Carotid Plaque, Arterial Stiffness Gradient, and Remodeling in Hypertension
The analysis of plaque mechanics along the longitudinal axis (bending strain) may provide useful information because repetitive bending strain of an atherosclerotic plaque can fatigue the wall material and result in plaque rupture. Whether essential hypertension is associated with a specific pattern of bending strain has not yet been determined. The study included 92 patients with an atherosclerotic plaque on the common carotid artery: 66 patients with essential hypertension, either treated or not, and 26 normotensive patients. A novel noninvasive echotracking system (ArtLab; Esaote, The Netherlands) was used to measure intima-media thickness, diameter, and distensibility at 128 sites on a 4-cm-long carotid segment. Carotid plaque was either less elastic than adjacent carotid artery (inward strain) or more elastic (outward strain). Inward strain was more frequently associated with an inward plaque remodeling, whereas an outward strain was more frequently associated with an outer remodeling. In multivariate logistic regression analysis, patients with essential hypertension were more likely to exhibit an inward strain of carotid plaque (odds ratio=6.9 [1.4 to 34.9]; P<0.02), independently of 2 factors favoring inward strain: an outer remodeling (odds ratio=4.6 [1.7 to 13.4]; P<0.005) and the absence of renin-angiotensin system blockers (odds ratio=4.8 [1.1 to 20.4]; P<0.05). In conclusion, arterial wall material of hypertensive patients was less elastic at the site of the plaque than upstream, and carotid was inwardly strained in the zone affected by plaque. This may generate a high level of stress concentrations and fatigue, exposing the plaque to a greater risk of rupture.
Hypertension is a major risk factor for coronary, cerebrovascular, and renal diseases and is the greatest cause of stroke.1 Half of stroke events are the result of cerebrovascular atherosclerosis, including carotid plaques. Hypertension increases the tensile stress applied on the carotid artery, thus carotid intima-media thickness (IMT) and stiffness, and favors atherosclerotic plaque progression.2–8 Hemodynamic disturbances caused by hypertension result in atherosclerotic plaque complications like fissuring, rupture, and hemorrhage, which are critical steps for plaque evolution and for ischemic stroke.
Plaque rupture has become identified as a critical step in the evolution of atherosclerotic plaque. It is of major importance to detect which plaques are vulnerable,9 even though not yet ruptured, and, specifically, to identify which patients will have a stroke. Rupture mechanisms are complex processes that are dependent on plaque morphology and composition and mechanical characteristics.9–11 Mildly stenotic carotid plaques with thin fibrous cap and lipid-rich core are more susceptible to rupture than plaques with a high degree of fibrosis and calcifications.9
To understand the mechanisms of plaque rupture, plaque mechanics is usually investigated in the circonferential direction.10–12 However, plaque rupture may involve shearing strain (or bending strain) of the arterial wall in the longitudinal direction (ie, between 2 adjacent zones of different radial strain).13–14 The development of multiarray high-resolution echotracking technology allows measuring pulsatile changes in diameter (radial strain) at various sites along the common carotid artery (CCA) and evaluating bending strain along the longitudinal axis.15 We described previously the longitudinal gradient of bending strain along a CCA bearing an atherosclerotic plaque and determined 2 distinct patterns.15 Pattern A describes an outward bending strain with a larger radial strain at the level of the plaque than at the adjacent CCA. The opposite (pattern B), which describes an inward bending strain, was more often observed in dyslipidemic and type 2 diabetic patients.15
However, the influence of hypertension has not been studied. Hypertension may stiffen the atherosclerotic plaque to a greater extent than adjacent normal carotid artery and favor pattern B. Indeed, the increase in tensile stress that applies to the atherosclerotic plaque may exaggerate cell signaling, resulting in a larger amount of fibrous material in the extracellular matrix.16–18 In addition, the mechanical fatigue of the atherosclerotic plaque (ie, repeated cycles of distensions and elastic recoils of the arterial wall) can induce microfissuring, rupture, and hemorrhage, leading to repairs with fibrous material.11,19
Thus, our working hypothesis was that hypertensive patients (HT) were more likely to exhibit an inward bending strain (pattern B) than an outward bending strain (pattern A). We took advantage of a 128 radio frequency line multiarray echotracking technology15 to characterize in vivo in humans the mechanical properties of adjacent segments along the CCA in the radial, circumferential, and longitudinal axes and at the site of plaque and in its vicinity.
