Spatial orientation of atherosclerotic plaque in non-branching coronary artery segments

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1 Atherosclerosis 152 (2000) Spatial orientation of atherosclerotic plaque in non-branching coronary artery segments A. Jeremias, H. Huegel, D.P. Lee, A. Hassan, A. Wolf, A.C. Yeung, P.G. Yock, P.J. Fitzgerald * Room H3554, Di ision of Cardio ascular Medicine, Center for Research in Cardio ascular Inter entions, Stanford Uni ersity Medical Center, Stanford Uni ersity School of Medicine, 300 Pasteur Dri e, Stanford, CA , USA Received 2 March 1999; received in revised form 13 September 1999; accepted 3 November 1999 Abstract It has been postulated that atherosclerotic plaque deposition is spatially related to regions of low shear in non-branching vessel segments. Intravascular ultrasound (IVUS) allows precise spatial orientation of coronary artery plaque formation in humans. The objective of this study was to test the hypothesis that coronary plaques have a higher prevalence on the myocardial side in regions that encounter low surface shear stress. IVUS allows the determination of the inner versus the outer curve of the vessel based on vascular and perivascular landmarks. We studied 30 consecutive patients pre-intervention using IVUS and measured vessel area, lumen area and plaque area (vessel-lumen area) during a motorized pullback at 1 mm intervals. Vessel segments near a side branch (within two times the diameter of the vessel) were excluded from analysis because of flow disturbances. All plaques were classified as concentric or eccentric and all eccentric plaques were further divided with respect to their spatial orientation in the vessel into quadrants: myocardial (inner curve, lower shear stress), epicardial (outer curve, higher shear stress) and lateral (two quadrants intermediate). A total of 613 cross-sections were analyzed in 14 left anterior descending, six left circumflex, and ten right coronary arteries. Plaque distribution was found to be concentric in 321 (52.4%) and eccentric in 292 (47.6%) cross sections. Of all eccentric plaques, 184 cross sections were oriented toward the myocardial side (62.6%) compared to only 54 toward the epicardial side (17.3%) and 54 in the 2 lateral quadrants (19.5%, P 0.001). No difference in plaque area ( vs mm 2 ), vessel area ( vs mm 2 ), or plaque thickness ( vs mm) was noted between myocardial or epicardial plaques. These results suggest that atherosclerotic plaques develop more frequently on the myocardial side of the vessel wall, which may relate to lower shear stress. However, plaque size is similar on the epicardial and myocardial side Elsevier Science Ireland Ltd. All rights reserved. Keywords: Coronary artery disease; Intravascular ultrasound; Shear stress 1. Introduction Atherosclerotic plaques in coronary arteries have been shown to be unevenly distributed within the coronary tree [1]. Lesions progress at nearly independent rates within the same patient exposed to the same risk factors and systemic hemodynamics [2]. Right coronary artery plaques progress at a more rapid rate than do lesions in the other coronary arteries [3]. These observations have led to the hypothesis that different flow patterns may determine the relative deposition and * Corresponding author. Tel ; fax orientation of localized coronary artery disease. Differences in wall shear stress [4,5], flow separation [6], variations in blood flow patterns [7] and turbulence [8] have been proposed as possible factors promoting atherosclerosis. Originally proposed by Caro et al. it has been suggested that low wall shear stress may retard the mass transport of atherogenic substances away from the wall, resulting in increased intimal accumulation of lipids [9]. Studies of plaque localization in the human carotid bifurcation have shown that regions of low flow velocity and wall shear stress are prone to develop atherosclerotic lesions, whereas areas of high shear stress are spared [5]. It is now recognized that arterial branching points are particularly susceptible to /00/$ - see front matter 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S (99)00461-X

2 210 A. Jeremias et al. / Atherosclerosis 152 (2000) plaque formation depending on the variation of local shear forces [10]. In a postmortem preparation of transparent coronary arteries, atherosclerotic plaques were localized almost exclusively on the outer wall at major bifurcations (the hips ) and along the inner wall of curved segments (the inseam ) [1]. A pathological study in carotid arteries [11] and an angiographic study in femoral arteries [12] confirmed the predilection of atherosclerosis for the inner curvature of the vessel at areas of low shear stress. Sabbah et al. have shown that the clearing rate of contrast material is slower along the inner wall, bordering the myocardium, suggesting that velocity is lower at that site compared to the outer wall [13]. Intravascular ultrasound (IVUS) imaging technology allows direct visualization of the distribution and morphology of atherosclerotic plaques in vivo and has greatly contributed to our understanding of plaque characteristics, especially in coronary arteries [14 16]. In two recent IVUS studies the distribution and the morphology of atheroma in the proximal left anterior descending coronary artery were described [17,18] and found to be in accordance with previous pathological data supporting the role of fluid dynamic factors in the development of atheroma opposite to branching points. However, in vivo data describing the distribution of atherosclerotic plaques in non-branching coronary artery segments is still lacking. The aim of the present study was, therefore, to examine the distribution of coronary atherosclerosis apart from major side branches in a systematic fashion using IVUS to test the hypothesis that atherosclerotic lesions are more frequently found along the inner walls of curved arterial segments. The principle of orientation within the vessel using IVUS has been described previously and is based on the visualization of various periadventitial structures (veins, pericardium) as well as congruent branching vessels [19]. These landmarks, unique in each coronary segment, provide accurate spatial orientation during the entire length of an IVUS imaging sequence for a particular vessel. 