A potential protective element of myocardial bridge against severe obstructive atherosclerosis in the whole coronary system

A potential protective element of myocardial bridge against severe obstructive atherosclerosis in... Background: Myocardial bridge (MB) is generally described as a congenital benign variation. Previous studies have suggested that MB prevents atherosclerotic plaques from accumulating within the bridge segment but promotes coronary stenosis in the proximal segment adjacent to MB. However, it is still not clear whether MB has positive or negative effects on severe obstructive atherosclerosis in the whole coronary artery system. Methods: In this study, 6774 patients with symptoms of angina who were clinically diagnosed coronary artery disease (CAD) or suspected CAD underwent coronary angiography (CAG) in our center. The presence of MB was diagnosed, and a retrospective analysis was performed between MB and severe obstructive CAD requiring percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) in the whole coronary system. Results: Among 6774 patients, 3583 (52.89%) were diagnosed with severe obstructive CAD (SOCAD) requiring a treatment of PCI or CABG and enrolled into the SOCAD group; and 3191 (47.11%) without SOCAD into the non- SOCAD group. Non-SOCAD and SOCAD groups had 512(16.05%) and 66(1.84%) patients with MB, respectively (P < 0.0001). The rate of SOCAD requiring PCI or CABG in patients with MB was much lower than that in patients without MB (11.42% vs. 56.76%, P < 0.0001). After adjusting for sex, age, diabetes mellitus, hypertension, and other risk factors, MB still had some positive role in preventing severe obstructive CAD (log-OR = − 2.134, p-value < 0.0001) through logistic regression. Conclusions: Our results provided a clue that MB might act as a potential protective element against severe obstructive atherosclerosis in the whole coronary artery system. Background clinically silent in many cases but is of interesting to Myocardial bridge (MB) is referred to muscle overlying clinical researchers due to its association with myocar- intramyocardial segment of an epicardial coronary ar- dial ischemia [4, 5]. tery, usually in the middle segment of the left anterior The golden standard of MB diagnosis in angiography descending coronary artery (LAD) [1, 2]. Some studies is defined as systolic milking effect produced by systolic reported anatomical properties of MB on atherosclerosis compression by the intramyocardial segment [6]. MB is evolution in LAD. Location, length, and thickness are the most common congenital coronary variation, and closely interrelated, and longer or thicker MBs are the prevalence of MB varies from less than 5% [1, 6] located significantly proximally in LAD [3]. Its charac- under angiography, to 23% with intravascular ultrasound teristic compression of the tunneled coronary segment is (IVUS) [6], to 55.6% under autopsy [7] due to the reason that short and thin bridges causing little systolic com- pression are easy to be ignored [8]. * Correspondence: jls1025@aliyun.com; drhe_renji@163.com Lisheng Jiang and Min Zhang contributed equally to this work. The presence of MB can be associated with various Department of Cardiology, Shanghai Jiao Tong University Affiliated Chest complications such as angina, acute myocardial infarc- Hospital, Shanghai, China tion, arrhythmias, and even sudden death [4, 9–18]. MB Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Jiang et al. BMC Cardiovascular Disorders (2018) 18:105 Page 2 of 7 can also be considered a benign variation of coronary ar- The presence of MB was recognized by the angio- teries [19], or a double-edged sword [5]. The cause of graphic finding of transient reduction in the lumen of angina is generally thought to be a distinct reduction of one epicardial coronary artery during systole as shown coronary artery flow due to muscular compression in Fig. 1. The severe obstructive coronary artery disease during systole [5, 20, 21]. Previous studies have sug- (SOCAD) requiring invasive treatment with PCI or gested that in the intramyocardial segments, the vessel is CABG was defined as the presence of stenosis over 75% protected from obstructive atherosclerosis, however, it is or occlusion in at least one major coronary artery, or not clear whether MB has positive or negative effects on stenosis less than 75% but over 50%, which was obstructive atherosclerosis in the whole coronary artery evaluated with an indication of PCI or CABG by coron- system. In the present study, we aimed at exploring a ary interventional cardiologist or cardiac surgeon. Ac- clinical relationship between MB and severe obstructive cording to angiography results, patients with SOCAD atherosclerosis requiring treatment with percutaneous underwent treatment with PCI or CABG and were coronary intervention (PCI) or coronary artery bypass enrolled into the SOCAD group; while patients without grafting (CABG) in the whole coronary artery system. severe obstructive coronary artery lesion were enrolled into the non-SOCAD group. The traditional risk factors including advanced age, Methods hypertension, diabetes mellitus (DM) and impaired glu- Study oversight cose tolerance (IGT), hyperlipidemia, chronic kidney This study is a retrospective observation based on disease (CKD), ischemic cerebrovascular disease (ICVD), hospital records from Renji Hospital, School of etc. were documented to be linked with atherosclerosis. Medicine, Shanghai Jiaotong University, China. The In the present study, both the incidence of MB and the authors assume responsibility for the accuracy and com- risk factors as above were therefore recorded and pleteness of the data and data analyses. analyzed. Data collection Statistical analyses From December 2012 to February 2015, 6774 patients Mean values with standard deviations and counts with with symptoms of angina who were