Increased Stiffness of the Carotid Wall Material in Patients With Spontaneous Cervical Artery Dissection
Background and Purpose— The cause of spontaneous cervical artery dissection (sCAD) is largely unknown. An underlying connective tissue disorder has often been postulated, but arterial mechanical properties have rarely been studied. The study aim was to determine the elastic properties of a cervical artery, the common carotid artery, and a distal muscular artery, the radial artery in sCAD patients.
Methods— We studied 32 patients with previous sCAD (median delay: 2.2 years) and 32 control subjects with similar age and blood pressure. Internal diameter, intima-media thickness, distensibility, and Young’s elastic modulus were determined at the site of the right and left common carotid arteries and the radial artery using noninvasive high-resolution echotracking systems.
Results— In patients with previous sCAD, cross-sectional distensibility and compliance of the affected carotid artery did not differ from those of the contralateral carotid artery. Young’s elastic modulus (ie, the stiffness of the wall material) was 58% higher (0.44±0.32 versus 0.28±0.15 kPa·103, P<0.001) and circumferential wall stress was 14% higher (56±12 versus 49±12 kPa, P<0.001) in sCAD patients than in controls. The highest tertile of common carotid artery Young’s elastic modulus was associated with an 8-fold higher risk of sCAD. Aortic stiffness, assessed from the carotid-femoral pulse wave velocity, and radial artery parameters did not differ between sCAD and controls.
Conclusions— Carotid arteries, but not aorta and radial artery, displayed abnormal elastic properties in sCAD patients. Higher stiffness of carotid wall material and circumferential wall stress could increase the risk of dissection in these patients.
Spontaneous cervical artery dissection (sCAD) is a major cause of stroke in young adults.1,2 The cause of sCAD is poorly understood but is likely multifactorial, involving both constitutional and environmental factors.2,3 Various constitutional abnormalities (eg, intracranial aneurysms, aortic root dilatation, ultrastructural abnormalities of dermal connective tissue components) have been found in sCAD,4–8 suggesting an underlying arteriopathy presumably related to a generalized extracellular matrix defect.8 Very few data are available concerning the geometric and elastic properties of conducting arteries in patients with previous sCAD.5,9 The study of the geometric and elastic properties of large arteries have improved our knowledge of the pathogenesis of monogenic diseases of the arterial wall complicated by arterial dissection and rupture, such as Marfan10 and vascular Ehlers-Danlos syndromes.11 Marfan and vascular Ehlers-Danlos patients have a higher circumferential wall stress than age-, blood pressure-, and sex-matched controls, which could explain the higher risk of arterial dissection.
In the present study, we used a high-resolution echotracking system to noninvasively characterize, in patients with previous sCAD, the arterial phenotype of conducting arteries: the common carotid arteries, the abdominal aorta, and a more distal and muscular artery, the radial artery (RA). We hypothesized that conducting arteries of sCAD patients would undergo a higher level of circumferential wall stress than control subjects.12,13 Because age, gender, and vascular risk factors are major determinants of arterial geometric and elastic properties, we compared sCAD patients with controls having similar age, sex ratio, and cardiovascular risk factors.
Patients and Methods
Among the 85 patients who were hospitalized for a sCAD in the department of Neurology of Sainte-Anne Hospital over an 8-year period (between the end of 1995 and the beginning of 2003), 35 were selected on geographical criteria to be contacted by mail and telephone. Among these 35 patients, one declined and 34 volunteered to participate. Among the remaining 34 patients, 2 were not available because of professional reasons; thus, 32 patients were recruited in the present study.
Cervical artery dissections were spontaneous. Cases with a traumatic cause, differing from a history of a minor precipitating event, which was elicited in some of our patients, were excluded from this study. The median delay between event and examination of sCAD was 2.2 years. Diagnosis of sCAD was made on the basis of magnetic resonance imaging and magnetic resonance angiography or digital subtraction angiography. Among 32 patients, 29 had a mural hematoma on cervical magnetic resonance imaging, and 3 had classical angiographic signs. One patient had a history of connective tissue disorder but did not meet the criteria of any of named syndrome. Initial clinical presentation was an ischemic stroke in 20 patients (62.5%), transient ischemic attack in 3 (9.4%), and isolated local signs in 9 (28.1%). Overall, there were 30 internal carotid artery and 13 vertebral artery dissections. Nine patients (28%) among 32 had multiple sCAD. Sixteen patients had unilateral carotid artery dissection.