The study cohort included 26 normotensive patients (NT) and 66 patients with essential hypertension, with or without antihypertensive treatment. Patients were recruited from the hypertension, vascular surgery, and nephrology departments of George Pompidou Hospital in Paris, and the neurology department of Sainte-Anne Hospital in Paris. They were included in the study if a plaque had been detected on the CCA during the routine workup, and then they were categorized as HT or NT. Patients were 50 to 80 years old and were included regardless of cardiovascular risk factor. All patients had an atherosclerotic plaque of the CCA with or without extension to the adjacent part of the bulb and plaque on the internal carotid artery. Plaque was defined according to the Mannheim consensus20 as a focal structure that encroaches into the arterial lumen of ≥0.5 mm or 50% of the surrounding IMT value or demonstrates a thickness of 1.5 mm as measured from the media-adventitia interface to the intima-lumen interface.
Essential hypertension was determined by systolic blood pressure (BP) ≥140 mm Hg, diastolic BP ≥90 mm Hg, or treatment with BP-lowering drugs. Fifty-seven among 66 HT were treated with ≥1 antihypertensive agents: 42 received angiotensin converting enzyme inhibitors or angiotensin II receptor blockers; 24 received calcium channel blockers; 10 received diuretics; and 27 received β-blockers. Diabetes was indicated by abnormal fasting plasma glucose levels or the current use of insulin or an oral hypoglycemic agent. Dyslipidemia was defined as abnormal fasting plasma cholesterol levels (LDL cholesterol >3.0 mmol/L [115 mg/dL]) or the current use of lipid-lowering agents. Smoking status was defined as current or past use versus never.
All patients signed informed consent. Data were recorded according to the requirements of the CNIL (Commission Nationale Informatique et Liberté, ie, national committee for protection of individuals in computer use; authorization number 546379).
The ultrasonic noninvasive investigation was performed in a room dedicated to echography after 15 minutes of recumbent rest. BP and arterial measurements were performed by an engineer (E.B.) and a doctoral student (H.B.) trained and certified in vascular echography.
Before the ultrasound examination, brachial BP measurements were taken using an oscillometric device (Collin) at 3-minute intervals for 20 minutes, and the average was taken as the casual BP level. Mean BP was calculated as diastolic BP+[(systolic BP−diastolic BP)/3]. Brachial pulse pressure (PP) was calculated as systolic BP−diastolic BP.
All patients underwent CCA measurements with a new multiarray echotracking system (ArtLab) based on classical high-resolution echotracking technology (WallTrack system), including the use of a 128 radio frequency line multiarray.15,21 This novel system determines arterial parameters with a very high precision and reproducibility and allowed us to dynamically take into account the entire carotid segment in real time. We thus had access to all major mechanical parameters along a 4-cm arterial segment: IMT, internal diameter, and pulsatile strain (distension) in the radial direction (Ds−Dd, where Ds is systolic internal diameter and Dd is diastolic internal diameter). Using the bidimensional acquisition mode, IMT and diameter measurements were obtained with a 21-μm resolution at each of the 128 sites of a 4-cm-long CCA segment. The arterial wall motion acquisition mode measures distension with a 1.7-μm spatial resolution at each of the 14 sites of a 2-cm-long CCA segment.15,21 Cross-sectional distensibility coefficient was calculated as ΔA/(A·ΔP), where A is the diastolic lumen area, ΔA is the stroke change in lumen area, and ΔP is PP, according to previous works3,4 and a recent expert consensus statement.22 Measurements were performed on the right CCA in case of plaques located on both right and left CCA; 12 patients among 92 had a plaque on both sides. Each carotid plaque was insonated in different axes to determine the position in which the major body of plaque was imaged. Transverse sections were performed to check that the lateral extension of the plaque was small (ie, <45° of angle.
