Eccentric atherosclerotic plaques with positive remodelling have a pericardial distribution: a permissive role of epicardial fat?
A three-dimensional intravascular ultrasound study of left anterior descending artery lesions
F Pratia,*,
E Arbustinib,
A Labellartec,
L Sommarivaa,
T Pawlowskic,
A Manzolia,
A Paganoa,
M Motolesec and
A Boccanellia
a San Giovanni Hospital, Rome, Italy
b Institute of Pathology, San Matteo, Pavia, Italy
c European Imaging Laboratory, European Hospital, Via Portuense 700, 00149 Rome, Italy
Received May 13, 2002;
accepted June 26, 2002
* Corresponding author. Fax: +39-06-65-38-845
f.prati{at}libero.it
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Abstract
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Aims The transversal distribution of coronary atherosclerotic plaques (AP) (myocardial vs pericardial) affects vessel remodelling. The aim of this study was to define the impact of transversal lesion distribution on vessel remodelling in proximal and distal coronary segments using a 3D intravascular ultrasound (IVUS) reconstruction.
Methods The study group included 70 lesions located in the left anterior descending artery within 5mm of the septal take-off, and imaged using 3D-IVUS. The take-off of the septal branch was used to divide the plaque into a myocardial and pericardial surface. The IVUS index of vessel remodelling was calculated as: [narrowest external elastic membrane (EEM) site cross-sectional area (CSA)reference EEM CSA)/reference EEM CSAx100]. The lesions with an intermediate vessel remodelling index (between 25% and +15%) were excluded from analysis.
Results Of the 38 APs with a pericardial distribution, 34 (89%) showed positive remodelling
. The distal lesions had a positive vessel remodelling index regardless of transversal plaque distribution. At multivariate analysis, pericardial distribution and the distal location of AP were the only independent variables predictive of positive remodelling.
Conclusions The transversal distribution of atherosclerotic plaque affects vessel remodelling in left anterior descending coronary lesions, probably because of an extravascular splinting effect. Distal lesions usually show positive remodellingregardless of transversal plaque distribution.
Key Words: Arterial remodelling Intravascular ultrasound Coronary artery disease
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1. Introduction
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The presence of atherosclerotic plaque (AP) in coronary arteries commonly leads to an asymmetric expansion of the vessel wall that is known as positive vessel remodeling;14 however, as previously reported, its absence is not uncommon.59
It has recently been suggested that positiveremodelling and cross-sectional plaque distribution may be reciprocally related, as positiveremodelling preferentially occurs in the lesionsfacing the pericardial side and is minimal or absent in the lesions facing myocardial tissue.10 A major limitation in evaluating the cross-sectional distribution of AP is the precise definition of the pericardial or myocardial hemi-arcs of the vessel wall. The intravascular ultrasound (IVUS) identification of septal branches, which emerge on the side of the vessel opposite the pericardium, can be used to divide the plaque into a myocardial and pericardial surface.
In this study, we used 3D-IVUS to image a consecutive series of plaques in the left anterior descending artery in order to study the relationship between positive vessel remodelling and plaque distribution. Furthermore, as a distal AP locationis a recognised predictor of positive vessel remodeling,11 we also investigated whether therelationship between positive remodelling and cross-sectional plaque distribution is maintained in distal coronary segments.
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2. Methods
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2.1. Lesion selection and patient population
We analysed all of the images of pre-intervention left anterior descending coronary arteries contained in the database of the European Imaging Laboratory (EIL) of the European Hospital in Rome, Italy. The take-off of the septal branches opposite the pericardium was used as a marker to divide the vessel wall into myocardial and pericardial hemi-arcs. Only the lesions identified by both IVUS and angiography, and located within 5mm of the take-off of a septal branch and 10mm of the reference sites, were included in the study and reconstructed using a 3D-IVUS algorithm.
An off-line angiographic analysis was made using a cranial view that shows septal branches on the left, and diagonal branches on the right. Thecoronary arteries were divided into proximal (segment 6), mid (segment 7), and distal segments (segment 8) according to the AHA-ACC classification.12 The IVUS and angiographic images were matched using an automated (0.5mm) IVUS image acquisition technique.