Patients with sCAD were compared with control subjects having similar age, sex ratio, and cardiovascular risk factors. Thirty-two control subjects with no history of cervical artery dissection were recruited either from the outpatient clinic for cardiovascular prevention at Georges Pompidou European Hospital or among the staff of Sainte-Anne Hospital. Twenty-one controls were recruited among staff members and 11 among outpatients consulting at the outpatient clinic for cardiovascular prevention. Only 2 staff members had hypertension (1 was treated and 1 had borderline hypertension and received no treatment), whereas all outpatients had hypertension. Thus, in each group (sCAD and controls), 12 subjects had sustained hypertension, treated or not. Standardized questionnaire summarizing the personal and family history and risk factors were completed at inclusion for sCAD patients and control subjects. This study was approved by the institutional ethic committee of Saint-Germain Hospital (Paris), and all subjects signed a written inform consent.
All patients and subjects were studied in a quiet room with controlled temperature of 22±1°C as previously described.14,15 Blood pressure was monitored with an oscillometric method (Dinamap model 845, Critikon). End-diastolic internal diameter, pulsatile changes in diameter, and intima-media thickness (IMT) were measured on the right and left common carotid artery (CCA) and on the right RA with high-precision echotracking devices (Wall Track System16 and NIUS 021 respectively), as previously described and validated.10,11,14,15
Because IMT and lumen diameter are, together with mean blood pressure, the determinants of circumferential wall stress, we calculated the latter and used the Lamé equation11,13 with σθ (kPa)=(MBP·Dm)/2hm (where MBP is mean blood pressure and Dm and hm are the mean values of internal diameter and wall thickness during the cardiac cycle). Circumferential wall stress represents the tensile stress that is applied in the tangential direction to the arterial wall to enlarge the lumen. Right and left common carotid arteries and RA pressure waveforms were recorded noninvasively with a pencil-type probe incorporating a high-fidelity Millar strain gauge transducer (SPT-301, Millar Instruments), as previously described and validated.10,12
The elastic properties of the artery as a hollow structure were assessed through arterial distensibility, determined from the systolic-diastolic variations in arterial cross-sectional area (ΔA) and local pulse pressure (ΔP), as previously described,15 assuming the lumen to be circular. Cross-sectional distensibility coefficient (DC) was calculated as DC=ΔA/A·ΔP, where A is the diastolic lumen area, ΔA is the systolic change in lumen area, and ΔP is local pulse pressure. Cross-sectional compliance coefficient (CC) was calculated as CC=ΔA/ΔP. Local carotid and RA pulse pressure, directly measured with aplanation tonometry, were used in these calculations. The elastic properties of the arterial wall material were estimated by the incremental Young’s elastic modulus (Einc), calculated as previously described15 as Einc=[3(1+A/WCSA)]/DC, where A is the diastolic lumen area, WCSA is the mean wall cross-sectional area, and DC is the cross-sectional distensibility.
Abdominal aorta diameter, relative change in aortic diameter during cardiac cycle, and carotid-femoral pulse-wave velocity were measured as previously described and validated.10,17 The augmentation index of the carotid pressure wave, ie, the percentage of pulse pressure attributable to a premature reflected pressure wave, was automatically computed by the Sphygmocor system (PWV Medical) as previously described.10–12
Qualitative data on carotid artery wall echostructure, obtained by RF signals and B-mode scans, were transformed into a quantitative phenotypic score, as previously described,19 and compared between sCAD and controls. Briefly, B-mode scans and RF signals were scored according to the presence of a normal double-line pattern, a triple signal pattern,19 and intermediate aspects, providing a phenotypic score ranging from 2 (strictly normal) to 7 (the most abnormal) for each carotid artery.
Quantitative variables were compared by means of unpaired Student t test or ANOVA. Associations between arterial parameters and quantitative factors were analyzed with robust multiple linear regression procedure (including diagnosis as dummy variable). A logistic regression was performed to determine the value of Young’s elastic modulus as a marker of sCAD. All tests were performed using NCSS 2000. Data are expressed as mean±SD; P<0.05 was considered significant, and tests were 2-sided.
