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Significance of anatomical properties of myocardial bridge on atherosclerosis evolution in the left anterior descending coronary artery
Atherosclerosis 186 (2006) 380–389
Significance of anatomical properties of myocardial bridge on atherosclerosis evolution in the left anterior descending coronary artery Yukio Ishikawa a,∗ , Yoshikiyo Akasaka a , Kinji Ito a , Yuri Akishima a , Masayo Kimura a , Hideko Kiguchi b , Ai Fujimoto c , Toshiharu Ishii a a
Department of Pathology, Toho University School of Medicine, 5-21-16 Ohmori-nishi, Ohta-ku, Tokyo 143-8540, Japan Department of Pathology, Saiseikai Kanagawaken Hospital, 6-6 Tomiya-cho, Kanagawa-ku, Yokohama 221-8601, Japan Department of Gastroenterology and Hepatology, Toho University Ohmori Hospital, 6-11-1 Ohmori-nishi, Ohta-ku, Tokyo 143-8541, Japan b
c
Received 25 January 2005; received in revised form 21 June 2005; accepted 11 July 2005 Available online 19 August 2005
Abstract Myocardial bridge (MB) is frequently detected in the left anterior descending coronary artery (LAD), and LAD intima under MB is significantly spared from atherosclerotic evolution. Significance of anatomical features of MB on the extent of atherosclerosis of LAD was histomorphometrically investigated. Full-length 200 LADs with MB and 100 control LADs without MB were cross-sectioned at 5 mm intervals, and atherosclerosis ratio and intimal lesion types were evaluated. In cases with MB located within 5 cm from the left coronary ostium, atherosclerosis ratio in the proximal part of LAD was significantly lower than in control group, but, in cases with MB locating more than 5 cm from the ostium, atherosclerosis ratio in this part was similar to that in control cases. MB thickness was significantly correlated with its length, and the longer the MB the more proximally it tended to be located in LAD. Atherosclerosis ratio under MB was lower in cases with thick or long MBs than in cases with thinner or shorter MBs. In addition, intimal lesion in segments proximal to MB tended to be eccentric. Our results suggest that these anatomical properties of MB are the critical modulators for atherosclerosis evolution in the entire course of LAD. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Myocardial bridge; Coronary artery; Atherosclerosis; Anatomy; Hemodynamics
1. Introduction Myocardial bridge (MB) is a common anatomical situation in the left anterior descending coronary artery (LAD) [1] in which part of LAD is covered by myocardial tissue. Since a detail description of MB [2], it has been designated
∗
Corresponding author. Tel.: +81 3 3762 4151; fax: 81 3 5493 5414. E-mail addresses: [email protected] (Y. Ishikawa), [email protected] (Y. Akasaka), [email protected] (K. Ito), [email protected] (Y. Akishima), [email protected] (M. Kimura), [email protected] (H. Kiguchi), [email protected] (A. Fujimoto), [email protected] (T. Ishii). 0021-9150/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2005.07.024
as intramural coronary artery, mural coronary artery, or coronary artery overbridging [3]. Frequency of MB in LAD is relatively high, sometimes over 50% by autopsy study [4]. It is widely accepted that arterial intima beneath MB is significantly spared from atherosclerotic changes [1,4]. This atherosclerosis suppression under MB compared with the coronary segments proximal to MB has been also evident in histopathologic [5–7] and image analysis [8] studies. It has been also suggested through morphological examination of endothelial shapes that hemodynamic changes leading to high shear stress in LAD segment under MB contribute to atherosclerosis suppression in this region [6]. This hypothesis is further supported by a morphological observation using a cholesterol-fed rabbit model [9]. These studies on LAD with
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MB indicate that hemodynamic alterations resulting from systolic compression by MB consistently influence distribution of atherosclerotic lesions. On the other hand, disturbed coronary flow due to systolic compression by MB may also evoke clinical symptoms of ischemic heart disease [3,10], ventricular fibrillation [11], atrioventricular block [12], and sudden cardiac death [13]. These conditions are probably caused by coronary ischemia due to retrograde blood flow from the coronary segment under MB into the segment proximal to MB through MB compression during systole. Such blood flow subsequently impedes coronary flow and causes persistent reduction of arterial diameter during systole [14,15]. Angiographically visible severe narrowing of LAD lumen by MB compression during systole may contribute to coronary ischemia [10]. An LAD deeply situated in the myocardium can be distorted by systolic compression of MB [16]. Considering these angiographic and morphological evidences [10,13,16], anatomical properties of MB, such as its location within LAD as well as its thickness and length, can be regarded as critical factors that directly influence extent of coronary stenosis and disturbed blood flow in LAD. In this study, we histomorphometrically investigated the relationship between various anatomical properties of MB and extent of atherosclerosis in human LAD. 2. Materials and methods 2.1. Materials MB group consisted of 200 autopsied cases with MB(s) in LAD but without any morphologically proven cardiovascular disease (Fig. 1). Control group similarly having no cardiovascular disease consisted of 100 autopsied cases without MB in LAD. They were obtained from consecutive autopsies at Ohmori Hospital of Toho University from 1998 to 2002. MB group consisted of 149 males and 51 females, with mean age 66.6 ± 13.7 years, and control group for 71 males and 29 females, with mean age 67.4 ± 14.7 years. There was no difference in distribution of age and sex between them. All the full-length LADs from the left coronary ostium to cardiac apex were removed from the hearts together with surrounding adipose and myocardial tissues. They were fixed with 10% formaldehyde and cross-sectioned at 5 mm intervals. They were embedded in paraffin, and thin-sections were treated with hematoxylin-eosin and elastica van Gieson’s stainings. Detailed observation often revealed the case having multiple MBs in an LAD. In such case, only the MB in the most proximal portion of LAD was considered. 2.2. Definitions of atherosclerosis ratio and atherosclerosis suppression ratio To assess atherosclerosis severity, the areas of intima and media in all sections were measured with automated image
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analysis system of Visual Measure 32 (Rise System, Sendai, Japan). The area ratio of intima to media was defined as atherosclerosis ratio. Atherosclerosis suppression ratio was expressed as a percentage indicating extent of atherosclerosis suppression in LAD under MB and was calculated as proportional decrease of mean atherosclerosis ratio of MB segments relative to mean atherosclerosis ratio of the three consecutive sections just proximal to MB [100 − (mean atherosclerosis ratio of MB segments/mean atherosclerosis ratio of the three sections just proximal to MB) × 100]. Usage of mean atherosclerosis ratio of the three sections just proximal to MB for calculation of atherosclerosis suppression ratio is because mean MB length in this study (1.44 ± 0.95 cm, as shown in Section 3) was almost equivalent to the length of three paraffin blocks, because LAD was cross-sectioned at 5 mm intervals. 2.3. MB location Distance from the left coronary ostium to the first segment at which LAD was covered by MB was defined as MB location. MB group was classified into three categories according to distribution of MB location: proximal location group with MB located within 3.5 cm, common location group with MB located from 4.0 to 5.0 cm, and distal location group with MB located over 5.0 cm. 2.4. MB length Number of sections with consecutive MB multiplied by 5 mm was defined as MB length. MB group was classified into three categories according to distribution of MB length: short MB group with less than 1.0 cm, common-length MB group with 1.5–2.0 cm, and long MB group with over 2.5 cm. 2.5. MB thickness Thickness of myocardial tissue bridging LAD was microscopically measured, and the highest value was defined as MB thickness for each case. MB group was classified into three categories according to distribution of MB thickness: thin MB group with less than 500 m, common-thickness MB group with 500–1000 m, and thick MB group with over 1000 m. 2.6. Classification of intimal lesions Intimal lesion type was classified into the four categories by detailed observation of arterial sections treated with hematoxylin-eosin and elastica van Gieason’ s stainings according to the AHA classification: [17] grade 1, normal intima or diffuse intimal thickening; grade 2, initial lesion or fatty streak; grade 3, preatheroma; grade 4, atheroma or complicated lesions, respectively. Normal intima has no
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Fig. 1. A case with MB in LAD: (a) part of LAD between arrows is covered by myocardial tissue and (b) longitudinal section of LAD with MB shows that the intima under MB is spared from atherosclerotic changes. Arrow indicates MB entrance. Proximal part (Prox) to MB covered by adipose tissue exhibits severely intimal thickening (elastic van Qeson’s staining, 5×).
