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wileyonlinelibrary.com/journal/cpf Clin Physiol Funct Imaging. 2021;41:342–354.1 | INTRODUCTION
Cardiovascular disease is a leading cause of morbidity and mortality in the industrialized world. To improve early diagnosis and facilitate early interventions of cardiovascular disease, improved knowledge
of the physiological and pathophysiological behaviour of the vascular system is needed. Measurements of the distension of arteries in the radial direction, that is the diameter change, form the basis for esti-mation of arterial wall stiffness. Increased stiffness of large arteries is an established /important risk factor for cardiovascular diseases
Received: 5 October 2020
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Accepted: 18 March 2021 DOI: 10.1111/cpf.12701O R I G I N A L A R T I C L E
Comparison of the multi- phasic longitudinal displacement of
the left and right common carotid artery in healthy humans
Yuxiang Zhu
1,2| Magnus Cinthio
1| Tobias Erlöv
1| Niclas Bjarnegård
3|
Åsa Rydén Ahlgren
4,51Department of Biomedical Engineering,
Faculty of Engineering, Lund University, Lund, Sweden
2Institute of Translational Medicine, School
of Medicine, Zhejiang University, Hangzhou, China
3Department of Diagnostics and Specialist
Medicine, Faculty of Health, Medicine and Caring Sciences, University of Linköping, Linköping, Sweden
4Department of Translational Medicine,
Lund University, Lund, Sweden
5Department of Medical Imaging and
Physiology, Skåne University Hospital, Lund University, Malmö, Sweden
Correspondence
Åsa Rydén Ahlgren, Department of Medical Imaging and Physiology, Clinical Physiology and Nuclear Medicine, Carl Bertil Laurells gata 9, 3rd floor, Skåne University Hospital, SE- 205 02 Malmö, Sweden.
Email: asa.ryden_ahlgren@med.lu.se Funding information
Heart Lung Foundation, Sweden; The Medical Faculty; Lund University; The Swedish Research Council; The Skåne County Research Council; Funds at Skåne University Hospital; Region Östergötland; Erasmus+ International Credit Mobility for incoming PhD students at Lund University
Abstract
Background: During the cardiac cycle, there is a multi- phasic bidirectional longitu-dinal movement (LMov) of the intima- media complex of large arteries, i.e. along the arteries. On the left side the common carotid artery (CCA) arises directly from the aortic arc, whereas on the right side the CCA originate from the innominate artery. Aim: The aim of this study was to compare LMov of the left and right CCA of healthy subjects to investigate whether the difference in anatomy is of importance for LMov. Material and Methods: The CCA’s of 93 healthy subjects were investigated using in- house developed ultrasound methods.
Results: Although the basic pattern were the same in the majority of subjects, several phases of LMov were significantly larger on the left side (the first retrograde phase,
p = 0.0006; the second antegrade, “returning” phase, p < 0.00001; and the rapid
retrograde phase of movement at the end of the cardiac cycle, p < 0.000001). In contrast, no significant side- difference in the amplitude of the first antegrade move-ment was seen. The maximal (peak- to- peak) LMov was significantly larger on the left side (p = 0.002).
Discussion and Conclusion: The side- differences found in LMov may be related to the difference in anatomy, including possible difference in distance to the heart and especially the presence of an extra bifurcation on the right side. Our data provide an important base for the further study of the relation between LMov and cardiovascu-lar risk factors and atherosclerosis.
K E Y W O R D S
arterial wall, axial displacement, diameter change, longitudinal motion, ultrasound
This is an open access article under the terms of the Creative Commons Attribution- NonCommercial- NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non- commercial and no modifications or adaptations are made.
© 2021 The Authors. Clinical Physiology and Functional Imaging published by John Wiley & Sons Ltd on behalf of Scandinavian Society of Clinical Physiology and Nuclear Medicine.
(Blacher et al., 1999; Laurent et al., 2006). In contrast to the diameter change, the movements of the arterial wall in the longitudinal direc-tion, that is along the arteries, have gained little attention. However, lately technical advancement in ultrasound technology has made it possible to measure the longitudinal movement. It has been demon-strated that there is a distinct longitudinal bidirectional displacement of the intima- media complex, the wall layers closest to the blood, of the same magnitude as the well- known diameter change, during the cardiac cycle (Cinthio et al., 2006; Persson et al., 2003; Svedlund & Gan, 2011a,b; Yli- Ollila et al., 2013; Zahnd et al., 2011a,b). In addition, the intima- media complex has been shown to exhibit a larger motion than the adventitial region, the wall layer closest to the surrounding tissue (Cinthio et al., 2006; Idzenga et al., 2012; Nilsson et al., 2010; Zahnd et al., 2011a,b). This has been shown to take place in the com-mon carotid artery (CCA) (Cinthio et al., 2006; Idzenga et al., 2012; Nilsson et al., 2010; Zahnd et al., 2011a,b), but also in other large arteries such as the aorta, the brachial and popliteal arteries (Cinthio et al., 2006). It has also been shown that healthy young subjects can display complex, multi- phasic markedly different patterns of longi-tudinal movement of the CCA, and that these patterns remain highly stable over a 4- month period (Ahlgren et al., 2012a). Recently, we have also shown that the patterns of longitudinal movement of the CCA seen in middle- aged and older subjects can be markedly differ-ent from those commonly seen in young, including the appearance of additional phases of movement, and thus new complex patterns of motion (Cinthio et al., 2018). Thus, the pattern of longitudinal movement changes with ageing (Cinthio et al., 2018), and as seen in young subjects, middle- aged and older healthy subjects can show markedly different pattern of movement. This raises the question of whether the pattern of longitudinal displacement can be a potential biomarker for future cardiovascular disease.
