Ultrasound in Med. & Biol., Vol. 41, No. 5, pp. 1342–1353, 2015 Copyright Ó 2015 World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved 0301-5629/$ - see front matter
http://dx.doi.org/10.1016/j.ultrasmedbio.2015.01.005
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Original Contribution PROFOUND INCREASE IN LONGITUDINAL DISPLACEMENTS OF THE PORCINE CAROTID ARTERY WALL CAN TAKE PLACE INDEPENDENTLY OF WALL SHEAR STRESS: A CONTINUATION REPORT z OM , ASA RYDEN AHLGREN,* STIG STEEN,y SIMON SEGSTEDT,z TOBIAS ERLO€V,z KJELL LINDSTR€ €BERG,y HANS W. PERSSON,z STEFANO RICCI,x PIERO TORTOLI,x and MAGNUS CINTHIOz TRYGVE SJO
* Clinical Physiology and Nuclear Medicine Unit, Department of Clinical Sciences, Lund University, Malm€ o, Sweden; Department of Thoracic Surgery, Sk ane University Hospital, Lund University, Lund, Sweden; z Biomedical Engineering, Faculty of Engineering, LTH, Lund University, Lund, Sweden; and x Information Engineering Department, University of Florence, Florence, Italy
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(Received 12 October 2014; revised 17 December 2014; in final form 16 January 2015)
Abstract—The mechanisms underlying longitudinal displacements of the arterial wall, that is, displacements of the wall layers along the artery, and the resulting intramural shear strain remain largely unknown. We have already found that these displacements undergo profound changes in response to catecholamines. Wall shear stress, closely related to wall shear rate, represents the viscous drag exerted on the vessel wall by flowing blood. The aim of the work described here was to study possible relations between the wall shear rate and the longitudinal displacements. We investigated the carotid arteries of five anesthetized pigs in different hemodynamic situations using in-house developed non-invasive ultrasound techniques. The study protocol included administration of epinephrine, norepinephrine and b-blockade (metoprolol). No significant correlation between longitudinal displacement of the intima–media complex and wall shear rate was found. This result suggests that one or multiple pulsatile forces other than wall shear stress are also working along arteries, strongly influencing arterial wall behavior. (E-mail: [email protected]) Ó 2015 World Federation for Ultrasound in Medicine & Biology. Key Words: Wall shear rate, Wall shear stress, Longitudinal movement, Arterial wall, Epinephrine, Norepinephrine, Catecholamines.
human arteries, the inner layers of the arterial wall, that is, the intima–media complex, move not only in the radial direction, but also in the longitudinal direction, that is, along the artery, during the cardiac cycle (Persson et al. 2002, 2003). To study this phenomenon, our group developed a non-invasive ultrasonic method for simultaneous high-resolution recording of both the longitudinal and radial movements of the arterial wall in vivo (Cinthio et al. 2005a, 2005b). Using this method, we have found that the longitudinal displacement of the intima–media complex is of the same magnitude as the well-known diameter change during the cardiac cycle (Cinthio et al. 2006). Importantly, we have also illustrated that the adventitial region exhibits the same basic pattern of longitudinal displacement, although the magnitude of the displacement is smaller. This means that intramural shear strain, and thus shear stress, is present (Cinthio et al. 2006). We have reported that this phenomenon can be detected in the carotid, popliteal and brachial arteries, as well as in the abdominal aorta, and thus seems
INTRODUCTION Cardiovascular disease is still a major cause of morbidity and mortality in the Western world. It is, therefore, essential to increase our knowledge of the cardiovascular system and cardiovascular diseases. Hemodynamic forces are considered important modulators of vascular tone and vascular remodeling and are increasingly implicated in atherogenesis. The longitudinal displacement of arteries, that is, the displacement along the artery, has for many years been assumed to be negligible compared with the radial displacement, that is, the diameter change (Nichols and O’Rourke 2005). However, by using modern ultrasound scanners it can be observed that in large Address correspondence to: Asa Ryden Ahlgren, Department of Clinical Physiology, DC, Inga Marie Nilssons gata 49, 3rd Floor, Sk ane University Hospital, SE-205 02 Malm€o, Sweden. E-mail: Asa. [email protected] Conflict of Interest: No conflicts of interest, financial or otherwise, are declared by the authors. 1342
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to be a general phenomenon in large human arteries (Cinthio et al. 2006). Substantial longitudinal displacements of the human carotid artery wall have recently been confirmed with other in-house developed ultrasonic techniques (Idzenga et al. 2012; Yli-Ollila et al. 2013; Zahnd et al. 2011). We have also recently reported that the longitudinal displacement of the common carotid artery (CCA) of healthy humans at rest can exhibit dramatically different patterns, also in patients of the same age and gender, and that these patterns of displacement are stable over a 4-mo period (Ahlgren et al. 2012a), thus raising the question: Is the pattern of the longitudinal displacement of the arterial wall a valuable marker for future risk for cardiovascular disease (Ahlgren et al. 2012a)? Recent studies reporting that the amplitude of the longitudinal displacement of the arterial wall is reduced in patients with carotid plaques, suspected coronary artery disease and type 2 diabetes (Svedlund and Gan 2011; Svedlund et al. 2011; Zahnd et al. 2011), as well as in patients with periodontal disease (Zahnd et al. 2012), suggest a positive answer to such a question. Changes in longitudinal displacement and intramural shear strain of the arterial wall have the potential to alter endothelial shear (Cinthio et al. 2006; Halliwill and Minson 2010) and to influence the circulation of the vasa vasorum, as well as the smooth muscles and the extracellular matrix in the media (Cinthio et al. 2006). In a study on the porcine carotid artery, we recently reported that the longitudinal displacements and intramural shear strain undergo profound changes in response to catecholamines, that is, our stress hormones epinephrine (adrenalin) and norepinephrine (noradrenalin), and changes in blood pressures (Ahlgren et al. 2012b). In many cases, the longitudinal displacement of the intima–media complex increased more than 200%. These findings might have important implications for vascular disease in both the short term and the long term, constituting a possible link between mental stress and cardiovascular disease and also indicating a possible influence in the context of atherosclerotic plaque rupture (Ahlgren et al. 2012b). However, the mechanisms underlying the longitudinal displacement and resulting intramural shear strain of the arterial wall are largely unknown, and the possible implications for cardiovascular disease are still unclear. Wall shear stress (WSS), given by the product of wall shear rate (WSR), that is, the blood velocity gradient at the vessel walls, and blood viscosity, represents the viscous drag exerted on the vessel wall by the flowing blood. WSS has important roles in acute adaptations to flow changes and vascular remodeling and in the development of atherosclerosis. Because WSS acts along the arteries, an obvious hypothesis is that WSS is an important factor
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in the longitudinal displacement of the arterial wall. The mechanical events within the arterial wall under the forces of pulsatile flow are currently being studied using mathe c 2013; matical models and simulations (Bukac and Cani Bukac et al. 2013; Fukui et al. 2007, Hodis and Zamir 2008, 2011a, 2011b; Warriner et al. 2008). The relation between WSS and the longitudinal displacement of the arterial wall has, however, not been addressed in vivo. Further, there are few non-invasive in vivo studies of WSR, and WSS, during different hemodynamic situations. The aim of the present work was, therefore, to study possible relations between WSR and longitudinal displacement of the arterial wall by investigating the response of the porcine common carotid artery to different hemodynamic situations. WSR was measured using the multigated spectral Doppler technique (Tortoli et al. 2006, 2011), implemented in the research system ULA-OP (Boni et al. 2012). The study protocol included intravenous infusion of epinephrine, intravenous boluses of norepinephrine, as well as b-blockade (using the b1-selective receptor antagonist metoprolol). The results of the WSR measurements are analyzed in relation to the recently presented data from measurements of the longitudinal displacement of the arterial wall (Ahlgren et al. 2012b). METHODS Material As recently reported (Ahlgren et al. 2012b), five 4mo-old pigs weighing 25 kg were used for this study. The study was approved by the Animal Research Ethics Committee, Lund University. Anesthesia was induced with an intramuscular injection of ketamine (30 mg/kg) and xylasin (4 mg/kg). Sodium thiopental (5–8 mg/kg) and atropine (0.015 mg/kg) were given intravenously before tracheotomy. Anesthesia and muscular paralysis were maintained with a continuous infusion of 10 mL/h NaCl (0.9%) solution containing ketamine (16 mg/mL) and pancuronium (0.6 mg/mL). After induction of anesthesia, the animals were tracheotomized and ventilated with pressure-regulated, volume controlled normoventilation (Servo Ventilator 300, Siemens, Solna, Sweden). Electrocardiogram (ECG), PaO2, PCO2 and O2 saturation were monitored. Blood pressure was continuously recorded intra-arterially (TestPoint, Capital Equipment, Billerica, MA, USA) in the right CCA. Body temperature was monitored using a thermistor in the esophagus. The temperature in the laboratory was kept constant. Measurements of wall shear rate Measurements were performed using ULA-OP, an advanced open platform for ultrasound research (Tortoli et al. 2009), connected to the LA523 probe (Esaote,
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Table 1. Study protocol for intravenously administered drugs* Order of administration 0 1 2 3 4 5
Drug ‘‘Baseline’’ Epinephrine infusion (low dose) Epinephrine infusion (higher dose) Epinephrine infusion 1 norepinephrine boluses 3 2 Epinephrine infusion 1 metoprolol Epinephrine infusion 1 metoprolol 1 norepinephrine boluses 3 2
* Exact doses are given in the text.