atherosclerotic lesion with no fibrous thickening, and diffuse intimal thickening is not a true atherosclerotic lesion, in which smooth muscle cells infiltrate into intima with an increase of extracellular matrix. Initial lesion contained increased number of scattering foamy macrophages, and fatty streak is characterized by an aggregation of foam cells in the intima. Preatheroma is a lesion intermediate between fatty streak and atheroma characterized by extracellular lipid
deposition. Atheroma contains lipid core with fibrocellular covering, and complicated lesions are comprised of superimposed features of atheroma lesion characterized by disruption, hematoma, thrombosis, or calcification. The most advanced lesion type in each arterial section was decided by three pathologists (YL, YA, and TI), and the basal lesion type which was observed in the most thinnest intima in each arterial section was also decided by the same three pathol-
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ogists from the ostium of the left coronary artery to 2.5 cm distance. 2.7. Statistical analyses In MB group, mean atherosclerosis ratio of MB segments was compared with those of segments proximal to MB and those of segments distal to MB by Student’s t-test. Association of atherosclerosis ratio with age was analyzed by Scheffe’ s F-test. Mean atherosclerosis ratio at intervals of 5 mm from the left coronary ostium in each location category of MB group was compared with that of control group by Student’s t-test. Association of MB location with MB length, and of MB location with MB thickness, were examined by Scheffe’s F-test. In addition, associations of MB length and MB thickness with atherosclerosis suppression ratio were examined by Scheffe’s F-test. Correlation between MB length and MB thickness was analyzed by Pearson’s correlation coefficient method. Atherosclerosis suppression ratio was compared between thin MB group with short MB (≤1.0 cm) and thick MB group with long MB (≥2.5 cm) by Student’s t-test to analyze influence of both MB length and MB thickness on atherosclerosis suppression. Extent of the most advanced lesion of the intima at intervals of 5 mm from the left coronary ostium was compared among the three location groups by Mann–Whitney’s Utest Extent of the most advanced lesion of MB segments was compared with that of segments proximal to MB and that of segments distal to MB by Mann–Whitney’s U-test. Extent of the basal lesion of the intima at intervals of 5 mm from the left coronary ostium to 2.5 cm except for segments under MB was compared among the three location groups by Mann–Whitney’s U-test. For all statistical analyses, differences were considered statistically significant if p < 0.05. In all bar graphs in Section 3, the values were expressed as the mean ± standard deviation (S.D.).
3. Results
Fig. 2. Atherosclerosis ratio in LAD under MB: (a) atherosclerosis ratio in MB segments is significantly lower than that in the segments proximal to MB. The segments distal to MB also show a lower atherosclerosis ratio than the segments proximal to MB. The number of sections examined in the three groups is 1755 sections in the segments proximal to MB, 567 for the segments under MB, and 1219 for the segments distal to MB, respectively and (b) atherosclerosis ratio in the segments proximal to MB increases significantly with age (p < 0.0001, Scheffe’s F-test), and the ratios in MB segments and segments distal to MB also increase with age (p < 0.05, Scheffe’s F-test). In all age groups, atherosclerosis ratio in MB segments as well as in the segments distal to MB is lower than that in the segments proximal to MB. Single asterisks indicate a significant difference of p < 0.0001 comparing to the segments proximal to MB; double asterisks indicate p < 0.05 (Student’s t-test).
3.2. Association of MB location with atherosclerosis ratio
3.1. Atherosclerosis ratio in MB segments In MB group, one MB was observed in 150 cases (75%), two MBs for 45 cases (22.5%), and three MBs for 5 cases (2.5%). Mean value of atherosclerosis ratio in the segments proximal to MB was 1.93 ± 0.99, MB segments for 0.86 ± 0.51, and the segments distal to MB for 0.98 ± 0.65. Atherosclerosis ratio of MB segments was significantly (p < 0.0001) lower than that in the segments proximal to MB (Fig. 2a), and this was consistent for all age groups (Fig. 2b). Atherosclerosis ratio in all the three LAD segments increased significantly with age (Fig. 2b), but atherosclerosis suppression ratio was not significantly different among age groups (data not shown).
Mean MB location was 4.39 ± 1.18 cm (minimum 1.5 cm, maximum 10.0 cm). Number of cases was 63 in proximal location group (46 males and 17 females, mean age 68.5 ± 11.0 years), 60 in common location group (42 males and 18 females, mean age 68.0 ± 12.4 years), and 77 in distal location group (61 males and 16 females, mean age 66.5 ± 12.6 years). Mean age and sex ratio were not significantly different among the three location groups. Atherosclerosis ratio at 5 mm intervals is shown in Fig. 3. Atherosclerosis ratio of control group [MB(−)] tended to increase up to 2 cm from the left coronary ostium and subsequently decreased mildly. Atherosclerosis ratio of proximal location group increased up to 1.5 cm from the ostium, then
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Fig. 3. Atherosclerosis ratio of LAD at intervals of 5 mm from the left coronary ostium to cardiac apex in MB groups and control group [MB(−)]. Bold line indicates the main region under MB in each location group. The variation in atherosclerosis ratio of distal location group shows similar tendency from the ostium to the apex as that of control group, except for the MB region (5.0–6.5 cm). In proximal and common location groups, atherosclerosis ratio from the ostium to 6.5 cm is significantly lower than that of control group. The segments proximal to MB (0–2.5 cm) in proximal and common location groups have significantly lower atherosclerosis ratios than those in control and distal location groups (* p < 0.05; ** p < 0.001). The number of cases examined in MB(−) are n = 100 from the ostium (0 cm) up to 6.5 cm, n = 88 at 7.0 cm, n = 81 at 7.5 cm, n = 76 at 8.0 cm, and n = 72 at 8.5 cm. The number of cases examined in the proximal location group are n = 63 from the ostium (0 cm) up to 6.0 cm, n = 60 at 6.5 cm, n = 57 at 7.0 cm, n = 55 at 7.5 cm, n = 52 at 8.0 cm, and 49 at 8.5 cm in the proximal location group. The number of cases in the common location group are n = 60 from the ostium (0 cm) up to 6.5 cm, n = 58 at 7.0 cm, n = 55 at 7.5 cm, n = 53 at 8.0 cm, and n = 50 at 8.5 cm. The number of cases in the distal location group are n = 77 from the ostium (0 cm) up to 6.5 cm, n = 74 at 7.0 cm, n = 71 at 7.5 cm, n = 68 at 8.0 cm, and n = 63 at 8.5 cm, respectively. MB(−), control group without MB; proximal, proximal location group; common, common location group; distal, distal location group.
Fig. 4. Atherosclerosis ratio (a) and atherosclerosis suppression ratio (b) in three location groups. (a) Atherosclerosis ratios in MB segments and the segments distal to MB are significantly lower than those in the segments proximal to MB in all location groups (* p < 0.0001, Student’s t-test). (b) There is no significant difference in atherosclerosis suppression ratio among three location groups.
decreased up to 3.5 cm, and showed no significant fluctuation from 3.5 cm to the apex. Comparison between atherosclerosis ratios of proximal location group and control group showed that it was significantly lower from the ostium to 5.5 cm in proximal location group than in control group. Change in atherosclerosis ratio of common location group was similar to that of proximal location group, and atherosclerosis ratio of common location group from the ostium to 6.5 cm was significantly lower than that of control group. However, atherosclerosis ratio of distal location group was similar to that of control group from the ostium to 4.5 cm, and tended to be lower than that of control group from 5.0 to 6.5 cm because of existence of MB. Atherosclerosis ratio in the segments under MB was significantly lower (p < 0.0001) than that in the segments proximal to MB in all location groups (Fig. 4a). Comparison of atherosclerosis suppression ratio among three location groups showed no significant difference (Fig. 4b). 3.3. Association of MB length with atherosclerosis ratio Mean MB length was 1.44 ± 0.95 cm (minimum 0.5 cm, maximum 5.0 cm). Number of cases was 108 in short MB
Fig. 5. Association between MB length and its location (a) and atherosclerosis suppression ratio (b). (a) MB location decreases significantly with MB length (p < 0.05; Scheffe’s F-test). (b) Atherosclerosis suppression ratio increases significantly with MB length (p < 0.05; Scheffe’s F-test).
