CLINICAL STUDIES
Remodeling after directional coronary atherectomy (with and without adjunct percutaneous transluminal coronary angioplasty): a serial angiographic and intravascular ultrasound analysis from the optimal atherectomy restenosis study
Alexandra J. Lansky, MDa,
Gary S. Mintz, MD, FACCa,
Jeffrey J. Popma, MD, FACCa,
Augusto D. Pichard, MD, FACCa,
Kenneth M. Kent, MD, PhD, FACCa,
Lowell F. Satler, MD, FACCa,
Donald S. Baim, MD, FACCa,
Richard E. Kuntz, MD, FACCa,
Charles Simonton, MD, FACCa,
Robert M. Bersin, MD, FACCa,
Tomaki Hinohara, MD, FACCa,
Peter J. Fitzgerald, MD, PhD, FACCa and
Martin B. Leon, MD, FACCa
a Intravascular Ultrasound Imaging and Angiographic Core Laboratories, The Washington Hospital Center, Washington, DC, USA
Manuscript received December 9, 1996;
revised manuscript received February 26, 1998,
accepted April 23, 1998.
Address for correspondence: Dr. Martin B. Leon, Director of Research, Cardiology Research Foundation, 110 Irving Street NW (4B-1), Washington, DC 20010
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Abstract
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Objectives. The intravascular ultrasound (IVUS) substudy of OARS (Optimal Atherectomy Restenosis Study) was designed to assess the mechanisms of restenosis after directional coronary atherectomy (DCA).
Background. Recent serial IVUS studies have indicated that late lumen loss after interventional procedures was determined primarily by the direction and magnitude of arterial remodeling, not by cellular proliferation.
Methods. Complete quantitative coronary angiography (QCA) and IVUS were obtained in 104 patients before and after intervention and during follow-up. All studies were performed after administration of 200 µg of intracoronary nitroglycerin. Angiographic measurements included minimum lumen diameter (MLD), interpolated reference diameter and diameter stenosis (DS). Intravascular ultrasound measurements included lesion and reference external elastic membrane (EEM), lumen and plaque+media cross-sectional area (CSA). The axial location of the lesion site was at the smallest follow-up lumen CSA; the reference segment was the most normal-looking cross section within 10 mm proximal to the lesion but distal to any major side branch. Results are reported as mean ± one standard deviation.
Results. The QCA reference decreased from 3.51 ± 0.46 mm to 3.22 ± 0.44 mm; the MLD decreased from 3.22 ± 0.47 mm to 2.03 ± 0.72 mm; and the DS increased from 8 ± 10% to 38 ± 20%. On IVUS, the decrease in lumen CSA (from 8.8 ± 2.5 mm2 to 5.5 ± 4.0 mm2) was associated with a significant decrease in EEM (from 19.7 ± 5.6 mm2 to 16.9 ± 6.2 mm2); there was no significant increase in P+M (from 10.9 ± 4.2 mm2 to 11.3 ± 3.9 mm2). A change in lumen correlated with a change in EEM (r = 0.790, p < 0.0001), not with a change in P+M (r = 0.133, p = 0.2258). A decrease in reference EEM (from 19.1 ± 7.7 mm2 to 17.6 ± 8.0 mm2) also correlated with a decrease in lesion EEM (r = 0.665, p < 0.0001). Results in restenotic lesions were similar.
Conclusion. Restenosis after optimal DCA is caused primarily by a decrease in EEM CSA that extends into contiguous reference segments.
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Abbreviations and Acronyms
| | CSA | = cross-sectional area | | DCA | = directional coronary atherectomy | | DS | = diameter stenosis | | EEM | = external elastic membrane | | IVUS | = intravascular ultrasound | | MLD | = minimum lumen diameter | | OARS | = Optimal Atherectomy Restenosis Study | | P+M | = plaque + media | | PTCA | = percutaneous transluminal coronary angioplasty | | QCA | = quantitative coronary angiography/angiographic |
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The Optimal Atherectomy Restenosis Study (OARS) was a multicenter study designed to evaluate the mechanisms and safety of an aggressive directional coronary atherectomy (DCA) strategy coupled with adjunct percutaneous transluminal coronary angioplasty (PTCA) to enhance the final results. The protocol included serial intravascular ultrasound (IVUS) imaging before intervention, after intervention (whether stand-alone DCA or after adjunct PTCA) and at 6 months to assess the mechanisms of lumen enlargement and restenosis. Targeted short-term procedural end points were angiographic residual diameter stenosis (DS) <10% and IVUS residual percentage of area occupied by plaque <50%.
