European Heart Journal Advance Access originally published online on August 31, 2007
European Heart Journal 2007 28(19):2326-2331; doi:10.1093/eurheartj/ehm255
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Effect of perindopril on coronary remodelling: insights from a multicentre, randomized study
1 Department of Interventional Cardiology, Thoraxcenter, Erasmus MC, Rotterdam, The Netherlands
2 Department of Cardiovascular Imaging, Otamendi Hospital, Azcuénaga 870, C1115AAB Buenos Aires, Argentina
Received 8 February 2007; revised 3 May 2007; accepted 18 May 2007; online publish-ahead-of-print 31 August 2007.
* Corresponding author. Tel/fax: +54 11 49648721. E-mail address: grodriguezgranillo{at}gmail.com
See page 2299 for the editorial comment on this article (doi:10.1093/eurheartj/ehm276)
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Abstract |
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Aims: This study sought to evaluate the effect of perindopril in coronary remodelling.
Methods and results: In this sub-study of a double-blind, multicentre trial, patients without clinical evidence of heart failure were randomized to perindopril 8 mg/day or placebo for at least 3 years and IVUS investigation was performed at both time-points. Positive and negative remodelling were defined as a relative increase (positive remodelling) or decrease (negative remodelling) of the mean vessel cross-sectional area (CSA) > 2 SD of the mean intra-observer difference. A total of 118 matched evaluable IVUS (711 matched 5 mm segments) were available at follow-up. After a median follow-up of 3.0 (inter-quartile range 1.9, 4.1) years, there was no significant difference in the change of plaque CSA between perindopril (360 segments) and placebo (351 segments) groups, P = 0.27. Conversely, the change in vessel CSA was significantly different between groups (perindopril –0.18 ± 2.4 mm2 vs. placebo 0.19 ± 2.4, P = 0.04). Negative remodelling occurred more frequently in the perindopril than in the placebo group (34 vs. 25%, P = 0.01). In addition, the placebo group showed a larger, although not significant, mean remodelling index (RI) than the perindopril group (1.03 ± 0.2 vs. 1.00 ± 0.2, P = 0.06). The temporal change in vessel dimensions assessed by the RI was significantly correlated with the change in plaque dimensions (r = 0.48, P < 0.0001).
Conclusion: In this sub-analysis of a multicentre, controlled study, long-term administration of perindopril was associated with a constrictive remodelling pattern without affecting the lumen.
Key Words: ACE-inhibitor • Progression • Remodelling • Atherosclerosis • Regression • EUROPA
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Introduction |
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By preventing encroachment of the lumen and hence coronary flow, outward (positive) remodelling of coronary vessels was initially regarded as beneficial.1 Notwithstanding, several studies have shown increased levels of inflammatory markers, larger lipid cores and pronounced medial thinning in positive remodelled vessels; being all factors related to the tendency of plaques to undergo rupture.2–5
Angiotensin-converting enzyme (ACE) inhibitors have demonstrated their efficacy in reducing mortality in both high- and low-risk patients.6,7 In parallel, ACE-inhibitors inhibit progressive left ventricular remodelling, a critical factor that determines life expentancy.8,9 More recently, ACE-inhibitors have shown to be effective in reversing vascular remodelling in the peripheral circulation.10,11
Atherosclerosis is a highly dynamic and multifocal disease, and coronary remodelling occurs diffusely within a vessel, even in seemingly healthy references.12 Accordingly, longitudinal studies have been recognized as the gold-standard for remodelling assessment.13
Driven by the significant regression of coronary atherosclerosis induced by lipid-lowering therapies,14 the PERindopril's Prospective Effect on Coronary aTherosclerosis by IntraVascular ultrasound Evaluation (PERSPECTIVE) trial evaluated the effect of long-term administration of perindopril on coronary plaque progression as assessed by angiography and intravascular ultrasound (IVUS) and demonstrated that the clinical benefit of ACE-inhibitors cannot be attributed to their effect on plaque size.15 We performed a post hoc analysis of the PERSPECTIVE study to assess the effect of perindopril in coronary remodelling. In addition, we evaluated the effect of perindopril on a surrogate of plaque composition.
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Methods |
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The EUROPA was a multicentre, randomized, double-blind, placebo-controlled study that evaluated the effect of perindopril on prevention of cardiovascular events in patients with coronary artery disease on 12 218 patients. PERSPECTIVE was a sub-study of the EUROPA trial that sought to explore the effect of perindopril on atherosclerosis progression/regression using coronary angiography and IVUS.