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Fig. 6. Associations of MB thickness with MB location (a), atherosclerosis suppression ratio (b), and MB length (c and d). (a) MB location decreases significantly with MB thickness (p < 0.0001; Scheffe’s F-test). (b) Atherosclerosis suppression ratio increases significantly with MB thickness (p < 0.0001; Scheffe’s F-test). (c) MB thickness increases significantly with MB length (p < 0.0001; Scheffe’s F-test). (d) Pearson’s correlation coefficient method also shows a positive correlation between MB thickness and length (p < 0.0001).
group less than 1.0 cm (80 males and 28 females, mean age 69.1 ± 11.5 years), 58 in common-length group from 1.5 to 2.0 cm (44 males and 14 females, mean age 67.3 ± 12.3 years), and 34 in long MB group over 2.5 cm (25 males and 9 females, mean age 66.7 ± 10.9 years). Mean age and sex ratio were not significantly different among three length groups. Mean MB location tended to decrease in proportion to its length (p < 0.05, Scheffe’s F-test), but there was only a small difference (0.5 cm) in mean MB location between short and long MB groups (Fig. 5a). Atherosclerosis suppression ratio tended to increase significantly (p < 0.05, Scheffe’s F-test) with MB length (Fig. 5b).
Association between MB thickness and MB location is shown in Fig. 6a. MB location tended to decrease in proportion to its thickness (p < 0.0001, Scheffe’s F-test). Atherosclerosis suppression ratio tended to increase significantly (p < 0.0001, Scheffe’s F-test) with MB thickness (Fig. 6b). In addition, as shown in Fig. 6c and d, MB
3.4. Association of MB thickness with atherosclerosis ratio Mean MB thickness was 856.5 ± 676.2 m (minimum 131 m, maximum 4940 m). Thin MB group consisted of 77 cases (59 males and 18 females, mean age 66.2 ± 11.7 years), common-thickness MB group for 64 cases (45 males and 19 females, mean age 70.1 ± 12.4 years), and thick MB group for 59 cases (45 males and 14 females, mean age 66.6 ± 11.7 years). Mean age and sex ratio were not significantly different among three thickness groups.
Fig. 7. Comparison of atherosclerosis suppression ratio between thin MB group with short MB (≤1.0 cm) and thick MB group with long MB (≥2.5 cm). Atherosclerosis suppression ratio is significantly greater in thick MB group with long MB than in thin MB group with short MB (Student’s t-test).
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thickness increased significantly with its length (p < 0.0001, Scheffe’s F-test), and correlation of MB thickness with MB length was also demonstrable by Pearson’s correlation coefficient method (p < 0.0001). Comparison of atherosclerosis suppression ratio between thin MB group with short MB and thick MB group with long MB yielded a significant difference (p < 0.05, Student’s t-test: Fig. 7).
3.5. Extent of intimal lesion in LAD Extent of the most advanced lesion in LAD intima at 5 mm intervals is shown in Fig. 8a. Each value at 5 mm intervals was expressed as the mean value of graded score. Extent of Table 1 Extent of the most advanced lesion Number of sections All cases with MB (n = 200) Proximal 1784 MB 584 Distal 1173
Mean grade (±S.D.)
Significance* (p)
3.2 ± 0.9 1.6 ± 0.9 1.9 ± 1.0
<0.0001
Classification by MB location Proximal location group (1.5–3.5 cm, n = 63) Proximal 401 3.3 ± 0.9 MB 199 1.8 ± 1.0 Distal 461 1.8 ± 1.0 Common location group (4.0–4.5 cm, n = 60) Proximal 509 3.1 ± 0.9 MB 179 1.5 ± 0.8 Distal 329 1.8 ± 1.0 Distal location group (5.0–10.0 cm, n = 77) Proximal 874 3.3 ± 0.9 MB 206 1.6 ± 0.9 Distal 383 2.0 ± 1.1 Classification by MB length Short MB group (≤1.0 cm, n = 108) Proximal 1002 3.2 ± 1.0 MB 161 1.7 ± 0.9 Distal 729 1.9 ± 1.0
Fig. 8. Extent of the most advanced lesion (a) and that of the basal lesion (b) at 5 mm intervals of LAD. (a) The figure shows extent of the most advanced lesion at intervals of 5 mm from the left coronary ostium to cardiac apex in MB groups and control group [MB(−)]. Bold line indicates the main region under MB in each location group. There is no difference in extent of the most advanced lesion among control group [MB(−)] and three location groups from the ostium up to 2.5 cm. This tendency is discrepant from the results of atherosclerosis ratio as shown in Fig. 3. In control group, the values gradually decrease from 2.5 up to 6.5 cm, but they abruptly decrease due to the presence of MB in three MB location groups. The numbers of cases examined in all groups are the same as those in Fig. 3. Raw data for Mann-Whitney’s U-test are omitted from this figure. MB(−), control group without MB; proximal, proximal location group; common, common location group; distal, distal location group. (b) The figure shows extent of the basal lesion from the ostium up to 2.5 cm in control group [MB(−)] and three location groups. The values of three location groups are significantly lower than that of control group in these regions. Significant p values by Mann–Whitney’s U-test are as follows: MB(−) vs. proximal for p = 0.0017, MB(−) vs. common for p = 0.042, and MB(−) vs. distal for p = 0.0001 at 0 cm; MB(−) vs. proximal for p = 0.0008, MB(−) vs. common for p < 0.0001, and MB(−) vs. distal for p < 0.0001 at 0.5 cm; MB(−) vs. proximal for p = 0.0015, MB(−) vs. common for p < 0.0001, and MB(−) vs. distal for p = 0.0002 at 1.0 cm; MB(−) vs. proximal for p = 0.0004, MB(−) vs. common for p < 0.0001, and MB(−) vs. distal for p = 0.001 at 1.5 cm; MB(−) vs. proximal for p < 0.0001, MB(−) vs. common for p = 0.0002, and MB(−) vs. distal for p = 0.0064 at 2.0 cm; MB(−) vs. proximal for p < 0.0001, MB(−) vs. common for p < 0.0001, and MB(−) vs. distal for p = 0.0028 at 2.5 cm.
Common-length group (1.5–2.0 cm, n = 58) Proximal 504 3.3 ± 0.9 MB 206 1.7 ± 1.0 Distal 293 1.9 ± 0.9 Long MB group (≥2.5 cm, n = 34) Proximal 278 3.3 ± 0.8 MB 217 1.5 ± 0.9 Distal 151 2.0 ± 1.1 Classification by MB thickness Thin MB group (<500 m, n = 77) Proximal 748 3.1 ± 1.0 MB 138 1.6 ± 0.9 Distal 437 1.8 ± 1.0 Common-thickness group (500–1,000 m, n = 64) Proximal 573 3.3 ± 0.9 MB 197 1.7 ± 1.0 Distal 394 2.0 ± 1.1 Thick MB group (>1000 m, n = 59) Proximal 463 3.3 ± 0.8 MB 249 1.6 ± 0.9 Distal 342 1.9 ± 1.0
<0.0001
<0.0001 NS <0.0001 NS <0.0001 <0.0001
<0.0001 0.0209 <0.0001 0.0087 <0.0001 <0.0001
<0.0001 0.0175 <0.0001 0.0484 <0.0001 0.0003
Proximal: segments proximal to MB; MB: segments under MB; Distal: segments distal to MB; NS: no significance. * Significance indicates the statistical difference comparing to the segments under MB by Mann–Whitney’s. U-test. Raw data for Mann–Whitney’s U-test are omitted from this table.