Clinical features of sCAD patients and controls are presented in Table 1. Both groups were comparable for sex, age, height, weight, body surface area, body mass index, systolic blood pressure, mean blood pressure, brachial pulse pressure, heart rate, hypercholesterolemia, cigarette smoking, and diabetes. Diastolic blood pressure was significantly higher in sCAD patients than in controls.
Arterial parameters of the right CCA were compared with those of the left CCA, both in sCAD and in controls. In each group, the only significant difference (2-way ANOVA, P<0.01) between right and left CCA parameters concerned the absolute and relative changes in diameter during cardiac cycle, which were higher at the site of the right CCA than the left (absolute changes in diameter: 411±144 versus 372±130 m·10−6, right versus left in sCAD; 534±221 versus 489±200 m·10−6, right versus left in controls; relative changes in diameter: 5.9±2.1% versus 5.3±1.8%, right versus left in sCAD; 7.9±3.6% versus 7.6±3.6%, right versus left in controls). No significant interaction was observed between the side of the investigated CCA (right versus left) and the group (sCAD versus controls).
In 16 patients with unilateral carotid artery dissection, we also compared arterial parameters of the ipsilateral CCA to those of the contralateral CCA. No significant difference was observed.
Under these conditions, we calculated the mean value of right and left CCA in each subject, either sCAD or control, and used it for further statistical analysis. Combined right and left CCA parameters are presented in Table 2. Absolute and relative changes in diameter during cardiac cycle were significantly lower in sCAD patients than in controls. Cross-sectional distensibility and compliance were significantly lower in sCAD than in controls but did not differ after adjustment on diastolic blood pressure. Internal diastolic diameter, IMT, wall cross-sectional area, and local pulse pressure did not differ between sCAD patients and controls.
Circumferential wall stress and Young’s elastic modulus (Einc) were significantly higher in sCAD patients than controls: +14% and +58%, respectively. The contribution of sCAD to CCA Young’s elastic modulus was tested in a multivariate analysis: sCAD explained 9.0% of the variance of the Young’s modulus, independently of age and mean blood pressure, in a model explaining 53% of the variance. To further assess the value of CCA Young’s elastic modulus as a marker of sCAD, we used a logistic model in which the lowest tertile of CCA Young’s elastic modulus served as reference (Table 3). The risk of sCAD increased with each tertile of Young’s modulus. Because controls are more frequently male than are cases, a subanalysis was performed in males only and showed that all differences between cases and controls remained significant in males, except for compliance. The carotid artery geometric and elastic properties of the patient who had a history of connective tissue disorder were within the mean±1SD of the sCAD group.
Other Arterial Parameters
Geometrical and functional parameters of the RA did not differ between sCAD and controls (Table 4). Diastolic diameter of the abdominal aorta and its relative change during cardiac cycle, carotid-femoral pulse-wave velocity, and carotid augmentation index did not differ between sCAD patients and controls (Table 5). The phenotypic score of the CCA was significantly higher in sCAD patients than in controls (6.1±1.4 versus 5.2±1.4, P=0.023).
The main result of the present study is the higher circumferential wall stress and stiffness of the carotid wall material in sCAD patients than in controls.
We used a biomechanical approach to detect changes in arterial wall mechanics, which could favor dissection. Conducting arteries undergo cyclic stress, which may alter the load-bearing elements of the arterial wall, like collagen, through the mechanical effects of fatigue. According to engineering principles, the fatiguing effect of cyclic stress is dependent on the number of cycles and the amplitude of stress.12,13 Aging and circumferential wall stress may be considered as practical estimates of the number of cycles and the amplitude of stress, respectively. Circumferential wall stress is tensile, as is the ratio of the wall tension (force; given by the law of Laplace) on wall thickness. We thus hypothesized that conducting arteries of sCAD patients would undergo a higher level of circumferential wall stress than those of control subjects. In sCAD patients, the increase in CCA circumferential wall stress, higher than in control (+14%), may explain the higher risk for dissection.
A well-characterized heritable connective tissue disorder has been identified in 1% to 5% of patients with sCAD.2,3 One fifth of patients have a clinically apparent but unnamed connective tissue disorder.2,3,6 Thus, it was mandatory to select sCAD patients without connective tissue disorder to determine the specific mechanical properties of conducting arteries in sCAD patients. In the present study, only 1 patient had a history of connective tissue disorder but did not meet the criteria of a named syndrome. Excluding this patient from the statistical analysis did not change the results.