Most studies on the relation between longitudinal movement of the arterial wall and atherosclerosis have so far focused on the am-plitude of longitudinal movement of the carotid artery wall, that is irrespective of the pattern of longitudinal movement. Exploring pu-tative relationship between longitudinal movement and atheroscle-rosis, Svedlund and Gan (2011a,b), reported that reduced maximal longitudinal movement seems to be associated with greater plaque burden in the carotid artery in mice and humans. In addition, there are indications that reduced longitudinal movement is associated with suspect (Svedlund et al., 2011) and manifest (Au et al., 2017) coronary artery disease. Further, recent studies have reported cor-relations between longitudinal motion and risk factors for athero-sclerosis (Taivainen et al., 2018; Taivainen et al., 2017; Zahnd et al., 2012). However, the relation between the longitudinal displacement and atherosclerosis is still not clear.
The mechanisms underlying the longitudinal movement of the ar-terial wall are largely unknown, and the complex, multiphasic pattern of movement in the CCA implies that several factors are involved (Ahlgren et al., 2012a; Cinthio et al., 2005). A study by Zahnd et al. (2015) has indicated that the amplitude of the longitudinal move-ment of the CCA is larger proximally than distally; that is increasing distance to the heart seems to affect the longitudinal movement of
the CCA (Zahnd et al., 2015), supporting the suggestion that the heart is one factor of importance for the longitudinal displacement of the carotid artery (Au et al., 2016; Cinthio et al., 2006). The left common carotid artery normally arises directly from the aortic arch. On the right side, the common carotid artery originates from the in-nominate (brachiocephalic) artery. Thus, the anatomy on the left and right side differs. At present, it is not known if this difference is of importance for the longitudinal displacement of the carotid artery.
The aim of this study was to compare the longitudinal movement of the intima- media complex of the left and right CCA of healthy sub-jects without major risk factors for cardiovascular disease to investi-gate whether the different anatomy on the right and left side are of importance for/influence the longitudinal movement. The measure-ments were performed using an in- house developed high- resolution noninvasive ultrasound method. In addition, lumen diameter, radial distention (the diameter change) and intima- media thickness (IMT) were also measured.
2 | MATERIALS AND METHODS
2.1 | Subjects
We recruited 100 healthy non- obese (body mass index <30) sub-jects: 60 men and 40 women (20– 65 years of age) from two different cohorts at Lund University and Linköping University, respectively. None of the patients reported previous cardiopulmonary disease, hypertension, diabetes or smoking, and none were taking any medi-cation. Lund cohort consisted of 33 subjects: 22 men and 11 women (20– 65 years of age), and Linköping cohort consisted of 67 subjects: 40 men and 27 women (52– 65 years of age), specifically recruited as being plaque free from a larger study. The Ethics Committee of Lund University and Linköping University approved the study, and informed consent was obtained from all subjects according to the Helsinki Declaration.
2.2 | Ultrasound examination of the carotid artery
An ultrasound system (Philips Epic 7 or Philips HDI 5000, Philips Medical System, Bothell, WA, USA, or LOGIQ E9, GE Healthcare, Wauwatosa, WI, USA) equipped with a 5– 12 MHz or 8– 18 MHz lin-ear array transducer was used for scanning. ECG was connected to the subject that rested comfortably in supine position for ten min-utes before the duplex scanning started. The room was kept quiet throughout the examination. The extracranial part of carotid artery was first thoroughly examined in longitudinal and short- axis view to screen for abnormalities such as atherosclerotic plaques. Thereafter, the aim was to obtain the best possible B- mode image of the com-mon carotid artery in the longitudinal direction, approximately 2 cm proximal to the carotid bifurcation. Predefined settings were used on the ultrasound system on which all kind of frame averaging were switched off. At least two zoomed B- mode cine- loops comprising4– 6 cardiac cycles with frame rate 55– 65 Hz were stored digitally. During the recording, the sonographer held the transducer gently in a stable position simultaneously as the subject gently paused breathing for a few seconds. The described scanning procedure was repeated on the other side of the neck. In all cases, the right side was recorded before the left. The same two experienced ultrasound technicians performed all examinations. Blood pressure was meas-ured with the auscultatory method immediately after the ultrasound scanning using a standard cuff on the upper arm. Figure 1 shows a schematic sketch of the examination and the anatomy of the upper aortic arch and the connected arteries.
