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International Journal of Cardiology 167 (2013) 883–888

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International Journal of Cardiology


journal homepage: www.elsevier.com/locate/ijcard

Relationship between myocardial bridges and reduced coronary atherosclerosis in


patients with angina pectoris☆
Sandra N. Verhagen a, Annemarieke Rutten b, Matthijs F. Meijs c, Ivana Isgum d, Maarten J. Cramer c,
Yolanda van der Graaf e, Frank L.J. Visseren a,⁎
a
Department of Vascular Medicine, University Medical Center Utrecht, The Netherlands
b
Department of Radiology, University Medical Center Utrecht, The Netherlands
c
Department of Cardiology, University Medical Center Utrecht, The Netherlands
d
Image Sciences Institute, University Medical Center Utrecht, The Netherlands
e
Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands

a r t i c l e i n f o a b s t r a c t

Article history: Background: A myocardial bridge (MB) is a band of myocardium covering a coronary artery segment, typically
Received 7 October 2011 located in the left anterior descending coronary artery (LAD). Bridged segments of the coronary artery are isolat-
Received in revised form 28 December 2011 ed from the influence of perivascular adipose tissue. The aims of this study were to investigate the relationship
Accepted 28 January 2012 between MBs and atherosclerosis in bridged LAD segments and to evaluate whether perivascular adipose tissue
Available online 3 March 2012
is involved in this relationship.
Methods: MBs were identified in the coronary arteries of patients referred for diagnostic cardiac CT. The calcium
Keywords:
Myocardial bridging
score of MBs of the LAD or, in patients without LAD-MBs, of a corresponding LAD segment at the same distance
Atherosclerosis from its origin and over the same length was measured.
Coronary calcium Results: Of 128 patients, 56 (44%) had in total 73 MBs. The mean MB length was 22± 14 mm and the median MB
thickness was 0.8 mm (interquartile range 0.3–2.1 mm). MBs in the LAD were present in 40 patients (31%). The
calcium score was 0 in 95% of the LAD segments with MBs compared with 52% of the corresponding LAD
segments without MBs. The association between LAD-MBs and calcium score (OR 0.06, 95% CI 0.01–0.25) was
not influenced by age and gender, but was attenuated by local perivascular adipose tissue thickness (OR 0.35,
95% CI 0.04–2.70).
Conclusions: Coronary artery segments covered with an MB have a lower calcium score than segments without
an MB. The association between MBs and calcium scores was influenced by local perivascular adipose tissue
thickness.
© 2012 Elsevier Ireland Ltd. All rights reserved.

1. Introduction comparable control groups or control segments were investigated.


Hemodynamic factors have been proposed to explain the absence of
The coronary arteries usually run an epicardial course and are sur- atherosclerosis in bridged coronary artery segments [10], but an
rounded by coronary perivascular adipose tissue. A variant of coronary alternative view is that bridged coronary arteries are protected
artery anatomy is the myocardial bridge (MB), whereby part of the cor- from the influence of perivascular adipose tissue by the overlying
onary artery runs through the myocardium. The reported prevalence of myocardium.
MBs varies between 5% and 86% [1–3]. MBs are most common in the left Most arteries are directly surrounded by perivascular adipose tissue,
anterior descending artery (LAD) [2]. Interestingly, coronary artery and the diffusion of pro-inflammatory cytokines and adipokines may
segments with MBs have been found to be free of atherosclerotic plaque locally affect the metabolism of the coronary artery wall by inducing
in autopsy [3–5] and CT [6–9] studies, although in the CT studies no endothelial dysfunction, monocyte chemotaxis, and smooth muscle
cell proliferation [11–13]. Indeed, it could be hypothesized that perivas-
cular adipose tissue stimulates atherosclerotic plaque formation from
outside to inside.
☆ Funding sources: This work was supported by the Leatare Foundation, Monaco and Abdominal obesity is a risk factor for the development of cardio-
the Catharijne Foundation, The Netherlands. There are no competing interests regarding vascular diseases by inducing systemic metabolic disturbances, such
this study. as inflammation, insulin resistance, dyslipidemia, and hypercoagul-
⁎ Corresponding author at: Department of Vascular Medicine, University Medical
Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands. Tel.: + 31 30
ability [14]. This is thought to be a consequence of adipose tissue dys-
2509111; fax: + 31 30 2505488. function, which is characterized by the secretion of pro-inflammatory
E-mail address: f.l.j.visseren@umcutrecht.nl (F.L.J. Visseren). cytokines and adipokines, such as tumor necrosis factor-α (TNF-α),

