(Circulation. 1999;99:3149-3154.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
From the Cardiac Catheterization and Intravascular Ultrasound Imaging Laboratories, Washington Hospital Center, Washington, DC.
Correspondence to Gary S. Mintz, MD, Cardiovascular Research Foundation, Washington Hospital Center, 110 Irving St NW, Suite 4B-1, Washington, DC 20010. E-mail gsm1{at}mhg.edu
| Abstract |
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Methods and ResultsWe used preintervention IVUS to define positive and negative/intermediate remodeling in a total of 777 lesions in 715 patients treated with nonstent techniques. Positive remodeling (lesion external elastic membrane area greater than average reference) was present in 313 lesions; intermediate/negative remodeling (lesion external elastic membrane area less than or equal to reference) was present in the other 464. Baseline clinical and angiographic characteristics were similar, except for a slightly higher percentage of insulin-dependent diabetic patients (10.2% versus 6.1%; P=0.054) in the negative/intermediate-remodeling group. Angiographic success and in-hospital and short-term complications were comparable in the 2 groups. There was no significant correlation between remodeling (as a continuous variable) and final lumen area (r=0.06) or final lesion plaque burden (r=0.17). At 18±13 months of clinical follow-up, both groups had similar rates of death and Q-wave myocardial infarction: 3.4% and 2.5% for the negative/intermediate-remodeling group versus 2.7% and 2.7% for the positive-remodeling group. However, the target-lesion revascularization (TLR) rate was 20.2% for the negative/intermediate-remodeling group versus 31.2% for the positive-remodeling group (P=0.007), and remodeling, as a continuous variable, was strongly correlated with probability of TLR (P=0.0001). By multivariable logistic regression analysis, diabetes (OR=2.3), left anterior descending artery location (OR=1.8), and remodeling (OR=5.9) were independent predictors of TLR.
ConclusionsPositive lesion-site remodeling is associated with a higher long-term TLR after a nonstent interventional procedure. Thus, long-term clinical outcome appears to be determined in part by preintervention lesion characteristics.
Key Words: angioplasty remodeling restenosis ultrasonics
| Introduction |
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We hypothesized that lesion-specific differences in the direction and magnitude of the vascular remodeling process may influence the long-term arterial response to catheter-based coronary intervention.
| Methods |
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12 months of
available follow-up. A total of 777 lesions in 715 patients were
identified. There were 531 males (74.3%) and 184 females (25.7%) with
a mean patient age of 61±11 years. Target-lesion location was left
main artery in 13 cases (1.7%), left anterior descending artery in 331
(42.6%), left circumflex artery in 100 (20.6%), and right
coronary artery in 273 (35.1%).
Clinical Demographics and Follow-Up
The hospital charts of all patients were reviewed independently
by a registered nurse to obtain clinical demographics and laboratory
results. Risk factors for coronary artery disease that were
tabulated included diabetes mellitus (only if treated medically),
hypertension (only if treated medically), and
hyperlipidemia (if treated medically or if serum
cholesterol was
240 mg/dL). NonQ-wave myocardial
infarction (MI) was defined as a creatine kinase (CK)-MB enzyme
elevation >5 times the upper limit of normal. Clinical follow-up was
performed by telephone contact or office visit at 1, 3, 6, 12, 18, and
24 months after the procedure. The occurrence of major late clinical
events was recorded, including death, Q-wave MI, and
ischemia-driven target-lesion-site
revascularization (TLR, whether
percutaneous or surgical). These events were all source
documented.