2. Material and methods 2.1. Patient population Intravascular ultrasound was performed in 30 patients (28 men and two women aged years). All patients underwent IVUS imaging before any catheter based intervention and none of the patients had undergone prior intracoronary intervention in the target vessel. All lesions were located in native vessels; vein graft lesions were excluded from analysis. Intracoronary nitroglycerin ( g) was given during all IVUS studies before imaging. Informed consent was obtained from all patients and the institutional review board approved the study Intra ascular ultrasound image acquisition and analysis A 3.2F (Microview, CVIS/Boston Scientific) IVUS imaging catheter with a single element transducer at the tip was used. The transducer was mechanically rotated within a protective sheath at 1800 rpm to provide cross-sectional images via an ultrasound diagnostic imaging console (ClearView, CVIS/Boston Scientific). The IVUS-catheter was tracked over a in. guide wire up to a position distal to the diseased segment. Ultrasound time gain compensation settings was adjusted to allow maximal gray scale differentiation. In every case a continuous motorized pullback of the ultrasound transducer was performed at a constant speed of 0.5 mm/second. All IVUS studies were recorded on 1/2-in high-resolution super VHS tapes for off-line analysis. Quantitative (cross-sectional) analysis of the IVUS images was performed using a commercially available software program (TapeMeasure, Indec). Validation of qualitative and quantitative IVUS analysis has been reported previously [14,15]. Plaque plus media crosssectional area was used as a measurement of plaque area, since media thickness can not be measured directly [20]. Maximal and minimal wall thickness measurements also included plaque plus media. End-systolic frames were selected at two-s intervals of the automated pullback; thus IVUS cross-sections were analyzed at 1 mm increments. All cross-sections located near a side branch (within two times the diameter of the vessel) were excluded from analysis to minimize confounding by flow turbulence. For each cross-section the following measurements were made: 1. vessel area (assumed to be equal to external elastic membrane area, since adventitial thickness can not be precisely determined), 2. lumen area, 3. plaque area (vessel area minus lumen area), 4. percent cross-sectional luminal stenosis (plaque area divided by vessel area), 5. maximal and minimal plaque thickness, and (6) plaque angle (measured from the geometric center of the lumen) as the circumferential span of plaque within the cross-section. The eccentricity index was calculated as previously suggested by Mintz et al. [20]. Briefly, the ratio of maximal to minimal plaque thickness was calculated, taken along the line through the center of the lumen. In this model, an eccentricity index of one would represent a completely concentric plaque. An eccentric lesion was defined by an eccentricity index of 3 or by the presence of an arc of disease free arterial wall within

3 A. Jeremias et al. / Atherosclerosis 152 (2000) the lesion. A three-layered appearance with an intimal thickening of 0.2 mm was considered the upper limit of a normal arterial wall [21]. Cross-sections with excessive calcification (calcium arc 90 ) were excluded from analysis because of acoustic shadowing of deeper structures, precluding accurate measurement of the vessel area. Lesions with 90 of calcium arc were measured by extrapolation assuming that the vessel circumference was circular and by axial movement of the transducer to identify the vessel area of adjacent non-calcified segments as described previously [22]. All cross-sections with eccentric plaque distribution were classified based on their plaque orientation being centered on the pericardial, myocardial or either lateral side of the vessel. For vessel orientation, perivascular IVUS landmarks were used [19], including: 1. coronary veins, 2. pericardium, 3. myocardium, and 4. side branches (Fig. 1). Based on these landmarks, the vessel was divided into four quadrants: myocardial quadrant (inner curve of the vessel), epicardial quadrant (outer curve of the vessel), and two lateral quadrants (intermediate). Each cross-section was grouped into one of the four quadrants (Fig. 2). In cases where the plaque angle exceeded Fig. 1. Perivascular and branching landmarks seen by intravascular ultrasound (IVUS) for spatial orientation in the coronary artery. The illustration in panel (A) represents the anatomical relationship between veins, pericardium and branching points in the left anterior descending artery. (B): Diagonal branch (asterix), (C): Septal branch (asterix), (D): pericardium (asterix), (E): vein (asterix) and (F): myocardium (asterix). Fig. 2. Example of an eccentric lesion oriented toward the myocardial side. The alignment grid demonstrates how each cross-section was divided into quadrants (A D): myocardial (A), epicardial (C) and two lateral (B D). Each lesion was categorized being centered on one of the four quadrants, depending on maximal plaque thickness.