Data from animal models, human autopsy studies, and analyses of retrieved atherectomy specimens 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 (1–14). Conversely, recent serial IVUS studies have indicated that late lumen loss after interventional procedures in nonstented lesions was determined primarily by the direction and magnitude of arterial remodeling, not by cellular proliferation (15). In support of this newer hypothesis, endovascular stents, which scaffold the inner vascular lumen preventing recoil and remodeling while exaggerating proliferative responses, have been shown to reduce restenosis in two randomized clinical trials (16,17).
We report the serial quantitative coronary angiographic (QCA) and IVUS analysis of the mechanisms of restenosis after optimum DCA plus adjunct PTCA from OARS.
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Methods
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Patient population.
Two hundred patients were enrolled in the OARS study; complete serial IVUS was performed in 104. Reasons for incomplete serial IVUS study included poor image quality (in any one study, including difficulty in identifying lumen and media-adventitia borders); failure to cross or advance the transducer beyond the lesion before intervention, after intervention or at follow-up; bail-out stenting or emergency coronary artery bypass graft operation; lack of follow-up angiography; and failure to perform IVUS imaging at angiographic follow-up. Reasons for failure to perform IVUS imaging at follow-up included follow-up angiography performed at a non-OARS center, clinical instability and reluctance of the physician to cross a severe lesion or a nonrestenotic "intermediate" lesion with the IVUS catheter.
There were 77 men and 27 women, aged 57 ± 11 years. Patient comorbidity rates were unstable angina in 83%, diabetes in 15%, hypertension in 41%, hyperlipidemia in 28% and cigarette smoking in 33%. Lesion location was left main artery in 1, left anterior descending artery in 55, left circumflex artery in 16 and right coronary artery in 32 patients. Lesions in seven patients were treated previously.
DCA procedure.
Atherectomy devices used were 7F in 94% of lesions, with 2.3 ± 1.1 catheter passes, 19 ± 10 cuts per lesion and 14 ± 8 mg of tissue retrieved. Adjunct PTCA was performed in 91 patients (87%), with a mean adjunct balloon size of 3.9 ± 0.6 mm.
QCA analysis.
All cineangiograms obtained before intervention, after intervention and at follow-up were acquired after administration of 200 µg of intracoronary nitroglycerin. Quantitative coronary angiographic analysis was performed by an independent core laboratory using an automated edge detection algorithm (CMS, MEDIS) and contrast-filled catheters as the calibration standard. The minimal lumen diameter (MLD), interpolated reference diameter and percent DS were measured before intervention, after intervention and at follow-up using the two sharpest views showing the stenosis. Lumen area was then calculated by assuming circular geometry. Angiographic restenosis was defined as a follow-up DS  50% (18).
IVUS imaging systems.
All IVUS images were acquired using one of two commercially available systems. The first system (InterTherapy/CVIS) used a single-element 25-MHz transducer coupled with an angled mirror mounted on the tip of a flexible shaft within a 3.9F short monorail polyethylene imaging sheath. The second system (Cardiovascular Imaging Systems) used a 30-MHz beveled transducer within either a 2.9F long monorail imaging sheath (a common distal lumen alternatively accommodated the imaging core or the guide wire but not both) or a 3.2F short monorail imaging catheter. With both systems the transducer was rotated at 1,800 rpm to produce the tomographic images, and it was withdrawn at 0.5 mm/s within the stationary imaging sheath by using a motorized transducer pullback device to perform the imaging sequence. The accuracy of motorized transducer pullback through a stationary imaging sheath has been validated in vivo (19). Studies were recorded on 0.5-in. high-resolution super-VHS videotape for offline analysis.
All IVUS studies obtained before intervention, after intervention and at follow-up were performed after administration of 200 µg of intracoronary nitroglycerin. The imaging catheter was advanced approximately 10 mm distal to the lesion, the motorized transducer pullback device was activated, and complete uninterrupted imaging runs were performed back to the aorto-ostial junction. This systematic approach facilitated identification of the target lesion and reference segment image slices on the serial ultrasound studies for comparative image analysis.
Quantitative IVUS measurements.
