European Heart Journal Advance Access originally published online on March 8, 2006
European Heart Journal 2006 27(14):1664-1670; doi:10.1093/eurheartj/ehi796
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Compensatory enlargement of human coronary arteries during progression of atherosclerosis is unrelated to atheroma burden: serial intravascular ultrasound observations from the REVERSAL trial
1 Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk F25, Cleveland, OH 44195, USA
2 Department of Diagnostic Radiology, The Cleveland Clinic Foundation, Cleveland, OH, USA
Received 8 October 2005; revised 17 December 2005; accepted 26 January 2006; online publish-ahead-of-print 8 March 2006.
* Corresponding author. Tel: +1 216 444 8130; fax: +1 216 445 7723. E-mail address: tuzcue{at}ccf.org
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Abstract |
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Aims On the basis of the evidence from autopsy studies, it is accepted that compensatory enlargement (remodelling) of coronary arteries during progression of atherosclerosis diminishes once atheroma burden (cross-sectional area stenosis) reaches
40%. Our aim was to evaluate whether atheroma burden is a limiting factor for coronary arterial remodelling using in vivo serial intravascular ultrasound (IVUS).
Methods and results From the cohort of the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial, we identified 210 focal coronary lesions at baseline IVUS. Of these, 128 lesions that had an increase in atheroma area at the 18-month follow-up IVUS were included in the analysis. Lesions were matched at baseline and follow-up. The increase in external elastic membrane (EEM) area for each mm2 increase in atheroma area was not significantly different in lesions with <40 and 
40% atheroma burden at baseline (1.62 vs. 1.28 mm2, P=0.30). There were no correlations between atheroma burden at baseline and change in EEM (r=0.02, P=0.86) or change in lumen (r=0.04, P=0.64) areas.
Conclusion Assessment of coronary arterial remodelling by serial IVUS revealed that compensatory remodelling is not limited by atheroma burden. Atheroma burden is not a determinant of arterial enlargement during the progression of atherosclerosis.
Key Words: Coronary artery disease • Remodelling • Intravascular ultrasound • Imaging
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Introduction |
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In a seminal article published in 1987, Glagov et al.1 demonstrated that coronary arteries enlarge in response to the development of atherosclerotic plaques. This phenomenon is commonly referred to as arterial remodelling. According to the analyses of Glagov et al.,1 the compensatory remodelling process maintained luminal dimensions during early atherosclerosis. Importantly, these investigators reported that the capacity for compensatory enlargement diminished as plaques reached a cross-sectional area stenosis (atheroma burden) of
40% and plaque growth beyond this point resulted in a reduction of luminal area. This initial histological autopsy study and subsequent histological2 and intravascular ultrasound (IVUS)3–5 studies of arterial remodelling were based on the examination of lesions with varying disease severity using a cross-sectional study design, in which data were obtained only at a single time point. However, using this approach, the temporal sequence of plaque growth, remodelling, and luminal compromise could only be inferred. Serial in vivo IVUS studies are more difficult to perform, but allow direct assessment of the plaque progression and remodelling response.6–10 We sought to examine the validity of Glagov's observation that coronary arteries lose their capacity for remodelling with increasing atheroma burden by using serial IVUS. The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial11,12 examined coronary disease progression during moderate or intensive lipid-lowering therapy. This trial represented an ideal setting for examining the serial remodelling response, because coronary atheroma, lumen, and vessel dimensions were evaluated by IVUS over time.
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Methods |
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Study population
The REVERSAL trial enrolled patients aged 30–75 years who required coronary angiography for a clinical indication and demonstrated at least one obstruction with angiographic luminal diameter narrowing of
20%.11,12 The target vessel for the IVUS interrogation (a single coronary artery per patient) must not have undergone percutaneous intervention, nor have an angiographic luminal narrowing of >50%. We screened the baseline IVUS tapes of the 502 patients who completed the REVERSAL trial to identify those who had a focal atherosclerotic lesion. Diffusely diseased arteries were excluded because of the relative difficulty in serial matching of the lesion sites in such arteries. The lesions were further screened for the absence of extensive calcification precluding accurate measurement of external elastic membrane (EEM) area. A single lesion was selected from each patient (the most proximal one in the case of multiple acceptable lesions). A total of 210 lesions met the inclusion criteria. Because we intended to examine Glagov's conclusion that remodelling prevents lumen loss until an atheroma burden of 40% and plaque growth beyond this point results in luminal compromise, we included the 128 lesions that showed plaque growth (i.e. an increase in atheroma area at follow-up) in the current analysis. The REVERSAL trial complied with the Declaration of Helsinki. The Institutional Review Board of the Cleveland Clinic Foundation approved research using this database.