0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ijcard.2012.01.091
884 S.N. Verhagen et al. / International Journal of Cardiology 167 (2013) 883–888

interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1) and addition, the presence of atherosclerotic plaque in the same bridged and matched LAD
segments was determined.
the inhibitor of fibrinolysis plasminogen activator inhibitor-1 (PAI-
1) [15]. 2.5. Measurement of perivascular adipose tissue thickness
We hypothesized that sections of coronary artery covered by an MB
do not show atherosclerotic changes and that this might be due to the The thickness of perivascular adipose tissue was measured in the region of interest
lack of exposure to perivascular adipose tissue at these sites. Therefore, in the LAD as the mean of two measurements from the myocardium to the pericardium
at the site of minimum and maximum thickness, respectively. Measurements where
the aims of the present study were to compare the extent of atheroscle-
performed on curved planar reformation views. Segments with MBs were not in
rosis, measured as coronary calcium, in coronary artery segments with contact with perivascular adipose tissue.
or without MBs in patients referred for angina pectoris, and to investi-
gate the potential role of perivascular adipose tissue in this relationship. 2.6. Data analyses

Analyses were performed with SPSS 18. Associations between the presence of an
2. Methods
MB (yes/no) and age, gender, and cardiometabolic risk factors were analyzed with
logistic regression analysis. Differences in the length and thickness of an MB with
2.1. Study participants and design
respect to its location were calculated and tested with Kruskal–Wallis test.
Differences in the calcium score of bridged and matched segments (0 versus >0) in
Consecutive patients (n= 128) referred to the University Medical Center Utrecht, The
patients with or without MBs were compared and significance was tested with
Netherlands, for diagnostic coronary angiography for stable or unstable angina pectoris
Chi-square. The relationship between MBs and calcium scores in the region of interest
were included in this cross-sectional study. Inclusion criteria were age 50–70 years and
was analyzed with univariate and multivariate logistic regression modeling. The calcium
stable sinus rhythm. Patients who had previously undergone PTCA or CABG, or who had
score in the region of interest (0 or >0) was used as dependent variable and the presence
serum creatinine levels >140 μmol/l or known iodine-based contrast allergy were exclud-
of an MB (yes/no) was used as independent variable. Different models were constructed
ed. The medical ethics committee approved the study and all participants gave their
to adjust for potential confounding factors, such as age and gender (model 2), calcium
written informed consent.
score (model 3), and local perivascular adipose tissue thickness (model 4).
Medical history was obtained using a standardized health questionnaire. Height,
In patients without MBs, perivascular adipose tissue was used as independent var-
weight, blood pressure, and the volume of epicardial adipose tissue [16] were measured.
iable in linear regression analyses with local calcium score as outcome. Calcium scores
Epicardial adipose tissue volume was defined as the adipose tissue between the ventricu-
were log-transformed (LN(calcium score + 1)) because scores were not normally dis-
lar wall and the visceral epicardium. Fasting blood was sampled to measure lipid, glucose,
tributed in the regions of interest.
and creatinine levels. Metabolic syndrome was diagnosed according to the Adult Treat-
ment Panel III (ATPIII) criteria as the presence of at least three or more metabolic abnor-
malities [17]. Because waist circumference was not available, a BMI ≥30 kg/m2 was 3. Results
considered indicative of obesity [18]. The number of coronary arteries (RCA, LAD, and
RCX) with ≥50% stenosis was evaluated on multiple conventional coronary angiography
projections to determine whether subjects had 0-, 1-, 2-, or 3-vessel disease [19]. Left
3.1. Baseline characteristics of study population
main artery stenosis was scored as 2-vessel disease [19].
In 56 of the 128 subjects (44%), 73 MBs were detected, and 44 of
2.2. CT technique and image analysis these MBs (in 43 subjects) had a thickness ≥0.3 mm. In 40 (31%) sub-
jects, MBs of the LAD were detected, and 27 of these MBs had a thick-
MBs were identified on retrospectively ECG-gated diagnostic cardiac CT scans ness ≥0.3 mm.
acquired with a 64 detector-row CT scanner (Brilliance 64, Philips Medical Systems,
Cleveland, OH, USA). Scan duration was 7–10 s. Standard coronary CT angiography