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the most advanced lesion of control group [MB(−)] tended to increase up to 1 cm from the left coronary ostium and decreased mildly from 2.0 up to 6.5 cm. These values of the three location groups with MB were similar to that of control group up to 2.0 cm from the left coronary ostium. However, extent of the most advanced lesion of proximal location group decreased from 2.5 up to 4.0 cm which were main parts covered by MB, then showed no significant change up to 6.0 cm, and mildly increased up to 7.5 cm. The values of common and distal location groups also decreased from 2.5 cm up to the peripheral parts of MB covering. The above result in the proximal LAD segments (0–2.5 cm in Fig. 8a) was discrepant from that of atherosclerosis ratio in the same segments, because extent of the most advanced lesion in these segments showed no significant difference between control group and MB groups while the mean values of atherosclerosis ratio in these segments demonstrated significant difference between them (Fig. 3). However, the further examination demonstrated that, in the proximal LAD segments (0–2.5 cm), extent of the basal lesion of control group was significantly higher than those of MB groups (Fig. 8b). In MB groups, the comparison of extent of the most advanced lesion among segments proximal to MB, segments under MB, and segments distal to MB are shown in Table 1. Extent of the most advanced lesion in segments under MB was significantly lower than that in segments proximal to MB irrespective of MB location, length, or thickness. In addition, the value was lower in segments under MB than that in segments distal to MB irrespective of MB length or thickness.
4. Discussion This study is the first to comprehensively examine the significance of anatomical properties of MB on extent of atherosclerosis in LAD. Present results indicate that atherosclerosis suppression distinctly takes place in LAD intima under MB, irrespective of MB location, thickness and length, and moreover that these anatomical properties of MB are critical to regulate atherosclerosis evolution not only in LAD intima under MB but also LAD intima proximal to MB. In previous studies, existence of MB in LAD causes atherosclerosis suppression in LAD intima under MB [1,4–7,14–16]. The present study also demonstrated that mean atherosclerosis ratio and extent of the most advanced lesion in MB segments were significantly lower than those in the segments proximal to MB. By scanning electron miaoscopy on the human LAD, endothelial cells proximal to MB are polygonal and flat in shape, whereas those beneath MB become spindle-shaped, engorged and aligned along the blood flow direction [6]. Since the first description of these two morphologically distinguishable endothelial cell shapes [18], it has been established through objective estimation of shear stress in a animal model that spindle-shaped endothelial cells are found in areas of high shear stress, and polygonal-
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shaped cells for low shear stress [19]. As for relation of hemodynamics to atherosclerosis, it is well appreciated that low shear stress is associated with atherosclerosis development because of mass transfer of lipids into subendothelial space [20]. In our previous cholesterol-fed rabbit model, ferritin permeability was suppressed in intra-myocardial segment having spindle-shaped endothelial cells compared with intra-adipose segment having polygonal-shaped endothelial cells [9]. There was no lipid deposition in the former segment, but obvious lipid deposition in the latter segment. From these findings [6,9,18–20], it is plausible that the significant decrease of both atherosclerosis ratio and extent of the most advanced lesion in MB segments in this study results from suppression of lipid infiltration into subendothelial space because of hemodynamic alterations toward higher shear stress in MB region. In this study, mean MB location was 4.39 cm from the left coronary ostium. This observation is basically consistent with previous anatomical studies, which reported values of 3.36–4.5 cm [4]. Our results also demonstrated that atherosclerosis ratio in the proximal segments of LAD (up to 2.5 cm away from the ostium) was significantly lower in proximal and common location groups than in the corresponding segments of control group. Age, sex, blood pressure level, and serum cholesterol level are generally considered to be the major coronary risk factors [21]. In this study, there was no significant difference in age and sex ratio among three location groups with MB and control group. In addition, in our previous study, distribution of atherosclerotic lesions in LAD was altered by presence of MB irrespective of serum cholesterol or blood pressure level [5]. We therefore consider that complex hemodynamic alterations of blood flow in LAD segments proximal to MB are the main cause of lower atherosclerosis ratio in the proximal LAD segments of proximal and common location groups compared with control group. Shear stress acting on endothelial cells is proportional to blood flow velocity and blood viscosity, and is inversely proportional to luminal diameter of the vessel [22]. Retrograde flow caused by squeezing of MB at systole can be observed by intracoronary ultrasound imaging and angiography in the segments proximal to MB, which may lead to negative blood flow velocity and higher pressure in the coronary segment proximal to MB than in the aorta [23,24]. In addition, compression by MB during systole may strongly influence magnitude of shear stress of blood flow in the coronary segments proximal to MB and may contribute to lower atherosclerosis ratio of proximal and common location groups compared with control group [22–24]. On the other hand, this study showed that atherosclerosis ratio in the proximal LAD segments up to 2.5 cm away from the ostium in distal MB location group was not different from that in control group. This is consistent with our hypothesis, because MB site in the distal MB location group would be too far away to affect magnitude of shear stress in the proximal LAD segments within 2.5 cm of the ostium.
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From above mentioned results on the relationship between atherosclerosis ratio and MB location, we focused on extent of atherosclerotic lesion in the proximal LAD segments up to 2.5 cm away from the left coronary ostium. In this region, extent of the most advanced lesion was not significantly different between control group and three location groups in spite of lower atherosclerosis ratio in proximal and common location groups than control group. On the other hand, the values of extent of the basal lesion in three location groups were significantly lower than that of control group. These results indicate that the different atherosclerosis ratios of MB groups from that of control group in the proximal LAD segments may be caused from the difference of extent of the basal lesion between the both. Although the accurate reason for a discrepant tendency between extent of the most advanced lesion and that of the basal lesion, it seems to be consistent that the shape of cut-surface of the advanced lesion occurring in the LAD segments proximal to MB is eccentric. Previous autopsy studies have reported MB length, with ranges of 3–69 mm [25], 4–28 mm [26], and 4–25 mm [27] and mean values of 19.7 mm [5], and 21.9 mm in males and 20.3 mm in females [16]. MB thickness has been reported to be 0.3–1.7 mm [27], with mean values of 2.0 mm [28]. In this study, mean MB length was 14.4 mm, which is not greatly different from previous values, but mean MB thickness was 856 m, which is somewhat thinner than previous values. The contrast between mean MB thickness in the present and previous studies probably results from differences in detection method of MBs, because MBs in our study were directly assessed with histomorphometry and we interpreted a very thin covering of myocardial tissue as MB as thick as it surrounded the whole circumference of LAD. Our statistical analyses demonstrated that longer MBs tended to be located more proximally in LAD, and that thicker MBs were located significantly more proximally. In addition, MB thickness was significantly correlated with its length. Ferreira et al. also reported that deeply situated MBs were longer than superficially situated MBs [16]. These observations of a close relationship between MB length and MB thickness indicate that these anatomical properties are tightly interrelated. Additionally, our study revealed greater atherosclerosis suppression in MB segments of thick and long MB groups compared with the corresponding thin and short MB groups. This difference in atherosclerosis suppression as a function of anatomical properties of MB probably originates from differences in contractile force exerted by MB muscle. Indeed, a previous angiographic study showed that MB affected a longer segment of LAD in hypertrophic hearts, which led to a greater degree of LAD compression [29], and an autopsy study indicated that the cases with thick MB were pathological [13]. Thus, we suggest that MB length and MB thickness are the critical anatomical properties regulating hemodynamic alterations in LAD and that the heart with a longer and/or thicker MB in a running course of LAD may be more vulnerable to myocardial ischemia due to a stronger compression on LAD.
Our results may be useful for a selection of patients who need therapeutic approach. While MB is frequently detected in the coronary arteries during detailed post-mortem examination, clinically symptomatic cases by MB have been relatively limited, and a recent issue has mentioned that further research is needed to define patients in whom MB is potentially pathologic [30]. The recent imaging techniques, such as intracoronary ultrasonography and multidetector computed tomography, make it possible to detect MB and are effective on the examination of MB length and thickness. Further pathological analyses of LAD in cases with myocardial ischemia or sudden death as well as long-term follow-up studies of pathological cases are necessary for an elucidation of a significance of anatomical properties of MB.