All measurements were performed at different levels of the carotid segment: 8 adjacent zones (each of 5-mm length [ie, 16 radio frequency lines]) were determined, starting from zone 1 upstream of the carotid bulb to zone 8 immediately near to the bulb. The anatomic localization of the plaque on the carotid segment was also recorded. Data (IMT, diameter, distension, distensibility) were averaged within each of the 8 zones. Thus, it was possible to compare all arterial parameters between various locations (upstream the plaque, on the plaque, and, in some cases, downstream the plaque) and to obtain longitudinal gradients along the carotid segment bearing the plaque. Distension gradient was calculated as the distension at the adjacent “normal” CCA (upstream the plaque) minus distension at the level of the plaque. It was used to determine the extent of longitudinal bending strain along the common carotid segment, analyzed according to the pattern A/B classification (Figure 1).15 Measurements were digitally stored for off-line analysis. The analysis of data acquired in “bidimensional” or “arterial wall motion” modes was performed using a custom-written software platform (Matlab R2006a 7.2; MathWorks, Inc., Natick, Mass).
CCA pressure waveform was recorded noninvasively with a pencil-type probe incorporating a high-fidelity Millar strain gauge transducer (SPT-301; Millar Instruments, Houston, Tex), as described previously.3 Carotid PP was calculated as carotid systolic BP−carotid diastolic BP. The accuracy of the probe has been validated in humans.3 In the 38 patients who had the largest plaques, and to avoid any risk of rupture attributable to the high external pressure imposed by applanation tonometry, we indirectly estimated carotid PP. For that purpose, carotid PP was calibrated from the carotid distension waveform according to Van Bortel et al23 and calculated as (MBP−DBPb)/[(Dm−Dd)/(Ds−Dd)], where MBP is mean blood pressure, DBPb is diastolic BP measured at the brachial level, and Dm is the mean internal carotid diameter. A significant positive correlation between carotid PP directly measured with applanation tonometry and carotid PP estimated from the carotid distension waveform has already been observed in a larger population in our laboratory (P.B. and S.L., unpublished data, 2004).
The short-term within-observer within-patient repeatability between 2 determinations of internal diameter and PP, taken at 15-minute intervals by a senior technician, has been published previously.3,4,24 We also evaluated, under similar conditions, the short-term within-observer within-patient repeatability between 2 determinations of bending stress: the absolute difference between measurement 1 and measurement 2 did not exceed 10% of the mean value.15
Data are expressed as mean±SD. Quantitative variables were compared by means of an unpaired or a paired (at the site of plaque and at the surrounding normal adjacent CCA) Student t test or Wilcoxon nonparametric test for each group. Categorical variables were compared by means of a χ2 test. Associations between arterial parameters and quantitative factors were analyzed with general linear model ANOVA.25 Associations between categorical variables were analyzed with a multivariate logistic regression analysis that allowed us to obtain the determinants of bending strain patterns. A value of P<0.05 was considered significant. Statistical analysis was performed using NCSS 2004 package software (Hintze JL; Kayswile, Utah).
Demographic and hemodynamic characteristics of the hypertensive and normotensive groups are shown in Table 1. HT were significantly older and had a higher brachial and carotid systolic BP (P<0.05) and PP (P<0.01) than NT. Both groups were comparable for gender, weight, height, diastolic and mean BP, and heart rate. No significant difference was observed between groups concerning the prevalence of hypercholesterolemia, diabetes, smoking, and cardiovascular treatments (statins or fibrates, antiplatelet drugs), except the use of antihypertensive drugs. No significant difference was observed as far as the incidence of vasculorenal disease (renal failure, stroke, or coronary heart disease) was concerned. The number of cardiovascular risk factors was significantly higher in HT than in NT.
