectional narrowing or plaque burden).54 55 Although the process after intervention may be different, adaptive arterial remodeling (an increase in EEM CSA) is the probable explanation for the occasional improvement in lumen dimensions seen during the follow-up period after catheter-based interventions.

This study does not determine the time course of the decrease in EEM CSA. Thus, it cannot exclude the contribution of acute passive elastic recoil after intervention.97 98 However, data from the Serial Ultrasound Restenosis Study 99 indicate that the decrease in arterial CSA is a late event (occurring between 1 and 6 months after angioplasty) and therefore is distinct from early passive elastic recoil.

Restenosis thus appears to be determined primarily by the direction and magnitude of the change in EEM CSA, in other words, by arterial remodeling (Fig 9Down). An increase in EEM CSA (compensatory arterial dilatation) is adaptive, whereas a decrease in EEM CSA leads to lumen compromise and restenosis.



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  		Figure 9. As shown in this schematic presentation, the change in lumen dimensions after catheter-based coronary interventions appears to be determined primarily by the direction and magnitude of the change in EEM CSA. An increase in EEM CSA (compensatory arterial dilatation) is adaptive, resulting in a decreased incidence of restenosis and an increased incidence of late lumen gain despite an increase in plaque mass analogous to adaptive arterial vasodilation early in the atherosclerotic disease process. A decrease in EEM CSA (arterial contraction) leads to lumen compromise and restenosis even in the absence of a net increase in P+M CSA.

Study Limitations
Because this is a study of patients presenting for follow-up largely as the result of symptomatic recurrence, it may represent a skewed population with an increased rate of restenosis because of the nature of the "clinical" follow-up. Nevertheless, it is a consecutive series of patients studied after intervention and at follow-up using serial IVUS.

The results of this study were dependent on accurate identification of the same anatomic cross section on serial ultrasound studies; this precluded blinded analysis. The use of a motorized transducer pullback to a reproducibly recognizable axial landmark at a known pullback speed coupled with careful attention to lesional and perilesional markings (and, if necessary, side-by-side and frame-by-frame comparisons) helped ensure identification of the same anatomic cross section on repeated imaging. This is attested to by the high reproducibility and low variability of the serial measurements. In addition, three-dimensional quantitative analysis of the entire length of target lesion (rather than just the narrowest cross section) might further enhance our understanding of this process.

Differences in vascular tone could have contributed to measurements of arterial and lumen dimensions. However, all patients were studied only after administration of significant doses of intracoronary nitroglycerin, and differences in vascular tone should not have affected measurement of P+M CSA.

Serial ultrasound analysis can measure only net changes in P+M CSA. Therefore, it cannot isolate cellular proliferation, matrix deposition, atherosclerosis progression/regression, or plaque stabilization/apoptosis from overall quantitative changes in P+M CSA. For example, it cannot exclude the possible contribution of progressive media atrophy to the changes in EEM and P+M CSA. However, because plaque accumulation is usually accompanied by media atrophy, we expect that most of the lesions already had significant media atrophy before treatment; additional (especially rapid) media atrophy during the follow-up interval would have been unusual.100

This study involved a heterogeneous patient and lesion mix, including primary and restenotic lesions in all three vessels and patients with and without unstable angina or diabetes mellitus. Therefore, for example, the analysis presented was not able to identify device-related or vessel-related differences in restenosis mechanisms. The numbers of lesions treated with each device were relatively small, and devices were usually followed by adjunct PTCA or were used in various combinations, depending on lesion morphology.

Clinical Implications
Treatment strategies to prevent restenosis have focused on limitation of cellular proliferation. Although previous trials may be criticized because of methodological problems, it may be that the underlying premise (ie, limitation of cellular proliferation will prevent restenosis) was overly simplistic. An increase in P+M CSA cannot account for the majority of late lumen loss in restenosis lesions, although cellular proliferation may be the initial "trigger" for arterial remodeling. Future investigation and treatment strategies, therefore, should emphasize arterial remodeling as well as tissue proliferation.

The identification of a decrease in EEM CSA as a major contributor to restenosis may explain the success of stent implantation in reducing restenosis.44 45 Serial intravascular ultrasound results have indicated that stents do not recoil chronically.101 Thus, even though there may be a stent-related increase in neointimal tissue proliferation, stents appear to reduce restenosis by withstanding the remodeling forces that lead to restenosis after other types of interventions.


*    Selected Abbreviations and Acronyms
 
CSA = cross-sectional area
DCA = directional coronary atherectomy
DS = diameter stenosis
EEM = external elastic membrane
IVUS = intravascular ultrasound
MLD = minimal lumen diameter
PTCA = percutaneous transluminal coronary angioplasty
P+M = plaque plus media


*    Acknowledgments
 
This study was supported in part by the Cardiology Research Foundation and the Medlantic Research Institute, Washington, DC.

Received September 21, 1995; revision received December 19, 1995; accepted December 21, 1995.


*    References
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 up arrowAbstract
 up arrowIntroduction
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 up arrowResults
 up arrowDiscussion
 *References
 

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