Acknowledgements This study was partly supported by a MEXT Grant (30101893) of Japan and the Project Research Grant (16-25) of Toho University School of Medicine.
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Significance of anatomical properties of myocardial bridge on atherosclerosis evolution in the left anterior descending coronary artery Yukio Ishikawa a,∗ , Yoshikiyo Akasaka a , Kinji Ito a , Yuri Akishima a , Masayo Kimura a , Hideko Kiguchi b , Ai Fujimoto c , Toshiharu Ishii a a
Department of Pathology, Toho University School of Medicine, 5-21-16 Ohmori-nishi, Ohta-ku, Tokyo 143-8540, Japan Department of Pathology, Saiseikai Kanagawaken Hospital, 6-6 Tomiya-cho, Kanagawa-ku, Yokohama 221-8601, Japan Department of Gastroenterology and Hepatology, Toho University Ohmori Hospital, 6-11-1 Ohmori-nishi, Ohta-ku, Tokyo 143-8541, Japan b
c
Received 25 January 2005; received in revised form 21 June 2005; accepted 11 July 2005 Available online 19 August 2005
Abstract Myocardial bridge (MB) is frequently detected in the left anterior descending coronary artery (LAD), and LAD intima under MB is significantly spared from atherosclerotic evolution. Significance of anatomical features of MB on the extent of atherosclerosis of LAD was histomorphometrically investigated. Full-length 200 LADs with MB and 100 control LADs without MB were cross-sectioned at 5 mm intervals, and atherosclerosis ratio and intimal lesion types were evaluated. In cases with MB located within 5 cm from the left coronary ostium, atherosclerosis ratio in the proximal part of LAD was significantly lower than in control group, but, in cases with MB locating more than 5 cm from the ostium, atherosclerosis ratio in this part was similar to that in control cases. MB thickness was significantly correlated with its length, and the longer the MB the more proximally it tended to be located in LAD. Atherosclerosis ratio under MB was lower in cases with thick or long MBs than in cases with thinner or shorter MBs. In addition, intimal lesion in segments proximal to MB tended to be eccentric. Our results suggest that these anatomical properties of MB are the critical modulators for atherosclerosis evolution in the entire course of LAD. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Myocardial bridge; Coronary artery; Atherosclerosis; Anatomy; Hemodynamics
1. Introduction Myocardial bridge (MB) is a common anatomical situation in the left anterior descending coronary artery (LAD) [1] in which part of LAD is covered by myocardial tissue. Since a detail description of MB [2], it has been designated
∗
Corresponding author. Tel.: +81 3 3762 4151; fax: 81 3 5493 5414. E-mail addresses: [email protected] (Y. Ishikawa), [email protected] (Y. Akasaka), [email protected] (K. Ito), [email protected] (Y. Akishima), [email protected] (M. Kimura), [email protected] (H. Kiguchi), [email protected] (A. Fujimoto), [email protected] (T. Ishii). 0021-9150/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2005.07.024
as intramural coronary artery, mural coronary artery, or coronary artery overbridging [3]. Frequency of MB in LAD is relatively high, sometimes over 50% by autopsy study [4]. It is widely accepted that arterial intima beneath MB is significantly spared from atherosclerotic changes [1,4]. This atherosclerosis suppression under MB compared with the coronary segments proximal to MB has been also evident in histopathologic [5–7] and image analysis [8] studies. It has been also suggested through morphological examination of endothelial shapes that hemodynamic changes leading to high shear stress in LAD segment under MB contribute to atherosclerosis suppression in this region [6]. This hypothesis is further supported by a morphological observation using a cholesterol-fed rabbit model [9]. These studies on LAD with
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MB indicate that hemodynamic alterations resulting from systolic compression by MB consistently influence distribution of atherosclerotic lesions. On the other hand, disturbed coronary flow due to systolic compression by MB may also evoke clinical symptoms of ischemic heart disease [3,10], ventricular fibrillation [11], atrioventricular block [12], and sudden cardiac death [13]. These conditions are probably caused by coronary ischemia due to retrograde blood flow from the coronary segment under MB into the segment proximal to MB through MB compression during systole. Such blood flow subsequently impedes coronary flow and causes persistent reduction of arterial diameter during systole [14,15]. Angiographically visible severe narrowing of LAD lumen by MB compression during systole may contribute to coronary ischemia [10]. An LAD deeply situated in the myocardium can be distorted by systolic compression of MB [16]. Considering these angiographic and morphological evidences [10,13,16], anatomical properties of MB, such as its location within LAD as well as its thickness and length, can be regarded as critical factors that directly influence extent of coronary stenosis and disturbed blood flow in LAD. In this study, we histomorphometrically investigated the relationship between various anatomical properties of MB and extent of atherosclerosis in human LAD. 2. Materials and methods 2.1. Materials MB group consisted of 200 autopsied cases with MB(s) in LAD but without any morphologically proven cardiovascular disease (Fig. 1). Control group similarly having no cardiovascular disease consisted of 100 autopsied cases without MB in LAD. They were obtained from consecutive autopsies at Ohmori Hospital of Toho University from 1998 to 2002. MB group consisted of 149 males and 51 females, with mean age 66.6 ± 13.7 years, and control group for 71 males and 29 females, with mean age 67.4 ± 14.7 years. There was no difference in distribution of age and sex between them. All the full-length LADs from the left coronary ostium to cardiac apex were removed from the hearts together with surrounding adipose and myocardial tissues. They were fixed with 10% formaldehyde and cross-sectioned at 5 mm intervals. They were embedded in paraffin, and thin-sections were treated with hematoxylin-eosin and elastica van Gieson’s stainings. Detailed observation often revealed the case having multiple MBs in an LAD. In such case, only the MB in the most proximal portion of LAD was considered. 2.2. Definitions of atherosclerosis ratio and atherosclerosis suppression ratio To assess atherosclerosis severity, the areas of intima and media in all sections were measured with automated image
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analysis system of Visual Measure 32 (Rise System, Sendai, Japan). The area ratio of intima to media was defined as atherosclerosis ratio. Atherosclerosis suppression ratio was expressed as a percentage indicating extent of atherosclerosis suppression in LAD under MB and was calculated as proportional decrease of mean atherosclerosis ratio of MB segments relative to mean atherosclerosis ratio of the three consecutive sections just proximal to MB [100 − (mean atherosclerosis ratio of MB segments/mean atherosclerosis ratio of the three sections just proximal to MB) × 100]. Usage of mean atherosclerosis ratio of the three sections just proximal to MB for calculation of atherosclerosis suppression ratio is because mean MB length in this study (1.44 ± 0.95 cm, as shown in Section 3) was almost equivalent to the length of three paraffin blocks, because LAD was cross-sectioned at 5 mm intervals. 2.3. MB location Distance from the left coronary ostium to the first segment at which LAD was covered by MB was defined as MB location. MB group was classified into three categories according to distribution of MB location: proximal location group with MB located within 3.5 cm, common location group with MB located from 4.0 to 5.0 cm, and distal location group with MB located over 5.0 cm. 2.4. MB length Number of sections with consecutive MB multiplied by 5 mm was defined as MB length. MB group was classified into three categories according to distribution of MB length: short MB group with less than 1.0 cm, common-length MB group with 1.5–2.0 cm, and long MB group with over 2.5 cm. 2.5. MB thickness Thickness of myocardial tissue bridging LAD was microscopically measured, and the highest value was defined as MB thickness for each case. MB group was classified into three categories according to distribution of MB thickness: thin MB group with less than 500 m, common-thickness MB group with 500–1000 m, and thick MB group with over 1000 m. 2.6. Classification of intimal lesions Intimal lesion type was classified into the four categories by detailed observation of arterial sections treated with hematoxylin-eosin and elastica van Gieason’ s stainings according to the AHA classification: [17] grade 1, normal intima or diffuse intimal thickening; grade 2, initial lesion or fatty streak; grade 3, preatheroma; grade 4, atheroma or complicated lesions, respectively. Normal intima has no
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Fig. 1. A case with MB in LAD: (a) part of LAD between arrows is covered by myocardial tissue and (b) longitudinal section of LAD with MB shows that the intima under MB is spared from atherosclerotic changes. Arrow indicates MB entrance. Proximal part (Prox) to MB covered by adipose tissue exhibits severely intimal thickening (elastic van Qeson’s staining, 5×).