The characteristics of patients with (n= 40) and without (n = 88) a
protocols were used, including the use of intravenous beta-blockers for patients with LAD-MB were comparable (Table 1), except that patients with a LAD-MB
a heart rate >65 beats/min (unless contraindicated), and images were acquired had more severe coronary artery disease, as determined with conven-
when the subject held his/her breath during inspiration. Imaging parameters were tional angiography, with ≥2 vessel disease being detected in 23 patients
slice collimation of 64 × 0.625 mm, gantry rotation time of 420 ms, tube voltage of
with a LAD-MB (58%) compared with 32 patients without a LAD-MB
120 kVp, tube current of 900 mAs. The contrast agent iopromide (Bayer-Schering AG,
Berlin, Germany) was injected intravenously (1.6–2.0 g iodine/s depending on the (36%) (p= 0.03). Total calcium scores were not statistically significantly
patient's body weight). The most motionless phase of the cardiac cycle, usually at different between the groups with or without a LAD-MB (median 135,
70–80% of the R–R interval, was chosen for analysis. The window settings were adjust- interquartile range 35–622 versus median 184, IQR 45–502, respective-
ed to enable optimal visualization of soft tissue. ly; p = 0.76). In addition, the prevalence of LAD stenosis ≥50% was sim-
ilar in the two groups, occurring in 21 (53%) and 46 (53%) patients with
2.3. Identification and measurement of MBs
and without a LAD-MB, respectively (p= 0.98). The same was true
MBs, defined as a coronary artery segment covered by myocardium, were detected on for the LAD calcium score: median score 61 (IQR 19–225) versus 107
contrast-enhanced scans. Although limited spatial resolution makes it difficult to visualize (IQR 15–242), respectively (p = 0.35). The mean length of LAD-MBs
MBs b 0.3 mm thick [20], we included these bridges in the analyses, because the absence of was 21.7 ±14.9 mm and the median thickness was 0.9 mm (IQR
atherosclerosis in thin MBs would be strong evidence in favor of our hypothesis. Measure- 0.3–2.2 mm) (Fig. 2). The mean length of diagonal branch MBs was
ments were performed on curved planar reformation views. The length of the MB was
19.8 ± 10.2 mm with a median thickness of 0.8 mm (IQR 0.3–2.1 mm),
defined as the length of the intramyocardial course of the coronary artery segment. The
thickness of an MB was measured at the widest part of the overlying myocardium and the mean length of marginal obtusis MBs was 24.0 ±14.0 mm
(Fig. 1). If the thickness of a MB could not be measured (b 0.3 mm), it was given the with a median thickness of 0.9 mm (IQR 0.1–1.7 mm). There were no
value of 0.3 mm. statistically significant differences in the length and thickness of MBs
in the LAD, diagonal branch, or marginal obtusis branch (p= 0.8 and
2.4. Measurement of calcium score in coronary artery segments p = 0.5 respectively).
Coronary artery calcium imaging was performed using multislice CT scanning.
Non-contrast scans, reconstructed with 3-mm-slice thickness and an increment of 3.2. Relation between LAD-MBs and local atherosclerosis
1.5 mm, were acquired during a single breath-hold. The Agatston calcium score was
chosen as measure of atherosclerosis and was calculated with dedicated software for Out of the 40 subjects with a LAD-MB, 2 (5%) had a calcium score >0
calcium scoring (ImageXplorer) [21]. For total calcium score, all regions with a density
in the bridged region, whereas 42 of the 88 subjects without a LAD-MB
>130 HU and a minimum size of 0.5 mm2 were identified as potential calcifications.
The peak density in HU and the area in mm2 in each selected region were calculated (48%) had a calcium score >0 in the matched LAD segment (pb 0.0001)
and multiplied by a weighting factor [22]. (Table 2a). Atherosclerotic plaque in bridged LAD segments was less
The calcium score within the LAD was also calculated. To compare coronary artery common than it was in corresponding LAD segments without MBs,
segments with and without MBs, an area of interest was selected for each subject. Subjects with plaque being detected in 2 patients (5%) versus 44 patients
with LAD-MBs (n= 40) were randomly paired with subjects without LAD-MBs (n= 88).
The calcium score of the intramyocardial artery segment was measured in patients with a
(50%), respectively (pb 0.0001).
LAD-MB and in a section of the LAD at the same distance from the origin of the left The presence of an MB compared with the absence of an MB in the
coronary artery and over the same length in subjects without a LAD-MB (Fig. 1). In LAD was associated with a lower calcium score in the bridged segment
S.N. Verhagen et al. / International Journal of Cardiology 167 (2013) 883–888 885