Validation of cross-sectional measurements by IVUS has been reported (20–26). Using computerized planimetry, we measured the external elastic membrane (EEM) and lumen cross-sectional areas (CSA) at the lesion site and at the reference segment. The plaque+media (P+M) CSA was calculated as EEM minus lumen CSA. The percentage of area occupied by plaque was calculated as P+M divided by EEM CSA. The EEM CSA (representing the area within the border between the hypoechoic media and echoreflective adventitia) has been shown to be a reproducible measure of total arterial area. When the plaque encompassed the catheter, the lumen was assumed to be the physical (not acoustic) size of the imaging catheter. Because media thickness cannot be measured accurately, P+M CSA was used as a measure of plaque. The percentage of the total arterial area occupied by plaque has also been termed the plaque burden or cross-sectional narrowing by other investigators.
The same anatomic lesion site and reference segment image slices were analyzed before intervention, after intervention and at follow-up; differences between time points were compared. By using one or more reproducible axial landmarks (eg, the aorto-ostial junction, large proximal or distal side branches, or uniquely shaped calcium deposits) and a known pullback speed, identical cross-sectional slices on serial studies could be identified for comparison. The lesion site image slice had an axial location within the stenosis at the smallest lumen CSA at follow-up (rather than at the smallest lumen CSA before or after intervention). In practice, the follow-up study was analyzed first to identify the target lesion image 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, the axial landmark was noted on the studies obtained before and after intervention, and the previously measured distance was used to identify the correct anatomic slice on the studies obtained before and after intervention. The reference segment image slice was the most normal-looking cross section (the largest lumen and the smallest percentage of plaque area) within 10 mm proximal to the lesion but distal to any major side branch. Once the target lesion image slice was identified, then the most normal-looking cross-section within 10 mm proximal to the lesion, but distal to any major side branch was selected from the study obtained before intervention. The method of selecting this reference segment has been reported previously and is designed to select an ultrasound reference within the arterial segment used to calculate the angiographic DS (27). The distance between the target lesion image slice and the reference segment image slice was measured (using seconds or frames of videotape) and used to identify the corresponding reference segment image slice on the IVUS studies obtained after intervention and at follow-up. Vascular and perivascular markings (often a large side branch just proximal to the reference segment) confirmed lesion site and reference segment image slice identification. The serial studies were analyzed side-by-side and frame-by-frame to ensure that the same sections were measured. This methodology and its reproducibility have been reported previously (15).
Statistics.
Statistical analysis was performed using StatView 4.02 (Abacus Concepts). Quantitative data are presented as mean ± one standard deviation. Qualitative data are presented as frequencies. Comparisons of categorical variables among groups were performed with  2 statistics or Fisher’s exact test. Comparisons of continuous variables were performed using unpaired Student’s t test, factorial analysis of variance or analysis of variance for repeated measures. Post-hoc intergroup comparisons (after analysis of variance for repeated measures) were performed using paired Student’s t test with the Bonferroni correction for multiple comparisons (to maintain an acceptable alpha-type error). A p value < 0.05 was considered significant except for the post-hoc intergroup comparisons (after analysis of variance for repeated measures), in which p < 0.017 was considered significant (0.05 divided by 3) (28,29).
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Results
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Serial QCA results.
Before intervention, the mean reference diameter was 3.39 ± 0.47 mm, the MLD 1.21 ± 0.39 mm and the DS 64 ± 10%. After intervention, the mean reference diameter increased to 3.51 ± 0.46 mm (p = 0.0781), the MLD increased to 3.22 ± 0.47 mm (p < 0.0001) and the DS decreased to 8 ± 10% (p < 0.0001). At follow-up, the reference diameter decreased to 3.22 ± 0.44 mm (p = 0.0154 compared with pre-intervention diameter and p < 0.0001 compared with postintervention diameter), the MLD decreased to 2.03 ± 0.72 mm (p < 0.0001 compared with both preintervention and postintervention diameters) and the DS increased to 38 ± 20% (p < 0.0001 compared with both to preintervention and postintervention diameters (Table 1). Restenosis was defined as a follow-up DS 50% and was noted in 28 patients (27%).
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Table 1 Quantitative Coronary Angiography and Intravascular Ultrasound Results in 104 Patients With Complete Studies
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Serial IVUS measurements.