atherosclerotic lesion with no fibrous thickening, and diffuse intimal thickening is not a true atherosclerotic lesion, in which smooth muscle cells infiltrate into intima with an increase of extracellular matrix. Initial lesion contained increased number of scattering foamy macrophages, and fatty streak is characterized by an aggregation of foam cells in the intima. Preatheroma is a lesion intermediate between fatty streak and atheroma characterized by extracellular lipid
deposition. Atheroma contains lipid core with fibrocellular covering, and complicated lesions are comprised of superimposed features of atheroma lesion characterized by disruption, hematoma, thrombosis, or calcification. The most advanced lesion type in each arterial section was decided by three pathologists (YL, YA, and TI), and the basal lesion type which was observed in the most thinnest intima in each arterial section was also decided by the same three pathol-
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ogists from the ostium of the left coronary artery to 2.5 cm distance. 2.7. Statistical analyses In MB group, mean atherosclerosis ratio of MB segments was compared with those of segments proximal to MB and those of segments distal to MB by Student’s t-test. Association of atherosclerosis ratio with age was analyzed by Scheffe’ s F-test. Mean atherosclerosis ratio at intervals of 5 mm from the left coronary ostium in each location category of MB group was compared with that of control group by Student’s t-test. Association of MB location with MB length, and of MB location with MB thickness, were examined by Scheffe’s F-test. In addition, associations of MB length and MB thickness with atherosclerosis suppression ratio were examined by Scheffe’s F-test. Correlation between MB length and MB thickness was analyzed by Pearson’s correlation coefficient method. Atherosclerosis suppression ratio was compared between thin MB group with short MB (≤1.0 cm) and thick MB group with long MB (≥2.5 cm) by Student’s t-test to analyze influence of both MB length and MB thickness on atherosclerosis suppression. Extent of the most advanced lesion of the intima at intervals of 5 mm from the left coronary ostium was compared among the three location groups by Mann–Whitney’s Utest Extent of the most advanced lesion of MB segments was compared with that of segments proximal to MB and that of segments distal to MB by Mann–Whitney’s U-test. Extent of the basal lesion of the intima at intervals of 5 mm from the left coronary ostium to 2.5 cm except for segments under MB was compared among the three location groups by Mann–Whitney’s U-test. For all statistical analyses, differences were considered statistically significant if p < 0.05. In all bar graphs in Section 3, the values were expressed as the mean ± standard deviation (S.D.).
3. Results
Fig. 2. Atherosclerosis ratio in LAD under MB: (a) atherosclerosis ratio in MB segments is significantly lower than that in the segments proximal to MB. The segments distal to MB also show a lower atherosclerosis ratio than the segments proximal to MB. The number of sections examined in the three groups is 1755 sections in the segments proximal to MB, 567 for the segments under MB, and 1219 for the segments distal to MB, respectively and (b) atherosclerosis ratio in the segments proximal to MB increases significantly with age (p < 0.0001, Scheffe’s F-test), and the ratios in MB segments and segments distal to MB also increase with age (p < 0.05, Scheffe’s F-test). In all age groups, atherosclerosis ratio in MB segments as well as in the segments distal to MB is lower than that in the segments proximal to MB. Single asterisks indicate a significant difference of p < 0.0001 comparing to the segments proximal to MB; double asterisks indicate p < 0.05 (Student’s t-test).
3.2. Association of MB location with atherosclerosis ratio
3.1. Atherosclerosis ratio in MB segments In MB group, one MB was observed in 150 cases (75%), two MBs for 45 cases (22.5%), and three MBs for 5 cases (2.5%). Mean value of atherosclerosis ratio in the segments proximal to MB was 1.93 ± 0.99, MB segments for 0.86 ± 0.51, and the segments distal to MB for 0.98 ± 0.65. Atherosclerosis ratio of MB segments was significantly (p < 0.0001) lower than that in the segments proximal to MB (Fig. 2a), and this was consistent for all age groups (Fig. 2b). Atherosclerosis ratio in all the three LAD segments increased significantly with age (Fig. 2b), but atherosclerosis suppression ratio was not significantly different among age groups (data not shown).
Mean MB location was 4.39 ± 1.18 cm (minimum 1.5 cm, maximum 10.0 cm). Number of cases was 63 in proximal location group (46 males and 17 females, mean age 68.5 ± 11.0 years), 60 in common location group (42 males and 18 females, mean age 68.0 ± 12.4 years), and 77 in distal location group (61 males and 16 females, mean age 66.5 ± 12.6 years). Mean age and sex ratio were not significantly different among the three location groups. Atherosclerosis ratio at 5 mm intervals is shown in Fig. 3. Atherosclerosis ratio of control group [MB(−)] tended to increase up to 2 cm from the left coronary ostium and subsequently decreased mildly. Atherosclerosis ratio of proximal location group increased up to 1.5 cm from the ostium, then
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Fig. 3. Atherosclerosis ratio of LAD at intervals of 5 mm from the left coronary ostium to cardiac apex in MB groups and control group [MB(−)]. Bold line indicates the main region under MB in each location group. The variation in atherosclerosis ratio of distal location group shows similar tendency from the ostium to the apex as that of control group, except for the MB region (5.0–6.5 cm). In proximal and common location groups, atherosclerosis ratio from the ostium to 6.5 cm is significantly lower than that of control group. The segments proximal to MB (0–2.5 cm) in proximal and common location groups have significantly lower atherosclerosis ratios than those in control and distal location groups (* p < 0.05; ** p < 0.001). The number of cases examined in MB(−) are n = 100 from the ostium (0 cm) up to 6.5 cm, n = 88 at 7.0 cm, n = 81 at 7.5 cm, n = 76 at 8.0 cm, and n = 72 at 8.5 cm. The number of cases examined in the proximal location group are n = 63 from the ostium (0 cm) up to 6.0 cm, n = 60 at 6.5 cm, n = 57 at 7.0 cm, n = 55 at 7.5 cm, n = 52 at 8.0 cm, and 49 at 8.5 cm in the proximal location group. The number of cases in the common location group are n = 60 from the ostium (0 cm) up to 6.5 cm, n = 58 at 7.0 cm, n = 55 at 7.5 cm, n = 53 at 8.0 cm, and n = 50 at 8.5 cm. The number of cases in the distal location group are n = 77 from the ostium (0 cm) up to 6.5 cm, n = 74 at 7.0 cm, n = 71 at 7.5 cm, n = 68 at 8.0 cm, and n = 63 at 8.5 cm, respectively. MB(−), control group without MB; proximal, proximal location group; common, common location group; distal, distal location group.
Fig. 4. Atherosclerosis ratio (a) and atherosclerosis suppression ratio (b) in three location groups. (a) Atherosclerosis ratios in MB segments and the segments distal to MB are significantly lower than those in the segments proximal to MB in all location groups (* p < 0.0001, Student’s t-test). (b) There is no significant difference in atherosclerosis suppression ratio among three location groups.
decreased up to 3.5 cm, and showed no significant fluctuation from 3.5 cm to the apex. Comparison between atherosclerosis ratios of proximal location group and control group showed that it was significantly lower from the ostium to 5.5 cm in proximal location group than in control group. Change in atherosclerosis ratio of common location group was similar to that of proximal location group, and atherosclerosis ratio of common location group from the ostium to 6.5 cm was significantly lower than that of control group. However, atherosclerosis ratio of distal location group was similar to that of control group from the ostium to 4.5 cm, and tended to be lower than that of control group from 5.0 to 6.5 cm because of existence of MB. Atherosclerosis ratio in the segments under MB was significantly lower (p < 0.0001) than that in the segments proximal to MB in all location groups (Fig. 4a). Comparison of atherosclerosis suppression ratio among three location groups showed no significant difference (Fig. 4b). 3.3. Association of MB length with atherosclerosis ratio Mean MB length was 1.44 ± 0.95 cm (minimum 0.5 cm, maximum 5.0 cm). Number of cases was 108 in short MB
Fig. 5. Association between MB length and its location (a) and atherosclerosis suppression ratio (b). (a) MB location decreases significantly with MB length (p < 0.05; Scheffe’s F-test). (b) Atherosclerosis suppression ratio increases significantly with MB length (p < 0.05; Scheffe’s F-test).