Intravascular ultrasound
The acquisition and measurement methodology of coronary IVUS images used in atherosclerosis progression–regression trials have been described in detail previously.11,13 Briefly, after administration of 100–300 µg of intracoronary nitroglycerin, a 30 MHz, 2.6 F (0.87 mm) IVUS catheter (Ultracross, Boston Scientific Scimed Inc., Maple Grove, MN, USA) was advanced into the target vessel for IVUS interrogation and the transducer was positioned distal to a side branch (distal fiduciary site). A motorized pullback system withdrew the transducer at a speed of 0.5 mm/s. During the pullbacks, images were obtained at 30 frames/s and were recorded on s-VHS videotape for off-line analysis. After digitization of the videotapes, measurements of EEM area (a measure of arterial area) and lumen area were performed in accordance with the standards of the European Society of Cardiology14 and American College of Cardiology.8 Measurements were performed at every 60th frame (i.e. every 1 mm), starting at a distal fiduciary site and ending at a proximal fiduciary site. Atheroma area was calculated as EEM area minus lumen area. For this study, the frame with the largest amount of atheroma relative to the arterial size on inspection of the lesion was identified as the lesion site. For the lesion sites, atheroma burden was then calculated as:
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Follow-up IVUS was performed after an 18-month treatment regimen with randomized double-blind atorvastatin 80 mg/day or pravastatin 40 mg/day. The IVUS interrogation was repeated under identical conditions at follow-up. Distances from the proximal and distal fiduciary sites, as well as plaque characteristics (e.g. calcifications and plaque shape) and perivascular structures, were used to match the lesion site at baseline and follow-up. The IVUS measurements were repeated at the lesion site at follow-up.
Assessment of arterial remodelling
To reproduce Glagov's finding that luminal compromise begins once an atheroma burden of 40% is reached, we correlated atheroma burden and lumen area using only the baseline data.1 Subsequently, we evaluated the relationship between atheroma burden at the beginning of the study, and the actual change in lumen area over time (i.e. serial approach). We evaluated the relationship between atheroma burden and EEM area using the same methods.
The primary outcome measure of this study was the homogeneity of regression slopes correlating the change in atheroma area with the change in EEM area in lesions with <40 and 40% atheroma burden at baseline. A difference in the regression slopes would demonstrate that for each mm2 change in atheroma area, the change in EEM area would be different for lesions with <40 and 40% atheroma burden. This would signify a differential remodelling response in the two groups of lesions. In addition, this outcome measure was evaluated after controlling for on-treatment (follow-up) LDL cholesterol and log-transformed C-reactive protein levels, in an effort to limit the possible effects of statins. The same outcome measure was also evaluated using different cut-off values for atheroma burden.
For further analysis, serial remodelling response was evaluated by change in EEM area/change in atheroma area, which was calculated as:8
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Data analysis
Analyses were performed with SPSS 11.5 for Windows (SPSS Inc., Chicago, IL, USA). Quantitative data are expressed as mean±SD and categorical data as n (%), unless stated otherwise. Comparison of baseline and follow-up data was performed with the paired t-test, except for the non-normally distributed C-reactive protein, for which Wilcoxon's signed rank test was used. Whether the category of remodelling differed in lesions with <40 and 40% atheroma burden was examined with Fisher's exact test. Relationships were assessed by linear regression analysis, and the homogeneity of regression slopes was tested by analysis of covariance. Spearman's rank correlation was used in the case non-normally distributed data (change in EEM area/change in atheroma area). The outcome measure of homogeneity of regression slopes correlating the change in atheroma area with the change in EEM area in lesions with <40 and 40% atheroma burden was re-evaluated with follow-up LDL cholesterol and log-transformed C-reactive protein levels entered into the model as covariates. Adjustments using these two parameters were performed in an effort to control for the possible effects of statins on remodelling. Two-sided P-values of less than 0.05 were considered significant. The alpha level was not adjusted for multiple testing.
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Characteristics of the study population
The clinical characteristics of the study population are presented in Table 1. Total cholesterol, LDL cholesterol, and triglycerides were lower, and HDL cholesterol was higher at follow-up when compared with baseline.
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IVUS data at baseline and follow-up
Of the 128 lesions analysed, 11(9%) were in the left main, 35 (27%) in left anterior descending, 46 (36%) in the left circumflex, and 36 (28%) in the right coronary artery. Range for atheroma burden was 28–77% at baseline. Twenty-eight lesions had <40% and 100 lesions had
40% atheroma burden. By definition, atheroma area was greater at follow-up (Table 2). This was associated with increased EEM and lumen areas at follow-up (P<0.001 for both).