The following were excluded: (1) low-quality IVUS images of proximal or distal target lesions and reference segments; (2) ostial plaques; (3) vessels with side branches between the AP and distal or proximal reference segments; (4) plaques withcalcific arcs >180° hampering the accurate assessment of the external elastic membrane (EEM) area at either the target lesion or reference segment site.
One hundred and forty-seven atheroscleroticlesions were analysed in 147 patients (one lesion per patient). Fifty-nine arteries were excluded from the final analysis because of an ostial target lesion location (three cases), low-quality IVUSimages (11 cases), the presence of diffuse calcific deposits in the target lesion (16 cases), an inability to match the IVUS and coronary angiography images (10 cases), an inability to identify a referencesegment with a plaque burden of less than 40% (19 cases).
The final study group therefore consisted of 88 atherosclerotic lesions: 37 came from baselineassessments of progression-regression studies; in the remaining 56 cases, IVUS was performed to evaluate lesions of intermediate angiographicseverity (34 cases) or for IVUS-guided interventional procedures (17 cases). Only 32 of the 88 lesions underwent angioplasty. The clinical characteristics of the patients are shown in Table 1. Familiarity for coronary artery disease was present if first degree relatives developed coronary artery disease at an early age: before 55 years in men and 65 years in women.
2.2. Intravascular ultrasound image acquisition and analysis
2.2.1. Image acquisition
The IVUS images were obtained using mechanical ultrasound imaging catheters at 30MHz (3.2FUltracross) and 40MHz (2.9F, Atlantis) (Cardiovascular Imaging Systems/Boston Scientific). After completing coronary angiography, the patients were given 7000U of heparin in the arterial sheet and 200µg of intracoronary nitroglycerin to prevent possible vasospasm. The imaging probe was positioned distally to the target lesions and withdrawn at a constant speed of 0.5mms1using a motorised pull-back device.
2.2.2. 3-D IVUS reconstruction and quantitative analyses
The IVUS studies were recorded on high-resolution S-VHS tapes for off-line analysis, and the images were then processed using a semi-automatedcontour detection algorithm to obtain a 3-D reconstruction. The algorithm detects the intimal leading edge and the external contour of the vessels, and has been extensively validated.13,14
The longitudinal view was used to define vessel architecture accurately, identify the presence of septal branches having a perpendicular take-off from the LAD, and to provide automated measurements of the minimal lumen area (MLA) and reference segment (Fig. 1). The lumen area (LA) and the area circumscribed by the EEM were measured at the narrowest lesion site (MLA site). The reference segment was defined as the most normal looking cross-section proximal or distal to the target lesion, and had to have a % cross-sectional narrowing of
40%. IVUS measurements of cross-sectional areas have been previously validated.15,16

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Fig. 1 Application of the semi-automated algorithm of contour detection to obtain a 3-D IVUS reconstruction of a mid left anterior descending coronary artery. The algorithm automatically detects the intimal leading edge (inner line) and the external contour of the vessels (outer line), and provides a longitudinal display of vessel architecture. The MLA cross-section (lower line) is identified 4mm from a septal take-off; the distal reference cross-section is located 8mm distally from the MLA cross-section (upper line).
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To evaluate plaque spatial distribution, the MLA cross-sections were divided into a myocardial and pericardial surface using the take-off of a septal branch emerging on the side of the vessel opposite the pericardium,17 and the plaque areas on both surfaces were measured. The AP was consideredas being pericardially distributed if the area onthe pericardial surface was larger than that on the myocardial surface, and vice versa. The anglebetween the mid-point of the septal branch and the point of maximal atheroma thickness was alsodetermined in order to provide an additionalestimate of vessel remodelling (Fig. 2).

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Fig. 2 Quantitative analysis of the MLA cross section obtained in the case shown in Fig. 1 To evaluate the spatial distribution of plaque thickness, the MLA cross-section is divided into a myocardial and pericardial surface with reference to the septal branch take-off adjacent to the MLA cross-section and emerging on the side of the vessel opposite the pericardium. In this case, the distribution of the atherosclerotic plaque is pericardial since it is located in the quadrant opposite the septal take-off (at 3 o'clock). The angle between the mid-point of the septal take-off and the point of maximum atheroma thickness is 140°.