The methodology of the EUROPA trial has been extensively described elsewhere.7 In brief, patients were eligible if they were aged 
18 years, without clinical evidence of heart failure and with evidence of coronary heart disease documented by previous myocardial infarction (>3 months before screening), percutaneous or surgical coronary revascularization (>6 months before screening), or angiographic evidence of at least 70% narrowing of one or more major coronary arteries.
In addition, for the IVUS sub-analysis patients required anatomically suitable vessels for the angiography/IVUS sub-study.
In a run-in period, enrolled patients received 4 mg/day oral perindopril for 2 weeks in addition to their normal medication, followed by 8 mg/day for 2 weeks if the initial dose was tolerated. At the end of the run-in period, patients were randomly assigned to perindopril 8 mg/day or placebo for 3 years.
The institutional ethics committees of all participating centres approved the study protocol and informed written consent was obtained from all patients.
Intravascular ultrasound acquisition
IVUS was acquired using 20, 30, and 40 MHz imaging catheters following coronary angiography. The catheter was advanced distal to an anatomically identifiable landmark, allowing the evaluation of a segment of at least 30 mm. Cine runs, before and during contrast injection, were performed to define the position of the IVUS catheter before the pullback was started. Using an automated pullback device, the transducer was withdrawn at a continuous speed of 0.5 mm/s until the ostium. IVUS data were acquired after the intracoronary administration of nitroglycerin and stored on S-VHS videotape. The videotapes were digitized on a computer system, transformed into the DICOM medical image standard and stored on an IVUS Picture Archiving and Communications System (PACS). After a 3-year follow-up period, patients underwent repeat catheterization and IVUS examination of the same region of interest (ROI) using an identical frequency IVUS imaging catheter.
Intravascular ultrasound analysis
Quantitative coronary ultrasound analysis was performed by an independent core laboratory (Cardialysis BV, Rotterdam, The Netherlands) using validated semi-automatic contour detection software (Curad, version 3.1, Wijk bij Duurstede, The Netherlands). The IntelliGateTM image-based gating method was applied to eliminate catheter-induced image artifacts, by retrospectively selecting end-diastolic frames.16
In order to avoid the significant impact of inter-observer variability,17 contour detection was performed by a single experienced IVUS analyst who was blinded for the randomization allocation and time-point of the study. Longitudinal and cross-sectional views were used to determine the contours.
The contours of the external elastic membrane (EEM) and the lumen-intima interface enclosed an area that was defined as the coronary plaque plus media area. Plaque burden (PB) was defined as [(EEMarea – Lumenarea)/EEMarea] x 100. Direct measurements [lumen and vessel cross-sectional area (CSA)] were also determined. In the baseline IVUS study, a ROI was identified using identifiable landmarks such as side-branches and the coronary ostium. At 3-year follow-up, the same matched ROI was identified using the original anatomical landmarks to determine the lumen and vessel dimensional changes over time and consequently to calculate the impact on plaque changes. In order to assess more precisely the heterogeneous remodelling pattern within a vessel, the ROIs were subsequently subdivided in matched 5 mm sub-segments independently of the length of the pullback in the original IVUS study. Segments with a PB < 10% were excluded.
Coronary remodelling was assessed using continuous and categorical variables. The remodelling index (RI) was defined as EEMarea at follow-up divided by the EEMarea at baseline.
Finally, we evaluated the number of segments presenting positive remodelling (defined as a relative increase in vessel CSA > 2 SD from the mean relative intra-observer difference) and negative remodelling (defined as a relative temporal decrease > 2 SD from the mean relative intra-observer difference).
IVUS tissue characterization
We used a computer-aided, in-house developed gray-scale value analysis programme for plaque characterization.18 Using the mean gray level of the adventitia as a threshold, plaque was classified as more (hyperechogenic) or less (hypoechogenic) bright in relation to the adventitia. Upper and calcified tissue was defined as tissue that has a mean gray value higher than the mean adventitial intensity plus two times its standard deviation. The echogenicity software calculated the distribution of the gray-values present in the adventitia layer. When this distribution was not normal (severely calcified vessels), the data were excluded for IVUS analysis since the acoustic shadowing obscures the media-adventitia interface thus introducing serious inaccuracy in the contour detection.
Statistical analysis
Discrete variables are presented as counts and percentages. Continuous variables are presented as means ± SD or medians (inter-quartile range) as indicated. Pearson correlation coefficients were performed in order to estimate correlations between measurements.
Differences between groups were assessed by paired and unpaired Student's t-test when applicable. Fisher's exact test was used for categorical variables. A two-sided P-value < 0.05 was required for statistical significance. All analyses were performed using SPSS version 13.0 software (Chicago, IL, USA).