clinically diagnosed percentages were used to describe baseline characteris- with coronary artery disease (CAD) or suspected CAD tics and the incidence of MB. Differences were calcu- underwent 6848 coronary angiographies in Renji lated separately in different subgroups according to Hospital. We conducted a retrospective study on MB by presence or absence of SOCAD or MB, and sex. The dif- retrieving these patients’ hospital records, including sex, ferences were evaluated using one-way analysis of vari- age, coronary risk factors, diagnoses of coronary angiog- ance for continuous variables and Fisher’s exact test for raphy and invasive treatments. All clinical diagnoses categorical variables. The association between SOCAD follow the standard of ICD-10. and MB was further evaluated in the context of logistic Fig. 1 The typical characteristics of MB under angiography. The box in diagram a represents the segment of myocardial bridge free of compressing in left anterior descending artery during diastole; the arrow in diagram b represents the compressing segment of myocardial bridge in the same artery during systole Jiang et al. BMC Cardiovascular Disorders (2018) 18:105 Page 3 of 7 regression model with or without interaction terms by group (proportions: 1.84% vs. 16.05%, respectively; adjusting for some baseline risk factors and the widely P < 0.0001). Besides, in the SOCAD group, there were used stepwise variable selection strategy based on older age (mean [±SD], 65.08 ± 10.55 years vs. 63.34 ± Akaike’s information criterion [22] was used to select 10.33 years; P < 0.0001), higher proportion of male those factors potentially associated with SOCAD. (74.83% vs. 52.74%, P < 0.0001), and higher rates of risk All P values were two-sided, and a P value of < 0.05 factors including, hypertension, diabetes and/or impaired was considered with statistical significances. The R pro- glucose tolerance, chronic kidney disease and ischemic gram, version 3.4.0, was used to perform statistical cerebrovascular disease. However, the rate of hyperlipid- analyses. emia in the SOCAD group was lower than that in the non-SOCAD group, which might be linked with the Results reason that patients in the SOCAD group were given an Findings of myocardial bridge intensive lipid-lowering therapy even before admission As listed in Table 1, out of the 6774 patients underwent (some of them had a long history of coronary heart angiography, 578 (319 male and 259 female)were diag- disease). nosed with MB including 571 located in the left anterior descending artery (LAD), 4 in left circumflex (LCX) and Incidence of SOCAD and risk factors between patients 3 in right coronary artery (RCA). with or without myocardial bridge As shown in Table 3, in comparison with the non-MB group, patients in the MB group had much lower rate of Incidence of MB and risk factors between patients with or SOCAD requiring PCI/CABG (11.42% vs. 56.76%, without SOCAD P < 0.0001), higher rate of female (44.81% vs. 34.72%, There were significant differences when comparing the P < 0.0001), younger age (mean [±SD], 61.10 ± 9.93 vs. incidence of MB between patients with or without 64.56 ± 10.49, P < 0.0001), and lower rates of risk factors SOCAD. As listed in Table 2, the incidence of MB in the including hypertension (50.00% vs.61.54%, P < 0.0001), SOCAD group was much lower than the non-SOCAD impaired glucose metabolism including DM and IGT (14.01% vs. 29.78%, P < 0.0001), ischemic cerebrovascu- lar diseases (3.63% vs. 6.71%, P = 0.0026), and chronic Table 1 Clinical characteristics in patients with myocardial kidney disease (1.21% vs.3.78%, P = 0.0006), but not for bridge (MB) hyperlipidemia (P = 0.934). Characteristics Values Incidence of MB, n/total (%) 578/6774 (8.53%) Differences on incidence of MB and clinical characteristics Location of MB: LAD , n (%) 571(98.79%) between male and female LCX , (%) 4 (0.69%) Compared with the male, the female patients had a RCA , (%) 3 (0.52%) higher proportion of MB (10.75% vs. 7.31%, P < 0.0001), much older age (66.09 ± 10.09 vs. 63.25 ± 10.56 years Age (years, mean ± SD) 61.10 ± 9.93 old, P < 0.0001), higher rate of hyperlipidemia (9.46% Sex vs. 6.35%, P < 0.0001), but much lower SOCAD Male, n (%) 319 (55.19%) requiring PCI or CABG (37.43%% vs. 61.43%, Female, n (%) 259 (44.81%) P < 0.0001) (Table 4). Hypertension, n (%) 289 (50.00%) DM , n (%) 59 (10.21%) Logistic regression Association intensities (log-ORs) between risk factors IGT , n (%) 22 (3.81%) f and severe obstructive atherosclerosis requiring PCI or DM/IGT , n (%) 81 (14.01%) CABG were reported in Table 4. There was a strong Hyperlipidemia, n (%) 42 (7.27%) negative linear relationship between MB and severe ob- Ischemic cerebrovascular disease, n (%) 21 (3.63%) structive atherosclerosis (log-OR = − 2.134, P < 0.0001), Chronic kidney disease, n (%) 7 (1.21%) and other significant risk factors (including inter- SOCAD , n (%) 66 (11.42%) action terms) included old age (P = 0.0025), female LAD, left anterior descending artery sex (P < 0.0001), hypertension (P < 0.0001), impaired glu- LCX, left circumflex cose metabolism (P < 0.0001), hyperlipidemia (P = 0.0436), RCA, right coronary artery interaction term between age and sex (P < 0.0001), inter- DM, diabetes mellitus IGT, impaired glucose tolerance action term between age and impaired glucose metabolism DM/IGT, diabetes mellitus/impaired glucose tolerance g (P = 0.0003), and interaction term between sex and hyper- SOCAD, severe obstructive coronary artery disease requiring treatment with percutaneous coronary intervention or coronary artery bypass grafting tension (P = 0.0122). Jiang et al. BMC Cardiovascular Disorders (2018) 18:105 Page 4 of 7 Table 2 Comparisons on incidence of myocardial bridge and risk factors in patients with or without SOCAD Event Non-SOCAD SOCAD P value N = 3191 (47.11%) N = 3583 (52.89%) Age (years, mean ± SD) 