4 212 A. Jeremias et al. / Atherosclerosis 152 (2000) Table 1 Baseline characteristics of the study population Characteristics Age a Gender (male/female) b 28/2 Unstable angina 4 (13.3) Previous myocardial infarction 10 (33.3) Cardio ascular risk factors History of smoking 18 (60) Dyslipidemia 13 (43.3) Diabetes mellitus 9 (30) Arterial hypertension 6 (20) a Mean standard deviation. b Number of patients. 90 or the plaque was distributed in between two quadrants, the quadrant with the maximal plaque thickness was chosen for grouping Statistical analysis All data is presented as the mean standard deviation. The comparison of the plaque distribution among the groups was performed by one-way ANOVA testing of the mean percentage of the distribution for each individual patient. Thus for each patient the percentage of individual plaque distribution was calculated and the mean myocardial, epicardial and lateral plaque orientation of the total group was derived form the individual percentage distribution. Data between the groups was compared using an unpaired Student s t-test; data not normally distributed between the groups was compared by the Mann Whitney rank sum test. A P value of 0.05 was considered statistically significant. 3. Results Of the 30 vessels undergoing IVUS morphometric analysis, 14 were the left anterior descending, six the left circumflex and ten the right coronary arteries. A total of 613 cross-sections were analyzed, 234 (38.2%) in the left anterior descending artery, 259 (42.2%) in the right coronary artery, and 120 (19.6%) in the left circumflex artery. Baseline characteristics of the patient population are presented in Table Eccentric ersus concentric plaque Plaque distribution was found to be concentric in 321 (52.4%) and eccentric in 292 (47.6%) cross-sections. Vessel area ( vs mm 2 ), plaque area ( vs mm 2 ) and maximal plaque thickness ( vs mm) were not significantly different between eccentric and concentric plaque Distribution of atherosclerotic plaque In all cases the visualization of the pericardium, one or more accompanying veins and side branches allowed a precise spatial orientation. Pericardium was identified in 29% of the cross-sections, veins were visualized in 41% of the cases and the myocardium was seen in 13%. Of the 292 eccentric plaques, 184 cross-sections were oriented toward the myocardial side as compared to only 54 cross-sections oriented toward the epicardial side and 54 toward the two lateral quadrants. Individual data for each patient are displayed in Table 2. When comparing the percentage of the plaque distribution derived from each individual patient, plaque was oriented significantly more often toward the myocardial side (62.6%) as compared to the epicardial (17.3%) or lateral (19.5%) side (P 0.001, Fig. 3). Comparing plaques oriented toward the myocardial and the pericardial quadrants, there was no difference in vessel area ( vs mm 2 ), plaque area ( vs mm 2, Fig. 4), plaque thickness ( vs mm) or plaque-angle ( vs ). 4. Discussion The results of the present study suggest that atherosclerotic plaques are more likely to develop at the inner side of curved non-branching coronary segments (myocardial side) in areas of lower shear stress. These areas are prone to flow separation and/or reversal, flow turbulence and eddying. However, no difference in plaque size and vessel size was observed between plaques oriented toward the myocardial versus the epicardial side Comparison to pre ious studies Wall shear stress in the arterial system is the tangential drag force produced by blood moving across the endothelial surface [23]. It is a function of the velocity gradient of blood near the endothelial surface and is directly proportional to blood flow and blood viscosity. Many studies have focused on fluid dynamic forces to explain the localized nature of coronary artery disease. Initially, high shear stress was thought to potentiate plaque formation by producing endothelial injury and disruption [24]. However, it is now recognized that regions of low shear stress are more susceptible to atheroma formation and many studies have demonstrated an association between low shear stress and atherosclerotic deposits [5,9,10]. In a pathological study of human carotid bifurcations, intimal plaques were found to form in the low stress region of the carotid sinus opposite to the flow divider and not in the high