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Results |
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Study population
A total of 118 patients who had completed IVUS investigation at baseline and follow-up were included in the study. Populations were well matched (Table 1). The mean age was 56.6 ± 8.9, 100 (83.3%) were male, 11 (9.2%) had diabetes mellitus, 59 (49.2%) had history of prior myocardial infarction and 30 (25.0%) had hypertension. With regards to concomitant baseline medication, 115 (95.8%) were on aspirin, 67 (55.8%) were receiving beta-blockers, 32 (26.7%) were receiving nitrates, 46 (38.3%) were on calcium channel blocker therapy and 91 (75.8%) were on lipid-lowering therapy. Coronary risk factors and baseline blood pressure were well balanced between groups (Table 1).
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At a median follow-up of 3.0 (range 1.9, 4.1) years, the rate of adverse events was minimal. Coronary revascularization [2 (3.3%) vs. 4 (6.9%), P = 0.38] and acute myocardial infarction [1 (1.7%) vs. 3 (5.2%), P = 0.30] rates were not statistically significant between perindopril and placebo groups. No deaths, strokes or admissions for heart failure were reported.
IVUS intra-observer variability
Fifteen cases (678 frames) were re-analysed by the same observer yielding minor differences between the 2 measurements. Relative differences for lumen, vessel, and plaque CSA were 1.43 ± 4.2%, 1.01 ± 3.4%, and 3.50 ± 8.5%, respectively. In addition, lumen (r2 = 0.99, P < 0.0001), vessel (r2 = 0.99, P < 0.0001), and plaque (r2 = 0.87, P < 0.0001) CSA measurements were highly correlated.
Intravascular ultrasound measurements
A total of 118 matched evaluable IVUS (711 matched 5 mm segments) were available at follow-up. Fifty-eight patients were excluded from the final analysis (29 from each group) due to sub-optimal IVUS quality (due to severely calcified vessels, severe artifacts or absence of clear anatomical landmarks). Quantitative IVUS results are shown in Table 2.
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In the perindopril group, the temporal change in mean plaque CSA compared with baseline was –0.15 ± 1.7 mm2 (P = 0.11). For the placebo group, the change was –0.01 ± 1.7 mm2 (P = 0.95), with a P-value of 0.27 between groups. The temporal change in mean vessel CSA was –0.18 ± 2.4 mm2 in the perindopril group and 0.19 ± 2.4 mm2 in the placebo group, with a P-value of 0.04 between groups. With regards to plaque hypoechogenicity, no significant difference was present between groups (perindopril –0.30 ± 1.7 mm2 vs. placebo –0.11 ± 1.7 mm2, P = 0.12). Both groups showed a highly heterogeneous remodelling pattern along the coronary segments (Figure 1). Nevertheless, the placebo group showed a larger mean RI than the perindopril group (1.03 ± 0.2 vs. 1.00 ± 0.2, P = 0.06). Of interest, negative remodelling was present in 124 (34.4%) segments in the perindopril group and in 86 (24.5%) segments in the placebo group. Conversely, positive remodelling was observed in 102 (28.3%) segments in the perindopril group and in 110 (31.3%) segments in the placebo group, with a significant (
2) difference between groups (P = 0.01). These changes are depicted in Table 3.
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Linear regression analysis
The temporal change in vessel dimensions assessed by the RI was significantly correlated to the change in plaque dimensions (r = 0.48, P < 0.0001). The degree of such correlation was higher in the perindopril group than in the placebo group (r = 0.58, P < 0.0001 and r = 0.36, P < 0.0001, respectively). As expected, the change in hypoechogenic content was highly related to the change in plaque (r = 0.95, P < 0.001) and vessel (r = 0.45, P < 0.001) CSA.
A strong relationship was found between changes in plaque and changes in vessel size (perindopril r = 0.62, P < 0.0001 and placebo r = 0.35, P < 0.0001). Such relation became stronger with increasing levels of PB at baseline (Figure 2A). In parallel, the placebo group showed a significant inverse relationship between the change in plaque and lumen CSA that was stronger at earlier stages of the disease (Figure 2B).
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plaque size and |
Discussion |
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The importance of coronary remodelling as a factor that has a major impact in the maintenance of lumen dimensions has been undoubtedly established.1 Recently, several investigators have linked this originally deemed protective compensatory response of the vessel to the presence of a more unstable phenotype and plaque rupture.2–5,19 Conversely, a paradoxical negative remodelling pattern has been associated with a more stable clinical presentation and lesion phenotype.2,20 To date, most studies have assessed coronary remodelling at a single time-point and focally within the vessel, using proximal and distal references as surrogates of vessel size before it becomes diseased. However, coronary atherosclerosis is commonly a diffuse disease and finding a healthy reference is hard to attain. Moreover, such diffuse pattern implies a heterogeneous behaviour of atherosclerotic disease within a single vessel. Yet, although the assessment of coronary remodelling using serial determinations is highly required it has been scarcely exploited.13,21
The findings of the present longitudinal in vivo study offer several insights towards the better understanding of the long-term effect that ACE-inhibitors have on coronary atherosclerosis.