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Atheroma burden and remodelling
There was an inverse relation between lumen area and atheroma burden when only the baseline data were used (r=–0.57, P<0.0001) (Figure 1). The correlation was evident when the analysis was limited to lesions with
40% atheroma burden at baseline (r=–0.51, P<0.001). However, there was no statistically significant correlation when this analysis was limited to lesions with <40% atheroma burden (r=–0.24, P=0.22) (P=0.51 for the heterogeneity of slopes for atheroma burden values <40 and 40%). However, very different results were observed with the serial approach. There was no relationship between the actual change in lumen area at follow-up and the atheroma burden (r=0.04, P=0.64), regardless of whether arteries had <40 or 40% atheroma burden (P=0.98 for the heterogeneity of slopes for atheroma burden values <40 and 40%).
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Similarly, when only the baseline data were used, there was a trend for an inverse relationship between cross-sectional area stenosis (atheroma burden) and EEM area (r=–0.17, P=0.06). However, there was no relationship between atheroma burden and change in EEM area over time (r=0.02, P=0.86).
There were significant correlations between changes in atheroma and EEM areas in lesions with both <40 (r=0.68, P<0.001) and 40% (r=0.73, P<0.001) atheroma burden (Figure 2). As the primary outcome measure, the increase in EEM area for each mm2 increase in atheroma area (i.e. slope of the regression line) was not significantly different in lesions with <40 and 40% atheroma burden at baseline (1.62 vs. 1.28 mm2, P=0.30). After controlling for on-treatment LDL cholesterol and C-reactive protein levels, the increase in EEM area for each mm2 increase in atheroma area was also not different in the two groups (1.56 vs. 1.27 mm2, P=0.38). Similarly, the slopes of the regression lines were not significantly different in lesions with baseline atheroma burden <50 and 50% (1.33 vs. 1.33 mm2, P=0.99) and <60 and 60% (1.32 vs. 1.45 mm2, P=0.77). There was no relationship between baseline atheroma burden and ‘change in EEM area/change in atheroma area’ when both parameters entered into the regression analysis as continuous variables (r=0.04, P=0.64). The category of the remodelling response was also not significantly different according to baseline atheroma burden (P=0.44) (Figure 3). Representative serial IVUS images of lesions with <40 and 40% atheroma burden are shown in Figure 4.
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Eccentricity and remodelling
There was no correlation between atheroma eccentricity index at baseline and change in EEM area/change in atheroma area (r=0.04, P=0.70). There was no correlation between minimum atheroma thickness at baseline and change in EEM area/change in atheroma area as well (r=–0.06, P=0.54). Coronary risk factors (age, male gender, current smoking, hypertension, diabetes and on-treatment total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, and log-transformed C-reactive protein levels) were not determinants of ‘change in EEM area/change in atheroma area’ either (P>0.30 for all).
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Discussion |
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Our serial IVUS observations demonstrate that the extent of coronary arterial enlargement in response to progression of atherosclerosis is not related to per cent cross-sectional stenosis (atheroma burden). The increase in EEM area for each mm2 increase in atheroma area is not significantly different in lesions with <40 and
40% atheroma burden and is independent of the eccentricity of the lesion at baseline.