Angiographic Analysis
All cineangiograms were analyzed by use of a
computer-assisted, automated edge-detection algorithm (ARTREK,
Quantitative Cardiac Systems) by a core laboratory that was blinded to
the IVUS and clinical findings. With the outer diameter of the
contrast-filled catheter used for calibration, minimal lumen diameter
(MLD) in diastole before intervention was measured from
multiple projections, and results from the single "worst" view
were recorded. Reference-segment diameter was averaged from
user-defined 5-mm-long angiographically normal segments proximal and
distal to the lesion but between any major side branches. Lesion length
was measured as the distance (in millimeters) from the proximal
shoulder to the distal shoulder in the projection with the least
amount of foreshortening. A focal stenosis had a length
10 mm. For the purposes of the present study, ostial lesions
were within 3 mm of the coronary ostia or <3 mm
distal to a major proximal side branch. An eccentric target lesion
appeared to have 3 times as much plaque on one side of the lesion as on
the other. Calcification was identified as readily apparent
radiopacities within the vascular wall at the site of the
stenosis. An angulated segment contained a bend >45° within
5 mm of the lesion. Ectasia was a lumen >20% larger than the
user-defined reference segments. Angiographic success was defined as a
final diameter stenosis <50% in the absence of major
complications. These represent standard qualitative and
quantitative analyses and definitions; all have all been
published previously.15
IVUS Imaging Protocol
All IVUS imaging studies were performed before any intervention
and only after intracoronary administration of 200 µg of
nitroglycerin. To perform the imaging run, the IVUS
catheter was advanced
10 mm distal to the lesion, the video
recorder turned on, the transducer pullback device
activated, and the entire artery imaged to the aorto-ostial
junction. The IVUS studies were performed with 1 of 2 commercially
available systems. The first system
(InterTherapy/Cardiovascular Imaging Systems Inc)
incorporated a single-element, 25-MHz transducer and an angled mirror
mounted on the tip of a flexible shaft that was rotated at 1800 rpm
within a 3.9F short monorail polyethylene imaging sheath to form planar
cross-sectional images in real time. The second system (Boston
Scientific Corporation/Cardiovascular Imaging Systems
Inc) incorporated a single-element, 30-MHz beveled transducer within
either a 3.2F short monorail or 2.9F long monorail common distal
lumenimaging catheter. With both systems, the transducer was
withdrawn automatically at 0.5 mm/s to perform the imaging
sequence.16 The use of a motorized transducer pullback
device and sheath-based imaging catheters permitted the transducer to
move at the same speed as the proximal end of the imaging core. IVUS
studies were recorded on 0.5-in high-resolution Super VHS tape for
offline analysis.
IVUS Analysis
Validation of plaque composition and measurements of external
elastic membrane (EEM) cross-sectional area (CSA), lumen CSA, and
plaque and media (P&M) CSA by IVUS have been reported
previously.17 18 19 Computer planimetry (TapeMeasure, Indec
Systems) was used to measure lesion-site and reference-segment EEM CSA
and lumen CSA. We measured EEM CSA, the area encompassed by the
ultrasonic media-adventitia border, by tracing the leading edge of the
adventitia; this has been shown to be a reproducible measure of total
arterial CSA. Because media thickness cannot be measured
accurately, P&M CSA (EEM CSA minus lumen CSA) was used as a measure of
atherosclerotic plaque.20 Cross-sectional narrowing (CSN;
P&M CSA divided by EEM CSA) has also been called the plaque burden or
the percent plaque area. The lesion site selected for analysis
was the image slice with the smallest lumen CSA; if there were several
image slices with an equally small lumen, the image slice with the
largest EEM CSA and P&M CSA was analyzed. The proximal and
distal reference segments were the most-normal-looking cross sections
within 10 mm proximal or distal to the lesion but before any side
branch. This method of selecting the lesion site and reference segments
to study remodeling has been published
previously.12 13
Definitions of Remodeling
For the purposes of the present analysis, we
determined remodeling by dividing the target-lesion EEM CSA by the
average of the proximal and distal reference-segment EEM CSA to create
a remodeling index. Positive remodeling was defined as a remodeling
index >1 and intermediate/negative remodeling as a remodeling index
1.0.
Statistics
Statistical analysis was performed with StatView 4.5 or
SAS (both SAS Institute Inc). Data are presented as mean±1 SD.
Categorical data were compared with Fisher's exact test. Continuous
variables were compared with unpaired t tests or
regression analysis. The primary end point was the association
of preintervention remodeling with TLR; remodeling was entered into the
analysis both as a categorical variable (positive versus
intermediate/negative) and as a continuous variable.
Univariate variables with a P value <0.2
were entered into the multivariate models. Forward
stepping was used to determine the independent predictors of TLR. In
addition, the 1-year TLR-free survival rate in the group with positive
versus intermediate/negative remodeling was plotted; statistical
significance was tested with the Mantel-Haenszel
2 test. A P value
0.05 was
considered significant.
| Results |
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Clinical, Angiographic, and IVUS Findings
Clinical characteristics and lesion location are shown in Table 1
. Insulin-treated diabetics and
patients with an elevated cholesterol level were more
common among those with intermediate/negative- versus
positive-remodeling lesions.
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There were only marginal differences in angiographic morphology between intermediate/negative- and positive-remodeling lesions: 59.7% versus 61.1% eccentric lesions (P=NS); 7.9% versus 8.9% type C lesions (P=NS); and 23.2% versus 31.2% type B2 lesions (P=0.06).
