In Vivo Association Between Low Wall Shear Stress and Plaque in Subjects With Asymmetrical Carotid Atherosclerosis
Background and Purpose It is known that atherosclerosis does not involve both carotid arteries to the same extent. Pathological investigations have demonstrated that lesions develop in regions of low wall shear stress. The aims of the present study were to verify the degree of carotid atherosclerosis asymmetry in a population-based study and to evaluate whether wall shear stress is lower in carotids with atherosclerotic lesions than in carotids without lesions.
Methods Participants in a cardiovascular disease prevention campaign (n=1166) were screened for carotid atherosclerosis by echo-Doppler examination. Of these, 23 subjects who presented plaque in the common carotid or bulb of one side and no plaque in the contralateral carotid tree were enrolled for common carotid wall shear stress measurement. Shear stress was calculated according to the following formula: Shear Stress=Blood Viscosity×Blood Velocity/Internal Diameter.
Results Of the 1166 subjects screened, 400 (34%) had plaque and/or stenosis in the carotids. Ninety subjects had lesions exclusively in the right carotid, 111 had lesions exclusively in the left, 70 had lesions in both carotids but with different degrees of severity, and only 129 had similar lesions in both carotids. In the 23 subjects in whom wall shear stress was measured, peak shear stress was 18.7±4.1 and 15.3±4.0 dynes·cm−2 (mean±SD) (P<.0001) in the side without and the side with plaque, respectively. Mean shear stress yielded similar results.
Conclusions The present results demonstrate that the atherosclerotic involvement of carotid arteries is usually asymmetrical and that wall shear stress is lower in the carotid arteries where plaques are present than in plaque-free arteries. These findings provide in vivo evidence for a strong association between shear stress and atherosclerotic lesions.
Atherosclerosis is usually regarded as a systemic disease caused or at least favored by risk factors, ie, hypertension, hyperlipidemia, diabetes mellitus, and cigarette smoking. However, atherosclerotic lesions occur more frequently in well-localized arterial districts, mainly coronary, extracranial carotid, and femoral arteries. Even within these arterial beds plaques are located in particular regions, while in others atherosclerosis is relatively rare, as demonstrated by autopsy studies. The preferential sites for LDL to deposit and atherosclerotic lesions to develop seem to lie in regions of low or oscillating shear stress.1 2 3 4 5 The wall shear stress is the frictional force exerted by the circulating blood column on the intimal surface of the arteries. One additional puzzling aspect of atherosclerosis involving symmetrical districts, ie, carotid and femoral arteries, is the asymmetry of lesions between the left and the right sides. Local factors, mainly the geometry of the arteries, have been suggested to play a role in determining atherosclerotic lesion localization.6 Indeed, the geometry of the vessel influences the blood flow pattern and therefore the wall shear stress,7 and that might offer a possible explanation for the asymmetry of lesions between left and right districts.
We have recently described a noninvasive method to measure wall shear stress in human CCAs and have demonstrated that it inversely relates to IMT of the arterial wall.8
The aims of the present study were to investigate the asymmetry of carotid atherosclerosis in a large cohort of subjects participating in a cardiovascular disease prevention campaign and to verify, in a subset of subjects, whether wall shear stress is lower in carotids with atherosclerotic lesions than in contralateral carotids without lesions.
Subjects and Methods
In the first part of the study, all participants in a regional cardiovascular disease prevention campaign examined between April 1994, the date of the start of the campaign, and June 1996 (659 men and 507 women) were screened for presence of coronary heart disease risk factors and carotid atherosclerosis. Details of this study have been given elsewhere.9
Blood pressure, height, and weight were measured by routine methods. BMI was computed as weight (kilograms) divided by height (meters) squared. Hypertension was defined as SBP ≥160 mm Hg and/or DBP ≥90 mm Hg and/or use of antihypertensive drugs.
Plasma lipids and blood glucose were measured by routine methods. Hyperlipidemia was defined as total cholesterol >5.17 mmol/L and/or triglycerides >2.26 mmol/L and/or use of lipid-lowering drugs. Diabetes was defined as fasting blood glucose ≥7.77 mmol/L and/or use of antidiabetic agents. Smoking habits and drug use were assessed by questionnaire. Current and previous smokers were grouped.