Lesion site results
After intervention, 31% of the increase in lumen CSA (from 2.0 ± 1.3 mm2 to 8.8 ± 2.5 mm2, p < 0.0001) was the result of an increase in EEM CSA (vessel expansion from 17.7 ± 5.7 mm2 to 19.7 ± 5.6 mm2, p < 0.0001); and 69% of the increase in lumen CSA was the result of a decrease in P+M CSA (from 15.6 ± 5.3 mm2 to 10.9 ± 4.2 mm2, p < 0.0001) (Table 1). The final percentage of plaque area was 57 ± 9%. Nineteen patients (18%) had a final QCA DS <10% and a final IVUS percentage of plaque area <50%.
At follow-up, the reduction in lumen CSA to 5.5 ± 4.0 mm2 (p < 0.0001 compared with both preintervention and postintervention lumen CSA) was associated with a decrease in EEM CSA (to 16.9 ± 6.2 mm2, p < 0.0001 compared with postintervention) and with no increase in P+M CSA to 11.3 ± 3.9 mm2 (p = 0.0656 compared with postintervention). Late lumen area loss (3.3 ± 3.3 mm2) correlated with the decrease in EEM CSA (2.8 ± 3.8 mm2, r = 0.790, p < 0.0001) but not with the increase in P+M CSA (0.4 ± 2.3 mm2, r = 0.133, p = 0.2258) (Fig. 1). The findings in the 97 de novo lesions were similar.
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Figure 1 Comparison of postintervention to follow-up serial intravascular ultrasound lesion site results. Change in lumen CSA (from postintervention to follow-up) correlated with the change in EEM CSA (r = 0.790, p < 0.0001) but not with the change in P+M CSA (r = 0.133, p = 0.2258).
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The serial IVUS changes in the lesions that were restenotic at follow-up are shown in Table 2. In this subset, the changes noted in the overall cohort were even more dramatic: a significant decrease in lumen CSA (p < 0.0001 vs. postintervention), a significant decrease in EEM CSA (p < 0.0001 vs. postintervention and p = 0.0023 vs. preintervention) and no change in P+M CSA (p = 0.4166 vs. postintervention).
Overall, 22 (20%) of 104 patients had a late increase in EEM CSA. Lesions with a late increase in EEM CSA were then compared with lesions with a late decrease in EEM CSA. This comparison showed (1) similar short-term vessel expansion (2.2 ± 3.1 mm2 vs. 2.0 ± 1.7 mm2, p = 0.7454) and short-term plaque removal (3.7 ± 3.2 mm2 vs. 4.8 ± 2.6 mm2, p = 0.1719); (2) no late lumen loss (0.5 ± 3.0 mm2) versus a 4.2 ± 2.3 mm2 decrease in lumen CSA (p < 0.0001); (3) similar postintervention QCA MLD (3.13 ± 0.54 mm vs. 3.22 ± 0.42 mm, p = 0.4303) and DS (8 ± 13% vs. 7 ± 10%, p = 0.8269); (4) a larger follow-up QCA MLD (2.46 ± 0.65 mm vs. 1.88 ± 0.68 mm, p = 0.0014) and a smaller follow-up DS (23 ± 17% vs. 41 ± 18%, p = 0.0001); (5) a 5% incidence of restenosis (compared with a 35% incidence of restenosis in lesions with a late decrease in EEM CSA, p = 0.0105); and (6) a 58% incidence of late lumen gain (compared with a 1% incidence of late lumen gain in lesions with a late decrease in EEM CSA, p < 0.0001).
Reference segment results
After intervention, the reference segment EEM CSA increased slightly from 18.3 ± 7.5 mm2 to 19.1 ± 7.7 mm2 (p < 0.0001); the reference lumen CSA increased slightly from 10.2 ± 3.9 mm2 to 10.8 ± 3.9 mm2 (p = 0.0001); and the P+M CSA did not change (8.1 ± 4.4 mm2 vs. 8.4 ± 4.6 mm2). At follow-up, changes in reference segment EEM and lumen CSA paralleled the lesion site. There was a decrease in reference segment EEM CSA (to 17.6 ± 8.0 mm2, p = 0.0156 compared with preintervention and p < 0.0001 compared with postintervention), a decrease in lumen CSA (to 9.5 ± 4.6 mm2, p = 0.0024 compared with preintervention and p < 0.0001 compared with postintervention) and no change in P+M CSA (8.1 ± 4.3 mm2). The decrease in reference lumen CSA (1.3 ± 2.0 mm2) correlated with the decrease in EEM CSA (1.6 ± 2.6 mm2, r = 0.781, p < 0.0001). The decrease in reference EEM CSA correlated with the decrease in lesion site EEM CSA (r = 0.665, p < 0.0001). These results are shown in Figures 2 and 3.