63.34 ± 10.33 65.08 ± 10.55 < 0.0001 Sex Male, n (%) 1683(52.74%) 2681(74.83%) < 0.0001 Female, n (%) 1508(47.26%) 902(25.17%) Myocardial bridge, n (%) 512(16.05%) 66(1.84%) < 0.0001 Hypertension, n (%) 1725(54.06%) 2377(66.34%) < 0.0001 DM , n (%) 527(16.52%) 1078(30.09%) < 0.0001 IGT , n (%) 124(3.89%) 197(5.50%) 0.0078 DM/IGT , n (%) 651(20.40%) 1275(35.58%) < 0.0001 Hyperlipidemia, n (%) 272(8.52%) 233(6.50%) 0.0016 Ischemic cerebrovascular disease, n (%) 178(5.58%) 259(7.23%) 0.0064 Chronic kidney disease, n (%) 83(2.60) 158(4.41%) < 0.0001 DM, diabetes mellitus IGT, impaired glucose tolerance DM/IGT, diabetes mellitus/impaired glucose tolerance SOCAD, severe obstructive coronary artery disease requiring treatment with percutaneous coronary intervention or coronary artery bypass grafting A negative log-OR means a protective effect against se- Discussion vere obstructive atherosclerosis, and vice versa. Log-ORs Currently, many studies consider MB as a contributing of age, hypertension, impaired glucose metabolism, inter- factor in myocardial ischemia, angina, myocardial infarc- action term between age and sex, and interaction term be- tion and arrhythmia [4, 9–17]. However, less atheroscler- tween sex and hypertension were positive, while log-ORs otic lesions are found in bridge segments in contrast to of MB, female sex, hyperlipidemia, and interaction be- non-bridged coronary arteries [18, 23–27]. Limited proof tween age and glucose metabolism were negative. The indicates that compression by contracting myocardial log-OR of myocardial bridge was − 2.134, suggesting a po- muscles may provide some potential anti-atherosclerotic tential protective element of MB against severe obstruct- mechanisms linked with the release of anticoagulant and ive atherosclerosis requiring PCI or CABG (Table 5). growth factors [18]. However, the overall protective or Table 3 Comparisons on incidence of SOCAD and risk factors in patients with or without myocardial bridge Event Without MB With MB P value N = 6196 (91.47%) N = 578 (8.52%) Age (years, mean ± SD) 64.56 ± 10.49 61.10 ± 9.93 < 0.0001 Sex Male, n (%) 4045(65.28%) 319(55.19%) < 0.0001 Female, n (%) 2151(34.72%) 259(44.81%) Hypertension, n (%) 3813(61.54%) 289(50.00%) < 0.0001 DM , n (%) 1546(24.95%) 59(10.21%) < 0.0001 IGT , n (%) 299(4.83%) 22(3.81%) 0.5441 DM/IGT , n (%) 1845(29.78%) 81(14.01%) < 0.0001 Hyperlipidemia, n (%) 463(7.47%) 42(7.27%) 0.934 Ischemic cerebrovascular disease, n (%) 416(6.71%) 21(3.63%) 0.0026 Chronic kidney disease, n (%) 234(3.78%) 7(1.21%) 0.0006 SOCAD , n (%) 3517(56.76%) 66(11.42%) < 0.0001 DM, diabetes mellitus IGT, impaired glucose tolerance DM/IGT, diabetes mellitus/impaired glucose tolerance SOCAD, severe obstructive coronary artery disease requiring treatment with percutaneous coronary intervention or coronary artery bypass grafting Jiang et al. BMC Cardiovascular Disorders (2018) 18:105 Page 5 of 7 Table 4 Comparisons on incidence of myocardial bridge and clinical characteristics between male and female Event Male Female P value N = 4364 (64.42%) N = 2410 (35.58%) Age (years, mean ± SD) 63.25 ± 10.56 66.09 ± 10.09 < 0.0001 Myocardial bridge, n (%) 319(7.31%) 259(10.75%) < 0.0001 Hypertension, n (%) 2617(59.97%) 1485(61.62%) 0.1855 DM , n (%) 1010(23.14%) 595(24.69%) 0.1274 IGT , n (%) 221(5.06%) 100(4.15%) 0.2371 DM/IGT , n (%) 1231(28.21%) 695(28.84%) 0.8594 Hyperlipidemia, n (%) 277(6.35%) 228(9.46%) < 0.0001 Ischemic cerebrovascular disease, n (%) 258(5.91%) 179(7.43%) 0.0174 Chronic kidney disease, n (%) 178(4.08%) 63(2.61%) 0.0016 SOCAD , n (%) 2681(61.43%) 902(37.43%) < 0.0001 DM, diabetes mellitus IGT, impaired glucose tolerance DM/IGT, diabetes mellitus/impaired glucose tolerance SOCAD, severe obstructive coronary artery disease requiring treatment with percutaneous coronary intervention or coronary artery bypass grafting detrimental role of MB in the whole coronary system but not at intramural segments [25]. Also, endothelial and knowledge on the mechanisms are still desired. cells proximal to MB were arranged in a pavement-like, According to previous studies, formation of athero- polygonal and flat appearance because of a high sheer sclerotic plaque can frequently be found at segment stress [27]. These pathologic changes in proximal segment proximal to the bridge, while the intramural segment may be due to the accumulation of ApoB, proliferating cell is typically absent [18, 23], but not in all cases [26]. nuclear antigens (PCNA) in smooth muscle cells and in- As supported by a morphological observation of cho- creased endothelial cell permeability [25]. lesterol-fed rabbits, foam cells and modified smooth Diagnosis of MB under coronary angiography is based muscle cells have the same distribution on a cellar on the typical “milking effect” and a “step down-step up” level with atheromatous plaques at proximal segments phenomenon induced by muscle compression during Table 5 Analysis of logistic regression (with interaction terms) log-OR Std. error z value P value (Intercept) −0.383 0.217 −1.762 0.0780 Age 0.010 0.003 3.019 0.0025 MB −2.134 0.137 −15.545 < 0.0001 Female sex −3.139 0.379 −8.285 < 0.0001 Hypertension 0.341 0.073 4.689 < 0.0001 Impaired glucose metabolism 1.160 0.215 5.389 < 0.0001 Hyperlipidemia −0.205 0.102 −2.018 0.0436 Ischemic cerebrovascular disease (ICVD) −0.025 0.136 −0.183 0.8545 Chronic kidney disease (CKD) 0.254 0.146 1.735 0.0828 Age × Sex (female vs. male) 0.028 0.006 4.852 < 0.0001 Age × Impaired glucose metabolism −0.012 0.003 −3.628 0.0003 MB × ICVD −12.698 179.070 −0.071 0.9435 Sex × Hypertension 0.301 0.120 2.507 0.0122 Sex ×Impaired glucose metabolism 0.118 0.067 1.770 0.0767 Hypertension × Impaired glucose metabolism −0.134 0.071 −1.881 0.0600 Impaired glucose metabolism × ICVD 0.175 0.124 1.416 0.1568 Impaired glucose metabolism including diabetes mellitus and impaired glucose tolerance