surements were performed using a commercial ultrasound system (HDI 5000, Philips Medical Systems, ATL Ultrasound, Bothell, WA, USA), equipped with a 38-mm 5- to 12-MHz linear array transducer. The image data were transferred to a PC for post-processing via HDI Laboratory (Philips Medical Systems, ATL Ultrasound, Bothell, WA, USA). During the recordings, the vessel was scanned in the longitudinal direction. The method used for measurements of the longitudinal movement (Cinthio et al. 2005a, 2005b) was implemented in MATLAB (The MathWorks, Natick, MA, USA).
Fig. 1. Schematic of the ultrasonic measurement of wall shear rate and longitudinal displacement of the intima–media complex of the porcine carotid artery. The white curve in the vessel lumen represents the blood flow profile used for measurement of wall shear rate. The box at the far wall represents the region selected for measurement of the longitudinal displacement of the intima–media complex.
Florence, Italy). The WSR was estimated from the multigated spectral Doppler data obtained from hundreds of small sample volumes aligned along an M-line intercepting the investigated vessel. The mean Doppler frequency was estimated for each sample volume and converted to velocity using the Doppler equation. This produced the velocity profile across the vessel, which was finally differentiated for WSR calculation, as described in Tortoli et al. (2006). Measurements of longitudinal displacement of the arterial wall The longitudinal displacement of the intima–media complex was measured using B-mode ultrasound as recently described (Ahlgren et al. 2012b). These mea-
Study protocol All measurements were performed with the pig lying on its back. WSR and longitudinal displacement of the intima–media complex of the left CCA were measured. Two experienced ultrasound technicians performed all the registrations, one recording the WSR and the other the longitudinal displacement. The measurements were performed at the same position on the vessel, immediately after each other. Care was taken to minimize the pressure of the transducers. Figure 1 is an ultrasonic B-mode image on which measurements of the longitudinal movement of the arterial wall were performed. The flow profile used to estimate the shear rate is schematically outlined. The study protocol is outlined in Table 1. After anesthesia was induced, three recordings of WSR and of longitudinal displacements of the CCA intima–media complex were performed (‘‘baseline’’). Next, epinephrine (adrenalin) was administered intravenously using a pump with an initial dose of 200 mg/h. After plateaus in blood pressure and heart rate were reached, the dose of epinephrine was increased to 400 mg/h. Depending on the responses in blood pressures and heart rate, the dose was in one case again lowered to 200 mg/h. At each level, repeated recordings of arterial wall movements and WSR were performed. Next, during continuous infusion of epinephrine, an intravenous bolus of 0.1 mg norepinephrine
Shear stress and longitudinal movements of arterial wall d A. R. AHLGREN et al.
(noradrenalin) was administered. Immediately after the bolus, repeated recordings of the arterial wall movements and WSR were performed for 5 min. About 10 min after the initial bolus of norepinephrine, that is, when its effect had waned, another intravenous bolus of 0.1 mg norepinephrine was administered, and arterial wall movements and WSR were again immediately repeatedly recorded. At least 10 min after the last bolus dose of norepinephrine, still during continuous intravenous infusion of epinephrine, an intravenous infusion of metoprolol 25 mg/h was started. To ensure as complete a b-blockade as possible, a bolus of 5 mg metoprolol was also given intravenously. Depending on the response (or lack of response), a second bolus of metoprolol was in some cases administered to ensure b-blockade. After about 3 min, the arterial wall movements and WSR were again repeatedly recorded. Next, during continuous simultaneous intravenous infusion of epinephrine and metoprolol, that is, during b-blockade, a bolus of 0.1 mg norepinephrine was administered intravenously. Immediately after administration of the bolus, WSR and arterial wall movements were repeatedly recorded. After another 10 min, still during continuous infusions of epinephrine and metoprolol, another bolus of norepinephrine was administered, and WSR and arterial wall movements were again repeatedly recorded. Statistics Least-squares regression analysis with calculation of Pearson’s product–moment correlation coefficient was used to evaluate the relations between WSR, longitudinal displacement and pulse pressure, respectively. p , 0.05 was taken as significant. Data are presented as the mean value 6 standard deviation (SD), unless otherwise stated. RESULTS Baseline Figure 2 is a typical WSR recording from the CCA of one pig at baseline, that is, when the pig was anesthetized, but before the administration of epinephrine. In the subjects studied, the mean peak (maximum) WSR was 1396 6 313 s21. The mean difference between the maximum and minimum WSRs (DWSR) during the cardiac cycle was 1105 6 365 s21. Wall shear rate during administration of catecholamines and b-blocker Figure 3(a–e) illustrates the changes in peak WSR in the individual subjects at baseline; during infusion of epinephrine (200 and 400 mg/h, respectively); after an additional norepinephrine bolus(es) of 0.1 mg; during
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Fig. 2. Wall shear rate profile recorded in the common carotid artery of a 4-mo-old pig at baseline, that is, after anesthesia was induced, but before administration of epinephrine. The maximum (peak) wall shear rate and the difference between the maximum and minimum wall shear rates (DWSR) were evaluated. B 5 peak and minimum wall shear rates used in the calculations.
simultaneous infusion of epinephrine and metoprolol, that is, during b-blockade; and after an additional bolus(es) of norepinephrine, that is, during b-blockade. Further, the corresponding changes in DWSR in the individual subjects are illustrated in Figure 4(a–e). During intravenous infusion of epinephrine, as well as after administration of boluses of norepinephrine, the peak WSR, as well as DWSR, increased in all subjects. However, when catecholamines were administered during b-blockade, b-blockade effectively counteracted the increase in WSR, as it also did when boluses of norepinephrine were administered.
Wall shear rate and longitudinal displacement of the intima–media complex The measurements of the longitudinal displacement of the intima-media complex (Ahlgren et al. 2012b) have now been analyzed in relation to the measurements of WSR. In four of five subjects, there were no significant correlations between peak WSR and longitudinal displacement of the intima–media complex (Fig. 5a–e). In one subject there was a positive correlation (R 5 0.47, p 5 0.03). In four of five subjects, there were no significant correlations between DWSR and longitudinal displacement of the intima–media complex (Fig. 6a–e). In one subject (the same as above), there was a possible correlation (R 5 0.43, p 5 0.05). Figure 7 illustrates the relative changes in longitudinal displacement of the intima–media complex in relation to the relative changes in DWSR rate in all subjects. No significant correlation between longitudinal
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Fig. 3. Peak WSR of the porcine carotid artery in five subjects (a–e) at baseline; during infusion of epinephrine (A 200 mg/ h and A 400 mg/h, respectively); after an additional norepinephrine bolus(es) of 0.1 mg (A 1 NA); during simultaneous infusion of epinephrine and metoprolol, that is, during b-blockade (A 1 b-block); and after an additional bolus(es) of norepinephrine, that is, during b-blockade (A 1 b-block 1 NA). Shaded boxes indicate the lower and upper quartiles and the median. Whiskers indicate the minimum and maximum values (n 5 5, z 5 122). Outliers are indicated by 1. Note the increase in peak WSR after administration of epinephrine and norepinephrine, and how this increase is counteracted by b-blockade. Sensitivity to epinephrine differed somewhat among the pigs; thus, the boxes for epinephrine 200 mg/h and 400 mg/h, respectively, include shear rates at both lower and higher blood pressures. WSR 5 wall shear rate.
displacement of the intima–media complex and DWSR was seen. The lack of correlation between WSR and longitudinal displacement of the intima–media complex was especially evident after administration of boluses of norepinephrine during b-blockade; b-blockade effectively counteracted increases in WSR, whereas, as recently reported (Ahlgren et al. 2012b), b-blockade was insufficient to counteract a pronounced increase in longitudinal
displacement of the intima–media complex and resulting intramural shear strain (Figs. 8 and 9). There were no significant correlations between peak WSR and pulse pressure, nor between DWSR and pulse pressure, in any subject (data not shown). Blood pressure data and their relation to the longitudinal displacement of the intima–media complex and intramural shear strain are presented in Ahlgren et al. (2012b).