Carotid Artery Parameters in HT
We compared the geometric (external and internal diameters and IMT) and mechanical (distension, distensibility, compliance, and circumferential wall stress) carotid parameters between plaque and adjacent CCA in each group (HT and NT; Table 2). In both groups, IMT and wall to lumen ratio were, by definition, higher at the plaque level than on the adjacent CCA. In HT, distension (Ds−Dd) of the plaque was significantly lower (−14%) than at the level of adjacent CCA, whereas this was not the case in NT. Despite similar mean BP, carotid PP was significantly higher (+23%) in HT than in NT. In HT, distensibility and compliance were significantly lower (−11% and −19%, respectively) at the site of the plaque than on the adjacent CCA, but this was not the case in NT. Among the 66 HT, 22 patients exhibited pattern A (arterial wall more extensible on the plaque than on the adjacent carotid artery), and 44 patients exhibited pattern B (arterial wall less extensible on the plaque). Among the 26 NT, 12 patients exhibited pattern A and 14 exhibited pattern B.
Arterial Parameters According to Functional Patterns
The 34 pattern A patients had a significantly lower (−7%) internal diameter on the plaque than on the adjacent CCA (Table 3), whereas the external diameter was not significantly different, indicating an inner remodeling (Figure 2). The opposite was observed among the 58 pattern B patients who had a significantly higher (+5%) external diameter on the plaque and a similar internal diameter, indicating an outer remodeling (Figure 2; Table 3).
By definition, in pattern A patients, distension and distensibility were significantly higher (+27% and +39%, respectively) at the level of the plaque than on the adjacent CCA. In pattern B patients, distension and distensibility were significantly lower (−31% and −28%, respectively) at the level of the plaque than on the adjacent CCA. The relationship between functional and remodeling patterns was analyzed in Figure 3. Among the 62 patients presenting an outer remodeling, the majority had a pattern B, whereas two thirds of the 30 patients describing an inner remodeling had a pattern A. In other words, pattern A was more frequently observed when an inward remodeling was present at the level of the atherosclerotic plaque, whereas pattern B was observed more frequently when an outward remodeling was present.
Determinants of Bending Strain Patterns
To analyze the determinants of the patterns of bending strain, we used a multivariate logistic regression analysis and selected pattern A as reference pattern. As shown in Table 4, patients with essential hypertension were more likely to exhibit pattern B (odds ratio=6.9 [1.4 to 34.9]; P<0.02), independently of 2 other factors favoring pattern B: an outer remodeling (odds ratio=4.6 [1.7 to 13.4]; P<0.005) and the absence of renin-angiotensin system (RAS) blockers (angiotensin converting enzyme inhibitors or angiotensin II receptor blockers; odds ratio=4.8 [1.1 to 20.4]; P<0.05). The use of calcium channel blockers, diuretics, or β-blockers was not associated with a specific pattern.
The main results of the present study are the following: (1) HT are 7-fold more likely to exhibit an inward bending strain at the site of the carotid plaque (ie, lower elasticity at the site of the plaque than in adjacent CCA) than an outward bending strain; (2) an inward bending strain is more often associated with an outer remodeling than an inner remodeling; and (3) blockers of the RAS are more often associated with an outward than inward bending strain, independently of hypertension and remodeling.
Consideration of Methods
The present study describes a combined approach capable of evaluating structural characteristics of carotid plaque with B-mode as well as functional properties with echo-tracking system. To characterize the elastic properties of the plaque and surrounding tissues along the longitudinal axis, we contrasted the mechanical behavior of the zone affected by a plaque with the neighbor “normal” CCA.