2.3 | Ultrasound image analysis of carotid artery
Longitudinal movement (amplitude and max velocity), end- diastolic lumen diameter and IMT, distension and arterial strain (the relative diameter change) were automatically measured using an in- house developed image analysis software (Nilsson et al., 2013; Nilsson et al., 2014). The algorithm was initiated by a mouse click in the middle of the lumen, and the luminal intima and media adventitial interface of each wall were automatically outlined (Figure 2). The reader could correct the position of the intima- media and adventitial interfaces manually before estimation of the vessel wall movement was made, and average data covering the full cardiac cycle were presented. In the averaged longitudinal movement, curve different phases of movement were present (Cinthio et al., 2018). Following manual identification of the first antegrade (positive) longitudinal phase during the cardiac cycle, the software automatically identified all the other phases of movement (Cinthio et al., 2018). Wheneverneeded manual adjustments of the markers were done to correct for errors. In addition, the maximal longitudinal movement during a cardiac cycle (LMovMax), that is the difference between the maximal antegrade position and the maximal retrograde position, irrespective of phase, was also measured. End- diastolic lumen diameter and IMT, distension and arterial strain are presented as the mean value based on three to five cardiac cycles. The mean values of two recordings on each side were used in the statistical analysis.
F I G U R E 1 A schematic figure of
the geometry of the upper aortic arch and the connected arteries. The left common carotid artery normally arises directly from the aortic arch. On the right side, the subclavian and common carotid artery both originate from the innominate (brachiocephalic) artery. Thus, the anatomy on the left and right side differ
F I G U R E 2 An ultrasound image of the right common carotid
artery. The red lines indicate the interface between lumen and intima and the blue line the interface between media and adventitia at the far wall. The red and blue lines at the far wall indicate the region of interest
2.4 | Statistics
Wilcoxon signed- rank test was used to test differences between ob-servations from the left and the right side. p< 0.05 was taken as sig-nificant. Data are presented as mean ±SD, unless otherwise stated.
3 | RESULTS
Ultrasound characteristics of the common carotid artery on both sides were available for 93 subjects (58 men, 35 women, mean age 52 years ±13, range 20– 65) without visible plaques in the ca-rotid arteries. Seven subjects were excluded due to limited image quality and/or high blood pressure at the examination (defined as >140 mmHg systolic pressure and /or >90 mmHg diastolic pressure) or finding of plaques.
3.1 | The longitudinal movement of the right
common carotid artery
A distinct multiphasic bidirectional longitudinal movement of the intima- media complex was observed in all subjects during the cardiac cycle. As recently presented (Cinthio, et al., 2018), five different phases of lon-gitudinal movement could be identified in most subjects. As recently described (Cinthio et al., 2018), the phases included a first antegrade movement (i.e. a movement in the direction of the blood flow) in early
systole (Phase A), starting close to the time when the lumen diameter is at is minimum, is seen. This phase was followed by a retrograde move-ment in systole (Phase B). Thereafter, a second antegrade movemove-ment during diastole (Phase C) was seen. At the end of the cardiac cycle, a rapid retrograde movement (Phase W), preceding Phase A, was seen. Further, an antegrade movement or velocity change (Phase X) could be observed, occurring at the time, or close to, the dicrotic notch was seen in the diameter change curve (Figure 3). As earlier reported (Cinthio et al., 2018), in the youngest subjects Phase X was not always present or very small. Further, as previously reported (Ahlgren et al., 2012a; Cinthio et al., 2018), the resulting pattern of longitudinal movement could show markedly different pattern between individual subjects (as seen in the wide ranges of amplitudes, see Table 1), and some of the re-sulting patterns were not seen in the youngest subjects, whereas other were more prevalent in the young, and not seen in the oldest ones. The mean, SD and range for the different phases of movement are given in Table 1. In Table 1 also LMovMax, the maximal longitudinal displace-ment during a cardiac cycle, the thickness of the intima- media complex (IMT), the distension (the diameter change), the minimum lumen diam-eter and arterial strain (the relative diamdiam-eter change) are given.