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Fig. 4. Difference between maximum and minimum wall shear rates during the cardiac cycle (DWSR) of the porcine carotid artery in five subjects (a–e) at baseline; during infusion of epinephrine (A 200 mg/h and A 400 mg/h, respectively); after an additional norepinephrine bolus(es) of 0.1 mg (A 1 NA); during simultaneous infusion of epinephrine and metoprolol, that is, during b-blockade (A 1 b-block); and after an additional bolus(es) of norepinephrine, that is, during bblockade (A 1 b-block 1 NA). Shaded boxes indicate the lower and upper quartiles and the median. Whiskers indicate the minimum and the maximum values (n 5 5, z 5 122). Outliers are indicated by 1. Note the increase in DWSR after administration of epinephrine and norepinephrine, and how this increase is counteracted by b-blockade. Sensitivity to epinephrine differed somewhat among the pigs, and thus, the boxes for epinephrine 200 mg/h, and 400 mg/h, respectively, include shear rates at both lower and higher blood pressures.
DISCUSSION We have illustrated, for the first time, that the recently reported profound changes in longitudinal displacement of the intima–media complex of the arterial wall in response to catecholamines can take place independently of blood flow WSR. In the present study, a large artery (about 4 mm in diameter) was investigated.
Furthermore, the measured shear rates were high (500 s21). The hematocrit in pigs of the age, size and type investigated is, from our experience, about 35%, as supported by Windberger et al. (2003), who investigated the blood of slightly older pigs. Under these conditions, the viscosity can be considered approximately constant. Thus, the WSRs estimated in this study are expected to
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Fig. 5. Longitudinal displacement of the intima–media complex of the porcine carotid artery in relation to peak wall shear rate in five subjects (a–e). There was no significant correlation between longitudinal displacement of the intima–media complex and peak wall shear rate in four of the five subjects. In one subject there was a significant correlation (b). Correlation coefficients (R) and p-values, as well as the slope (k), are given.
be proportional to WSS. The independence of longitudinal displacement of the arterial wall and WSS strongly suggests that one or multiple pulsatile forces other than WSS are also working along the arteries, influencing arterial wall behavior. Identification of these forces will substantially improve our understanding of the cardiovascular system and vascular mechanics.
The WSR and the longitudinal displacement of the intima–media complex of the porcine carotid artery were measured during different hemodynamic situations using a study protocol including intravenous infusion of epinephrine and intravenous bolus doses of norepinephrine, as well as b-blockade (metoprolol). Adrenaline and noradrenaline, the catecholamines, are the major
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Fig. 6. Longitudinal displacement of the intima–media complex of the porcine carotid artery in relation to the difference between maximum and minimum wall shear rates (DWSR) in five subjects (a–e). There was no significant correlation between longitudinal displacement of the intima–media complex and DWSR in four of the five subjects. In one subject there was a possible correlation (b). Correlation coefficients (R) and p-values, as well as the slope (k), are given.
circulating hormones that play a role in the control of vascular tone and underlie the well-known fight-andflight reaction. Catecholamines are also widely used as drugs in intensive care units. Adrenaline is a potent stimulant of a-, b1- and b2-adrenergic receptors, receptors that many cells in the body possess, and its effects on target organs are thus complex. Particularly prominent
are the actions on the heart, where it acts directly on the b1-receptors and on vascular and other smooth muscle. The actions of adrenaline and noradrenaline differ mainly in the ratio of their effectiveness in stimulating a- and b2receptors; noradrenaline is a potent a-agonist and has relatively little effect on b2-receptors. Adrenaline and noradrenaline are approximately equipotent in
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Fig. 7. Relative changes in longitudinal displacement of the intima–media complex of the porcine carotid artery wall in relation to relative changes in the difference between maximum and minimum wall shear rates (DWSR) in all subjects. No significant correlation between longitudinal displacement of the intima–media complex and DWSR was observed.
stimulating b1-receptors (Westfall and Westfall 2005). By use of a very simplified analysis of the effects of a- and b-receptor activation on the vasculature and the heart, activation of a-receptors causes vasoconstriction; activation of b1-receptors increases heart rate and contractility and therefore cardiac output; and activation of b2–receptors causes vasodilation. Metoprolol, also used in this study, is a selective b1-receptor blocker (b1-selective receptor antagonist), widely used in the treatment of hypertension and cardiac diseases.
During the initial intravenous infusion of epinephrine and after additional bolus(es) of norepinephrine, WSR increased compared with baseline. Both epinephrine and norepinephrine activate b1-adrenoceptors on the heart, increasing heart rate and contractility and, therefore, cardiac output. Under a very simplified analysis, this is expected to increase WSR, as seen in this study. However, when the catecholamines were administered during b-blockade, the b-blockade effectively counteracted the increase in WSR, even when boluses of
Fig. 8. Difference between maximum and minimum wall shear rates (DWSR) (C) and previously presented data (Ahlgren et al. 2012b) on the longitudinal displacement (A) of the intima-media complex of the porcine carotid artery at baseline, during infusion of epinephrine (A 200 mg/h and A 400 mg/h, respectively), after an additional norepinephrine bolus(es) of 0.1 mg (A 1 NA); during simultaneous infusion of epinephrine and metoprolol, that is, during b-blockade (A 1 b-block); and after an additional bolus(es) of norepinephrine, that is, during b-blockade (A 1 b-block 1 NA). Solid lines represent mean values of DWSR. Dashed lines represent mean values of the longitudinal displacement. Presented data on shear rate are based on median values of 122 measurements (z 5 30, n 5 5).
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Fig. 9. Original recordings of the WSR profile (solid line) and longitudinal displacement of the intima–media complex (dashed line) of the carotid artery in one pig at baseline (a); after a bolus of norepinephrine during infusion of epinephrine (b); and after a bolus of norepinephrine during infusion of epinephrine and b-blockade (metoprolol) (c). The registrations of wall shear rate and longitudinal displacement were performed at the same position on the vessel, immediately after one another. In the figure, the change in diameter (the diameter change curve) in each recording, measured according to Cinthio et al. (2010) and Nilsson et al. (2012), has been used to synchronize the two recordings (defining end-diastole in the first cardiac cycle shown). Note the difference in WSR between administration of a bolus of norepinephrine without b-blockade (b) and administration of a bolus of norepinephrine during infusion of metoprolol (c). It can be clearly seen that WSR was lower during b-blockade. Thus, metoprolol counteracted the increase in WSR. In contrast, metoprolol was insufficient to counteract a pronounced increase in longitudinal displacement of the intima–media complex of the arterial wall (c). Thus, a pronounced increase in longitudinal displacement of the intima–media complex can take place independently of WSR. WSR 5 Wall sheer rate.