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Figure 2 Comparison of postintervention to follow-up serial IVUS reference segment results. Change in lumen CSA (from postintervention to follow-up) correlated with the change in EEM CSA (r = 0.781, p < 0.0001) but not with the change in P+M CSA (r = 0.155, p = 0.1627).
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Figure 3 Change in reference segment EEM CSA (from postintervention to follow-up) correlated with the change in lesion site EEM CSA (r = 0.665, p < 0.0001).
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The changes in reference segments in lesions treated with stand-alone DCA were similar. At follow-up, there was a significant decrease in lumen CSA (9.9 ± 3.0 mm2 to 7.9 ± 2.9 mm2, p = 0.0109) and a significant decrease in EEM CSA (17.7 ± 5.4 mm2 to 14.8 ± 4.0 mm2, p = 0.0361). The changes in reference segments in lesions that were restenoic at follow-up were exaggerated compared with those of the overall cohort (Table 2), as evidenced by a decrease in EEM CSA (p = 0.01 vs. preintervention and p = 0.0008 vs postintervention), a decrease in lumen CSA (p = 0.0143 vs. preintervention and p = 0.0003 vs. postintervention) and no change in P+M CSA. An example of late target lesion and reference segment changes is shown in Figure 4.
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Table 3 Subset Intravascular Ultrasound Analyses of Changes in the Cross-sectional Area of Lumen External Elastic Membrane and Plaque+Media
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Figure 4 Cineangiograms (center) and IVUS images from a left circumflex lesion treated with DCA and adjunct PTCA after intervention (A) and at follow-up (B). Each IVUS image is accompanied by a duplicate image that is labeled (bottom images). In each of the labeled images, the EEM is outlined in black, and the lumen is outlined in white. A, After intervention, the proximal reference EEM CSA measured 11.4 mm2, the lumen CSA measured 7.4 mm2 and the P+M CSA measured 4.0 mm2. After intervention, the lesion site EEM CSA measured 12.9 mm2, the lumen CSA measured 7.1 mm2 and the P+M CSA measured 5.6 mm2. The residual lesion site percentage of plaque area was 44%. B, at follow-up, the reference segment EEM CSA decreased to 7.0 mm2, the lumen CSA decreased to 2.5 mm2, and the P+M CSA increased to 4.5 mm2. At follow-up, the lesion site EEM CSA decreased to 6.0 mm2, the lumen CSA was assumed to be the physical size of the IVUS imaging catheter (1.0 mm2), and the P+M CSA increased to 5.0 mm2.
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Subset analyses.
In lesions restenotic at follow-up compared with lesions not restenotic at follow-up, there was a greater late decrease in lumen CSA that was associated with a greater late decrease in EEM CSA but not with a greater increase in P+M CSA. There were no significant differences in change in lumen CSA, change in EEM CSA, or change in P+M CSA in (1) patients with new lesions as opposed to previously treated lesions, (2) in patients treated with stand-alone DCA compared with patients treated with adjunct PTCA, and (3) in patients with lesions located in the left anterior descending artery versus left circumflex coronary artery versus right coronary artery (there was also no increase in angiographic restenosis in patients with lesions in the left anterior descending artery). Similarly, there were no significant differences between patients with unstable angina and those with stable angina, between patients with hypercholesterolemia and patients without hypercholesterolemia, and between patients with and without hypertension. There was a greater increase in P+M CSA in diabetic patients compared with a tendency for greater decrease in EEM CSA in nondiabetic patients (although the decrease in lumen CSA was similar in these two groups, paralleling the similar angiographic restenosis rates).
Comparison of minimum lumen area by IVUS compared with QCA.
Before intervention, minimum lumen CSA by IVUS and QCA correlated moderately well (r = 0.611, p < 0.0001), with a mean difference of 0.78 ± 1.02 mm2. After intervention, minimum lumen CSA correlated less strongly (r = 0.453, p < 0.0001), with a mean difference of 0.45 ± 2.52 mm2. At follow-up, minimum lumen CSA again correlated moderately well (r = 0.623, p < 0.0001), with a mean difference of 1.91 ± 2.67 mm2.