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Fig. 6. Associations of MB thickness with MB location (a), atherosclerosis suppression ratio (b), and MB length (c and d). (a) MB location decreases significantly with MB thickness (p < 0.0001; Scheffe’s F-test). (b) Atherosclerosis suppression ratio increases significantly with MB thickness (p < 0.0001; Scheffe’s F-test). (c) MB thickness increases significantly with MB length (p < 0.0001; Scheffe’s F-test). (d) Pearson’s correlation coefficient method also shows a positive correlation between MB thickness and length (p < 0.0001).
group less than 1.0 cm (80 males and 28 females, mean age 69.1 ± 11.5 years), 58 in common-length group from 1.5 to 2.0 cm (44 males and 14 females, mean age 67.3 ± 12.3 years), and 34 in long MB group over 2.5 cm (25 males and 9 females, mean age 66.7 ± 10.9 years). Mean age and sex ratio were not significantly different among three length groups. Mean MB location tended to decrease in proportion to its length (p < 0.05, Scheffe’s F-test), but there was only a small difference (0.5 cm) in mean MB location between short and long MB groups (Fig. 5a). Atherosclerosis suppression ratio tended to increase significantly (p < 0.05, Scheffe’s F-test) with MB length (Fig. 5b).
Association between MB thickness and MB location is shown in Fig. 6a. MB location tended to decrease in proportion to its thickness (p < 0.0001, Scheffe’s F-test). Atherosclerosis suppression ratio tended to increase significantly (p < 0.0001, Scheffe’s F-test) with MB thickness (Fig. 6b). In addition, as shown in Fig. 6c and d, MB
3.4. Association of MB thickness with atherosclerosis ratio Mean MB thickness was 856.5 ± 676.2 m (minimum 131 m, maximum 4940 m). Thin MB group consisted of 77 cases (59 males and 18 females, mean age 66.2 ± 11.7 years), common-thickness MB group for 64 cases (45 males and 19 females, mean age 70.1 ± 12.4 years), and thick MB group for 59 cases (45 males and 14 females, mean age 66.6 ± 11.7 years). Mean age and sex ratio were not significantly different among three thickness groups.
Fig. 7. Comparison of atherosclerosis suppression ratio between thin MB group with short MB (≤1.0 cm) and thick MB group with long MB (≥2.5 cm). Atherosclerosis suppression ratio is significantly greater in thick MB group with long MB than in thin MB group with short MB (Student’s t-test).
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thickness increased significantly with its length (p < 0.0001, Scheffe’s F-test), and correlation of MB thickness with MB length was also demonstrable by Pearson’s correlation coefficient method (p < 0.0001). Comparison of atherosclerosis suppression ratio between thin MB group with short MB and thick MB group with long MB yielded a significant difference (p < 0.05, Student’s t-test: Fig. 7).
3.5. Extent of intimal lesion in LAD Extent of the most advanced lesion in LAD intima at 5 mm intervals is shown in Fig. 8a. Each value at 5 mm intervals was expressed as the mean value of graded score. Extent of Table 1 Extent of the most advanced lesion Number of sections All cases with MB (n = 200) Proximal 1784 MB 584 Distal 1173
Mean grade (±S.D.)
Significance* (p)
3.2 ± 0.9 1.6 ± 0.9 1.9 ± 1.0
<0.0001
Classification by MB location Proximal location group (1.5–3.5 cm, n = 63) Proximal 401 3.3 ± 0.9 MB 199 1.8 ± 1.0 Distal 461 1.8 ± 1.0 Common location group (4.0–4.5 cm, n = 60) Proximal 509 3.1 ± 0.9 MB 179 1.5 ± 0.8 Distal 329 1.8 ± 1.0 Distal location group (5.0–10.0 cm, n = 77) Proximal 874 3.3 ± 0.9 MB 206 1.6 ± 0.9 Distal 383 2.0 ± 1.1 Classification by MB length Short MB group (≤1.0 cm, n = 108) Proximal 1002 3.2 ± 1.0 MB 161 1.7 ± 0.9 Distal 729 1.9 ± 1.0
Fig. 8. Extent of the most advanced lesion (a) and that of the basal lesion (b) at 5 mm intervals of LAD. (a) The figure shows extent of the most advanced lesion at intervals of 5 mm from the left coronary ostium to cardiac apex in MB groups and control group [MB(−)]. Bold line indicates the main region under MB in each location group. There is no difference in extent of the most advanced lesion among control group [MB(−)] and three location groups from the ostium up to 2.5 cm. This tendency is discrepant from the results of atherosclerosis ratio as shown in Fig. 3. In control group, the values gradually decrease from 2.5 up to 6.5 cm, but they abruptly decrease due to the presence of MB in three MB location groups. The numbers of cases examined in all groups are the same as those in Fig. 3. Raw data for Mann-Whitney’s U-test are omitted from this figure. MB(−), control group without MB; proximal, proximal location group; common, common location group; distal, distal location group. (b) The figure shows extent of the basal lesion from the ostium up to 2.5 cm in control group [MB(−)] and three location groups. The values of three location groups are significantly lower than that of control group in these regions. Significant p values by Mann–Whitney’s U-test are as follows: MB(−) vs. proximal for p = 0.0017, MB(−) vs. common for p = 0.042, and MB(−) vs. distal for p = 0.0001 at 0 cm; MB(−) vs. proximal for p = 0.0008, MB(−) vs. common for p < 0.0001, and MB(−) vs. distal for p < 0.0001 at 0.5 cm; MB(−) vs. proximal for p = 0.0015, MB(−) vs. common for p < 0.0001, and MB(−) vs. distal for p = 0.0002 at 1.0 cm; MB(−) vs. proximal for p = 0.0004, MB(−) vs. common for p < 0.0001, and MB(−) vs. distal for p = 0.001 at 1.5 cm; MB(−) vs. proximal for p < 0.0001, MB(−) vs. common for p = 0.0002, and MB(−) vs. distal for p = 0.0064 at 2.0 cm; MB(−) vs. proximal for p < 0.0001, MB(−) vs. common for p < 0.0001, and MB(−) vs. distal for p = 0.0028 at 2.5 cm.
Common-length group (1.5–2.0 cm, n = 58) Proximal 504 3.3 ± 0.9 MB 206 1.7 ± 1.0 Distal 293 1.9 ± 0.9 Long MB group (≥2.5 cm, n = 34) Proximal 278 3.3 ± 0.8 MB 217 1.5 ± 0.9 Distal 151 2.0 ± 1.1 Classification by MB thickness Thin MB group (<500 m, n = 77) Proximal 748 3.1 ± 1.0 MB 138 1.6 ± 0.9 Distal 437 1.8 ± 1.0 Common-thickness group (500–1,000 m, n = 64) Proximal 573 3.3 ± 0.9 MB 197 1.7 ± 1.0 Distal 394 2.0 ± 1.1 Thick MB group (>1000 m, n = 59) Proximal 463 3.3 ± 0.8 MB 249 1.6 ± 0.9 Distal 342 1.9 ± 1.0
<0.0001
<0.0001 NS <0.0001 NS <0.0001 <0.0001
<0.0001 0.0209 <0.0001 0.0087 <0.0001 <0.0001
<0.0001 0.0175 <0.0001 0.0484 <0.0001 0.0003
Proximal: segments proximal to MB; MB: segments under MB; Distal: segments distal to MB; NS: no significance. * Significance indicates the statistical difference comparing to the segments under MB by Mann–Whitney’s. U-test. Raw data for Mann–Whitney’s U-test are omitted from this table.