log-OR: log-odds ratio. A negative log-OR means a protective effect against severe obstructive coronary artery disease (SOCAD) requiring treatment with percutaneous coronary intervention or coronary artery bypass grafting on the premise that the presence of SOCAD was coded as 1 and non-SOCAD was coded as 0 Jiang et al. BMC Cardiovascular Disorders (2018) 18:105 Page 6 of 7 systole [6]. Though coronary angiography is now the CT scanning showed that the presence of MB was asso- gold standard and is most widely used in diagnosing ciated with a lower Agatston Calcium Score in the MB, it has some technical restrictions compared with bridged segments [29]. The presence of an MB may also other new imaging techniques, such as intravenous influence arterial tissue through the alteration of ultrasound (IVUS), intracoronary Doppler ultrasound, hemodynamic forces. According to previous study [24], multi-detector computed tomography, and intracoronary any atherosclerosis in the MB-segment is suppressed pressure devices [1, 3, 7]. In other words, the percentage histopathologically and ultrastructurally. Abrupt changes of MB varies with different diagnostic method and of endothelial cell morphology in the intima beneath the equipment. In this retrospective study, the overall bridge were observed with scanning electron micros- incidence of MB was 8.53%, but the female had higher copy, which indicates that the arterial tissue beneath the morbidity of MB than the male (10.75% vs. 7.31%, bridge is protected by hemodynamic factors. In P < 0.0001). In the non-SOCAD group, the rate of MB cholesterol-fed rabbits, the intima in the MB segment was much higher than that in the SOCAD group covered by myocardial tissue was free of atherosclerotic (16.05% vs. 1.84%, P < 0.0001); whereas, in patients with lesions, and the endothelial cells were spindle-shaped MB, the rate of SOCAD requiring treatment with PCI or and engorged [25], which also indicates that the protect- CABG was much lower than that in patients without ive element of MB against atherosclerosis might be MB (11.42% vs 56.76%, P < 0.0001). Take this in linked with an alteration of endothelial permeability due account, we speculated that MB might produce a poten- to hemodynamic force changes tending towards a higher tial positive role against severe obstructive atheroscler- shear stress. Based on the documented studies as above, osis in the whole coronary artery system. Accordingly, the role of myocardial bridges to suppress coronary ath- we analyzed the relationship between MB and severe ob- erosclerosis might be potential, but it still deserves structive atherosclerosis by adjusting for age, sex, hyper- further scientific research in biochemical and patho- tension, impaired glucose metabolism, hyperlipidemia, physiological fronts. ischemic cerebrovascular diseases, and chronic kidney Despite the presence of MB can be associated with diseases. Based on our results, there seemed to be a clue various complications such as angina, acute myocar- that MB might produce a potential protective element dial infarction, arrhythmias, and even sudden death against severe obstructive atherosclerosis in the whole [4, 9–17], it can also be considered a benign variation coronary artery system (log-OR = − 2.134; P < 0.0001). of coronary arteries [19]. So, the treatment of MB is Hyperlipidemia is a significant risk factor of CAD, still uncertain due to the lack of convincing evidence. which is a wide-accepted truth [28]. In the present study, In clinical practice, beta-blockers are usually the first however, we observed that the rate of hyperlipidemia in choice of treatment in symptomatic patients [30], SOCAD group was lower than that in non-SOCAD other treatments including coronary stents and surgi- group. We must mention that, it is not interpreted from cal interventions such as myotomy or bypass are also our result that hyperlipidemia is negatively associated considered a second-line option. According to a re- with severe obstructive CAD because of the reasons that cent systematic review and pooled analysis raised by patients without SOCAD didn’t receive intensive Enrico Cerrato and colleagues [31], patients with lipid-lowering management, whereas patients with symptomatic isolated MB generally have a good SOCAD (some of them had a long history of coronary long-term prognosis; pharmacological treatment alone, heart disease) received an intensive lipid-lowering ther- especially with beta-blockers, can improve angina in apy even before admission according to the current most cases. In other words, their study clearly sup- guidelines. ports that MB is a benign variation of coronary Although the possible mechanisms of atherogenic pro- arteries. tection of MB is unknown, there is still some supported evidence. Loukas et al. [18] found that the bridged seg- ments demonstrated weaker proliferative activities of Limitations of this study Ki-67 (a cellular marker for proliferation), and a de- There are some limitations in our study, including its creased count of smooth muscle cells and macrophages. non-randomization because of retrospective nature This phenomenon might be explained with that the and lack of standardization when MB was diagnosed MB-related contracting myocardium compression stimu- with coronary angiography. Considering the unreli- lates the release of anticoagulant and growth factors, ability of patient’s subjective statement, smoking and which could produce a synergistic effect in preventing family history for CAD, two major risk factors for the endothelium from denudation, inflammation, and re- CAD, were not included in the present study. Fur- sultant atherosclerosis in vessels with MB and possibly thermore, it is also difficult for us to interpret the in the whole coronary system. 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A potential protective element of myocardial bridge against severe obstructive atherosclerosis in the whole coronary system