3.2 | Comparison of the longitudinal
movement of the left and right common carotid artery
In subjects ≤50 years (n = 21, range 20– 47; mean age 30 ± 7), the basic pattern of longitudinal movement of the common carotid arteryF I G U R E 3 Longitudinal movement (solid line) of the intima- media complex and the corresponding diameter change (dashed line) in
relation to ECG (bottom trace) in the right common carotid artery of a 35- year- old female. For longitudinal movement, a positive deflection denotes movement in the direction of blood flow. The rings mark the onset of a distinct antegrade movement in early systole (Phase A). It is followed by a distinct retrograde movement in late systole (Phase B) and a second antegrade movement in diastole (Phase C). Phase A is preceded by a distinct retrograde movement (Phase W) at the end of the ‘local’ diastole. An antegrade movement or small velocity change occurs at the time, or close to, when the dicrotic notch is seen in the diameter change curve (Phase X, dashed oval)
TA B L E 1 The mean, standard deviation and range for displacement and velocity of the different phases of the longitudinal movement, as
well as for lumen diameter, distention, relative diameter change (strain) and the intima- media thickness (IMT), of the arterial wall of the right and left common carotid artery, and resulting p- values for all subjects, as well as subdivided into subjects <50 and subjects >50 years of age, respectively
Left Right Difference
p- value Mean (SD) Range Mean (SD) Range Mean (SD)
All Phase A (µm) 149 (127) 0– 726 178 (158) 0– 935 −29 (146) 0.13 Phase B (µm) 383 (195) 60– 1158 322 (212) 45– 1120 61 (166) 0.0006 Phase C (µm) 332 (244) 19– 1446 251 (230) 21– 1344 82 (153) <0.0001 Phase W (µm) 119 (96) 1– 492 73 (80) 0– 361 47 (70) <0.0001 Phase X (µm) 19 (32) 0– 131 16 (28) 0– 137 3 (26) 0.23 LMovMax (µm) 456 (234) 115– 1577 397 (231) 96– 1407 59 (194) 0.002
Max Vel Phase A (mm/s) 2.9 (2.1) 0– 11.3 3.3 (2.4) 0.0– 11.4 −0.4 (2.2) 0.14
Max Vel Phase B (mm/s) 3.8 (1.5) 1·3– 9.4 3.3 (1.7) 1.4– 10.7 0.5 (1.4) 0.0002
Max Vel Phase C (mm/s) 3.2 (2.1) 0.4– 11.7 2.8 (2.3) 0.0– 12.4 0.4 (1.5) 0.005
Max Vel Phase W (mm/s) 3.2 (2.2) 0.0– 10.7 2.0 (2.2) 0.0– 10.3 1.2 (1.8) <0.0001
Max Vel Phase X (mm/s) 0.3 (1.6) −3.8– 4.6 0.0 (1.4) −3.8– 4.0 0.3 (1.3) 0.13
Diameter (µm) 5830 (506) 4911– 7622 5847 (602) 4382– 8320 −17 (455) 0.8 Distention (µm) 559 (188) 281– 1083 587 (165) 332– 1040 −28 (101) 0.006 Arterial strain (%) 9.6 (3.4) 5.0– 19.2 10.1 (2.9) 5.7– 18.3 −0.5 (1.7) 0.002 IMT (µm) 665 (136) 409– 1107 668 (127) 449– 1003 −3 (102) 0.69 Age <50 years Phase A (µm) 210 (172) 6– 726 252 (173) 24– 758 −42 (134) 0.19 Phase B (µm) 614 (203) 377– 1158 532 (233) 168– 1120 82 (195) 0.13 Phase C (µm) 631 (270) 260– 1446 480 (301) 74– 1344 151 (206) 0.006 Phase W (µm) 136 (94) 13– 424 66 (80) 2– 303 70 (74) 0.001 Phase X (µm) 3 (6) 0– 23 1 (2) 0– 8 2 (5) 0.07 LMovMax (µm) 689 (278) 377– 1577 587 (268) 274– 1407 103 (188) 0.03
Max Vel Phase A (mm/s) 4.1 (2.5) 0.4– 11.3 4.4 (2.0) 1.2– 8.8 −0.3 (2.2) 0.52
Max Vel Phase B (mm/s) 5.4 (1.7) 2.6– 9.4 4.4 (1.9) 1.4– 7.9 1 (1.9) 0.1
Max Vel Phase C (mm/s) 6.1 (2.2) 2.6– 11.7 5.4 (2.9) 1.4– 12.4 0.6 (1.9) 0.33
Max Vel Phase W (mm/s) 3.8 (2.0) 0.7– 8.4 1.8 (1.8) 0.1– 7.1 2 (2.1) 0.0005
Max Vel Phase X (mm/s) −1.1 (1.4) −3.8– 1.6 −1.5 (1.2) −3.8– 0.8 0.4 (1.3) 0.27
Diameter (µm) 5663 (412) 4911– 6482 5605 (541) 4382– 6431 57 (446) 0.52 Distention (µm) 779 (167) 397– 1083 749 (128) 418– 933 30 (111) 0.29 Arterial strain (%) 13.9 (3.2) 7.8– 19.2 13.5 (2.9) 8.2– 18.3 0.3 (2.7) 0.61 IMT (µm) 577 (82) 486– 834 567 (65) 463– 701 10 (66) 0.52 Age >50 years Phase A (µm) 131 (106) 0– 423 157 (148) 0– 935 −26 (150) 0.32 Phase B (µm) 316 (131) 60– 641 261 (162) 45– 776 55 (157) 0.002 Phase C (µm) 245 (151) 19– 611 184 (152) 21– 798 61 (127) 0.0002 Phase W (µm) 114 (96) 1– 492 75 (81) 0– 361 40 (67) <0.0001 Phase X (µm) 24 (34) 0– 131 20 (31) 0– 137 3 (39) 0.37 LMovMax (µm) 388 (167) 115– 1066 341 (187) 96– 939 46 (195) 0.02
Max Vel Phase A (mm/s) 2.6 (1.9) 0– 8.3 3.0 (2.4) 0.0– 11.4 −0.5 (2.3) 0.21
Max Vel Phase B (mm/s) 3.3 (1.2) 1.3– 6.9 2.9 (1.5) 1.4– 10.7 0.4 (1.2) 0.0004
was the same on the right and left side, that is the different phases of movement described above could be identified on both sides, and when visually inspected, the relationship between the different phases of movement was approximately the same. However, when measured, two of the distinct phases of movement were significantly larger on the left side: Phase C; the second ‘returning’ antegrade movement (p = 0.006) and Phase W; the rapid retrograde movement at the end of the cardiac cycle; (p = 0.001, Table 1). The maximum ve-locity of this retrograde phase (W) was also significantly larger on the left side (p = 0.0005). No significant differences in the amplitude of the other phases of longitudinal displacement on the two sides could be detected. LMovMax, that is the difference between the maximal antegrade position and the maximal retrograde position, irrespective of phase, was significantly larger on the left side (p = 0.03). Figure 4 shows examples of curves of the longitudinal movement obtained from the right and the left CCA in five subjects aged <50 years.