norepinephrine were administered. The selective b1-receptor blocker metoprolol used in this study is known to decrease heart rate and contractility and, therefore, cardiac output. This is expected to counteract the increase in WSR, after infusion of catecholamines, as seen in this study. We found no convincing correlation between longitudinal displacement of the intima–media complex and WSR. This was most obvious when boluses of norepinephrine were administered during b-blockade; metoprolol effectively counteracted the increase in WSR, whereas at the same time, metoprolol was insufficient to counteract a sharp rise in pulse pressure and an accompanying sharp increase in longitudinal displacement and intramural shear strain of the arterial wall. The findings described in this article are in line with our recent findings that the increase in longitudinal displacement of the porcine carotid wall seems to be strongly related to a-adrenoceptor activation and increase in pulse pressure; at the lowest pulse pressures, the longitudinal displacement of the intima–media complex was very small or not detectable, but after a surge of norepinephrine and accompanying high blood pressures, the longitudinal bidirectional displacement of the intima–media complex profoundly increased (Ahlgren et al. 2012b). Our present results are also in line with the findings in a limited in vivo trial on the human CCA (Nilsson et al. 2009) aiming to measure the shear-induced longitudinal elastic modulus of the arterial wall. The results of that study indicated that either the longitudinal elastic modulus of the arterial wall is much lower (1000 times) than the values reported
for exposed vessels in vitro, or WSS is not the only force acting along the arterial wall. Blood vessels are considered to be under the influence of two primary hemodynamic forces: the circumferential force, or wall tension, which originates from the blood pressure, working perpendicular to the wall, and the frictional force, or WSS, which results from the blood flow along the vessel wall, thus working along the arteries. This study clearly indicates that a marked increase in longitudinal displacement of the intima–media complex can take place independently of WSS from blood flow. An important question is thus: What force or forces, if not related to WSS from flowing blood, are responsible for the longitudinal displacement of the arterial wall and its marked changes in response to catecholamines? One hypothesis is that the pulsatile displacement of the heart might contribute to such displacement. It is well known that the base of the heart moves substantially toward the ventricular apex in systole (Simonson and Schiller 1989), and this might have an impact on the aortic arch and its branches. However, it is worth recalling that distinct longitudinal displacement and intramural shear strain are also seen in the human popliteal artery (Cinthio et al. 2006), which is quite a distance from the heart. Moreover, the inner layers of the wall, the intima–media complex, exhibit a larger displacement than the outer layer of the wall, the adventitial region. Another factor to consider is the pulse wave. As stated above, the pulse wave is considered to work perpendicular to the wall. However, in human CCAs, the timing of the different phases of longitudinal displacement in relation
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to the distension of the artery, that is, the diameter change, has shown good agreement with the expected arrival of the pulse wave and reflected pulse wave, respectively (Cinthio et al. 2006). As recently reported (Ahlgren et al. 2012b), the study protocol used resulted in a wide range of arterial blood pressures, and as stated above, in the present experiment we found significant correlations between pulse pressure and longitudinal displacement of the intima–media complex and intramural shear strain, respectively. Another interesting observation is that during strong a-adrenoceptor activation (during higher levels of epinephrine and, especially, after norepinephrine boluses) the pattern of longitudinal displacement changed and became multiphasic (Ahlgren et al. 2012b). There are probably several possible explanations for this. However, taken together this leads to the question of whether the longitudinal displacement of the arterial wall is induced by the pulse wave or by other wave phenomena. Another hypothesis is that smooth muscle cell contraction and/or reorientation at the site of measurement contribute to the longitudinal displacement of the wall. Thus, one interesting question is if a receptors act directly on the carotid artery at the site of measurement, in addition to causing a higher pulse pressure because of the higher peripheral resistance. Other factors likely to be of importance to longitudinal displacements of the arterial wall include the elastic properties and axial prestretch of the arteries, as well as elastic recoil. Tozzi et al. (2001), in a study of pigs using piezoelectric crystals sutured on the artery, reported a significant length reduction in the CCA during the cardiac cycle. Further, there is arterial wall tethering (Hodis and Zamir 2009; Nichols and O’Rourke 2005). Clearly, further studies are needed to clarify these issues. Study limitations In the study described here, the longitudinal displacement was measured using one ultrasound machine (HDI 5000), and the WSR was measured using another one (ULA-OP). Therefore, throughout the experiment, we had to repeatedly change the probe to measure the longitudinal displacement or the WSR at the very same location of the left CCA. This means that our measurements of WSR and longitudinal displacement of the intima–media complex were not simultaneous, although performed immediately one after the other. Having simultaneous measurements is especially important when studying the effect of norepinephrine boluses. Norepinephrine has a very short half-time with a rapid fall in circulating levels when given as a bolus (Westfall and Westfall 2005). Thus, in analysis of the possible relation between shear rate and longitudinal displacement, great care was taken to ensure that the measurements were performed very close to each other when blood pressures
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were at approximately the same level, that is, when the effects of the catecholamines were approximately the same. In vivo estimation of WSS is based on the assumption that the arterial wall is not moving in the longitudinal direction during the cardiac cycle. However, it was previously found that the arterial wall moves in the direction of blood flow and opposite blood flow during different parts of the cardiac cycle; furthermore, the magnitudes of displacements changes. In the present study, the velocity of the blood was far higher than the velocity of the longitudinal displacement of the arterial wall: on the order of 1 m/s compared with about 0.015 m/s (unpublished data). For this reason, the shape of the velocity profile can be assumed to be affected to a very small extent. Hence, the error in the estimation of the WSS can be expected to be negligible (only a few percent). It would be of great interest to be able to separate the intima and the media and to discriminate putative differences in movements between these layers. This was not possible with the present technique and the available probes. Therefore, we chose to describe the movement of an echo in the intima–media complex. The behavior of the intima might differ substantially from that of other wall layers (Cinthio et al. 2006, Zhang et al. 2007). CONCLUSIONS The present study shows, for the first time, that a profound increase in longitudinal displacement of the intima–media complex of the arterial wall can take place independently of WSR and, thus, independently of WSS from the blood flow. This strongly suggests that one or multiple pulsatile forces other than WSS from the blood flow are also working along the arteries, strongly influencing arterial wall behavior. Identification of these factors will substantially improve our understanding of the cardiovascular system and vascular mechanics. Acknowledgments—We thank Mrs. Ann-Kristin J€onsson and Mrs. Elzbieta Krolikowska for skillful technical assistance.—This study was supported by grants from the Swedish Research Council (2009-5519, 2012-3552), the Medical Faculty of Lund University, the Sk ane County Council’s Research and Development Foundation, Funds at Sk ane University Hospital, the Swedish Foundation for International Cooperation in Research and Higher Education (IG2011-2056).
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Shear stress and longitudinal movements of arterial wall d A. R. AHLGREN et al. Boni E, Bassi L, Dallai A, Guidi F, Ramalli A, Ricci S, Housden R, Tortoli P. A Reconfigurable and programmable FPGA based system for non-standard ultrasound methods. IEEE Trans Ultrasound Ferroelectr Freq Control 2012;59:1378–1385. c S. Longitudinal displacement in viscoelastic arteries: A Bukac M, Cani novel fluid-structure interaction computational model, and experimental validation. Math Biosci Eng 2013;10:295–318. c S, Glowinski R, Tambaca J, Quaini A. Fluid–structure Bukac M, Cani interaction in blood flow capturing non-zero longitudinal structure displacement. J Comput Phys 2013;235:515–541. Cinthio M, Ahlgren AR, Bergkvist J, Jansson T, Persson HW, Lindstr€ om K. Longitudinal movements and the resulting shear strain of the arterial wall. Am J Physiol Heart Circ 2006;291:H394–H402. Cinthio M, Ahlgren AR, Jansson T, Eriksson A, Persson HW, Lindstr€ om K. Evaluation of an ultrasonic echo-tracking method for measurements of arterial wall movements in two dimensions. IEEE Trans Ultrason Ferroelectr Freq Control 2005a;52:1300–1311. Cinthio M, Jansson T, Ahlgren AR, Persson HW, Lindstr€om K. New improved and modified method for measurements of arterial wall movements in longitudinal and radial directions. In: Proceedings, IOMP’s 14th International Conference of Medical Physics, Nuremberg, 14–17 September 2005. Proc Biomed Technik 2005b;50 (Suppl vol 1, Pt II):869–870. Cinthio M, Jansson T, Ahlgren AR, Lindstr€om K, Persson HW. A method for arterial diameter change measurements using ultrasonic B-mode data. Ultrasound Med Biol 2010;36:1504–1512. Fukui T, Parker KH, Imai Y, Tsubota K, Ishikawa T, Wada S, Yamaguchi T. Effect of wall motion on arterial wall shear stress. J Biomed Sci Eng 2007;2:58–68. Halliwill JR, Minson T. Retrograde shear: Backwards into the future? Am J Physiol Heart Circ Physiol 2010;298:H1126–H1127. Hodis S, Zamir M. Solutions of the Maxwell viscoelastic equations for displacement and stress distributions within the arterial wall. Phys Rev E 2008;78:021914. Hodis S, Zamir M. Arterial wall tethering as a distant boundary condition. Phys Rev E 2009;80:051913. Hodis S, Zamir M. Coupled radial and longitudinal displacements and stresses within the arterial wall in pulsatile flow under tethered and free-wall conditions. Phys Rev E 2011a;83:051923. Hodis S, Zamir M. Mechanical events within the arterial wall under the forces of pulsatile flow: A review. J Mech Behav Biomed Mater 2011b;4:1595–1602. Idzenga T, Holewijn S, Hansen HHG, de Korte CL. Estimating cyclic shear strain in the common carotid artery using radiofrequency ultrasound. Ultrasound Med Biol 2012;38:2229–2237. Nichols WW, O’Rourke MF. McDonald’s blood flow in arteries: Theoretical, experimental and clinical principles. 5th ed. London: Arnold; 2005. Nilsson T, Ricci S, Ahlgren AR, Janson T, Lindstr€om K, Tortoli P, Persson HWP, Cinthio M. Methods for measurements of the longitudinal movement and the shear induced longitudinal elastic modulus of the arterial wall. Proc IEEE Ultrason Symp 2009;317–320. € Nilsson T., Segstedt S., Ahlgren A.R., Ricci S., Ostling G., Tortoli P., Nilsson J., Jansson T., Persson H. W. and Cinthio M., A robust and fast method for arterial lumen diameter and intima-media thickness measurements, 2012 IEEE Ultrasonics Symposium Proceedings, Dresda, Ottobre 2012, DOI: 10.1109/ULTSYM. 2012.0421, pp. 1678-1681.