All measurements of plaque mechanics were performed at the level of the CCA. Indeed, in our population, plaques of the internal carotid artery were often stenotic, calcified, and the algorithm of the ArtLab system was not adapted to the interface recognition in such plaques. This algorithm was rather developed to assess thickened walls or small plaques, like those observed at the site of the CCA. We have chosen to take into account measurements of right CCA to reduce intraindividual and interindividual variability.26
As discussed previously,15 we gave more importance to the values of radial wall strain than to distensibility, compliance, or Young’s elastic modulus because strain was directly measured as the relative change in diameter and required no mechanical assumption. We applied an arterial model in which the artery was an elastic ring of uniform elasticity and wall thickness. Although this was not the case, the thickness of the plaque was very moderate (Tables 2 and 3⇑) at this stage of moderate atherosclerosis (ie, no significant stenosis) in contrast to cases of severe stenosis reported in the literature.11,12,14 The validation of arterial mechanics at the level of the plaque is limited because we cannot extrapolate thickness values of the plaque to the entire carotid segment. Indeed, plaque represents a quarter or a third of the artery circumference. Finite elements modelization is thus required to better determine local arterial mechanics, including Young’s elastic modulus, which represents the stiffness of the wall material. Mean BP was not significantly different between HT and NT because most of HT were treated. Thus, it was possible to compare the mechanical characteristics of the carotid artery for a similar mean BP level.
Patients were selected according to the presence of a plaque at the level of the CCA, detected during the routine workup. To increase the likeliness of finding a carotid plaque, only patients >50 years of age were selected. Thus, as shown in Table 1, our population was representative of elderly patients with atherosclerosis, complicated, in half of them, by a vasculorenal event (coronary heart disease, renal failure, or stroke).
Interpretation of Findings
Strain gradient along the CCA can be considered an indicator of the disturbed integrity of the vessel wall and hence a possible predictor of vessel wall fragility leading to plaque rupture. In the present study, HT were 7-fold more likely to exhibit an inward bending strain at the site of the carotid plaque than an outward bending strain. In other words, arterial wall material of HT was less elastic at the site of the plaque than upstream, and carotid was inwardly strained in the zone affected by plaque.
These results suggest that the changes in plaque composition and geometry associated with hypertension increase the stiffness of the wall material and limit the strain of the whole carotid wall induced by pulsatile pressure. Various mechanisms can be suggested. First, the increase in tensile stress that applies to the atherosclerotic plaque may exaggerate cell signaling, resulting in a larger amount of fibrous material in the extracellular matrix.16–18 Second, the mechanical fatigue of the atherosclerotic plaque (ie, repeated cycles of distensions and elastic recoils of the arterial wall) can induce microfissuring, rupture, and hemorrhage, leading to repairs with fibrous material.19 Third, hypertension may favor the production of advanced glycation end products, which cause cross-bridges between macromolecules of the extracellular matrix27,28 and stiffen the plaque.
The relationship between longitudinal strain gradient and plaque rupture is not unequivocal. Rupture is associated with stress concentrations, which are affected by plaque lipid composition, fibrous cap thickness, plaque area, plaque shoulder, histology, and inflammation.9–11 Plaque mechanics is generally analyzed in a cross-section, and circumferential stress concentrations were found to be maximum at the shoulder of the fibrous cap of an asymmetrical plaque with increased lumen convexity.9–11 However, heterogeneity of arterial mechanics should also be analyzed along the longitudinal axis because it may generate stress concentrations at the junction of distensible and stiff areas. In addition, fatigue, which refers to a chronic failure process induced by repetitive loading, may lead to plaque rupture through stress levels that are much lower than the critical stress.11,19 Repetitive bending strain of an atherosclerotic plaque in the longitudinal axis may fatigue the wall material and result in plaque rupture. Whether stress concentrations and fatigue generated by an inward bending stress expose the plaque to a greater risk of rupture than stress concentrations and fatigue generated by an outward bending stress remains to be determined.