Echo-Doppler examination was performed with an electrocardiogram-triggered high-resolution ATL Ultramark 9 HDI instrument (Advanced Technology Laboratories, Inc) equipped with a 5- to 10-MHz multifrequency linear probe.
The CCA, CB, ICA, and external carotid artery were studied in longitudinal and transverse planes with anterior, lateral, and posterior approaches. Each segment was classified as follows: normal, absence of plaque and stenosis; with plaque, localized lesion encroaching the lumen of thickness ≥1.3 mm, no spectral broadening or only in deceleration phase of systole, and systolic peak flow velocity (VSP) <120 cm/s; with stenosis, spectral broadening throughout systole and/or VSP ≥120 cm/s.10
Normal segments were scored 0, those with plaque were scored 1, and those with stenosis were scored 2. A global score for each side was computed by adding the scores of all segments.
For the second part of the study, which sought to verify the possible association between wall shear stress and carotid atherosclerosis, it was decided to enroll subjects presenting plaque in the CCA and/or CB of one side and no lesions in the contralateral carotid tree. This approach has the advantage of avoiding the possible confounding effect of classic risk factors on atherosclerotic lesion development. An exclusion criterion was the presence of stenosis in any carotid segment. One hundred sixty-five subjects with these characteristics were found in the whole population participating in the prevention campaign. Twenty-five subjects who were examined in the last 6 months and lived in the town of Catanzaro and its suburbs were recalled. Of these, 2 refused and 23 gave informed consent and were enrolled for the second part of the study.
The examinations for wall shear stress measurement were performed in the morning in a room at 22°C, and the participants were fasting from the previous evening. Coffee was not allowed. The subjects were kept in supine position with the head slightly extended. Echo-Doppler examination was performed as specified above. Internal arterial diameter at the R (IDR) and T (IDT) wave of the electrocardiogram, IMT, and VSP and mean centerline blood flow velocity (VM) measurements were performed in the CCAs, 1 to 2 cm proximal to the CB, always upstream to the plaque, as previously described.8 The sonographer, who was the same throughout the study, recorded the examination on a videotape. A reader, who was the same throughout the study and blinded with regard to the subject investigated, performed the measurement of ID and IMT. For each participant, three measurements (concerning the anterior, lateral, and posterior projections of the far wall) were performed on each side. The average of the three measurements was used to calculate the IMT. Coefficients of variation for IDR, VSP, and VM measurements were 1.09±0.42 (range, 0.60 to 1.54), 3.14±2.05 (range, 1.17 to 6.30), and 5.39±1.41 (range, 4.00 to 7.32), respectively.8
Blood viscosity (η) was measured in vitro, at 37°C, on the same day of the echo-Doppler examination and within 2 hours of blood withdrawal from an antecubital vein, with the use of a cone/plate viscometer (Wells-Brookfield DV III) equipped with a cp-40 spindle. The blood was anticoagulated with heparin (35 IU/mL). The results obtained at shear rate 225 s−1 were used for shear stress calculation. Coefficient of variation for η measurement was 2.72±1.69 (range, 0.96 to 4.90).8
Peak (τP) and mean (τM) wall shear stresses were calculated according to the following formulas: where γS and γM represent the systolic and mean wall shear rates, respectively. Wall shear rates are not directly measured in this model but can be calculated with a poiseuillean parabolic model of velocity distribution across the arterial lumen,11 according to the following formulas: Coefficients of variation for τP and τM calculations were 4.00±2.20 (range, 1.91 to 7.63) and 5.00±2.41 (range, 2.62 to 8.71), respectively.8
Systolic (TSS) and diastolic (TSD) tensile stresses, that is, the force exerted by blood pressure acting perpendicularly on the vessel wall, were calculated from the modified law of Laplace, according to the following formulas: where SBP and DBP are expressed in dynes per square centimeter and ID and IMT in centimeters.12
Blood flow (BF) was computed as the product of mean cross-sectional velocity, assumed to be half the VM, and area, according to the following formula: The Reynolds number (R) was calculated according to the following formula: where ρ is the blood density (assumed to be 1.060×103 kg/m3). A Reynolds number value <1000 is usually considered characteristic of laminar flow.