Quantitative angiographic data are presented in Table 2
. There was a trend for
intermediate/negative-remodeling lesions to be less severe (smaller
preintervention MLD, larger preintervention diameter stenosis);
after intervention, there was a trend towards greater residual stenosis
with intermediate/negative remodeling.
|
Quantitative IVUS findings are also presented in Table 2
. Preintervention, lesions with intermediate/negative
remodeling had larger reference EEM and P&M CSA; conversely, these
lesions had smaller lesion EEM and P&M CSA and CSN. After intervention,
lesions with intermediate/negative remodeling had a smaller lesion
lumen CSA and CSN. There was no significant correlation between IVUS
reference lumen CSA (r=0.06), IVUS final lesion lumen CSA
(r=0.06), or IVUS final lesion CSN (r=0.17) and
the remodeling index.
Device Use, Procedural Success Rates, and In-Hospital
Complications
Lesions with positive remodeling were treated with directional
atherectomy more often than lesions with intermediate/negative
remodeling: 174 (55.6%) versus 184 (40.0%) (P=0.001). The
reverse was observed with respect to balloon angioplasty alone: 75
(24%) versus 184 (40%) (P=0.001). Both
intermediate/negative- and positive-remodeling lesions had the same
rate of treatment with rotational atherectomy (23.1% versus 21.7%)
and excimer laser angioplasty (4.1% versus 3.8%).
Angiographic success was comparable in the 2 groups: 98.5% versus 97.9% for intermediate/negative versus positive remodeling (P=1.0). Major in-hospital complications (death/Q-wave MI/urgent revascularization) occurred in 8 patients in each group (1.9% versus 2.7%, respectively; P=0.46). The presence of any CK-MB enzyme elevation after intervention was found in 111 (26.4%) versus 70 (23.7%) patients, respectively (P=0.56), and nonQ-wave MI occurred in 44 (10.4%) versus 33 (11.1%) (P=0.66).
Clinical Follow-Up
At follow-up, both groups had similar rates of death and Q-wave MI
(Table 3
). However, the TLR rate was
significantly lower for the intermediate/negative-remodeling group: 76
(20.2%) versus 84 (31.2%) patients (P=0.001). TLR-free
1-year survival rate was significantly higher in the
intermediate/negative-remodeling group (P=0.0017; Figure 2
). Additionally, logistic regression
analysis showed that the probability of TLR correlated strongly
with the remodeling index as a continuous variable
(P=0.0001).
|
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Multivariable logistic regression analysis was used to determine the independent predictors of TLR. The following categories of variables were entered into the multivariate model: clinical (diabetes), lesion (left anterior descending coronary artery location), procedural (directional atherectomy and balloon angioplasty use), and IVUS (reference lumen CSA, final lumen CSA, final lesion CSA, and remodeling index). History of diabetes (OR, 2.3; 95% CI, 1.5 to 3.7; P=0.0004), left anterior descending coronary artery location (OR, 1.8; 95% CI, 1.1 to 2.9; P=0.0093), and an increasing remodeling index (OR, 5.9; 95% CI, 2.0 to 17.2; P=0.0011) were independent predictors of TLR.
| Discussion |
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IVUS Assessment of Remodeling
De novo stenoses have been classified into positive-,
intermediate-, or negative-remodeling categories by comparison of the
lesion site with the reference segment.13 In that study,
positive remodeling was defined as a preintervention lesion site
arterial area larger than the proximal reference,
intermediate remodeling as a preintervention lesion site
arterial area smaller than the proximal reference but
larger than the distal reference, and negative remodeling as a
preintervention lesion site arterial area smaller than the
distal reference.13 In another study,12 the
magnitude of arterial remodeling was determined by
comparison of the target-lesion EEM CSA with a proximal reference,
allowing for the maximum amount of arterial tapering. In
various studies,12 13 21 native coronary artery
lesions have been shown to exhibit positive remodeling in 35% to 54%
and inadequate or negative arterial remodeling in 15% to
34%.
In the present study, lesions were classified as having characteristics of intermediate/negative remodeling (60% of the total cohort) versus positive remodeling (40%). There were more insulin-treated diabetic patients in the intermediate/negative-remodeling group, which confirms a previous report from our laboratory.22 Others have reported more smoking among patients with lesions with intermediate or negative remodeling,21 more hypercholesterolemia among patients with lesions with positive remodeling,21 more frequent unstable clinical presentation among patients with lesions with positive remodeling,23 24 and more fibrocalcific plaque elements in lesions with intermediate/negative remodeling.12 21 25 The latter 2 findings suggest that positive-remodeling lesions are "younger" and less stable, whereas intermediate/negative-remodeling lesions are "older" and more mature.
Remodeling and TLR
The present study suggests that the pattern of remodeling is
not just a pathological curiosity. Lesions with positive remodeling had
more revascularization events despite a larger
final IVUS lumen CSA after the interventional procedure.