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2.2.3. Definition of positive and negative remodelling
The IVUS vessel remodelling index was calculated as: [EEM cross-sectional area (CSA) measured at narrowest lesion sitereference EEM CSA]/reference EEM CSAx100]. The target lesions were divided into three groups: group 1 with positive remodelling (vessel remodelling index >5%), group 2 with negative remodelling (vessel remodelling index <5%), and group 3 with intermediate remodelling (vessel remodelling index between 5% and +5%).
2.2.4. Qualitative IVUS assessment
The composition of the target lesions wasassessed at the site of the MLA using the following classification:
- fibrous plaques: lesions with a predominant dense fibrous composition that produces bright heterogeneous echoes whose echoreflectivity is the same or more than that of the adventitia;
- calcific plaques: lesions having a total calcific arc (highly echogenic segments that aredenser than the adventitia and cause acoustic shadowing) of more than 90°;
- soft plaques: highly cellular fibromuscularlesions or lesions with diffuse lipid infiltration whose echo-reflectivity is less than that of the adventitia.
2.3. Statistical analysis
The continuous data are presented as mean values±standard deviation (SD), and the categorical data as percentages. The continuous variables were compared using the unpaired Student t-test orone-way analysis of variance with Bonferroni's procedure. The categorical variables were compared by means of chi-square analysis. A P value of <0.05 was considered significant. Logistic regression was used to identify the predictors of compensatory enlargement and coronary shrinkage. The independent variables were entered in the order of the strength of their association with the dependent variable at univariate analysis.
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3. Results
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Of the 88 lesions selected on the basis of the inclusion criteria, positive remodelling was present in 44 cases (50%), negative remodelling in 26 (30%) and intermediate remodelling in 18 (20%), all of which were excluded from the analysis. Of the 44 plaques with positive remodelling, 34 (77%) had a pericardial and 10 (23%) a myocardial distribution
. Plaques with positive remodelling accounted for 89% (34/38) of all of the plaques with a pericardial distribution
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The plaque and vessel areas were larger in the pericardial than the myocardial group (Table 2). The angle between the mid-point of the septal take-off to the point of maximal atheroma thickness was greater in the lesions with positive than in those with negative remodelling (101.2°±50.3° vs 50.4°±29.6°,
). There was also a significant positive correlation between this angle and the vessel remodelling index (Fig. 3).

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Fig. 3 Linear regression analysis shows a significant positive correlation between the angle from the mid-point of the septal take-off to the point of maximum atheroma thickness and the vessel remodelling index.
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The distal lesions had a positive vessel remodelling index regardless of transversal plaque distribution (Fig. 4). Positive remodelling was found in 16/18 plaques: eight with a myocardial and eight a pericardial distribution. Only two of the 18 distal lesions showed negative remodelling (Table 3). The vessel remodelling index was higher in the distal than the proximal and mid APs (15.1±18.0% vsrespectively 6.7±25.3% and 0.1±15.2%)
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Fig. 4 Mean vessel remodeling index values of atherosclerotic plaques grouped into proximal, mid and distal lesions on the basis of their location. The lesions with a myocardial distribution are indicated by solid circles, and those with a pericardial distribution by empty circles. Unlike mid and proximal lesions, distal lesions have positive vessel remodelling index values regardless of their transversal distribution.
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At univariate analysis, pericardial distribution and a distal location were the only variables predictive of vessel remodelling (Table 3). Multivariate analysis performed by means of the logistic regression model confirmed that they were independent predictors of positive remodelling (Table 4).
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4. Discussion
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Our data show that the cross sectional transversal distribution of AP in proximal left anterior descending coronary arteries is related to vessel wallremodelling while it does not affect vessel remodelling in distal districts. These findings support the hypothesis that the extravascular splintingeffect exerted by myocardial tissue hampers the positive remodelling of coronary walls caused by atherosclerotic plaque growth.