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Abstract

Background: Myocardial bridge (MB) is generally described as a congenital benign variation. Previous studies have suggested that MB prevents atherosclerotic plaques from accumulating within the bridge segment but promotes coronary stenosis in the proximal segment adjacent to MB. However, it is still not clear whether MB has positive or negative effects on severe obstructive atherosclerosis in the whole coronary artery system. Methods: In this study, 6774 patients with symptoms of angina who were clinically diagnosed coronary artery disease (CAD) or suspected CAD underwent coronary angiography (CAG) in our center. The presence of MB was diagnosed, and a retrospective analysis was performed between MB and severe obstructive CAD requiring percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) in the whole coronary system. Results: Among 6774 patients, 3583 (52.89%) were diagnosed with severe obstructive CAD (SOCAD) requiring a treatment of PCI or CABG and enrolled into the SOCAD group; and 3191 (47.11%) without SOCAD into the non- SOCAD group. Non-SOCAD and SOCAD groups had 512(16.05%) and 66(1.84%) patients with MB, respectively (P < 0.0001). The rate of SOCAD requiring PCI or CABG in patients with MB was much lower than that in patients without MB (11.42% vs. 56.76%, P < 0.0001). After adjusting for sex, age, diabetes mellitus, hypertension, and other risk factors, MB still had some positive role in preventing severe obstructive CAD (log-OR = − 2.134, p-value < 0.0001) through logistic regression. Conclusions: Our results provided a clue that MB might act as a potential protective element against severe obstructive atherosclerosis in the whole coronary artery system. Background clinically silent in many cases but is of interesting to Myocardial bridge (MB) is referred to muscle overlying clinical researchers due to its association with myocar- intramyocardial segment of an epicardial coronary ar- dial ischemia [4, 5]. tery, usually in the middle segment of the left anterior The golden standard of MB diagnosis in angiography descending coronary artery (LAD) [1, 2]. Some studies is defined as systolic milking effect produced by systolic reported anatomical properties of MB on atherosclerosis compression by the intramyocardial segment [6]. MB is evolution in LAD. Location, length, and thickness are the most common congenital coronary variation, and closely interrelated, and longer or thicker MBs are the prevalence of MB varies from less than 5% [1, 6] located significantly proximally in LAD [3]. Its charac- under angiography, to 23% with intravascular ultrasound teristic compression of the tunneled coronary segment is (IVUS) [6], to 55.6% under autopsy [7] due to the reason that short and thin bridges causing little systolic com- pression are easy to be ignored [8]. * Correspondence: jls1025@aliyun.com; drhe_renji@163.com Lisheng Jiang and Min Zhang contributed equally to this work. The presence of MB can be associated with various Department of Cardiology, Shanghai Jiao Tong University Affiliated Chest complications such as angina, acute myocardial infarc- Hospital, Shanghai, China tion, arrhythmias, and even sudden death [4, 9–18]. MB Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Jiang et al. BMC Cardiovascular Disorders (2018) 18:105 Page 2 of 7 can also be considered a benign variation of coronary ar- The presence of MB was recognized by the angio- teries [19], or a double-edged sword [5]. The cause of graphic finding of transient reduction in the lumen of angina is generally thought to be a distinct reduction of one epicardial coronary artery during systole as shown coronary artery flow due to muscular compression in Fig. 1. The severe obstructive coronary artery disease during systole [5, 20, 21]. Previous studies have sug- (SOCAD) requiring invasive treatment with PCI or gested that in the intramyocardial segments, the vessel is CABG was defined as the presence of stenosis over 75% protected from obstructive atherosclerosis, however, it is or occlusion in at least one major coronary artery, or not clear whether MB has positive or negative effects on stenosis less than 75% but over 50%, which was obstructive atherosclerosis in the whole coronary artery evaluated with an indication of PCI or CABG by coron- system. In the present study, we aimed at exploring a ary interventional cardiologist or cardiac surgeon. Ac- clinical relationship between MB and severe obstructive cording to angiography results, patients with SOCAD atherosclerosis requiring treatment with percutaneous underwent treatment with PCI or CABG and were coronary intervention (PCI) or coronary artery bypass enrolled into the SOCAD group; while patients without grafting (CABG) in the whole coronary artery system. severe obstructive coronary artery lesion were enrolled into the non-SOCAD group. The traditional risk factors including advanced age, Methods hypertension, diabetes mellitus (DM) and impaired glu- Study oversight cose tolerance (IGT), hyperlipidemia, chronic kidney This study is a retrospective observation based on disease (CKD), ischemic cerebrovascular disease (ICVD), hospital records from Renji Hospital, School of etc. were documented to be linked with atherosclerosis. Medicine, Shanghai Jiaotong University, China. The In the present study, both the incidence of MB and the authors assume responsibility for the accuracy and com- risk factors as above were therefore recorded and pleteness of the data and data analyses. analyzed. Data collection Statistical analyses From December 2012 to February 2015, 6774 patients Mean values with standard deviations and counts with with symptoms of angina who were clinically diagnosed percentages were used to describe baseline characteris- with coronary