Fig. 1. Detection of myocardial bridges (MBs), measurement of MB length and thickness, and measurement of calcium score of coronary artery segments with and without an MB.
The following MB properties were measured: distance to origin (A), length (B), and thickness (C). Calcium score was measured in bridged coronary artery segments and corre-
sponding segments in subjects without an MB. In subjects without an MB (D), calcium score was measured in a segment at the same distance to origin and over the same length
as in subjects with an MB (E). (Selected regions are indicated with a yellow arrow.) Calcium score was measured in the region of interest (F) (G). (Blue: regions with a density of
>130 Houndsfield Units (HU).) (Yellow: selected region). Perivascular adipose tissue thickness was measured in the regions of interest (H).

(OR 0.06, 95% CI 0.01–0.25) (Table 2b). This association did not substan- MB of the LAD were comparable. The inverse association between
tially change after adjusting for age, gender, or total coronary calcium MBs and local calcium scores was independent of age, gender, and
score, and after exclusion of patients with an MB with a thickness total coronary artery calcium score, but was influenced by the thickness
b3 mm (OR 0.08, 95% CI 0.02–0.37). of local perivascular adipose tissue.
The inverse association between MBs and local calcium score was The absence of atherosclerosis in coronary artery segments covered
attenuated after adjusting for local perivascular adipose tissue thickness by an MB has been reported in post-mortem and imaging studies
(OR 0.35, 95% CI 0.04–2.70). The mean thickness of perivascular adipose [1,3,5–9,23]. By comparing bridged LAD segments to matched control
tissue in the region of interest was significantly associated with the local segments, we could confirm that the absence of atherosclerosis is due
coronary calcium score per millimeter in the 88 subjects without an MB to the MB and is not a random observation. This is in line with earlier
(β adjusted for age and gender (OR 0.21, 95% CI 0.07–0.34)). findings of studies investigating the severity of atherosclerosis relative
to the distance from the ostium in groups with and without MBs
3.3. Determinants of presence of myocardial bridges at any location [5,23]. Moreover, although this study was only hypothesis generating,
we demonstrated that perivascular adipose tissue has a role in the
The presence of an MB at any location was not associated with age association between MBs and atherosclerosis.
(per year OR 1.00, 95% CI 0.95–1.07), male gender (OR 1.60, 95% CI In a post-mortem study it was shown that the intima of bridged LAD
0.74–3.47), or other risk factors for cardiovascular disease, such as segments is thinner, indicating less atherosclerotic transformation, than
smoking, diabetes, BMI, LDL-cholesterol, triglycerides, epicardial that of comparable segments of coronary arteries without an MB [4].
adipose tissue volume, and presence of the metabolic syndrome Furthermore, the extent of atherosclerosis in each subsequent LAD
(Table 3). Moreover, the extent of coronary artery disease, expressed cross-section is less in LAD segments with an MB than in segments
as the number of diseased vessels, total calcium score, and calcium without an MB [5,23]. CT studies have shown that bridged segments
score of the LAD, was also not associated with the presence of an MB. are less affected by, or are even free of, atherosclerosis [7,9,20], although
corresponding segments without MB were not evaluated. An ultra-
4. Discussion sound study revealed atherosclerotic plaque in 9.5% of bridged coronary
artery segments compared with 81.5% of corresponding segments with-
In this cross-sectional study of patients referred for investigation of out an MB [24].
stable or unstable angina pectoris, coronary artery segments covered The mechanism by which bridged coronary artery segments are
with an MB had a lower calcium score compared with segments protected against atherosclerosis remains to be elucidated. That the
without an MB. The characteristics of patients with and without an association between MBs and local calcium scores changed after
886 S.N. Verhagen et al. / International Journal of Cardiology 167 (2013) 883–888

Table 1
Patient characteristics.