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Persson M, Ahlgren AR, Eriksson A, Jansson T, Persson HW, Lindstr€om K. Non-invasive measurement of arterial longitudinal movement. Proc IEEE Ultrason Symp 2002;2:1739–1742. Persson M, Ahlgren AR, Jansson T, Eriksson A, Persson HW, Lindstr€om K. A new non-invasive ultrasonic method for simultaneous measurements of longitudinal and radial arterial wall movements: First in vivo trial. Clin Physiol Funct Imaging 2003;23: 247–251. Simonson JS, Schiller NB. Descent of the base of the left ventricle: An echocardiographic index of left ventricular function. J Am Soc Echocardiogr 1989;2:25–35. Svedlund S, Eklund C, Robertsson P, Lomsky M, Gan LM. Carotid artery longitudinal displacement predicts 1-year cardiovascular outcome in patients with suspected coronary artery disease. Arterioscler Thromb Vasc Biol 2011;31:1668–1674. Svedlund S, Gan LM. Longitudinal common carotid artery wall motion is associated with plaque burden in man and mouse. Atherosclerosis 2011;217:120–124. Tortoli P, Bassi L, Dallai A, Guidi F, Ricci S. ULA-OP: An advanced open platform for ultrasound research. IEEE Trans Ultrason Ferroelect Freq Control 2009;566:2207–2216. Tortoli P, Morganti T, Bambi G, Palombo C, Ramnarine KV. Noninvasive simultaneous assessment of wall shear rate and wall distension in carotid arteries. Ultrasound Med Biol 2006;32:1661–1670. Tortoli P, Palombo C, Ghiadoni L, Bini G, Francalanci L. Simultaneous ultrasound assessment of brachial artery shear stimulus and flowmediated dilation during reactive hyperemia. Ultrasound Med Biol 2011;37:1561–1570. Tozzi P, Hayoz D, Oedman C, Mallabiabarrena I, von Segesser LK. Systolic axial artery length reduction: An overlooked phenomenon in vivo. Am J Physiol Heart Circ Physiol 2001;280:H2300–H2305. Warriner R, Johnston KW, Cobbold RSC. A viscoelastic model of arterial wall motion in pulsatile flow: Implications for Doppler ultrasound clutter assessment. Physiol Meas 2008;29:157–179. Westfall TC, Westfall DP. Adrenergic agonists and antagonists. In: Brunton L, Chabner B, Knollman B, (eds). Goodman and Gilman’s the pharmacological basis of therapeutics. 11th ed. New York: McGraw-Hill; 2005. p. 237–249. Windberger U, Bartholovitsch A, Plasenzotti R, Korak KJ, Heinze G. Whole blood viscosity, plasma viscosity and erythrocyte aggregation in nine mammalian species: Reference values and comparison of data. Exp Physiol 2003;88:431–440. Yli-Ollila H, Laitinen T, Weckstr€om M, Laitinen TM. Axial and radial waveforms in common carotid artery: An advanced method for studying arterial elastic properties in ultrasound imaging. Ultrasound Med Biol 2013;39:1168–1177. Zahnd G, Boussel L, Marion A, Durand M, Moulin P, Serusclat A, Vray D. Measurement of two-dimensional movement parameters of the carotid artery wall for early detection of arteriosclerosis: A preliminary clinical study. Ultrasound Med Biol 2011;37:1421–1429. Zahnd G, Vray D, Serusclat A, Alibay D, Bartold M, Brown A, Durand M, Jamieson LM, Kapellas K, Maple-Brown LJ, O’Dea K, Moulin P, Celermajer DS, Skilton MR. Longitudinal displacement of the carotid wall and cardiovascular risk factors: Associations with aging, adiposity, blood pressure and periodontal disease independent of cross-sectional distensibility and intima-media thickness. Ultrasound Med Biol 2012;38:1705–1715. Zhang W, Liu Y, Kassab GS. Flow-induced shear strain in intima of porcine coronary arteries. J Appl Physiol 2007;103:587–593.
http://dx.doi.org/10.1016/j.ultrasmedbio.2015.01.005
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Original Contribution PROFOUND INCREASE IN LONGITUDINAL DISPLACEMENTS OF THE PORCINE CAROTID ARTERY WALL CAN TAKE PLACE INDEPENDENTLY OF WALL SHEAR STRESS: A CONTINUATION REPORT z OM , ASA RYDEN AHLGREN,* STIG STEEN,y SIMON SEGSTEDT,z TOBIAS ERLO€V,z KJELL LINDSTR€ €BERG,y HANS W. PERSSON,z STEFANO RICCI,x PIERO TORTOLI,x and MAGNUS CINTHIOz TRYGVE SJO
* Clinical Physiology and Nuclear Medicine Unit, Department of Clinical Sciences, Lund University, Malm€ o, Sweden; Department of Thoracic Surgery, Sk ane University Hospital, Lund University, Lund, Sweden; z Biomedical Engineering, Faculty of Engineering, LTH, Lund University, Lund, Sweden; and x Information Engineering Department, University of Florence, Florence, Italy
y
(Received 12 October 2014; revised 17 December 2014; in final form 16 January 2015)
Abstract—The mechanisms underlying longitudinal displacements of the arterial wall, that is, displacements of the wall layers along the artery, and the resulting intramural shear strain remain largely unknown. We have already found that these displacements undergo profound changes in response to catecholamines. Wall shear stress, closely related to wall shear rate, represents the viscous drag exerted on the vessel wall by flowing blood. The aim of the work described here was to study possible relations between the wall shear rate and the longitudinal displacements. We investigated the carotid arteries of five anesthetized pigs in different hemodynamic situations using in-house developed non-invasive ultrasound techniques. The study protocol included administration of epinephrine, norepinephrine and b-blockade (metoprolol). No significant correlation between longitudinal displacement of the intima–media complex and wall shear rate was found. This result suggests that one or multiple pulsatile forces other than wall shear stress are also working along arteries, strongly influencing arterial wall behavior. (E-mail: [email protected]) Ó 2015 World Federation for Ultrasound in Medicine & Biology. Key Words: Wall shear rate, Wall shear stress, Longitudinal movement, Arterial wall, Epinephrine, Norepinephrine, Catecholamines.