In subjects >50 years of age (n = 72, mean age 58 ± 4, range 52– 65 years), Phase C and Phase W were also significantly larger on the left side (p = 0.0002 and p < 0.00001, respectively, Table 1). In addition, in this age group also the amplitude of Phase B, the first retrograde movement, was also significantly larger on the left side (p = 0.002). Moreover, the maximal velocity of these three phases was significantly higher on the left side (Phase B
p = 0.0004, Phase C p = 0.003 and Phase W p < 0.00001, Table 1).
Figure 5 shows example of curves of the longitudinal movement obtained from the right and the left CCA in five subjects aged >50 years. In this age group, 8 of 72 subjects, that is 11%, also showed dramatically different pattern of movement on the two sides; one side could show forward- oriented pattern while the other side show backward- oriented pattern. In seven of these subjects, the pattern of movement was ‘backward oriented’ on the left side, and ‘forward oriented’ on the right side (Figure 6), but in one subject, the reverse was seen. Figure 6 shows three ex-amples of this marked side difference. This finding was the reason
we have chosen to analyse the material in the two subgroups aged <50 and >50 years.
When all subjects were analysed as one group, as was our initial intention, the results were in line with the results presented above; the amplitude of Phase B, the first retrograde movement, was sig-nificantly larger on the left side (p = 00006, Table 1), and its maximal velocity was higher (p = 0.0002). In addition, Phase C, the second antegrade, ‘returning’ movement was significantly larger on the left side (p < 0.00001) and its maximal velocity was higher (p = 0.005). Furthermore, the amplitude of Phase W, the rapid retrograde move-ment at the end of the cardiac cycle, was significantly larger on the left side (p < 0.000001) and its velocity was higher (p < 0.000001). In contrast, no significant difference in amplitude or maximal ve-locity of Phase A or Phase X was seen. LMovMax was significantly larger on the left side (p = 0.002). Arterial strain, the relative diame-ter change, was significantly lower on the left side (p = 0.002). This side difference in arterial strain was stronger when only subjects >50 years were analysed (p < 0.00001), and not detected in the group <50 years. No significant side difference in end- diastolic di-ameter or IMT was seen (Table 1).
4 | DISCUSSION
This study of healthy subjects, without atherosclerotic plaques in the CCA, shows that there are significant differences in am-plitudes of the complex multiphasic longitudinal displacement of the CCA with somewhat larger displacements on the left side compared to the right side, and that this side difference seems to develop and increase with ageing. Thus, in subjects <50 years, the basic pattern of displacement was visually the same on the two sides although some phases of displacement were significantly larger on the left side. In contrast, in subjects >50 years, although only seen in a minority of the subjects, the pattern of displacement
Left Right Difference
p- value Mean (SD) Range Mean (SD) Range Mean (SD)
Max Vel Phase C (mm/s) 2.3 (1.1) 0.4– 5.6 2.0 (1.4) 0.0– 7.5 0.3 (1.0) 0.003
Max Vel Phase W (mm/s) 3.0 (2.2) 0.0– 10.7 2.1 (2.3) 0.0– 10.3 1 (1.7) <0.0001
Max Vel Phase X (mm/s) 0.7 (1.3) −1.5– 4.6 0.5 (1.1) −3.6– 4.0 0.2 (1.3) 0.27
Diameter (µm) 5879 (523) 4947– 7622 5918 (603) 4927– 8320 −39 (458) 0.55
Distention (µm) 494 (140) 281– 842 540 (143) 332– 1040 −45 (92) 0.001
Arterial strain (%) 8.4 (2.2) 5.0– 14.7 9.1 (2.0) 5.7– 14.6 −0.7 (1.3) <0.0001
IMT (µm) 691 (138) 409– 1107 698 (126) 449– 1003 −6 (110) 0.5
TA B L E 1 (Continued)
F I G U R E 4 Original tracings (i.e. not filtered, not averaged) of the longitudinal movement of the intima- media complex of the far
wall (solid line) and the corresponding diameter change (dashed line) of the left and right common carotid artery in five healthy subjects <50 years of age (a– e). Gender and age are given in the figures. Small circles represent the start of the antegrade longitudinal movement in early systole (Phase A). For longitudinal movement, a positive deflection denotes the movement in the direction of blood flow. The pattern of the multiphasic longitudinal movement is basically the same on the left and right side although the amplitude of the phases can differ
(a)
(b)
(c)
(d)