artery disease (CAD) or suspected CAD tics and the incidence of MB. Differences were calcu- underwent 6848 coronary angiographies in Renji lated separately in different subgroups according to Hospital. We conducted a retrospective study on MB by presence or absence of SOCAD or MB, and sex. The dif- retrieving these patients’ hospital records, including sex, ferences were evaluated using one-way analysis of vari- age, coronary risk factors, diagnoses of coronary angiog- ance for continuous variables and Fisher’s exact test for raphy and invasive treatments. All clinical diagnoses categorical variables. The association between SOCAD follow the standard of ICD-10. and MB was further evaluated in the context of logistic Fig. 1 The typical characteristics of MB under angiography. The box in diagram a represents the segment of myocardial bridge free of compressing in left anterior descending artery during diastole; the arrow in diagram b represents the compressing segment of myocardial bridge in the same artery during systole Jiang et al. BMC Cardiovascular Disorders (2018) 18:105 Page 3 of 7 regression model with or without interaction terms by group (proportions: 1.84% vs. 16.05%, respectively; adjusting for some baseline risk factors and the widely P < 0.0001). Besides, in the SOCAD group, there were used stepwise variable selection strategy based on older age (mean [±SD], 65.08 ± 10.55 years vs. 63.34 ± Akaike’s information criterion [22] was used to select 10.33 years; P < 0.0001), higher proportion of male those factors potentially associated with SOCAD. (74.83% vs. 52.74%, P < 0.0001), and higher rates of risk All P values were two-sided, and a P value of < 0.05 factors including, hypertension, diabetes and/or impaired was considered with statistical significances. The R pro- glucose tolerance, chronic kidney disease and ischemic gram, version 3.4.0, was used to perform statistical cerebrovascular disease. However, the rate of hyperlipid- analyses. emia in the SOCAD group was lower than that in the non-SOCAD group, which might be linked with the Results reason that patients in the SOCAD group were given an Findings of myocardial bridge intensive lipid-lowering therapy even before admission As listed in Table 1, out of the 6774 patients underwent (some of them had a long history of coronary heart angiography, 578 (319 male and 259 female)were diag- disease). nosed with MB including 571 located in the left anterior descending artery (LAD), 4 in left circumflex (LCX) and Incidence of SOCAD and risk factors between patients 3 in right coronary artery (RCA). with or without myocardial bridge As shown in Table 3, in comparison with the non-MB group, patients in the MB group had much lower rate of Incidence of MB and risk factors between patients with or SOCAD requiring PCI/CABG (11.42% vs. 56.76%, without SOCAD P < 0.0001), higher rate of female (44.81% vs. 34.72%, There were significant differences when comparing the P < 0.0001), younger age (mean [±SD], 61.10 ± 9.93 vs. incidence of MB between patients with or without 64.56 ± 10.49, P < 0.0001), and lower rates of risk factors SOCAD. As listed in Table 2, the incidence of MB in the including hypertension (50.00% vs.61.54%, P < 0.0001), SOCAD group was much lower than the non-SOCAD impaired glucose metabolism including DM and IGT (14.01% vs. 29.78%, P < 0.0001), ischemic cerebrovascu- lar diseases (3.63% vs. 6.71%, P = 0.0026), and chronic Table 1 Clinical characteristics in patients with myocardial kidney disease (1.21% vs.3.78%, P = 0.0006), but not for bridge (MB) hyperlipidemia (P = 0.934). Characteristics Values Incidence of MB, n/total (%) 578/6774 (8.53%) Differences on incidence of MB and clinical characteristics Location of MB: LAD , n (%) 571(98.79%) between male and female LCX , (%) 4 (0.69%) Compared with the male, the female patients had a RCA , (%) 3 (0.52%) higher proportion of MB (10.75% vs. 7.31%, P < 0.0001), much older age (66.09 ± 10.09 vs. 63.25 ± 10.56 years Age (years, mean ± SD) 61.10 ± 9.93 old, P < 0.0001), higher rate of hyperlipidemia (9.46% Sex vs. 6.35%, P < 0.0001), but much lower SOCAD Male, n (%) 319 (55.19%) requiring PCI or CABG (37.43%% vs. 61.43%, Female, n (%) 259 (44.81%) P < 0.0001) (Table 4). Hypertension, n (%) 289 (50.00%) DM , n (%) 59 (10.21%) Logistic regression Association intensities (log-ORs) between risk factors IGT , n (%) 22 (3.81%) f and severe obstructive atherosclerosis requiring PCI or DM/IGT , n (%) 81 (14.01%) CABG were reported in Table 4. There was a strong Hyperlipidemia, n (%) 42 (7.27%) negative linear relationship between MB and severe ob- Ischemic cerebrovascular disease, n (%) 21 (3.63%) structive atherosclerosis (log-OR = − 2.134, P < 0.0001), Chronic kidney disease, n (%) 7 (1.21%) and other significant risk factors (including inter- SOCAD , n (%) 66 (11.42%) action terms) included old age (P = 0.0025), female LAD, left anterior descending artery sex (P < 0.0001), hypertension (P < 0.0001), impaired glu- LCX, left circumflex cose metabolism (P < 0.0001), hyperlipidemia (P = 0.0436), RCA, right coronary artery interaction term between age and sex (P < 0.0001), inter- DM, diabetes mellitus IGT, impaired glucose tolerance action term between age and impaired glucose metabolism DM/IGT, diabetes mellitus/impaired glucose tolerance g (P = 0.0003), and interaction term between sex and hyper- SOCAD, severe obstructive coronary artery disease requiring treatment with percutaneous coronary intervention or coronary artery bypass grafting tension (P = 0.0122). Jiang et al. BMC Cardiovascular Disorders (2018) 18:105 Page 4 of 7 Table 2 Comparisons on incidence of myocardial bridge and risk factors in patients with or without SOCAD Event Non-SOCAD SOCAD P value N = 3191 (47.11%) N = 3583 (52.89%) Age (years, mean ± SD) 63.34 ± 10.33 65.08 ± 10.55 < 0.0001 Sex Male, n (%) 1683(52.74%) 2681(74.83%) < 0.0001 