Recent studies23 24 26 27 have implicated positive remodeling in the pathogenesis of unstable coronary syndromes. The present study suggests that lesions with positive remodeling may also have a less-favorable long-term outcome after nonstent, catheter-based interventions. It has long been recognized that unstable angina and post-MI lesions have a higher rate of clinical and angiographic restenosis.28 Lesions with positive remodeling may be more biologically active. This increased biological activity may cause both an unstable clinical presentation and more late revascularization events. It has recently been shown29 that the early proliferative response to nonstent, catheter-based interventions is quantitatively related to late negative remodeling, the main mechanism of restenosis in these lesions.30 31
Conversely, lesions with intermediate/negative remodeling may not have the capacity to actively constrict ("negatively remodel") late after intervention. This may also be due to the inherent characteristics of such lesions. They were unable to adapt to the initial growth of the atherosclerotic plaque with a positive-remodeling response during atherogenesis. Similarly, they may be less "proliferative" or "reactive" after injury associated with catheter-based intervention.32 In addition, a recent study33 suggested that TLR as a measure of clinical restenosis is less common in smokers, and 2 previous reports21 34 indicated that intermediate/negative-remodeling lesions are more common in smokers.
There may also be a mechanical explanation. Arterial expansion is an important mechanism of lumen enlargement after all catheter-based interventions. Assuming that restenosis is, in part, a proportionate response to vascular and perivascular trauma, lesions with positive remodeling (which already have increased their arterial dimensions significantly) may have more trauma associated with the procedure-induced arterial expansion. This is supported by the finding in the present study that the probability of TLR increases with increasing values of the remodeling index. Furthermore, baseline positive remodeling may be associated with a larger postintervention plaque burden, which might amplify the impact on lumen dimensions of late negative remodeling.35
Limitations
This was a retrospective analysis. Clinical outcome (ie,
TLR) may have potential bias due to patient selection at
follow-up.33 The definition of lesion-site remodeling in
the present study could have been influenced by the degree of
reference-segment remodeling. In the overall cohort, greater plaque
accumulation and positive remodeling at the reference segment could
have artificially produced the appearance of intermediate/negative
remodeling at the lesion site. Introduction of the remodeling index as
a continuous variable both in the multivariate
analysis and in the assessment of TLR-free survival helped to
reduce the bias introduced by categorical definitions. Previous
investigators have used other definitions of adequate, adaptive, or
positive remodeling; some of these definitions differ from that used in
the present study, and they differ among each other as well.
Introduction of the remodeling index as a continuous variable may
have helped to alleviate the discrepancies introduced by different
arbitrary categorical definitions. Finally, the present study
addresses the impact of preintervention lesion remodeling on the
outcome of nonstent interventions. Stenting is now the predominant type
of coronary intervention.
Conclusions
The baseline (preintervention) pattern of lesion-site remodeling
appears to have important prognostic implications on long-term clinical
outcome after catheter-based, nonstent coronary interventions.
Positive remodeling appears to have a worse prognosis (more frequent
need for subsequent revascularization) than
intermediate/negative remodeling.
Clinical Implications
These findings suggest that positive-remodeling lesions should be
targeted for treatment with interventions that have been shown to
reduce restenosis, ie, stents. Conversely, negative-remodeling
lesions may be suitable for a provisional stent-implantation
strategy.
| Acknowledgments |
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Received December 31, 1998; revision received March 15, 1999; accepted April 9, 1999.