on the two sides could be strikingly different, on one side being ‘forward- oriented’ and on the other side ‘backward oriented’. Our finding that in younger subjects the complex, multiphasic pattern of longitudinal displacement was basically the same on the two sides, shows that factors other than difference in anatomy, with different origin of the CCA, seems to be far more important for the resulting complex pattern of displacement, although our results show that the difference in anatomy, with an extra bifurcation on the right side, indeed may influence the amplitude of displace-ment. Our finding highlights the importance of investigating the CCA on the same side when comparing data between different subjects /groups, and the importance of being cautious when drawing conclusions regarding pattern and amplitudes of the lon-gitudinal displacements of the CCA. Our results form an impor-tant basis for the study of changes in the pattern and amplitudes of the longitudinal displacement in relation to cardiovascular risk factors and in the development of atherosclerotic plaques in the CCA, not seldom being unilateral. Further, it gives new information for interpreting the complex relationship between ventricular and vascular function.
To the best of our knowledge, this is the first study to analyse putative side difference in the pattern of longitudinal displacement of the carotid artery. In healthy subjects, the pattern of longitudinal displacement of the CCA can markedly differ between individuals, both in young and older ages (Ahlgren et al., 2012a; Cinthio et al., 2018), which explains the wide ranges of displacements seen in this study (Table 1). The phases of movement/displacement which were significantly larger on the left side as compared to the right side, include the first retrograde movement in systole (in our study de-noted phase B), and the following antegrade movement (phase C). These phases have been suggested to be related to the movement of the heart (such as left ventricular AV- plane displacement and left ventricular torsion (Au et al., 2016; Cinthio et al., 2006). In addition, the rapid retrograde displacement at the end of the cardiac cycle (phase W) was significantly larger on the left side. Also, LMovMax, that is the difference between the maximal antegrade displacement and the maximal retrograde displacement was significantly larger on the left side. As mentioned above, Zahnd et al. (2015) have reported that the amplitude of the longitudinal movement of the CCA seems to be larger proximally than distally. Whether the distances from the heart to the measurement site in left and right CCA, respectively, differ are currently unclear. Thus, we cannot tell if the site of mea-surement on the left CCA is closer to the heart than the measure-ment site on the right CCA. However, the distance to the heart and especially the fact that on the left side there is only one bifurcation between the heart and the site of measurement, while on the right side there are two, might be factors of importance for the resulting
longitudinal displacement of the CCA and may explain the larger am-plitudes found on the left side.
Interestingly, in this study, no significant difference was seen in the first antegrade displacement (Phase A) between the right and the left CCA. Further, the antegrade displacement seen at the same time or close to, the dicrotic notch in the diameter change curve (Phase X), that is close to, or at the time of, aortic valve closure, did not significantly differ between the two sides. This might indicate that these two phases are less dependent/influenced by the presence of the additional bifurcation and possible difference in distance to the heart.
Another mechanism that might be involved in the longitudinal movement of the arterial wall, and maybe especially in Phase W, is described by Fukui et al. (Fukui et al., 2007), and shown in an arterial phantom model by Salles et al. (Salles et al., 2015). As the diameter increases, the tissue stretches in the circumferential direction. If the tissue is not elastic enough, it needs to recruit tissue from a more dis-tal position, not yet distended, and therefore a retrograde movement starts. This possible mechanism, as the other, is likely dependent on both the local properties of the arterial wall and the geometry of the artery, including distance to bifurcations, and theoretically may be influenced by the different anatomy on the two sides. Blood flow shear stress, acting parallel to the vessel wall, has also been sug-gested to be an important factor for the longitudinal displacement of the arterial wall (Au et al., 2016; Cinthio et al., 2006). However, in a pharmacological study on the porcine CCA, we have shown that a pronounced increase in longitudinal displacement of the arterial wall can take place independently of wall shear stress (Ahlgren et al., 2015). In this study, we did not measure shear rate or shear stress. Another factor involved might be pulse pressure. In pharmacologi-cal experiments on the porcine CCA, we found strong correlations between pulse pressure and the longitudinal displacement (Ahlgren et al.,2012b). In this study, we have no data on the blood pressures in the carotid arteries, that is we do not know if the blood pressure between the right and left carotid artery differ.