ANOVA was used to compare continuous variables among subjects with different carotid atherosclerosis localization and τP, τM, vessel diameter, blood velocity, tensile stress, blood flow, and IMT among carotids without plaque and those with one or two plaques. The χ2 test was used to compare the prevalence of coronary heart disease risk factors among subjects with different carotid atherosclerosis localization. τP, τM, vessel diameter, blood velocity, tensile stress, blood flow, and IMT all had normal distribution. Therefore, the paired t test was used to compare these variables between the side with and the side without plaque.
Among the 1166 participants in the cardiovascular disease prevention campaign, 400 (34%) had plaque and/or stenosis in the carotid tree. Fig 1⇓ shows the distribution of atherosclerotic lesions according to the score and the side involved. Ninety subjects had lesions only on the right side, 111 had lesions only on the left side, 70 had lesions on both sides but with different scores, and only 129 subjects had the same involvement of both carotid arteries.
Table 1⇓ shows clinical and biochemical characteristics of all subjects with plaque and/or stenosis. Those with bilateral carotid involvement were significantly older, and those with different scores also had higher SBP levels than subjects with monolateral carotid atherosclerosis. Similar results were obtained when men and women were analyzed separately. The prevalence of men was higher in the group of subjects with both carotid arteries involved at the same degree. The prevalence of diabetes mellitus, hypertension, hyperlipidemia, and cigarette smoking was similar in the four groups.
Table 2⇓ shows clinical and biochemical characteristics of the 23 subjects participating in the second part of the study. Seven subjects had one plaque localized in the CCA, 10 had one plaque in the CB, 2 had plaques in the CCA and CB, and 4 had plaques in the CB and in the ICA. All subjects with hypertension and diabetes mellitus were on medication.
τP and τM in the side without and the side with plaque were 18.7±4.1 versus 15.3±4.0 and 10.1±2.8 versus 8.8±3.1, respectively (Fig 2⇓). The difference was highly statistically significant by paired t test. Nineteen subjects had markedly higher and 2 had slightly higher values of τP in the side without lesions, 1 had the same τP in both sides, and 1 had lower values in the side without plaque. Similar findings were observed after exclusion of subjects with hypertension (n=17; τP: 19.3±4.0 versus 15.5±4.2, side without versus side with plaque, respectively [P<.0001]; τM: 10.4±2.8 versus 8.8±3.4 [P<.003]), subjects with diabetes mellitus (n=20; τP: 18.4±4.0 versus 15.3±4.0 [P<.0001]; τM: 10.0±2.9 versus 9.0±3.3 [P<.01]), smokers (n=13; τP: 17.7±4.0 versus 14.8±3.9 [P<.001]; τM: 9.1±2.7 versus 7.9±2.4 [P<.002]), women (n=11; τP: 19.1±4.0 versus 15.6±4.3 [P<.0001]; τM: 10.5±2.6 versus 9.1±3.3 [P=.05]), men (n=12; τP: 18.3±4.3 versus 15.1±4.0 [P<.0006]; τM: 9.7±3.0 versus 8.6±3.1 [P=.002]), and those on medication (n=14; τP: 19.1±4.0 versus 15.4±4.2 [P<.0001]; τM: 10.3±3.0 versus 9.1±3.7 [P=.02]). Furthermore, subjects with plaque localized only at the CCA (n=7; τP: 17.9±3.8 versus 15.4±4.8 [P<.0001]; τM: 10.5±2.7 versus 9.5±4.0 [P<.0001]) and those with plaque localized downstream to the CCA (n=14; τP: 18.8±4.4 versus 15.3±4.0 [P<.0001]; τM: 9.7±2.9 versus 8.7±3.0 [P=.01]) had similar results.
Table 3⇓ shows ID, blood velocity, IMT, tensile stress, blood flow, and Reynolds’ number in the side without and the side with lesion. Significantly higher values of ID and IMT and lower values of TSS, TSD, and blood velocity were found in the side with plaque. Tensile stress values were similar to those obtained on the same arterial segment in an in vitro study.12 Blood flow and Reynolds number were similar in both sides.