All cases No (LAD) MB (LAD) MB


N = 128 N = 88 N = 40

Age (years) 61 ± 6 61 ± 5 61 ± 6
Male gender, n (%) 89 (70) 59 (67) 30 (75)
Current smoking, n (%) 42 (32) 29 (32) 13 (32)
Diabetes mellitus, n (%) 24 (19) 17 (19) 7 (18)
Stable angina pectoris, n (%) 100 (78) 68 (77) 32 (80)
History of unstable angina pectoris, n (%) 8 (6) 5 (6) 3 (8)
History of myocardial infarction, n (%) 29 (23) 21 (23) 8 (20)
Body mass index (kg/m²) 28 ± 4 28 ± 4 27 ± 4
Systolic blood pressure (mm Hg) 151 ± 22 151 ± 22 152 ± 24
Diastolic blood pressure (mm Hg) 81 ± 13 81 ± 12 81 ± 15
Glucose (mmol/l) 5.8 (5.2–6.8) 5.8 (5.2–6.9) 5.8 (5.1–6.6)
Total cholesterol (mmol/l) 4.6 ± 1.2 4.5 ± 1.1 4.9 ± 1.2
LDL-cholesterol (mmol/l) 2.6 ± 1.0 2.5 ± 1.0 2.7 ± 1.1
Triglycerides (mmol/l) 1.5 (1.1–2.1) 1.5 (1.0–2.1) 1.4 (1.1–2.4)
HDL-cholesterol (mmol/l) 1.3 ± 0.3 1.3 ± 0.3 1.3 ± 0.4
Metabolic syndrome n (%) 55 (43) 37 (42) 18 (45)

Medication
Blood-pressure lowering agents, n (%) 115 (90) 78 (89) 37 (93)
Lipid-lowering agents, n (%) 100 (78) 65 (74) 35 (88)
0 vessel disease 19 (15) 14 (16) 5 (13)
1-vessel disease 54 (42) 42 (48) 12 (29)
2-vessel disease 37 (28) 20 (23) 17 (43)
3-vessel disease 18 (14) 12 (14) 6 (15)
Stenosis >50% of the LAD, n (%) 67 (52) 46 (52) 21 (53)
Epicardial adipose tissue volume (cm3) 110 ± 44 113 ± 46 103 ± 39
Local perivascular adipose tissue (mm) – 9.0 ± 3.2 0
Calcium score of the LAD (Agatston) 92 (16–232) 107 (15–242) 61 (19–225)
Total calcium score (Agatston) 181 (37–544) 184 (35–622) 135 (45–502)

Presence of MB:
No MB 72 (56) 72 (82) 0 (0)
MB (LAD), n (%) 40 (30) 0 (0) 40 (100)
MB (1st diagonal branch), n (%) 5 (3) 2 (2) 3 (5)
MB (2nd diagonal branch), n (%) 4 (2) 3 (3) 1 (3)
MB (1st marginal obtusis branch), n (%) 13 (10) 9 (10) 4 (10)
MB (2nd marginal obtusis branch), n (%) 8 (6) 7 (8) 1 (3)
MB (intermediate branch), n (%) 2 (2) 1 (1) 1 (3)