In this study, the number of subjects >50 years of age was larger than the group <50 years of age, which may have influenced our results, having lower statistical power when analysing the younger subjects separately. Our initial intention was to only study all sub-jects as a whole group. However, during the work with analysing the ultrasound files we observed that in younger subjects, when visually inspected, the basic pattern of displacement was visually similar on the two sides. In contrast, it became obvious that in some people, although few, the basic pattern of movement was strikingly different on the two sides. Since this was only seen in subjects >50 years, in combination with our visual impression when analysing the ultra-sound files that slight differences in the relationship between the
F I G U R E 5 Original tracings (i.e. not filtered, not averaged) of the longitudinal movement of the intima- media complex of the far
wall (solid line) and the corresponding diameter change (dashed line) of the left and right common carotid artery in five healthy subjects >50 years of age (a– e). Gender and age are given in the figures. Small circles represent the start of the antegrade longitudinal movement in early systole (Phase A). For longitudinal movement, a positive deflection denotes the movement in the direction of blood flow. The basic pattern of the multiphasic longitudinal movement is the same on the left and right side although the amplitude of the phases can differ
(a)
(b)
(c)
(d)
F I G U R E 6 Original tracings (i.e. not filtered, not averaged) of the longitudinal movement of the intima- media complex of the far wall
(solid line) and the corresponding diameter change (dashed line) of the left and right common carotid artery in three healthy subjects >50 years of age (a– c). Gender and age are given in the figures. Small circles represent the start of the antegrade longitudinal movement in early systole (Phase A). For longitudinal movement, a positive deflection denotes the movement in the direction of blood flow. Note that the pattern of the multiphasic longitudinal movement is markedly different on the right and the left side in these subjects
Left
Right
(a)
(b)
different phases of movement seem to become more prominent with age, we have chosen not only to analyse all subjects as one group, but also to analyse young and subjects >50 years separately. The age 50 years does not represent a major shift in known physi-ology, and the age split was arbitrarily chosen to make our results easier to describe. Or findings do not mean that different pattern of movement on the two sides cannot be seen in younger subjects, for example with risk factors, and this is an issue for future studies. Thus, in this study it seems that with ageing the difference between the two sides increases. The reason for this is not known, but may be related to the normal age- related changes in the heart, such as changes in left ventricular AV- displacement and left ventricular tor-sion, the age- related elongation of the aorta and/or the also well- known age- related changes in arterial stiffness of the aorta and the CCA. This study cannot explain the peculiar finding that in some sub-jects >50 years the pattern of longitudinal displacement was clearly forward oriented on one side and clearly backward oriented on the other side. Further, we do not know if these findings have clinical importance. However, our findings stress that conclusions regarding the influence of, for example atherosclerosis must be drawn cau-tiously. It has been reported that the presence of atherosclerotic plaques and stenosis in the carotid artery seems to be associated with greater antegrade displacement (Tat et al., 2016), and it has been hypothesized that the presence of atherosclerotic plaque al-ters the direction of longitudinal motion. In the present study, none of the subjects had visible plaques in the carotid arteries, but still some had predominantly antegrade displacement. Interestingly, in studies on the left CCA, Taivainen et al. (2018) reported associations between longitudinal movement/motion parameters and traditional risk factors for cardiovascular disease with findings of increased an-tegrade and reduced retrograde amplitudes as the number of risk factors increased.
In pharmacological experiments, we have previously shown that adrenaline and noradrenaline, that is the catecholamines, profoundly influence the longitudinal displacement of the porcine carotid artery (Ahlgren et al., 2012b). Given this information, an adequate question is if difference in sympathetic activity when investigating the two sides may explain our results. However, our participants all rested at least 10 min in the supine position before measurements of the arterial wall movements were performed, and the room was kept quiet throughout the examination. Thus, it seems unlikely that difference in sympathetic activity could ex-plain our results, although, as the registrations were not performed simultaneously, small differences in blood pressure and heart rate cannot be excluded.
There are very few studies on putative side differences in longi-tudinal displacement of the CCA. Svedlund and Gan (2011a,b) using commercial vector velocity imaging found no significant differences between the left and right side. With the technique used, they mea-sured the total maximal longitudinal displacement over a cardiac cycle over a segment of the wall, that is the different phases of lon-gitudinal displacement could not be analysed. In the present study, the maximal longitudinal displacement during the cardiac cycle, that
is the difference between the maximal antegrade displacement and the maximal retrograde displacement (LMovMax), that is irrespec-tive of phase, was significantly larger on the left side. In the study of Svedlund and Gan (2011a,b) the number of subjects investigated was low, which can be one explanation for the conflicting results.
An interesting question is if there are side differences in other measures of the CCA. In the present study of healthy, normotensive and relatively young subjects, no significant side difference in IMT, an established marker of cardiovascular risk, between the left and the right CCA was seen. A side difference in IMT between the left and the right common carotid artery has, however, been reported, for example in a large cohort of untreated hypertensive patients IMT was found to be larger on the left side than on the right (Rodríguez Hernández et al., 2003), but there are also studies not detecting a side difference in IMT. Surprisingly, due to the numerous studies on arterial stiffness, there are to the best of our knowledge, few data on putative side difference in CCA stiffness; most studies on the CCA typically have explored one side, mostly the right. In this study, the relative diameter change, arterial strain, was lower on the left side, which may indicate higher stiffness on this side.