Table 4⇓ shows the results of the ANOVA among carotids without plaque, with only one plaque, and with two plaques. ID increased with increasing number of plaques, although not significantly. Blood flow velocity decreased with increasing number of plaque, but statistical significance was reached only for VSP. IMT markedly increased from vessels without plaque to those with two plaques. τP significantly decreased with increasing number of plaques, whereas τM, although showing the same trend, was only marginally significant. TSS and TSD decreased with increasing number of plaques, but the results did not reach statistical significance. Blood flow and Reynolds number were similar in the three groups.
The present results demonstrate that carotid atherosclerosis is usually asymmetrical and that τP and τM are lower in carotid arteries where atherosclerotic plaques are located than in contralateral plaque-free carotids. The reduction is accounted for by increased diameter and decreased blood flow velocity. These findings provide in vivo evidence for a strong association between low shear stress and atherosclerotic lesions.
The observation that plaques do not involve, in the same subject, both carotid arteries to the same extent is not new and is well known to students of atherosclerosis.4 13 However, to our knowledge there are no previous studies that have directly addressed this question in a large number of subjects. Many studies investigating carotid endarterectomy and the prognosis of carotid lesions14 15 16 17 18 have reported a different localization and severity of lesions between the two carotid arteries in the same subject. More recently, two reports of the Atherosclerosis Risk in Communities Study have provided further information. In the first report, 4491 (33.6%) of the 13 376 participants had plaque, and 858 (6.4%) had plaque with acoustic shadowing. Seven hundred fifty-eight individuals with plaque with acoustic shadowing had complete examination for both carotid arteries, and only 167 (26%) had lesions on both sides.19 Data concerning all participants who had plaque were not given. In the second study the relationship between IMT at different sites within the extracranial carotid artery was described.20 The highest correlation was observed between IMT measured in the left and right CCA, but it was fairly low (r=.49). The authors concluded that although the general association between sites supports the systemic nature of atherosclerosis, the lack of tight agreement supports the focal nature of the process. The studies specifically designed to evaluate carotid atherosclerosis asymmetry have been performed in relatively few patients and did not report the prevalence of asymmetry in the population.6 7 The results of the first part of the present study show that almost 50% of subjects with carotid lesions have only one side involved and one third of the remaining 50% have different degrees of lesion severity in the two carotid arteries. Although these findings clearly show that carotid atherosclerosis is usually asymmetrical, the scoring system used (0=normal, 1=plaque, 2=stenosis of any degree) might have underestimated the real prevalence of asymmetry. However, the prevalence of classic coronary heart disease risk factors was similar among subjects with different types of atherosclerosis localization. Subjects with bilateral carotid atherosclerosis were older than those with monolateral involvement, suggesting diffusion of the lesions with aging.
In recent years it has been postulated that low shear stress might induce intimal thickening and atherosclerosis development. Wall shear stress is directly proportional to blood flow velocity and viscosity and inversely proportional to vessel diameter. The reduction of shear stress contributes to an increased fluid residence time and therefore to increased transport of atherogenic particles, thus interfering with endothelial metabolism.21 22 Platelets and macrophages more probably adhere to endothelium in regions of increased residence time,23 and in human endothelial cells the tissue plasminogen activator secretion rate decreases with decreasing values of shear stress, at least in in vitro experiments.24 Furthermore, recent evidence suggests that shear stress modulates the transcription of genes for nitric oxide synthase, platelet-derived growth factor, and transforming growth factor-β1, all factors involved in vascular remodeling.25 26 27 28 29 30 31 32 On the whole, reduced shear stress seems to increase the local production of mitogenic substances.
In the 23 subjects undergoing wall shear stress measurement in the second part of the present study, both τP and τM were significantly lower in the side where plaques were located than in the plaque-free carotid. Several aspects of this finding need to be addressed.
It has been assumed that CCA shear stress reflects the hemodynamic condition downstream, ie, in the CB and ICA. In vitro studies have demonstrated that the normally axially aligned blood flow of the CCA changes at the bifurcation, causing complex secondary flow patterns.4 33 34 Helical flow pattern and vortex formation do not allow exact knowledge of the angle between the axis of the flowing blood and that of the ultrasound beam and might therefore determine overestimation or underestimation of blood velocity. Furthermore, the CB is a dilated, widened area without a uniform bore, and therefore it is unreliable to measure shear stress directly there. However, shear stress in the CB and ICA is mainly determined by CCA blood velocity and diameter and by bifurcation angle and local diameters. A previous study investigated the role of bifurcation angle and ICA-CCA area ratio in carotid atherosclerosis asymmetry.7 The authors found that only area ratio asymmetry was significantly associated with carotid atherosclerosis asymmetry, although this explained only 12.6% of the variation. In the present study we have followed a different approach and have investigated the possible association between carotid atherosclerosis and CCA blood velocity and diameter. Although the shear stress measured in the CCA should be associated directly only with plaque in the same arterial segment, its influence downstream could allow study of its relationship with atherosclerotic lesions in the entire carotid tree. Our results support this hypothesis since, after exclusion of subjects with lesions only in the CCA, shear stress was still significantly lower in the affected side.