Female, n (%) 1508(47.26%) 902(25.17%) Myocardial bridge, n (%) 512(16.05%) 66(1.84%) < 0.0001 Hypertension, n (%) 1725(54.06%) 2377(66.34%) < 0.0001 DM , n (%) 527(16.52%) 1078(30.09%) < 0.0001 IGT , n (%) 124(3.89%) 197(5.50%) 0.0078 DM/IGT , n (%) 651(20.40%) 1275(35.58%) < 0.0001 Hyperlipidemia, n (%) 272(8.52%) 233(6.50%) 0.0016 Ischemic cerebrovascular disease, n (%) 178(5.58%) 259(7.23%) 0.0064 Chronic kidney disease, n (%) 83(2.60) 158(4.41%) < 0.0001 DM, diabetes mellitus IGT, impaired glucose tolerance DM/IGT, diabetes mellitus/impaired glucose tolerance SOCAD, severe obstructive coronary artery disease requiring treatment with percutaneous coronary intervention or coronary artery bypass grafting A negative log-OR means a protective effect against se- Discussion vere obstructive atherosclerosis, and vice versa. Log-ORs Currently, many studies consider MB as a contributing of age, hypertension, impaired glucose metabolism, inter- factor in myocardial ischemia, angina, myocardial infarc- action term between age and sex, and interaction term be- tion and arrhythmia [4, 9–17]. However, less atheroscler- tween sex and hypertension were positive, while log-ORs otic lesions are found in bridge segments in contrast to of MB, female sex, hyperlipidemia, and interaction be- non-bridged coronary arteries [18, 23–27]. Limited proof tween age and glucose metabolism were negative. The indicates that compression by contracting myocardial log-OR of myocardial bridge was − 2.134, suggesting a po- muscles may provide some potential anti-atherosclerotic tential protective element of MB against severe obstruct- mechanisms linked with the release of anticoagulant and ive atherosclerosis requiring PCI or CABG (Table 5). growth factors [18]. However, the overall protective or Table 3 Comparisons on incidence of SOCAD and risk factors in patients with or without myocardial bridge Event Without MB With MB P value N = 6196 (91.47%) N = 578 (8.52%) Age (years, mean ± SD) 64.56 ± 10.49 61.10 ± 9.93 < 0.0001 Sex Male, n (%) 4045(65.28%) 319(55.19%) < 0.0001 Female, n (%) 2151(34.72%) 259(44.81%) Hypertension, n (%) 3813(61.54%) 289(50.00%) < 0.0001 DM , n (%) 1546(24.95%) 59(10.21%) < 0.0001 IGT , n (%) 299(4.83%) 22(3.81%) 0.5441 DM/IGT , n (%) 1845(29.78%) 81(14.01%) < 0.0001 Hyperlipidemia, n (%) 463(7.47%) 42(7.27%) 0.934 Ischemic cerebrovascular disease, n (%) 416(6.71%) 21(3.63%) 0.0026 Chronic kidney disease, n (%) 234(3.78%) 7(1.21%) 0.0006 SOCAD , n (%) 3517(56.76%) 66(11.42%) < 0.0001 DM, diabetes mellitus IGT, impaired glucose tolerance DM/IGT, diabetes mellitus/impaired glucose tolerance SOCAD, severe obstructive coronary artery disease requiring treatment with percutaneous coronary intervention or coronary artery bypass grafting Jiang et al. BMC Cardiovascular Disorders (2018) 18:105 Page 5 of 7 Table 4 Comparisons on incidence of myocardial bridge and clinical characteristics between male and female Event Male Female P value N = 4364 (64.42%) N = 2410 (35.58%) Age (years, mean ± SD) 63.25 ± 10.56 66.09 ± 10.09 < 0.0001 Myocardial bridge, n (%) 319(7.31%) 259(10.75%) < 0.0001 Hypertension, n (%) 2617(59.97%) 1485(61.62%) 0.1855 DM , n (%) 1010(23.14%) 595(24.69%) 0.1274 IGT , n (%) 221(5.06%) 100(4.15%) 0.2371 DM/IGT , n (%) 1231(28.21%) 695(28.84%) 0.8594 Hyperlipidemia, n (%) 277(6.35%) 228(9.46%) < 0.0001 Ischemic cerebrovascular disease, n (%) 258(5.91%) 179(7.43%) 0.0174 Chronic kidney disease, n (%) 178(4.08%) 63(2.61%) 0.0016 SOCAD , n (%) 2681(61.43%) 902(37.43%) < 0.0001 DM, diabetes mellitus IGT, impaired glucose tolerance DM/IGT, diabetes mellitus/impaired glucose tolerance SOCAD, severe obstructive coronary artery disease requiring treatment with percutaneous coronary intervention or coronary artery bypass grafting detrimental role of MB in the whole coronary system but not at intramural segments [25]. Also, endothelial and knowledge on the mechanisms are still desired. cells proximal to MB were arranged in a pavement-like, According to previous studies, formation of athero- polygonal and flat appearance because of a high sheer sclerotic plaque can frequently be found at segment stress [27]. These pathologic changes in proximal segment proximal to the bridge, while the intramural segment may be due to the accumulation of ApoB, proliferating cell is typically absent [18, 23], but not in all cases [26]. nuclear antigens (PCNA) in smooth muscle cells and in- As supported by a morphological observation of cho- creased endothelial cell permeability [25]. lesterol-fed rabbits, foam cells and modified smooth Diagnosis of MB under coronary angiography is based muscle cells have the same distribution on a cellar on the typical “milking effect” and a “step down-step up” level with atheromatous plaques at proximal segments phenomenon induced by muscle compression during Table 5 Analysis of logistic regression (with interaction terms) log-OR Std. error z value P value (Intercept) −0.383 0.217 −1.762 0.0780 Age 0.010 0.003 3.019 0.0025 MB −2.134 0.137 −15.545 < 0.0001 Female sex −3.139 0.379 −8.285 < 0.0001 Hypertension 0.341 0.073 4.689 < 0.0001 Impaired glucose metabolism 1.160 0.215 5.389 < 0.0001 Hyperlipidemia −0.205 0.102 −2.018 0.0436 Ischemic cerebrovascular disease (ICVD) −0.025 0.136 −0.183 0.8545 Chronic kidney disease (CKD) 0.254 0.146 1.735 0.0828 Age × Sex (female vs. male) 0.028 0.006 4.852 < 0.0001 Age × Impaired glucose metabolism −0.012 0.003 −3.628 0.0003 MB × ICVD −12.698 179.070 −0.071 0.9435 Sex × Hypertension 0.301 0.120 2.507 0.0122 Sex ×Impaired glucose metabolism 0.118 0.067 1.770 0.0767 Hypertension × Impaired glucose metabolism −0.134 0.071 −1.881 0.0600 Impaired glucose metabolism × ICVD 0.175 0.124 1.416 0.1568 Impaired glucose metabolism including diabetes mellitus and impaired glucose tolerance log-OR: log-odds ratio. A negative log-OR means a protective effect against severe