human arteries, the inner layers of the arterial wall, that is, the intima–media complex, move not only in the radial direction, but also in the longitudinal direction, that is, along the artery, during the cardiac cycle (Persson et al. 2002, 2003). To study this phenomenon, our group developed a non-invasive ultrasonic method for simultaneous high-resolution recording of both the longitudinal and radial movements of the arterial wall in vivo (Cinthio et al. 2005a, 2005b). Using this method, we have found that the longitudinal displacement of the intima–media complex is of the same magnitude as the well-known diameter change during the cardiac cycle (Cinthio et al. 2006). Importantly, we have also illustrated that the adventitial region exhibits the same basic pattern of longitudinal displacement, although the magnitude of the displacement is smaller. This means that intramural shear strain, and thus shear stress, is present (Cinthio et al. 2006). We have reported that this phenomenon can be detected in the carotid, popliteal and brachial arteries, as well as in the abdominal aorta, and thus seems
INTRODUCTION Cardiovascular disease is still a major cause of morbidity and mortality in the Western world. It is, therefore, essential to increase our knowledge of the cardiovascular system and cardiovascular diseases. Hemodynamic forces are considered important modulators of vascular tone and vascular remodeling and are increasingly implicated in atherogenesis. The longitudinal displacement of arteries, that is, the displacement along the artery, has for many years been assumed to be negligible compared with the radial displacement, that is, the diameter change (Nichols and O’Rourke 2005). However, by using modern ultrasound scanners it can be observed that in large Address correspondence to: Asa Ryden Ahlgren, Department of Clinical Physiology, DC, Inga Marie Nilssons gata 49, 3rd Floor, Sk ane University Hospital, SE-205 02 Malm€o, Sweden. E-mail: Asa. [email protected] Conflict of Interest: No conflicts of interest, financial or otherwise, are declared by the authors. 1342
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to be a general phenomenon in large human arteries (Cinthio et al. 2006). Substantial longitudinal displacements of the human carotid artery wall have recently been confirmed with other in-house developed ultrasonic techniques (Idzenga et al. 2012; Yli-Ollila et al. 2013; Zahnd et al. 2011). We have also recently reported that the longitudinal displacement of the common carotid artery (CCA) of healthy humans at rest can exhibit dramatically different patterns, also in patients of the same age and gender, and that these patterns of displacement are stable over a 4-mo period (Ahlgren et al. 2012a), thus raising the question: Is the pattern of the longitudinal displacement of the arterial wall a valuable marker for future risk for cardiovascular disease (Ahlgren et al. 2012a)? Recent studies reporting that the amplitude of the longitudinal displacement of the arterial wall is reduced in patients with carotid plaques, suspected coronary artery disease and type 2 diabetes (Svedlund and Gan 2011; Svedlund et al. 2011; Zahnd et al. 2011), as well as in patients with periodontal disease (Zahnd et al. 2012), suggest a positive answer to such a question. Changes in longitudinal displacement and intramural shear strain of the arterial wall have the potential to alter endothelial shear (Cinthio et al. 2006; Halliwill and Minson 2010) and to influence the circulation of the vasa vasorum, as well as the smooth muscles and the extracellular matrix in the media (Cinthio et al. 2006). In a study on the porcine carotid artery, we recently reported that the longitudinal displacements and intramural shear strain undergo profound changes in response to catecholamines, that is, our stress hormones epinephrine (adrenalin) and norepinephrine (noradrenalin), and changes in blood pressures (Ahlgren et al. 2012b). In many cases, the longitudinal displacement of the intima–media complex increased more than 200%. These findings might have important implications for vascular disease in both the short term and the long term, constituting a possible link between mental stress and cardiovascular disease and also indicating a possible influence in the context of atherosclerotic plaque rupture (Ahlgren et al. 2012b). However, the mechanisms underlying the longitudinal displacement and resulting intramural shear strain of the arterial wall are largely unknown, and the possible implications for cardiovascular disease are still unclear. Wall shear stress (WSS), given by the product of wall shear rate (WSR), that is, the blood velocity gradient at the vessel walls, and blood viscosity, represents the viscous drag exerted on the vessel wall by the flowing blood. WSS has important roles in acute adaptations to flow changes and vascular remodeling and in the development of atherosclerosis. Because WSS acts along the arteries, an obvious hypothesis is that WSS is an important factor
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in the longitudinal displacement of the arterial wall. The mechanical events within the arterial wall under the forces of pulsatile flow are currently being studied using mathe c 2013; matical models and simulations (Bukac and Cani Bukac et al. 2013; Fukui et al. 2007, Hodis and Zamir 2008, 2011a, 2011b; Warriner et al. 2008). The relation between WSS and the longitudinal displacement of the arterial wall has, however, not been addressed in vivo. Further, there are few non-invasive in vivo studies of WSR, and WSS, during different hemodynamic situations. The aim of the present work was, therefore, to study possible relations between WSR and longitudinal displacement of the arterial wall by investigating the response of the porcine common carotid artery to different hemodynamic situations. WSR was measured using the multigated spectral Doppler technique (Tortoli et al. 2006, 2011), implemented in the research system ULA-OP (Boni et al. 2012). The study protocol included intravenous infusion of epinephrine, intravenous boluses of norepinephrine, as well as b-blockade (using the b1-selective receptor antagonist metoprolol). The results of the WSR measurements are analyzed in relation to the recently presented data from measurements of the longitudinal displacement of the arterial wall (Ahlgren et al. 2012b). METHODS Material As recently reported (Ahlgren et al. 2012b), five 4mo-old pigs weighing 25 kg were used for this study. The study was approved by the Animal Research Ethics Committee, Lund University. Anesthesia was induced with an intramuscular injection of ketamine (30 mg/kg) and xylasin (4 mg/kg). Sodium thiopental (5–8 mg/kg) and atropine (0.015 mg/kg) were given intravenously before tracheotomy. Anesthesia and muscular paralysis were maintained with a continuous infusion of 10 mL/h NaCl (0.9%) solution containing ketamine (16 mg/mL) and pancuronium (0.6 mg/mL). After induction of anesthesia, the animals were tracheotomized and ventilated with pressure-regulated, volume controlled normoventilation (Servo Ventilator 300, Siemens, Solna, Sweden). Electrocardiogram (ECG), PaO2, PCO2 and O2 saturation were monitored. Blood pressure was continuously recorded intra-arterially (TestPoint, Capital Equipment, Billerica, MA, USA) in the right CCA. Body temperature was monitored using a thermistor in the esophagus. The temperature in the laboratory was kept constant. Measurements of wall shear rate Measurements were performed using ULA-OP, an advanced open platform for ultrasound research (Tortoli et al. 2009), connected to the LA523 probe (Esaote,
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Table 1. Study protocol for intravenously administered drugs* Order of administration 0 1 2 3 4 5
Drug ‘‘Baseline’’ Epinephrine infusion (low dose) Epinephrine infusion (higher dose) Epinephrine infusion 1 norepinephrine boluses 3 2 Epinephrine infusion 1 metoprolol Epinephrine infusion 1 metoprolol 1 norepinephrine boluses 3 2
* Exact doses are given in the text.
surements were performed using a commercial ultrasound system (HDI 5000, Philips Medical Systems, ATL Ultrasound, Bothell, WA, USA), equipped with a 38-mm 5- to 12-MHz linear array transducer. The image data were transferred to a PC for post-processing via HDI Laboratory (Philips Medical Systems, ATL Ultrasound, Bothell, WA, USA). During the recordings, the vessel was scanned in the longitudinal direction. The method used for measurements of the longitudinal movement (Cinthio et al. 2005a, 2005b) was implemented in MATLAB (The MathWorks, Natick, MA, USA).
Fig. 1. Schematic of the ultrasonic measurement of wall shear rate and longitudinal displacement of the intima–media complex of the porcine carotid artery. The white curve in the vessel lumen represents the blood flow profile used for measurement of wall shear rate. The box at the far wall represents the region selected for measurement of the longitudinal displacement of the intima–media complex.
Florence, Italy). The WSR was estimated from the multigated spectral Doppler data obtained from hundreds of small sample volumes aligned along an M-line intercepting the investigated vessel. The mean Doppler frequency was estimated for each sample volume and converted to velocity using the Doppler equation. This produced the velocity profile across the vessel, which was finally differentiated for WSR calculation, as described in Tortoli et al. (2006). Measurements of longitudinal displacement of the arterial wall The longitudinal displacement of the intima–media complex was measured using B-mode ultrasound as recently described (Ahlgren et al. 2012b). These mea-
Study protocol All measurements were performed with the pig lying on its back. WSR and longitudinal displacement of the intima–media complex of the left CCA were measured. Two experienced ultrasound technicians performed all the registrations, one recording the WSR and the other the longitudinal displacement. The measurements were performed at the same position on the vessel, immediately after each other. Care was taken to minimize the pressure of the transducers. Figure 1 is an ultrasonic B-mode image on which measurements of the longitudinal movement of the arterial wall were performed. The flow profile used to estimate the shear rate is schematically outlined. The study protocol is outlined in Table 1. After anesthesia was induced, three recordings of WSR and of longitudinal displacements of the CCA intima–media complex were performed (‘‘baseline’’). Next, epinephrine (adrenalin) was administered intravenously using a pump with an initial dose of 200 mg/h. After plateaus in blood pressure and heart rate were reached, the dose of epinephrine was increased to 400 mg/h. Depending on the responses in blood pressures and heart rate, the dose was in one case again lowered to 200 mg/h. At each level, repeated recordings of arterial wall movements and WSR were performed. Next, during continuous infusion of epinephrine, an intravenous bolus of 0.1 mg norepinephrine
Shear stress and longitudinal movements of arterial wall d A. R. AHLGREN et al.
(noradrenalin) was administered. Immediately after the bolus, repeated recordings of the arterial wall movements and WSR were performed for 5 min. About 10 min after the initial bolus of norepinephrine, that is, when its effect had waned, another intravenous bolus of 0.1 mg norepinephrine was administered, and arterial wall movements and WSR were again immediately repeatedly recorded. At least 10 min after the last bolus dose of norepinephrine, still during continuous intravenous infusion of epinephrine, an intravenous infusion of metoprolol 25 mg/h was started. To ensure as complete a b-blockade as possible, a bolus of 5 mg metoprolol was also given intravenously. Depending on the response (or lack of response), a second bolus of metoprolol was in some cases administered to ensure b-blockade. After about 3 min, the arterial wall movements and WSR were again repeatedly recorded. Next, during continuous simultaneous intravenous infusion of epinephrine and metoprolol, that is, during b-blockade, a bolus of 0.1 mg norepinephrine was administered intravenously. Immediately after administration of the bolus, WSR and arterial wall movements were repeatedly recorded. After another 10 min, still during continuous infusions of epinephrine and metoprolol, another bolus of norepinephrine was administered, and WSR and arterial wall movements were again repeatedly recorded. Statistics Least-squares regression analysis with calculation of Pearson’s product–moment correlation coefficient was used to evaluate the relations between WSR, longitudinal displacement and pulse pressure, respectively. p , 0.05 was taken as significant. Data are presented as the mean value 6 standard deviation (SD), unless otherwise stated. RESULTS Baseline Figure 2 is a typical WSR recording from the CCA of one pig at baseline, that is, when the pig was anesthetized, but before the administration of epinephrine. In the subjects studied, the mean peak (maximum) WSR was 1396 6 313 s21. The mean difference between the maximum and minimum WSRs (DWSR) during the cardiac cycle was 1105 6 365 s21. Wall shear rate during administration of catecholamines and b-blocker Figure 3(a–e) illustrates the changes in peak WSR in the individual subjects at baseline; during infusion of epinephrine (200 and 400 mg/h, respectively); after an additional norepinephrine bolus(es) of 0.1 mg; during
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Fig. 2. Wall shear rate profile recorded in the common carotid artery of a 4-mo-old pig at baseline, that is, after anesthesia was induced, but before administration of epinephrine. The maximum (peak) wall shear rate and the difference between the maximum and minimum wall shear rates (DWSR) were evaluated. B 5 peak and minimum wall shear rates used in the calculations.