adjusting for local perivascular adipose tissue suggests that perivascular cytokines and adipokines secreted by perivascular adipose tissue and
adipose tissue influences this association. There is more perivascular thus inhibit the atherosclerotic process.
adipose tissue at sites of atherosclerosis [25], and this tissue can secrete An increase in shear stress at the site of an MB has been proposed
pro-inflammatory adipokines and cytokines [26]. In vitro, adipose as explanation for the decrease in atherosclerosis [10,28]. Endothelial
tissue-conditioned medium induces the adhesion of monocytes to cells beneath an MB are spindle shaped, indicating that they are sub-
endothelial cells and the migration of monocytes [11,12]. In mice, jected to high shear stress, whereas endothelial cells in other regions
perivascular adipose tissue has been found to promote the migration show a polygonal distribution, indicating that they are subjected to
of macrophages towards the vascular wall [27]. As perivascular adipose low shear stress [10]. An increase in shear stress is thought to hinder
tissue does not come into contact with the vascular wall if there is an monocyte adhesion and lipid transfer across the vascular wall. An ar-
MB, the latter may protect the vascular wall against proinflammatory gument against the role of hemodynamic forces is that endothelial
cell function is impaired at the site of an MB [24], and endothelial dys-
function is associated with a high intravascular pressure. Enhanced
lymphatic drainage caused by compression during systole has recent-
ly been proposed as an alternative explanation for the reduced ath-
erosclerotic burden in bridged segments [29]. Moreover, coronary
artery segments proximal to an MB are affected more by atheroscle-
rosis than are proximal segments in subjects without MB [5]. Intra-
vascular pressure is higher in segments proximal to an MB than in
the bridged segment itself [30], and increased pressure on the vascu-
lar wall and non-laminar flow give rise to advanced plaque [5,23,31].
The prevalence of MBs is high in subjects with a history of myocardial
infarction (46%), and MB thickness is greater in these subjects than in
subjects without a history of myocardial infarction [5]. It can be con-
cluded that MB thickness is associated with the extent of atheroscle-
rosis in the coronary artery segment proximal to the MB. Owing to
Fig. 2. Length and maximal thickness of myocardial bridges (MBs). Boxplot depicting MB
the low occurrence of calcified plaque in bridged segments, we
length (left y-axis) and MB thickness (right y-axis). LAD: left anterior descending artery;
DIAG diagonal branches; MO: marginal obtusis branches of the circumflex coronary were not able to evaluate the association between MB thickness and
artery. atherosclerosis in the present study.
S.N. Verhagen et al. / International Journal of Cardiology 167 (2013) 883–888 887

Table 2 atherosclerotic plaque is a sign of atherosclerosis of the vascular wall


Calcium content in segments of the left anterior descending (LAD) coronary artery with and not of plaque rupture. For this reason, we also investigated athero-
a myocardial bridge (MB) and corresponding regions without an MB.
sclerosis by determining the presence of atherosclerotic plaque.
a: Calcium score in LAD segments with an MB and in LAD segments without an MB Information on the presence of plaque confirmed the results obtained
Calcium score*: 0.0 0.1–10.0 10.0–120.0 using calcium score. Intravascular ultrasound has been used to detect
MBs and to determine plaque composition [30], and this imaging
No myocardial bridge of the LAD 46 (52%) 24 (27%) 18 (21%)
Myocardial bridge of the LAD 38 (95%) 1 (3%) 1 (3%) method could be used to further explore the role of perivascular adipose
* difference between LAD segments with and without MB: p b 0.0001 tissue.
In conclusion, in patients with stable and instable angina pectoris,
b: Relationship between presence of an MB and calcium score adjusted for
coronary artery segments covered with an MB have a lower Agatston
confounding factors
calcium score than segments without an MB. The association between
Model OR (95% CI)*
MB and calcium score was influenced by the thickness of perivascular
Myocardial bridge (yes/no) 1 0.06 (0.01–0.25)† adipose tissue adjacent to the coronary artery segment.
2 0.05 (0.01–0.22)†
3 0.01 (0.00–0.13)†
4 0.35 (0.04–2.70)
Acknowledgments
Model 1: Crude.
Model 2: Adjusted for age and gender. We gratefully acknowledge the contribution of Mrs. J. Sykes (a native
Model 3: Model II additionally adjusted for total coronary artery calcium score.
speaker of the English language). The authors of this manuscript have
Model 4: Model II additionally adjusted for local perivascular adipose tissue thickness
of the LAD. certified that they comply with the Principles of Ethical Publishing in
* OR indicates the change in local log-transformed calcium score (0 or > 0) in the pres- the International Journal of Cardiology.
ence of a myocardial bridge compared to absence of a myocardial bridge.

p b 0.0001.
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