5 A. Jeremias et al. / Atherosclerosis 152 (2000) shear stress region along the inner wall [5]. The pattern of plaque localization in human coronary arteries is similar to that observed at the carotid bifurcation, as atherosclerosis develops almost exclusively at the outer wall of major bifurcations [1]. The increased tendency of plaque formation at coronary bifurcations has also been confirmed in vivo using IVUS [17,18,25,26]. Several studies have attempted to relate the pattern of atheroma distribution in the coronary arteries to estimated shear stress. In the Harvard Atherosclerosis Reversibility Project pilot study, 20 patients were enrolled and followed over a period of 3 years to study the relation of wall shear stress to atherosclerosis progression [27]. A finite-difference model of the Navier Stokes equation was used to assess vessel wall shear stress at numerous points along the vessel and plaque progression was monitored by quantitative coronary angiography. In 15 of the 20 arterial segments there was a significant correlation between low shear stress and an increased rate of atherosclerosis progression. Krams et al. evaluated endothelial shear stress and 3-dimensional geometry as factors determining the development of atherosclerosis in a human right coronary artery in vivo [28]. By combining a 3-dimensional reconstruction of the vessel from angiography and IVUS with computational fluid dynamics, it was possible to correlate endothelial shear stress to atherosclerotic plaque formation. Wall thickness was significantly larger and shear stress was significantly less at the inner curve of the vessel. There was an inverse relationship between wall thickness and shear stress for each velocity level under study. Using IVUS imaging in the catheterization laboratory permits an optimal technique to investigate the distribution of coronary atheroma as a function of vessel curvature using direct visualization of plaque Table 2 Plaque distribution and cardiovascular risk factors for each individual patient No. Vessel a RF b Total no. of CS c Con Ecc M E L 1 RCA D (67.2) 22 (32.8) 15 (68.2) 6 (27.3) 1 (4.5) 2 RCA DM 10 9 (90) 1 (10) (100) 3 RCA DM, D, S, F (55.6) 12 (44.4) 11 (91.7) 1 (8.3) 0 4 RCA S 17 6 (35.3) 11 (64.7) 10 (90.9) 1 (9.1) 0 5 LAD DM, D, F (80) 4 (20) 2 (50) 2 (50) 0 6 LAD DM (57.1) 9 (42.9) 7 (77.8) 2 (22.2) 0 7 LAD D 9 1 (11.1) 8 (88.9) 6 (75) 1 (12.5) 1 (12.5) 8 LAD 13 9 (69.2) 4 (30.8) 2 (50) 2 (50) 0 9 LAD H, S, F 8 7 (87.5) 1 (12.5) 1 (100) LAD F 10 5 (50) 5 (50) 5 (100) RCA S 13 9 (69.2) 4 (30.8) 2 (50) 2 (50) 0 12 LAD DM, H, S (100) 9 (52.9) 4 (23.5) 4 (23.5) 13 LCX D, S, F 28 6 (21.4) 22 (78.6) 17 (77.3) 1 (4.5) 4 (18.2) 14 LCX D 22 2 (9.1) 20 (90.9) 18 (90) 2 (10) 0 15 LCX D, S 17 6 (35.3) 11 (76.5) 7 (53.8) 2 (15.4) 2 (15.4) 16 LCX D, S (100) 0 17 LCX H, D, S (87.5) 2 (12.5) (100) 18 LCX DM, D (76.2) 5 (23.8) 4 (80) 1 (20) 0 19 RCA S (53.3) 14 (46.7) 7 (50) 7 (50) 0 20 LAD DM, H 14 3 (21.4) 11 (78.6) 8 (72.7) 0 3 (27.3) 21 RCA D, S (41.4) 17 (58.6) 13 (76.5) 0 4 (23.5) 22 LAD DM, S 19 4 (21.1) 15 (78.9) 10 (66.7) 1 (6.7) 4 (26.7) 23 LAD H (61.9) 8 (38.1) 6 (75) 2 (25) 0 24 RCA H, S, F (48) 13 (52) 2 (15.4) 0 11 (84.6) 25 LAD S 19 5 (26.3) 14 (73.7) 2 (14.3) 8 (57.1) 4 (28.6) 26 RCA DM, D, S (72.4) 8 (27.6) 6 (75) 1 (12.5) 1 (12.5) 27 LAD S (82.6) 4 (17.4) 4 (100) LAD S (43.7) 18 (56.3) 4 (22.2) 7 (38.9) 7 (38.9) 29 RCA 12 2 (16.7) 10 (83.3) 4 (40) 1 (10) 5 (50) 30 LAD D, S 8 6 (75) 2 (25) 2 (100) 0 0 Total % % % % % a Vessel (RCA, right coronary artery; LAD, left anterior descending coronary artery; LCX, left circumflex coronary artery). b