An interesting question is whether the larger amplitude of longi-tudinal displacement found on the left side have clinical importance, that is if the difference can be of importance for development of atherosclerotic plaques and /or plaque rupture and ischemic stroke. Interestingly, several studies have reported that the incidence of ischaemic stroke is higher in the left hemisphere than in the right (Hedna et al., 2013; Naess et al., 2006; Rodríguez Hernández et al., 2003; Selwaness et al., 2014), and that atherosclerotic plaque in the left carotid artery seems to be more vulnerable than in the right (Selwaness et al., 2014). It has been speculated that this might be due to difference in left and right vessel geometry, which in turn may in-fluence the haemodynamic forces acting on the arteries (Selwaness et al., 2014). However, although clinical ischaemic strokes and TIAs are reported to be more frequently left- sided than right- sided, this difference has not been confirmed for infarcts on MRI (Portegies et al., 2015). Possibly, left- sided strokes and TIAs are clinically more easily recognized (Portegies et al., 2015). This study cannot answer the question of whether our findings of larger displacement on the left side might be a factor of clinical importance for plaque rupture, plaque vulnerability and ischaemic stroke, and future studies are needed to explore this interesting issue.
In this study, we sometimes use ‘forward oriented’ and ‘back-ward oriented’ when briefly describing the pattern of longitudinal displacement in an attempt to give the reader a quick/easy impres-sion of the pattern. This is basically a description of our visually judgement based on our visual impression; forward- oriented mean-ing that ‘the area under the curve’ was larger in the direction of the blood flow, that is up to the head, than in the direction against the blood flow, and this was mostly accompanied by a phase A larger than B. Backward- oriented pattern having the largest area ‘under the curve’ in the direction against blood flow, mostly accompanied by phase B being larger than A. In some subjects, the pattern was something in between.
In this study, two experienced technicians performed all ultra-sound examinations. The recording of the longitudinal motion of the common carotid artery were performed about 2 cm proximal to the bifurcation. The image plane chosen was in each case the one that gave the most distinct visualization of both the far and near wall of the artery with distinct visualization of the intima- media, however, we tried to have the same image plane on the both sides, that is consistent between the two sites. Thus, minor differences due to slightly different transducer position/scanning planes on the two sides cannot be excluded. Another possible rea-son for minor differences is that during the off- line analysis, the reader selects a region of interest (ROI) along the CCA, which in turn is influenced by where the best defined echo- lines are seen along the carotid artery. In this study, we did not choose to inves-tigate the sites in the carotid artery that are the most related to atherosclerosis, such as the bifurcation or the proximal internal carotid artery, because of the turbulent flow and complex geome-try at these locations, but these locations can also be considered for future studies.
In conclusion, this study shows that several phases of the longitu-dinal displacement of the CCA are significantly larger on the left side as compared to the right. Further, this side difference seems to de-velop and increase with ageing. The side difference might be related to the different anatomy on the left and right side of the arterial tree, including possible difference in distance to the heart and especially the fact that there is an ‘extra’ bifurcation on the right side. However, the findings that the basic complex pattern of movement in younger subjects was the same on both sides show that factors other than the anatomical difference, with different origin of the CCA on the two sides, are far more important for the resulting multiphasic pattern of movement. Our findings of side difference in longitudinal displace-ment of the CCA stress the importance of investigating the CCA on the same side when comparing data between different subjects / groups. Our present data, as well as our recent study on age- related changes in the right CCA (Cinthio et al., 2018), also show the impor-tance of being cautious when drawing conclusions regarding pattern and amplitudes of the longitudinal displacements of the CCA. Our results form an important basis for future studies of changes in the pattern and amplitudes of the longitudinal displacement in the devel-opment of atherosclerosis and cardiovascular disease.
ACKNOWLEDGEMENTS
We thank late Professor Toste Länne for his contribution. This study was supported by grants from the Erasmus+ International Credit Mobility for incoming PhD student mobility in Lund University, the Medical Faculty of Lund University, the Swedish Research Council, Funds at Skåne University Hospital and the Skåne County Research Council. Heart and Lung Foundation, Sweden and ALF Grants, Region Östergötland, Linköping, Sweden. We thank Ann- Kristin Jönsson for skilled assistance.
CONFLIC T OF INTEREST
The authors have no conflict of interests.
ORCID
Åsa Rydén Ahlgren https://orcid.org/0000-0001-5942-9467
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How to cite this article: Zhu Y, Cinthio M, Erlöv T, et al.
Comparison of the multi- phasic longitudinal displacement of the left and right common carotid artery in healthy humans.
Clin Physiol Funct Imaging. 2021;41:342– 354. https://doi.