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the most advanced lesion of control group [MB(−)] tended to increase up to 1 cm from the left coronary ostium and decreased mildly from 2.0 up to 6.5 cm. These values of the three location groups with MB were similar to that of control group up to 2.0 cm from the left coronary ostium. However, extent of the most advanced lesion of proximal location group decreased from 2.5 up to 4.0 cm which were main parts covered by MB, then showed no significant change up to 6.0 cm, and mildly increased up to 7.5 cm. The values of common and distal location groups also decreased from 2.5 cm up to the peripheral parts of MB covering. The above result in the proximal LAD segments (0–2.5 cm in Fig. 8a) was discrepant from that of atherosclerosis ratio in the same segments, because extent of the most advanced lesion in these segments showed no significant difference between control group and MB groups while the mean values of atherosclerosis ratio in these segments demonstrated significant difference between them (Fig. 3). However, the further examination demonstrated that, in the proximal LAD segments (0–2.5 cm), extent of the basal lesion of control group was significantly higher than those of MB groups (Fig. 8b). In MB groups, the comparison of extent of the most advanced lesion among segments proximal to MB, segments under MB, and segments distal to MB are shown in Table 1. Extent of the most advanced lesion in segments under MB was significantly lower than that in segments proximal to MB irrespective of MB location, length, or thickness. In addition, the value was lower in segments under MB than that in segments distal to MB irrespective of MB length or thickness.
4. Discussion This study is the first to comprehensively examine the significance of anatomical properties of MB on extent of atherosclerosis in LAD. Present results indicate that atherosclerosis suppression distinctly takes place in LAD intima under MB, irrespective of MB location, thickness and length, and moreover that these anatomical properties of MB are critical to regulate atherosclerosis evolution not only in LAD intima under MB but also LAD intima proximal to MB. In previous studies, existence of MB in LAD causes atherosclerosis suppression in LAD intima under MB [1,4–7,14–16]. The present study also demonstrated that mean atherosclerosis ratio and extent of the most advanced lesion in MB segments were significantly lower than those in the segments proximal to MB. By scanning electron miaoscopy on the human LAD, endothelial cells proximal to MB are polygonal and flat in shape, whereas those beneath MB become spindle-shaped, engorged and aligned along the blood flow direction [6]. Since the first description of these two morphologically distinguishable endothelial cell shapes [18], it has been established through objective estimation of shear stress in a animal model that spindle-shaped endothelial cells are found in areas of high shear stress, and polygonal-
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shaped cells for low shear stress [19]. As for relation of hemodynamics to atherosclerosis, it is well appreciated that low shear stress is associated with atherosclerosis development because of mass transfer of lipids into subendothelial space [20]. In our previous cholesterol-fed rabbit model, ferritin permeability was suppressed in intra-myocardial segment having spindle-shaped endothelial cells compared with intra-adipose segment having polygonal-shaped endothelial cells [9]. There was no lipid deposition in the former segment, but obvious lipid deposition in the latter segment. From these findings [6,9,18–20], it is plausible that the significant decrease of both atherosclerosis ratio and extent of the most advanced lesion in MB segments in this study results from suppression of lipid infiltration into subendothelial space because of hemodynamic alterations toward higher shear stress in MB region. In this study, mean MB location was 4.39 cm from the left coronary ostium. This observation is basically consistent with previous anatomical studies, which reported values of 3.36–4.5 cm [4]. Our results also demonstrated that atherosclerosis ratio in the proximal segments of LAD (up to 2.5 cm away from the ostium) was significantly lower in proximal and common location groups than in the corresponding segments of control group. Age, sex, blood pressure level, and serum cholesterol level are generally considered to be the major coronary risk factors [21]. In this study, there was no significant difference in age and sex ratio among three location groups with MB and control group. In addition, in our previous study, distribution of atherosclerotic lesions in LAD was altered by presence of MB irrespective of serum cholesterol or blood pressure level [5]. We therefore consider that complex hemodynamic alterations of blood flow in LAD segments proximal to MB are the main cause of lower atherosclerosis ratio in the proximal LAD segments of proximal and common location groups compared with control group. Shear stress acting on endothelial cells is proportional to blood flow velocity and blood viscosity, and is inversely proportional to luminal diameter of the vessel [22]. Retrograde flow caused by squeezing of MB at systole can be observed by intracoronary ultrasound imaging and angiography in the segments proximal to MB, which may lead to negative blood flow velocity and higher pressure in the coronary segment proximal to MB than in the aorta [23,24]. In addition, compression by MB during systole may strongly influence magnitude of shear stress of blood flow in the coronary segments proximal to MB and may contribute to lower atherosclerosis ratio of proximal and common location groups compared with control group [22–24]. On the other hand, this study showed that atherosclerosis ratio in the proximal LAD segments up to 2.5 cm away from the ostium in distal MB location group was not different from that in control group. This is consistent with our hypothesis, because MB site in the distal MB location group would be too far away to affect magnitude of shear stress in the proximal LAD segments within 2.5 cm of the ostium.
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From above mentioned results on the relationship between atherosclerosis ratio and MB location, we focused on extent of atherosclerotic lesion in the proximal LAD segments up to 2.5 cm away from the left coronary ostium. In this region, extent of the most advanced lesion was not significantly different between control group and three location groups in spite of lower atherosclerosis ratio in proximal and common location groups than control group. On the other hand, the values of extent of the basal lesion in three location groups were significantly lower than that of control group. These results indicate that the different atherosclerosis ratios of MB groups from that of control group in the proximal LAD segments may be caused from the difference of extent of the basal lesion between the both. Although the accurate reason for a discrepant tendency between extent of the most advanced lesion and that of the basal lesion, it seems to be consistent that the shape of cut-surface of the advanced lesion occurring in the LAD segments proximal to MB is eccentric. Previous autopsy studies have reported MB length, with ranges of 3–69 mm [25], 4–28 mm [26], and 4–25 mm [27] and mean values of 19.7 mm [5], and 21.9 mm in males and 20.3 mm in females [16]. MB thickness has been reported to be 0.3–1.7 mm [27], with mean values of 2.0 mm [28]. In this study, mean MB length was 14.4 mm, which is not greatly different from previous values, but mean MB thickness was 856 m, which is somewhat thinner than previous values. The contrast between mean MB thickness in the present and previous studies probably results from differences in detection method of MBs, because MBs in our study were directly assessed with histomorphometry and we interpreted a very thin covering of myocardial tissue as MB as thick as it surrounded the whole circumference of LAD. Our statistical analyses demonstrated that longer MBs tended to be located more proximally in LAD, and that thicker MBs were located significantly more proximally. In addition, MB thickness was significantly correlated with its length. Ferreira et al. also reported that deeply situated MBs were longer than superficially situated MBs [16]. These observations of a close relationship between MB length and MB thickness indicate that these anatomical properties are tightly interrelated. Additionally, our study revealed greater atherosclerosis suppression in MB segments of thick and long MB groups compared with the corresponding thin and short MB groups. This difference in atherosclerosis suppression as a function of anatomical properties of MB probably originates from differences in contractile force exerted by MB muscle. Indeed, a previous angiographic study showed that MB affected a longer segment of LAD in hypertrophic hearts, which led to a greater degree of LAD compression [29], and an autopsy study indicated that the cases with thick MB were pathological [13]. Thus, we suggest that MB length and MB thickness are the critical anatomical properties regulating hemodynamic alterations in LAD and that the heart with a longer and/or thicker MB in a running course of LAD may be more vulnerable to myocardial ischemia due to a stronger compression on LAD.
Our results may be useful for a selection of patients who need therapeutic approach. While MB is frequently detected in the coronary arteries during detailed post-mortem examination, clinically symptomatic cases by MB have been relatively limited, and a recent issue has mentioned that further research is needed to define patients in whom MB is potentially pathologic [30]. The recent imaging techniques, such as intracoronary ultrasonography and multidetector computed tomography, make it possible to detect MB and are effective on the examination of MB length and thickness. Further pathological analyses of LAD in cases with myocardial ischemia or sudden death as well as long-term follow-up studies of pathological cases are necessary for an elucidation of a significance of anatomical properties of MB.
Acknowledgements This study was partly supported by a MEXT Grant (30101893) of Japan and the Project Research Grant (16-25) of Toho University School of Medicine.
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