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Discussion
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Restenosis remains a major limitation to percutaneous coronary revascularization. The restenotic lesion is thought to be a proliferative lesion in which an exaggeration of the normal reparative processes, after angioplasty-induced local vessel trauma, leads to proliferation of both cellular and matrix components, causing an increased tissue mass and restenosis (1,7,10,12–14,30–43). As the understanding of this process has advanced, attempts have been made to block restenosis by interfering with this pathologic restenosis cascade (44). Although the results in animal models have been impressive, pharmacologic trials using antiproliferative agents in humans have been strikingly ineffective (45–49). In recent animal and clinical studies, investigators have begun to question the predominant role of cellular proliferation in restenosis, suggesting that remodeling (the late decrease in arterial CSA) might result in lumen compromise and might be a major contributing factor to the development of restenosis (50–60).
Previous serial IVUS restenosis studies.
Serial IVUS analysis has been used to study mechanisms of restenosis (15,61). In a previous study (15), 73% of the late lumen loss was accounted for by a decrease in EEM CSA. This decrease in EEM CSA was termed "remodeling." Restenotic lesions had a greater decrease in EEM and lumen CSA, but only a slightly greater increase in P+M CSA. The change in lumen CSA correlated more strongly with the change in EEM than with the change in P+M CSA. The change in EEM CSA was bidirectional. Despite a greater increase in P+M CSA, lesions with an increase in EEM CSA had no change in lumen CSA, increased late lumen gain and decreased restenosis (15). There were three limitations to that study. First, it was a nonconsecutive series of patients; second, it included multiple devices (balloon angioplasty, DCA, rotational atherectomy and excimer laser angioplasty with and without the use of adjunct PTCA or DCA); and third, it did not address the time course of the IVUS events. Kimura et al. (61) reported a consecutive series of patients treated with PTCA or DCA and studied with IVUS before intervention and immediately, 24 h, 1 month and 6 months after intervention. That study also showed an increase in EEM CSA (or positive remodeling) between 24 h and 1 month after intervention and a decrease in EEM CSA (or negative remodeling) between 1 month and 6 months after intervention. Again, the change in lumen CSA correlated more strongly with the change in EEM than with the change in P+M CSA.
Lesion site changes after DCA.
The present study is an analysis of a consecutive series of patients treated with DCA (with or without adjunct PTCA) in whom IVUS was performed before intervention, after intervention and at follow-up. Late lumen loss and restenosis were associated primarily with a decrease in EEM CSA. Finally, the importance of a late decrease in EEM CSA was substantiated by the positive impact of a late increase in EEM CSA (observed in 20% of patients).
Subset analyses substantiated the overall cohort analysis with one notable exception. In diabetic patients lesions had a greater increase in P+M CSA than lesions in nondiabetic patients. This may explain the increased rate of restenosis in diabetic patients (compared with nondiabetic patients) that has been noted in previous studies, including one serial IVUS study (62).
Reference segment changes after DCA (with or without adjunct PTCA).
The QCA and IVUS analyses in the present series showed that late lumen loss extended into contiguous reference segments that are typically used to calculate angiographic DS. Two explanations are possible. First, there may be a diffuse remodeling process after DCA (with or without adjunct PTCA) that is most severe at the lesion and extends into the reference segments. Second, because reference segments were measured within 10 mm of the center of the lesion and a typical PTCA balloon is 20 mm long, the reference segments analyzed may have been affected by the interventional procedure.