Another important result of our study concerns the relationships between functional and remodeling patterns. An inward bending strain was more frequently associated with an outer remodeling, whereas an outward bending strain was more frequently associated with an inner remodeling pattern (Figure 3). The outer remodeling pattern was strictly defined by a higher external diameter on the plaque than on the adjacent normal CCA, without any reduction of the vessel lumen. According to the Glagov’s theory,29 we also included in this group 28 patients who had a “mixed” pattern of outer remodeling (ie, both a higher external diameter and a lower internal diameter at the level of the plaque). This “mixed” pattern most often included large carotid plaque. According to Glagov’s theory,29 arterial adaptation at the site of an atherosclerotic plaque leads first to an outer remodeling without change in the lumen area until a final stage is reached, in which no further compensation is possible and the lumen area is reduced. Therefore, we based our definition of the remodeling patterns on the value of external diameter. Because patients included in the present study most often had a small noncalcified atherosclerotic plaque, it is likely that pattern B belongs to an early stage of the development of the atherosclerotic plaque, and that pattern A represents a subsequent stage. A detailed MRI analysis of carotid plaque composition, combined with an echotracking investigation of the functional pattern and a finite elements modelization in real geometry, are required to better understand the mechanisms through which an increase in external diameter of the carotid artery at the site of the plaque favors an inward bending strain.30,31
In the present study, we observed an inverse relationship between the use of RAS blockers (angiotensin converting enzyme inhibitors or angiotensin II receptor blockers) and the inward bending strain. In other words, in patients using RAS blockers, arterial stiffening more likely predominates on the adjacent CCA and not on the plaque. The multivariate analysis shows that this relationship was independent of the hypertensive status and the type of remodeling. Interpretation of this finding should be done with caution because this was not a randomized comparison. Particularly, several confounding factors, including indication bias, may have contributed to these results. If it were to be confirmed by controlled studies, this finding would suggest that RAS blockers contribute to make the carotid artery more flexible at the site of the plaque. This is in line with several studies showing that angiotensin II plays a role in the composition of the fibrous cap, whereas angiotensin converting enzyme inhibitors and angiotensin II receptor blockers can reduce fibrosis around the lipid core of the plaque. The beneficial effects of RAS blockers likely involve their anti-inflammatory activity, reducing plaque progression in animal models of atherosclerosis,32 increasing plaque stabilization by inhibition of matrix metalloproteinase–induced plaque rupture,33 and more generally reducing fibrosis.34 Whether a more flexible carotid artery is at increased risk of rupture because of the higher strain applied to the fragile plaque material, or it could protect against rupture because the wall material is less fibrotic, more homogeneous, and less prone to mechanical fatigue, is unknown.35,36 Results of large therapeutic trials favor the latter possibility.
In conclusion, the arterial wall material of HT was less elastic at the site of the carotid plaque than upstream, and carotid was inwardly strained in the zone affected by plaque. This inward bending strain was also more often associated with an outer remodeling than an inner remodeling and the lack of use of RAS blockers, independently of the hypertensive status.
Determining noninvasively the carotid bending strain, a major parameter of plaque mechanics along the longitudinal axis, may provide useful information concerning the risk of plaque rupture and subsequent cardiovascular events, including stroke. Indeed, repetitive bending strain of an atherosclerotic plaque can fatigue the wall material and result in plaque rupture. We have shown, in this study and in a previous one, that hypertension, type 2 diabetes, and dyslipidemia are significant determinants of inward bending strain and risk factors for stroke. However, the link between stroke and the inward bending strain of a carotid plaque has not been demonstrated. Indeed, whether stress concentrations and fatigue generated by an inward bending stress expose the plaque to a greater risk of rupture than stress concentrations and fatigue generated by an outward bending stress remains to be determined. In addition, a detailed MRI analysis of carotid plaque composition, combined with an echotracking investigation of the functional pattern and a finite elements modelization in real geometry, are required to better understand the mechanisms leading to an inward bending strain. Finally, the effects of antihypertensive agents on carotid plaque mechanics should be studied in controlled clinical trials and analyzed in relationship with the results of large outcome therapeutic trials.
Sources of Funding
This study was funded by INSERM, University Paris-Descartes, and Assistance Publique-Hôpitaux de Paris.
Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.
- Received May 6, 2008.
- Revision received May 29, 2008.
- Accepted August 4, 2008.
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