The relationship between the transversal distribution of AP and vessel wall remodelling haspreviously been described by Ward et al.,10 who studied 65 left anterior descending artery lesions. Comparing the 25 lesions predominantly involving the pericardial arc with the 40 myocardial lesions, they found a significantly higher remodelling index in the former (0.02±0.07 vs 1.10±0.32,
). It is worth noting that the authors distinguished myocardial and pericardial cross-section distribution by applying different anatomical landmarks, such as the visualization of the pericardium, and septal and diagonal branches, whereas our data were obtained using an integrated 3D-IVUS/angiographic approach to apply the single anatomical criterion of septal take-off identification.
We confirmed that the transversal distribution of AP influences vessel remodelling in left anterior descending coronary arteries. The significant positive correlation between the remodelling index and the angle from the mid-point of the septal take-off to the point of maximal plaque thickness underlines the impact of transversal plaque distribution on remodelling processes. Furthermore, positive remodelling was found in only 10/70 lesions (14%) in which the angle from the mid-point of the septal take-off to the point of maximal plaque thicknesswas less than 84° (calculated as the mode of the analysed values), and which therefore had a marked myocardial location. These observations support the hypothesis that, as they are unimpaired by myocardial extravascular resistance, lesionsfacing the pericardium undergo a vessel expansion that is also favoured by the permissive role of epicardial fat. This preliminary finding needs to be confirmed by further studies. The possibility thata rim of fat tissue separates the proximal left anterior coronary artery from the underlying myocardium exists as an anatomical variant but it is unlikely to contrast the splinting effect of themyocardium during systole.
An interesting finding of our study is the fact that the transversal distribution of atherosclerotic plaque affected the pattern of vessel remodelling only in the non-distal segments. As shown in Fig. 4, unlike proximal and mid lesions, distal lesions with a myocardial distribution had a positive vesselremodelling index (10±3%). Furthermore none of the six lesions with a myocardial distribution underwent negative remodelling. It is reasonable to speculate that myocardial extravascular resistance was incapable of limiting the vessel enlargement elicited by plaque growth in distal lesions. Differences in cardiac mechanics between the proximal and distal segments of the left ventricle mayexplain the reduced impact of extravascular myocardial resistance to vessel remodelling in the distal district.18,19
4.1. Advantages of 3D-IVUS assessments
The use of a 3D-reconstruction of the IVUS images enabled a longitudinal display of the vessel wall and facilitated lesion selection and septal branches identification. A more accurate assessment of the amount of calcium in each target lesion cross-section was obtained by using the outer longitudinal contour of the vessel, which enabled the selection of lesions whose calcified arc was more than 90°.
In a previous study of a large population, Mintzet al.7 found that the arc of superficial lesion calcium was the only predictor of vessel remodelling. However, they excluded lesions with calcium deposit shadowing more than 60°, because of difficulties in identifying the external EEM. Differences in the selection of calcified lesions may therefore explain the discrepancy between the results ofour study (in which plaque calcifications did not predict negative vessel remodelling) and previous observations.
4.2. Limitations
Many hypotheses have been suggested as to the determinants of vessel remodelling: the not unusual coexistence of positive and negative vessel remodelling in the same artery suggests that it is a focal phenomenon likely modulated by local haemodynamic alterations. The use of 3D reconstruction techniques that allow the visualization of vessel curvatures will make possible to study the relationships between spatial wall characteristics and haemodynamic factors such as shear stress.20
Because only LAD lesions were analysed, we cannot even speculate whether the myocardium also has a splinting effect in other coronary arteries.
In this study, the myocardial vs pericardial location of AP was defined assuming that the transversal orientation of the septal take-off measured in a cross-section other than the MLA remains unchanged during IVUS pull-back, but it is known that vessel curvatures may modify the orientation of the transducer. However, as the septal take-offs were adjacent to the MLA (within 5mm of the lesion), it is unlikely that the transversal orientation of the transducer would change.
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5. Conclusions
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The cross-sectional myocardial or pericardial distribution of left anterior descending coronary lesions is related to vessel remodelling, with positiveremodelling being hampered by a myocardial location probably because of an extravascular splinting effect. In distal coronary segments, where positive remodelling is commonly found, therewas no relationship between the cross-sectional distribution of atherosclerotic plaques and vessel remodelling.
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