Dynamic changes in angiographic reference vessel diameters after PTCA have been noted previously (63–65). These changes have been attributed to technical artifacts (eg, differences in vasomotor tone or responses to nitroglycerin, inaccurate calibration or different angiographic projections) as well as to tissue growth within the reference vessel (41). Beatt et al. (64) showed a late reduction in both the MLD (–0.37 mm and –0.42 mm, p < 0.0001) and the reference lumen dimension (–0.17 mm and –0.26 mm, p < 0.0001) at 90 and 120 days, respectively. Similarly, Nobuyoshi et al. (65) demonstrated a decrease in both the MLD (–0.34 mm, p < 0.001) and reference lumen (–0.17 mm, p < 0.05), which appeared to stabilize after 6 months. Using the same QCA system as was used in the current study, Adelman et al. (66) reported a decrease in reference lumen dimension from 3.15 ± 0.46 mm after intervention (DCA with or without adjunct PTCA) to 3.03 ± 0.51 mm at follow-up, less than the 3.51 ± 0.46 mm to 3.22 ± 0.44 mm decrease in the present study. In Adelman et al. the final DS was 25.5 ± 11.2% (compared with 8 ± 10% in the present study), and adjunct PTCA was used in only 28% of patients (compared with 87% in the present study). More aggressive atherectomy, adjunct PTCA, or both in the present study may account for this difference. With late reductions in reference dimensions, the percent DS measurement (the conventional index of lesion severity and restenosis) will be underestimated (64,67–69).
Limitations.
The present study represents a subset analysis from the total cohort of 200 patients in OARS. However, the demographic data in this subset were not statistically different from those in the overall OARS cohort for patients (76% men, 78% with unstable angina and 17% with diabetes), lesions (54% in the left anterior descending artery, 6% restenotic lesions, QCA reference size of 3.44 mm), procedure (95% 7F device, 2.3 passes and 19.1 cuts, 15 mg of tissue retrieved and 87% adjunct PTCA with a mean balloon size of 3.9 mm), results (QCA final DS, 8%; IVUS percentage of plaque area, 58%) and restenosis rate (29%).
The results of this study were dependent on accurate identification of the same anatomic cross section on serial IVUS studies; this requirement precluded blinded analysis. Identification of the same anatomic cross section on repeated imaging was ensured by 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).
Differences in vascular tone could have contributed to measurement variations of EEM and lumen dimensions. However, all patients were studied after administration of significant doses (200 µg) of intracoronary nitroglycerin; differences in vascular tone should not have affected measurement of P+M CSA. In addition, there was little long-term increase in P+M CSA, even in the restenotic lesions.
In the OARS study, time course of the changes in EEM CSA were not obtained; therefore, remodeling could not be separated from passive elastic recoil. In the present study, lesion site EEM CSA at follow-up was not statistically compared with preintervention. However, the SURE (serial ultrasound restenosis) Trial studied patients treated with PTCA and DCA before and immediately after intervention, 24 h after intervention, and after 1 and 6 months of follow-up. There was little change in EEM CSA within the first 24 h after intervention, an increase in EEM CSA between 24 h and 1 month and a decrease in EEM CSA between 1 and 6 months (63). As in the present study, the changes in follow-up lumen CSA paralleled the changes in EEM CSA, but not the changes in P+M CSA. Lastly, in the SURE Trial serial measurements of the reference segment EEM CSA paralleled measurements of the lesion site EEM CSA, supporting a similar finding in OARS. The ABACAS (Adjunct Balloon Angioplasty Coronary Atherectomy Study, Fitzgerald, personal communication) included postintervention, 3-month and 6-month IVUS analysis. Preliminary results show that EEM CSA increased between postintervention and 3 months and decreased between 3 months and 6 months. Thus, in both SURE and ABACAS there is first an increase in the EEM CSA early in the follow-up period followed by a decrease in the EEM CSA late in the follow-up period. Therefore, the late decrease in EEM CSA is distinct from passive elastic recoil.
Intravascular ultrasound can only measure net changes in the P+M CSA; therefore, cellular proliferation and apoptosis (or lesion contraction) could coexist, and cellular proliferation could go unrecognized. Similarly, IVUS can measure only the changes in EEM CSA; therefore, it cannot separate the effect of active adventitial constriction from a passive response to a decrease in P+M CSA.
In the present study we could not definitively separate the long-term effects of DCA from those of adjunct PTCA. There were few lesions treated with DCA alone. However, preliminary results of ABACAS also showed no difference (in serial IVUS results) between lesions randomly assigned to receive adjunct PTCA and lesions randomly assigned to stand-alone DCA.
Some of the changes in IVUS cross-sectional measurements were small.
Conclusions.
Late lumen loss after DCA (with or without adjunct PTCA) appeared to be associated mainly with a decrease in EEM CSA rather than with plaque regrowth. The changes in EEM CSA were paralleled by similar but smaller changes in contiguous reference segments (Table 3).
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Footnotes
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This study was supported in part by Devices for Vascular Intervention and by Cardiology Research Foundation.
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References
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