Overall, no significant differences regarding the temporal changes in plaque and lumen size were present between patients assigned to perindopril and placebo. Nevertheless, there was a significant difference between groups regarding the change in vessel size.
Negative remodelling occurred more frequently in the perindopril group than the placebo group. It is noteworthy though that, as a result of a parallel non-significant plaque regression effect, this slight constrictive effect had no impact on the lumen size. Similarly, the placebo group showed a larger mean RI than the perindopril group and a trend towards an enlargement of the coronaries with no change in plaque size, resulting in a non-significant increase of the lumen area.
The observed effect of perindopril on vessel remodelling might potentially be owed to the reduction in metalloproteinase levels induced by ACE-inhibitors,22 since these enzymes have a central role in the pathophysiology of vessel remodelling.12 Lipid lowering therapy with statins has recently shown to promote negative remodelling. The pathophysiology of such finding might be attributed to the inhibition of matrix metalloproteinase production.23 Statins and ACE-inhibitors thus have a common inflammatory target related to coronary remodelling and plaque stabilization.
Contrasts with histopathology
Coronary remodelling has been long believed a vessel response to accommodate increasing burden of plaque without affecting the lumen patency.1 In his study, Glagov made a static assessment of the correlation between plaque and vessel size in explanted left main coronary arteries. Our results are in line with the study of Glagov with respect to the fact that coronary remodelling is a phenomenon that occurs from very early stages of the disease and is mainly driven by the progressive accumulation of plaque within the vessel wall. Nevertheless, in our study, the strength of the relationship between changes in plaque CSA and changes in lumen CSA decreased with increasing levels of stenosis at baseline (Figure 1). Conversely, Glagov established that the positive correlation between vessel size and plaque size was stronger in sections with stenoses 
20% and that an abrupt drop in lumen area was evident only after the obstruction reached 30–40%.1 In brief, our results contradict Glagov's in the sense that control group patients showed higher remodelling capacity (and lumen manteinance) when the baseline severity of the disease was higher. It is noteworthy, however, that Glagov's seminal investigation was performed in the left main coronary artery, a coronary segment with a more benign plaque composition,24 whereas it has previously been shown that the remodelling pattern of plaques is highly related to the underlying composition of plaques.5 It should be emphasized as well that statins, which have been shown to have a significant effect on plaque14 and vessel23 size, are currently administrated in an almost unrestricted fashion to cardiovascular patients, whereas two decades ago they were limited to patients with hypercholesterolemia. Finally, it is worth mentioning that, although there was no significant difference between groups regarding the change of hypoechogenic tissue, the administration of perindopril induced a significant beneficial shift in the echogenicity of plaques compared with baseline.
The findings of the present study confirm that coronary atherosclerosis is a highly dynamic disease. Moreover, the constrictive, yet lumen-preserving, effect shown has previously been associated with a more stable phenotype of lesions and better clinical presentation, suggesting that this pattern is associated with plaque stabilization.
Study limitations
A substantial number of vessels were excluded from the analysis due to sub-optimal image quality, principally due to the presence of severely calcified vessels. Nevertheless, we want to emphasize that this was essential to have a highly accurate assessment of the vessel contours. Only a single coronary artery was assessed by IVUS potentially being not representative of the entire coronary tree. Moreover, different IVUS catheters and consoles were used over a 3-year period, potentially influencing the results. Nevertheless, individual serial assessments were performed using identical IVUS catheters. To correct for any dimensional discrepancies, the results of the 30 MHz catheter were adjusted using a previously reported mathematical algorithm.25 Larger studies in higher risk patients using IVUS as primary endpoint might conclusively determine the role of ACE-inhibitors in atherosclerosis natural history.
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Conclusion |
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Our findings convey the relationship between plaque progression and coronary remodelling. In this study, perindopril was associated with a constrictive remodelling pattern without affecting the lumen, suggesting that this pattern is associated with plaque stabilization.
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Acknowledgement |
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The PERSPECTIVE study was supported by Servier, France. The sponsor was not involved in the data collection and/or data analyses.
Supplementary material
Supplementary material is available at European Heart Journal online.
Conflict of interest: none declared.
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References |
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