obstructive coronary artery disease (SOCAD) requiring treatment with percutaneous coronary intervention or coronary artery bypass grafting on the premise that the presence of SOCAD was coded as 1 and non-SOCAD was coded as 0 Jiang et al. BMC Cardiovascular Disorders (2018) 18:105 Page 6 of 7 systole [6]. Though coronary angiography is now the CT scanning showed that the presence of MB was asso- gold standard and is most widely used in diagnosing ciated with a lower Agatston Calcium Score in the MB, it has some technical restrictions compared with bridged segments [29]. The presence of an MB may also other new imaging techniques, such as intravenous influence arterial tissue through the alteration of ultrasound (IVUS), intracoronary Doppler ultrasound, hemodynamic forces. According to previous study [24], multi-detector computed tomography, and intracoronary any atherosclerosis in the MB-segment is suppressed pressure devices [1, 3, 7]. In other words, the percentage histopathologically and ultrastructurally. Abrupt changes of MB varies with different diagnostic method and of endothelial cell morphology in the intima beneath the equipment. In this retrospective study, the overall bridge were observed with scanning electron micros- incidence of MB was 8.53%, but the female had higher copy, which indicates that the arterial tissue beneath the morbidity of MB than the male (10.75% vs. 7.31%, bridge is protected by hemodynamic factors. In P < 0.0001). In the non-SOCAD group, the rate of MB cholesterol-fed rabbits, the intima in the MB segment was much higher than that in the SOCAD group covered by myocardial tissue was free of atherosclerotic (16.05% vs. 1.84%, P < 0.0001); whereas, in patients with lesions, and the endothelial cells were spindle-shaped MB, the rate of SOCAD requiring treatment with PCI or and engorged [25], which also indicates that the protect- CABG was much lower than that in patients without ive element of MB against atherosclerosis might be MB (11.42% vs 56.76%, P < 0.0001). Take this in linked with an alteration of endothelial permeability due account, we speculated that MB might produce a poten- to hemodynamic force changes tending towards a higher tial positive role against severe obstructive atheroscler- shear stress. Based on the documented studies as above, osis in the whole coronary artery system. Accordingly, the role of myocardial bridges to suppress coronary ath- we analyzed the relationship between MB and severe ob- erosclerosis might be potential, but it still deserves structive atherosclerosis by adjusting for age, sex, hyper- further scientific research in biochemical and patho- tension, impaired glucose metabolism, hyperlipidemia, physiological fronts. ischemic cerebrovascular diseases, and chronic kidney Despite the presence of MB can be associated with diseases. Based on our results, there seemed to be a clue various complications such as angina, acute myocar- that MB might produce a potential protective element dial infarction, arrhythmias, and even sudden death against severe obstructive atherosclerosis in the whole [4, 9–17], it can also be considered a benign variation coronary artery system (log-OR = − 2.134; P < 0.0001). of coronary arteries [19]. So, the treatment of MB is Hyperlipidemia is a significant risk factor of CAD, still uncertain due to the lack of convincing evidence. which is a wide-accepted truth [28]. In the present study, In clinical practice, beta-blockers are usually the first however, we observed that the rate of hyperlipidemia in choice of treatment in symptomatic patients [30], SOCAD group was lower than that in non-SOCAD other treatments including coronary stents and surgi- group. We must mention that, it is not interpreted from cal interventions such as myotomy or bypass are also our result that hyperlipidemia is negatively associated considered a second-line option. According to a re- with severe obstructive CAD because of the reasons that cent systematic review and pooled analysis raised by patients without SOCAD didn’t receive intensive Enrico Cerrato and colleagues [31], patients with lipid-lowering management, whereas patients with symptomatic isolated MB generally have a good SOCAD (some of them had a long history of coronary long-term prognosis; pharmacological treatment alone, heart disease) received an intensive lipid-lowering ther- especially with beta-blockers, can improve angina in apy even before admission according to the current most cases. In other words, their study clearly sup- guidelines. ports that MB is a benign variation of coronary Although the possible mechanisms of atherogenic pro- arteries. tection of MB is unknown, there is still some supported evidence. Loukas et al. [18] found that the bridged seg- ments demonstrated weaker proliferative activities of Limitations of this study Ki-67 (a cellular marker for proliferation), and a de- There are some limitations in our study, including its creased count of smooth muscle cells and macrophages. non-randomization because of retrospective nature This phenomenon might be explained with that the and lack of standardization when MB was diagnosed MB-related contracting myocardium compression stimu- with coronary angiography. Considering the unreli- lates the release of anticoagulant and growth factors, ability of patient’s subjective statement, smoking and which could produce a synergistic effect in preventing family history for CAD, two major risk factors for the endothelium from denudation, inflammation, and re- CAD, were not included in the present study. Fur- sultant atherosclerosis in vessels with MB and possibly thermore, it is also difficult for us to interpret the in the whole coronary system. 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Journal

BMC Cardiovascular DisordersSpringer Journals

Published: May 29, 2018

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