simultaneous infusion of epinephrine and metoprolol, that is, during b-blockade; and after an additional bolus(es) of norepinephrine, that is, during b-blockade. Further, the corresponding changes in DWSR in the individual subjects are illustrated in Figure 4(a–e). During intravenous infusion of epinephrine, as well as after administration of boluses of norepinephrine, the peak WSR, as well as DWSR, increased in all subjects. However, when catecholamines were administered during b-blockade, b-blockade effectively counteracted the increase in WSR, as it also did when boluses of norepinephrine were administered.
Wall shear rate and longitudinal displacement of the intima–media complex The measurements of the longitudinal displacement of the intima-media complex (Ahlgren et al. 2012b) have now been analyzed in relation to the measurements of WSR. In four of five subjects, there were no significant correlations between peak WSR and longitudinal displacement of the intima–media complex (Fig. 5a–e). In one subject there was a positive correlation (R 5 0.47, p 5 0.03). In four of five subjects, there were no significant correlations between DWSR and longitudinal displacement of the intima–media complex (Fig. 6a–e). In one subject (the same as above), there was a possible correlation (R 5 0.43, p 5 0.05). Figure 7 illustrates the relative changes in longitudinal displacement of the intima–media complex in relation to the relative changes in DWSR rate in all subjects. No significant correlation between longitudinal
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Fig. 3. Peak WSR of the porcine carotid artery in five subjects (a–e) at baseline; during infusion of epinephrine (A 200 mg/ h and A 400 mg/h, respectively); after an additional norepinephrine bolus(es) of 0.1 mg (A 1 NA); during simultaneous infusion of epinephrine and metoprolol, that is, during b-blockade (A 1 b-block); and after an additional bolus(es) of norepinephrine, that is, during b-blockade (A 1 b-block 1 NA). Shaded boxes indicate the lower and upper quartiles and the median. Whiskers indicate the minimum and maximum values (n 5 5, z 5 122). Outliers are indicated by 1. Note the increase in peak WSR after administration of epinephrine and norepinephrine, and how this increase is counteracted by b-blockade. Sensitivity to epinephrine differed somewhat among the pigs; thus, the boxes for epinephrine 200 mg/h and 400 mg/h, respectively, include shear rates at both lower and higher blood pressures. WSR 5 wall shear rate.
displacement of the intima–media complex and DWSR was seen. The lack of correlation between WSR and longitudinal displacement of the intima–media complex was especially evident after administration of boluses of norepinephrine during b-blockade; b-blockade effectively counteracted increases in WSR, whereas, as recently reported (Ahlgren et al. 2012b), b-blockade was insufficient to counteract a pronounced increase in longitudinal
displacement of the intima–media complex and resulting intramural shear strain (Figs. 8 and 9). There were no significant correlations between peak WSR and pulse pressure, nor between DWSR and pulse pressure, in any subject (data not shown). Blood pressure data and their relation to the longitudinal displacement of the intima–media complex and intramural shear strain are presented in Ahlgren et al. (2012b).
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Fig. 4. Difference between maximum and minimum wall shear rates during the cardiac cycle (DWSR) of the porcine carotid artery in five subjects (a–e) at baseline; during infusion of epinephrine (A 200 mg/h and A 400 mg/h, respectively); after an additional norepinephrine bolus(es) of 0.1 mg (A 1 NA); during simultaneous infusion of epinephrine and metoprolol, that is, during b-blockade (A 1 b-block); and after an additional bolus(es) of norepinephrine, that is, during bblockade (A 1 b-block 1 NA). Shaded boxes indicate the lower and upper quartiles and the median. Whiskers indicate the minimum and the maximum values (n 5 5, z 5 122). Outliers are indicated by 1. Note the increase in DWSR after administration of epinephrine and norepinephrine, and how this increase is counteracted by b-blockade. Sensitivity to epinephrine differed somewhat among the pigs, and thus, the boxes for epinephrine 200 mg/h, and 400 mg/h, respectively, include shear rates at both lower and higher blood pressures.
DISCUSSION We have illustrated, for the first time, that the recently reported profound changes in longitudinal displacement of the intima–media complex of the arterial wall in response to catecholamines can take place independently of blood flow WSR. In the present study, a large artery (about 4 mm in diameter) was investigated.
Furthermore, the measured shear rates were high (500 s21). The hematocrit in pigs of the age, size and type investigated is, from our experience, about 35%, as supported by Windberger et al. (2003), who investigated the blood of slightly older pigs. Under these conditions, the viscosity can be considered approximately constant. Thus, the WSRs estimated in this study are expected to
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Fig. 5. Longitudinal displacement of the intima–media complex of the porcine carotid artery in relation to peak wall shear rate in five subjects (a–e). There was no significant correlation between longitudinal displacement of the intima–media complex and peak wall shear rate in four of the five subjects. In one subject there was a significant correlation (b). Correlation coefficients (R) and p-values, as well as the slope (k), are given.
be proportional to WSS. The independence of longitudinal displacement of the arterial wall and WSS strongly suggests that one or multiple pulsatile forces other than WSS are also working along the arteries, influencing arterial wall behavior. Identification of these forces will substantially improve our understanding of the cardiovascular system and vascular mechanics.
The WSR and the longitudinal displacement of the intima–media complex of the porcine carotid artery were measured during different hemodynamic situations using a study protocol including intravenous infusion of epinephrine and intravenous bolus doses of norepinephrine, as well as b-blockade (metoprolol). Adrenaline and noradrenaline, the catecholamines, are the major
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Fig. 6. Longitudinal displacement of the intima–media complex of the porcine carotid artery in relation to the difference between maximum and minimum wall shear rates (DWSR) in five subjects (a–e). There was no significant correlation between longitudinal displacement of the intima–media complex and DWSR in four of the five subjects. In one subject there was a possible correlation (b). Correlation coefficients (R) and p-values, as well as the slope (k), are given.
circulating hormones that play a role in the control of vascular tone and underlie the well-known fight-andflight reaction. Catecholamines are also widely used as drugs in intensive care units. Adrenaline is a potent stimulant of a-, b1- and b2-adrenergic receptors, receptors that many cells in the body possess, and its effects on target organs are thus complex. Particularly prominent
are the actions on the heart, where it acts directly on the b1-receptors and on vascular and other smooth muscle. The actions of adrenaline and noradrenaline differ mainly in the ratio of their effectiveness in stimulating a- and b2receptors; noradrenaline is a potent a-agonist and has relatively little effect on b2-receptors. Adrenaline and noradrenaline are approximately equipotent in
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Fig. 7. Relative changes in longitudinal displacement of the intima–media complex of the porcine carotid artery wall in relation to relative changes in the difference between maximum and minimum wall shear rates (DWSR) in all subjects. No significant correlation between longitudinal displacement of the intima–media complex and DWSR was observed.
stimulating b1-receptors (Westfall and Westfall 2005). By use of a very simplified analysis of the effects of a- and b-receptor activation on the vasculature and the heart, activation of a-receptors causes vasoconstriction; activation of b1-receptors increases heart rate and contractility and therefore cardiac output; and activation of b2–receptors causes vasodilation. Metoprolol, also used in this study, is a selective b1-receptor blocker (b1-selective receptor antagonist), widely used in the treatment of hypertension and cardiac diseases.