The present study does not allow speculation about possible causes for the different shear stress between the two CCAs. It is unlikely that plaques have influenced this result: first, the measurement was always performed upstream to the plaque; second, subjects with stenosis of any degree were excluded for possible blood flow reduction or turbulence; third, the Reynolds number, a predictor of turbulence, was similar in both carotid arteries; and finally, the exclusion of subjects with plaque in the CCA did not alter the results. Furthermore, in subjects without carotid atherosclerosis we also found a different shear stress between the two sides.8 Congenital (origin, length, curvature, and size of the two CCAs) and/or acquired factors might be responsible for different flow velocity and vessel diameter in the two CCAs. However, the final result would be a different shear stress between left and right sides. When classic risk factors are present, plaques could develop in the side where shear stress is lower.
The lower shear stress in the side with plaque is accounted for by both increased diameter and decreased blood velocity. The variation in the opposite direction of these two variables, while causing a reduction of shear stress, probably guarantees the preservation of blood flow. It is known that older individuals have larger CCA lumen than younger individuals.35 Furthermore, we have described a reduction of blood velocity with age.8 These findings combined probably explain the reduction of shear stress with age, the higher prevalence of plaques in older subjects, and the thicker IMT in older subjects and in subjects with plaque.
For coronary arteries, it has been postulated that atherosclerotic lesions occupying up to 40% of the potential lumen area induce an increase in blood flow velocity and a consequent vessel dilatation, probably to restore wall shear stress.36 An overcompensation could be responsible for the enlarged diameters observed in these situations. The findings of the present study do not exclude the possibility that plaque development may precede carotid enlargement. It is also possible that vessel dilatation precedes (in some cases) and follows (in others) the development of the atherosclerotic lesions. Furthermore, we found that in the diseased CCAs, upstream to the lesions, tensile stress values are lower than those in contralateral arteries because of the decreased ID-IMT ratio. This might suggest an adaptive remodeling response of the arterial wall. However, in patients undergoing hemodialysis the marked increase in blood flow on the side of the arteriovenous fistula was associated with significant increase in arterial diameter but not in wall thickness, thus causing an increase in tensile stress.37 The interaction between flow conditions and vessel size and structure is likely to be complex and needs further investigation.
The finding that shear stress significantly decreases with increasing atherosclerosis severity might suggest a strong interaction between local and systemic factors. We hypothesize that as shear stress decreases, because of aging or of other factors altering blood velocity and/or viscosity, the arterial wall becomes more prone to damage and lower systemic risk profiles are sufficient to cause lesions. However, further studies are needed to test this hypothesis.
In conclusion, a complex interaction between systemic and local factors is probably responsible for atherosclerosis development. The identification and definition of the role of these factors may help to clarify the pathogenesis of this disease and to improve the clinical and therapeutic approaches.
Selected Abbreviations and Acronyms
|γM||=||mean wall shear rate|
|γS||=||systolic wall shear rate|
|τM||=||mean wall shear stress|
|τP||=||peak wall shear stress|
|BMI||=||body mass index|
|CCA||=||common carotid artery|
|DBP||=||diastolic blood pressure|
|ICA||=||internal carotid artery|
|IDR||=||internal diameter at the R wave|
|IDT||=||internal diameter at the T wave|
|SBP||=||systolic blood pressure|
|TSD||=||diastolic tensile stress|
|TSS||=||systolic tensile stress|
|VM||=||mean centerline velocity|
|VSP||=||systolic peak velocity|
- Received December 5, 1996.
- Revision received February 14, 1997.
- Accepted February 14, 1997.
- Copyright © 1997 by American Heart Association
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