Arterial remodelling is the mechanism by which the luminal size is preserved despite the development of an atherosclerotic plaque. This phenomenon was first systematically described in a histopathological study by Glagov et al.1 Using 136 left main coronary arteries obtained at autopsy, these investigators demonstrated a positive correlation between internal elastic membrane area (a measure of arterial area) and plaque area, which showed that arteries enlarge as atherosclerosis progresses. In addition, there was a negative correlation between atheroma burden and lumen area in lesions with 40% atheroma burden. Importantly, this correlation was not observed in lesions with <40% atheroma burden. Therefore, it was concluded that the compensatory enlargement sharply declines after coronary lesions occupy 40% of the arterial area. This conclusion has been widely accepted.3,4,15–18
However, there are theoretical limitations with this approach. Because atheroma burden is calculated as (internal elastic membrane area–lumen area)/internal elastic membrane area,1 the relationship between lumen area and atheroma burden can be described as the relationship between a and (b–a)/b. Therefore, mathematically, as a decreases, (b–a)/b will increase. This can explain the smaller lumen areas with larger atheroma burden. In fact, results from other histopathological studies do not completely support the conclusion that compensation fails when stenosis reaches 40%. In one study, there was an increase in lumen area with increasing plaque area, suggesting that more severely diseased arteries had greater over-compensation.19 Interestingly, in the same study, there was an inverse relationship between lumen area and atheroma burden, which paralleled the results of Glagov et al.1 This discrepancy demonstrates the contradictory interpretations conveyed by studying the relationship between lumen area and plaque area, rather than lumen area vs. a function of lumen area (i.e. atheroma burden). The limitation of studying arterial remodelling by correlation analysis of mathematically related variables has also been reported in an IVUS study.20 Because of the limitations of the assessing arterial remodelling at a single time point, the American College of Cardiology/European Society of Cardiology clinical expert consensus document on IVUS has stated that evidence of remodelling would be best directly derived from measurements obtained at different time points (i.e. serial assessment).8
We found important differences when we analysed remodelling using the two approaches. The comparison of single time point assessment that uses only the baseline data with serial assessment that uses both baseline and follow-up data provides insights into the reasons for the discrepancy. The former approach is the method introduced by Glagov and co-workers. Using this method, we could reproduce the findings of these investigators, demonstrating compensatory remodelling in lesions with <40% atheroma burden, but a lack of compensation once atheroma burden reaches 40%. However, the results were very different when remodelling was assessed over the 18-month follow-up period. This serial approach revealed that lesions with 40% atheroma burden have the same remodelling behaviour as lesions with <40% atheroma burden. This serial approach explores the relationship between lumen area and atheroma burden by adding a third independent variable (i.e. lumen area at follow-up) to the relationship. The addition of this variable to the correlation analysis weakens the possibility of an inevitable correlation between mathematically related variables. Because of this additional variable in the serial assessment, the time-dependent phenomena of remodelling and luminal compromise during plaque progression could be explored, demonstrating that atheroma burden is not a determinant of compensatory remodelling of coronary arteries.
Glagov et al.1 also proposed that earlier (i.e. less stenotic) lesions are usually more eccentric, and the presence of a larger arc of disease-free arterial wall in these lesions accounts for their greater capacity for compensatory remodelling. We found no relationship between atheroma eccentricity index and the serial remodelling response, which does not support this hypothesis. We found no relationship between minimum atheroma thickness (another measure of disease-free arterial wall) and remodelling either.
Limitations
Serial IVUS studies are limited by difficulties in matching single cross-sections at different time points because of the diffuse nature of atherosclerosis. Therefore, in contemporary serial IVUS trials studying progression and/or regression of atherosclerosis, volumetric assessment of disease burden is preferred over two-dimensional measurements.11,13 However, to be able to reproduce the results of Glagov et al.,1 we choose the two-dimensional approach of these investigators. Although every effort was made to match the lesion sites at baseline and follow-up, matching may have been imperfect in some cases. The included lesions were identified in patients undergoing either a moderate or an aggressive lipid-lowering regimen. Therefore, our results describe observations in lesions with progression of disease, despite lipid-lowering therapy. As treatment with statins may alter the remodelling response,9,21 we did a secondary analysis of the outcome measure using LDL cholesterol and C-reactive protein levels as covariates. Even though these two variables did not influence the lack of relationship between atheroma burden and remodelling, there is still a possibility that our findings may not be applicable to lesions of patients not undergoing statin treatment. Similarly, these findings may not be applicable to diffuse or overtly calcified lesions, which were not included in this study.
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Conclusions |
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Assessment of arterial remodelling using serial in vivo IVUS reveals that atheroma burden (per cent cross-sectional area stenosis) is not a determinant of the extent of coronary arterial enlargement during disease progression. We demonstrate that serial assessment of atherosclerotic disease provides novel insights into the relationship between the plaque progression and the remodelling response.
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Acknowledgements |
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We thank Timothy Crowe, William A. Magyar, Deborah Hansen, Tammy Churchill, Benlan Wong, and Aaron Loyd at The Cleveland Clinic Foundation Intravascular Ultrasound Core Laboratory for their technical support. The REVERSAL trial was funded by Pfizer. This substudy is partially funded by the National Institutes of Health, National Center for Research Resources, General Clinical Research Center Grant MO1 RR-018390. P.S. was supported by a postdoctoral fellowship grant of the Ohio Affiliate of the American Heart Association. A Ralph Reader Overseas Research Fellowship from the National Heart Foundation of Australia supports S.J.N.
Conflict of interest: I.S. received an educational grant from Pfizer. E.M.T. has received research support and lecture honoraria from Pfizer. S.J.N. received lecture honoraria from Pfizer. S.E.N. has received research support from and is an unpaid consultant to Pfizer.
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