During the initial intravenous infusion of epinephrine and after additional bolus(es) of norepinephrine, WSR increased compared with baseline. Both epinephrine and norepinephrine activate b1-adrenoceptors on the heart, increasing heart rate and contractility and, therefore, cardiac output. Under a very simplified analysis, this is expected to increase WSR, as seen in this study. However, when the catecholamines were administered during b-blockade, the b-blockade effectively counteracted the increase in WSR, even when boluses of
Fig. 8. Difference between maximum and minimum wall shear rates (DWSR) (C) and previously presented data (Ahlgren et al. 2012b) on the longitudinal displacement (A) of the intima-media complex of the porcine carotid artery at baseline, during infusion of epinephrine (A 200 mg/h and A 400 mg/h, respectively), after an additional norepinephrine bolus(es) of 0.1 mg (A 1 NA); during simultaneous infusion of epinephrine and metoprolol, that is, during b-blockade (A 1 b-block); and after an additional bolus(es) of norepinephrine, that is, during b-blockade (A 1 b-block 1 NA). Solid lines represent mean values of DWSR. Dashed lines represent mean values of the longitudinal displacement. Presented data on shear rate are based on median values of 122 measurements (z 5 30, n 5 5).
Shear stress and longitudinal movements of arterial wall d A. R. AHLGREN et al.
a
b
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Fig. 9. Original recordings of the WSR profile (solid line) and longitudinal displacement of the intima–media complex (dashed line) of the carotid artery in one pig at baseline (a); after a bolus of norepinephrine during infusion of epinephrine (b); and after a bolus of norepinephrine during infusion of epinephrine and b-blockade (metoprolol) (c). The registrations of wall shear rate and longitudinal displacement were performed at the same position on the vessel, immediately after one another. In the figure, the change in diameter (the diameter change curve) in each recording, measured according to Cinthio et al. (2010) and Nilsson et al. (2012), has been used to synchronize the two recordings (defining end-diastole in the first cardiac cycle shown). Note the difference in WSR between administration of a bolus of norepinephrine without b-blockade (b) and administration of a bolus of norepinephrine during infusion of metoprolol (c). It can be clearly seen that WSR was lower during b-blockade. Thus, metoprolol counteracted the increase in WSR. In contrast, metoprolol was insufficient to counteract a pronounced increase in longitudinal displacement of the intima–media complex of the arterial wall (c). Thus, a pronounced increase in longitudinal displacement of the intima–media complex can take place independently of WSR. WSR 5 Wall sheer rate.
norepinephrine were administered. The selective b1-receptor blocker metoprolol used in this study is known to decrease heart rate and contractility and, therefore, cardiac output. This is expected to counteract the increase in WSR, after infusion of catecholamines, as seen in this study. We found no convincing correlation between longitudinal displacement of the intima–media complex and WSR. This was most obvious when boluses of norepinephrine were administered during b-blockade; metoprolol effectively counteracted the increase in WSR, whereas at the same time, metoprolol was insufficient to counteract a sharp rise in pulse pressure and an accompanying sharp increase in longitudinal displacement and intramural shear strain of the arterial wall. The findings described in this article are in line with our recent findings that the increase in longitudinal displacement of the porcine carotid wall seems to be strongly related to a-adrenoceptor activation and increase in pulse pressure; at the lowest pulse pressures, the longitudinal displacement of the intima–media complex was very small or not detectable, but after a surge of norepinephrine and accompanying high blood pressures, the longitudinal bidirectional displacement of the intima–media complex profoundly increased (Ahlgren et al. 2012b). Our present results are also in line with the findings in a limited in vivo trial on the human CCA (Nilsson et al. 2009) aiming to measure the shear-induced longitudinal elastic modulus of the arterial wall. The results of that study indicated that either the longitudinal elastic modulus of the arterial wall is much lower (1000 times) than the values reported
for exposed vessels in vitro, or WSS is not the only force acting along the arterial wall. Blood vessels are considered to be under the influence of two primary hemodynamic forces: the circumferential force, or wall tension, which originates from the blood pressure, working perpendicular to the wall, and the frictional force, or WSS, which results from the blood flow along the vessel wall, thus working along the arteries. This study clearly indicates that a marked increase in longitudinal displacement of the intima–media complex can take place independently of WSS from blood flow. An important question is thus: What force or forces, if not related to WSS from flowing blood, are responsible for the longitudinal displacement of the arterial wall and its marked changes in response to catecholamines? One hypothesis is that the pulsatile displacement of the heart might contribute to such displacement. It is well known that the base of the heart moves substantially toward the ventricular apex in systole (Simonson and Schiller 1989), and this might have an impact on the aortic arch and its branches. However, it is worth recalling that distinct longitudinal displacement and intramural shear strain are also seen in the human popliteal artery (Cinthio et al. 2006), which is quite a distance from the heart. Moreover, the inner layers of the wall, the intima–media complex, exhibit a larger displacement than the outer layer of the wall, the adventitial region. Another factor to consider is the pulse wave. As stated above, the pulse wave is considered to work perpendicular to the wall. However, in human CCAs, the timing of the different phases of longitudinal displacement in relation
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to the distension of the artery, that is, the diameter change, has shown good agreement with the expected arrival of the pulse wave and reflected pulse wave, respectively (Cinthio et al. 2006). As recently reported (Ahlgren et al. 2012b), the study protocol used resulted in a wide range of arterial blood pressures, and as stated above, in the present experiment we found significant correlations between pulse pressure and longitudinal displacement of the intima–media complex and intramural shear strain, respectively. Another interesting observation is that during strong a-adrenoceptor activation (during higher levels of epinephrine and, especially, after norepinephrine boluses) the pattern of longitudinal displacement changed and became multiphasic (Ahlgren et al. 2012b). There are probably several possible explanations for this. However, taken together this leads to the question of whether the longitudinal displacement of the arterial wall is induced by the pulse wave or by other wave phenomena. Another hypothesis is that smooth muscle cell contraction and/or reorientation at the site of measurement contribute to the longitudinal displacement of the wall. Thus, one interesting question is if a receptors act directly on the carotid artery at the site of measurement, in addition to causing a higher pulse pressure because of the higher peripheral resistance. Other factors likely to be of importance to longitudinal displacements of the arterial wall include the elastic properties and axial prestretch of the arteries, as well as elastic recoil. Tozzi et al. (2001), in a study of pigs using piezoelectric crystals sutured on the artery, reported a significant length reduction in the CCA during the cardiac cycle. Further, there is arterial wall tethering (Hodis and Zamir 2009; Nichols and O’Rourke 2005). Clearly, further studies are needed to clarify these issues. Study limitations In the study described here, the longitudinal displacement was measured using one ultrasound machine (HDI 5000), and the WSR was measured using another one (ULA-OP). Therefore, throughout the experiment, we had to repeatedly change the probe to measure the longitudinal displacement or the WSR at the very same location of the left CCA. This means that our measurements of WSR and longitudinal displacement of the intima–media complex were not simultaneous, although performed immediately one after the other. Having simultaneous measurements is especially important when studying the effect of norepinephrine boluses. Norepinephrine has a very short half-time with a rapid fall in circulating levels when given as a bolus (Westfall and Westfall 2005). Thus, in analysis of the possible relation between shear rate and longitudinal displacement, great care was taken to ensure that the measurements were performed very close to each other when blood pressures
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were at approximately the same level, that is, when the effects of the catecholamines were approximately the same. In vivo estimation of WSS is based on the assumption that the arterial wall is not moving in the longitudinal direction during the cardiac cycle. However, it was previously found that the arterial wall moves in the direction of blood flow and opposite blood flow during different parts of the cardiac cycle; furthermore, the magnitudes of displacements changes. In the present study, the velocity of the blood was far higher than the velocity of the longitudinal displacement of the arterial wall: on the order of 1 m/s compared with about 0.015 m/s (unpublished data). For this reason, the shape of the velocity profile can be assumed to be affected to a very small extent. Hence, the error in the estimation of the WSS can be expected to be negligible (only a few percent). It would be of great interest to be able to separate the intima and the media and to discriminate putative differences in movements between these layers. This was not possible with the present technique and the available probes. Therefore, we chose to describe the movement of an echo in the intima–media complex. The behavior of the intima might differ substantially from that of other wall layers (Cinthio et al. 2006, Zhang et al. 2007). CONCLUSIONS The present study shows, for the first time, that a profound increase in longitudinal displacement of the intima–media complex of the arterial wall can take place independently of WSR and, thus, independently of WSS from the blood flow. This strongly suggests that one or multiple pulsatile forces other than WSS from the blood flow are also working along the arteries, strongly influencing arterial wall behavior. Identification of these factors will substantially improve our understanding of the cardiovascular system and vascular mechanics. Acknowledgments—We thank Mrs. Ann-Kristin J€onsson and Mrs. Elzbieta Krolikowska for skillful technical assistance.—This study was supported by grants from the Swedish Research Council (2009-5519, 2012-3552), the Medical Faculty of Lund University, the Sk ane County Council’s Research and Development Foundation, Funds at Sk ane University Hospital, the Swedish Foundation for International Cooperation in Research and Higher Education (IG2011-2056).
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