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I. Iakovou, G. S. Mintz, G. Dangas, A. Abizaid, R. Mehran, Y. Kobayashi, A. J. Lansky, E. D. Aymong, E. Nikolsky, G. W. Stone, et al. Increased CK-MB release is a "trade-off" for optimal stent implantation: an intravascular ultrasound study J. Am. Coll. Cardiol., December 3, 2003; 42(11): 1900 - 1905. [Abstract] [Full Text] [PDF] |
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M. Sahara, H. Kirigaya, Y. Oikawa, J. Yajima, K. Ogasawara, H. Satoh, K. Nagashima, H. Hara, Y. Nakatsu, and T. Aizawa Arterial remodeling patterns before intervention predict diffuse in-stent restenosis: An intravascular ultrasound study J. Am. Coll. Cardiol., November 19, 2003; 42(10): 1731 - 1738. [Abstract] [Full Text] [PDF] |
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F. Prati, T. Pawlowski, R. Gil, A. Labellarte, A. Gziut, E. Caradonna, A. Manzoli, A. Pappalardo, F. Burzotta, and A. Boccanelli Stenting of Culprit Lesions in Unstable Angina Leads to a Marked Reduction in Plaque Burden: A Major Role of Plaque Embolization?: A Serial Intravascular Ultrasound Study Circulation, May 13, 2003; 107(18): 2320 - 2325. [Abstract] [Full Text] [PDF] |
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C. Briguori, J. Tobis, T. Nishida, M. Vaghetti, R. Albiero, C. Di Mario, and A. Colombo Discrepancy between angiography and intravascular ultrasound when analysing small coronary arteries Eur. Heart J., February 1, 2002; 23(3): 247 - 254. [Abstract] [Full Text] [PDF] |
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H. Okura, M. Hayase, S. Shimodozono, H. N. Bonneau, P. G. Yock, and P. J. Fitzgerald Impact of pre-interventional arterial remodeling on subsequent vessel behavior after balloon angioplasty: a serial intravascular ultrasound study J. Am. Coll. Cardiol., December 1, 2001; 38(7): 2001 - 2005. [Abstract] [Full Text] [PDF] |
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J.J Piek, E Boersma, M Voskuil, C di Mario, E Schroeder, C Vrints, P Probst, B de Bruyne, C Hanet, E Fleck, et al. The immediate and long-term effect of optimal balloon angioplasty on the absolute coronary blood flow velocity reserve. A subanalysis of the DEBATE study Eur. Heart J., September 2, 2001; 22(18): 1725 - 1732. [Abstract] [PDF] |
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P. Schoenhagen, K. M. Ziada, D. G. Vince, S. E. Nissen, and E. M. Tuzcu Arterial remodeling and coronary artery disease: the concept of "dilated" versus "obstructive" coronary atherosclerosis J. Am. Coll. Cardiol., August 1, 2001; 38(2): 297 - 306. [Abstract] [Full Text] [PDF] |
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D Fukuda, T Kawarabayashi, A Tanaka, Y Nishibori, H Taguchi, Y Nishida, K Shimada, and J Yoshikawa Lesion characteristics of acute myocardial infarction: an investigation with intravascular ultrasound Heart, April 1, 2001; 85(4): 402 - 406. [Abstract] [Full Text] |
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H. Okura, Y. Morino, A. Oshima, M. Hayase, M. R. Ward, J. J. Popma, R. E. Kuntz, H. N. Bonneau, P. G. Yock, and P. J. Fitzgerald Preintervention arterial remodeling affects clinical outcome following stenting: an intravascular ultrasound study J. Am. Coll. Cardiol., March 15, 2001; 37(4): 1031 - 1035. [Abstract] [Full Text] [PDF] |
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M. Nakamura, H. Nishikawa, S. Mukai, M. Setsuda, K. Nakajima, H. Tamada, H. Suzuki, T. Ohnishi, Y. Kakuta, T. Nakano, et al. Impact of coronary artery remodeling on clinical presentation of coronary artery disease: an intravascular ultrasound study J. Am. Coll. Cardiol., January 1, 2001; 37(1): 63 - 69. [Abstract] [Full Text] [PDF] |
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P. Wexberg, M. Gyongyosi, W. Sperker, K. Kiss, P. Yang, A. Hassan, G. Pasterkamp, and D. Glogar Pre-existing arterial remodeling is associated with in-hospital and late adverse cardiac events after coronary interventions in patients with stable angina pectoris J. Am. Coll. Cardiol., November 15, 2000; 36(6): 1860 - 1869. [Abstract] [Full Text] [PDF] |
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G. Pasterkamp, D. P.V de Kleijn, and C. Borst Arterial remodeling in atherosclerosis, restenosis and after alteration of blood flow: potential mechanisms and clinical implications Cardiovasc Res, March 1, 2000; 45(4): 843 - 852. [Abstract] [Full Text] [PDF] |
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S. G. Worthley, G. Helft, V. Fuster, A. G. Zaman, Z. A. Fayad, J. T. Fallon, and J. J. Badimon Serial In Vivo MRI Documents Arterial Remodeling in Experimental Atherosclerosis Circulation, February 15, 2000; 101(6): 586 - 589. [Abstract] [Full Text] [PDF] |
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R. Mehran, G. Dangas, G. S. Mintz, A. J. Lansky, A. D. Pichard, L. F. Satler, K. M. Kent, G. W. Stone, and M. B. Leon Atherosclerotic Plaque Burden and CK-MB Enzyme Elevation After Coronary Interventions : Intravascular Ultrasound Study of 2256 Patients Circulation, February 15, 2000; 101(6): 604 - 610. [Abstract] [Full Text] [PDF] |
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