Cardiovascular risk factors (RF: D, dyslipidemia; DM, diabetes mellitus; S, smoking; F, family history; H, hypertension) and plaque distribution for each patient. c Total number of cross-sections (total number of CS) refers to number of cross-sections measured by intravascular ultrasound; cross-sections were divided into concentric (Con) and eccentric (ECC) plaque and all eccentric plaque were further divided into myocardial (M), epicardial (E) and lateral (L) with respect to their orientation within the vessel. Data is expressed as number (percent) of cross-sections. Total refers to total number and mean percent of cross-sections.

6 214 A. Jeremias et al. / Atherosclerosis 152 (2000) evaluated and the vessel area was divided into two semicircles with the same area by a line that was parallel to the pericardium. This method of characterization is substantially different from our approach in which each cross-section was measured and classified into one quadrant depending on the orientation of the maximal plaque thickness. Furthermore, in the present study the complete vessel was evaluated at 1 mm increments excluding only branching points. Thus areas of high, medium and low plaque burden were included in the analysis to yield a broad insight into plaque distribution over the entire length of the vessel. An additional difference is that Tsutsui et al. examined coronary sites with mild disease patterns and did not exclude the effects of branch vessels Limitations Fig. 3. Distribution (%) of the IVUS cross-sections in the four quadrants (myocardial, epicardial, and two lateral). In the present study, no conclusion can be drawn regarding the relation of the degree of the vessel curvature to the plaque location or plaque thickness. Plaque distribution can only be related to inner or outer curve. It may be of interest to analyze the relationship between plaque accumulation and degree of vessel curvature but this is currently confined by technical limitations of the IVUS system. 5. Conclusions Fig. 4. Vessel area (VA) and plaque area (PA) in lesions oriented toward the myocardial and the epicardial side. Results are not significant. burden across a wide range of vessel types in nonbranching segments. We found a significant difference in plaque distribution in all three major coronary arteries (left anterior descending, left circumflex and right coronary artery) in our patient cohort. More than 60% of all atherosclerotic plaques were oriented toward the myocardial side at the inner curve of the vessel. To potentially minimize the effects of velocity variation due to vessel branching, we only analyzed segments that were distant from any side branch. It is of interest to note that the measurements of plaque thickness and area were not different between myocardial and epicardial-oriented lesions. This is in contrast to the finding of Tsutsui et al. where plaque area and plaque thickness at the myocardial side were significantly larger [29]. In this study 55 coronary sites from 37 patients were This study provides evidence that human atherosclerotic lesions form more frequently along the inner walls (myocardial side) of coronary arteries away from arterial branching points. These sites are prone to low shear stress, in which flow separation, flow reversal, turbulence, and eddying occur. Acknowledgements Dr Jeremias was supported by a grant from the German Academic Exchange Service (DAAD, Bonn, Germany). References [1] Asakura T, Karino T. Flow patterns and spatial distribution of atherosclerotic lesions in human coronary arteries. Circ Res 1990;66: [2] Gibson CM, Sandor T, Stone PH, Pasternak RC, Rosner B, Sacks FM. Quantitative angiographic and statistical methods to assess serial changes in coronary luminal diameter and implications for atherosclerosis regression trials. Am J Cardiol 1992;69: [3] Bruschke AV, Wijers TS, Kolsters W, Landmann J. The anatomic evolution of coronary artery disease demonstrated by

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