Interestingly, we previously observed a significant increase in circumferential wall stress in 2 monogenic diseases complicated by sCAD.10,11 Patients with vascular Elhers—Danlos syndrome have a higher carotid circumferential wall stress, compared with age-, blood pressure-, and gender-matched controls,10 because of a lower IMT. In patients with Marfan syndrome, the enlargement of the ascending aorta leads to an increase in circumferential wall stress.10 In sCAD patients of the present study, the higher circumferential wall stress (+14%) was lower than that in vascular Elhers-Danlos syndrome (+43%) or Marfan syndrome (+37%).10,11
To further analyze the mechanical properties of the carotid artery wall, we calculated the Young’s elastic modulus, which provides direct information about the elastic properties of the wall material.15 Patients with sCAD had a 58% higher Young’s elastic modulus than controls, indicating a stiffer wall material. In multivariate analysis, Young’s elastic modulus proved to be a good marker of sCAD (Table 3). For a given circumferential wall stress, Young’s elastic modulus was higher in sCAD patients than controls but lower in vascular Ehlers-Danlos patients than controls.11 These data indicate that the mechanical properties of the carotid artery wall material are different between sCAD and vascular Ehlers-Danlos, and suggest a proper pathogenesis for sCAD. In previous works concerning hypertensive patients and animals,14,15,19 and monogenic diseases of the arterial wall,9,10 we demonstrated that the Young’s elastic modulus of the artery was influenced not only by the respective amounts of elastic and stiff materials but also by their 3-dimensional organization and their effects on smooth muscle cell growth and phenotype. In addition, the natural history of the diseases differs,20,21 with a very low risk of recurrence of dissection or ischemic event (0.3% per year) in patients with a previous sCAD.20
The abnormal elastic properties in sCAD patients are restricted to the carotid arteries, with no significant change in elastic and geometrical properties at the site of the RA and the abdominal aorta. These data are consistent with the natural history of the disease.
The increased stiffness of the CCA in sCAD patients unlikely represent a scar of a previous dissection, in contrast to aneurysms, which frequently persist after carotid artery dissection.22 Abnormal elastic properties were observed at the site of the CCA in sCAD patients independently of the site of dissection (ipsilateral or controlateral, carotid or vertebral artery) and the number of dissected arteries.
Very few data are available concerning the geometric and elastic properties of conducting arteries in patients with sCAD. Only 1 study compared the geometric properties of the carotid artery in patients with spontaneous internal carotid artery dissection and control subjects by ultrasonography.9 The authors showed an increase in the systolic change in diameter at the site of the CCA in sCAD, in contrast to what we observed. This discrepancy may be caused by the methodology used for diameter measurement. Classical bidimensional echography may overestimate the systolic change in diameter, compared with echotracking systems.14–18 In addition, systolic change in diameter is highly influenced by local pulse pressure. Thus, the elastic properties of the carotid artery, ie, distensibility (ΔA/A·ΔP) or compliance, are best determined through the measurement of both systolic change in diameter and local pulse pressure.12,14–17 Local pulse pressure has not been measured in this previous work.9 In the present study, CCA distensibility was lower in sCAD than in controls, and this difference was no more significant after adjustment to diastolic blood pressure.
The heterogeneity of the CCA echostructure was studied with an echographic phenotypic score previously used in patients with renal fibromuscular dysplasia.19 In the present study, sCAD patients had a 17% higher phenotypic score than controls (6.1±1.4 versus 5.2±1.4; P=0.023). Although the increase was small, compared with that observed in the CCA of patients with fibromuscular dysplasia (+62%),19 this indicates a higher heterogeneity of the CCA echostructure in sCAD patients than in controls. We suggest that the increase in the stiffness of the wall material was anisotropic, thus enhancing concentrations of circumferential tensile stress and increasing the risk of arterial dissection. We can speculate that arterial dissection may occur preferentially at a younger age because the wall material, which is highly heterogeneous and anisotropic in younger affected patients, becomes more homogeneous with aging and arteriosclerosis in response to various mechanisms, including an increased number of collagen and elastin cross-links, less prone to arterial dissection.
Although the abnormal arterial mechanical properties described could represent a constitutional risk factor for sCAD, environmental factors such as infection or minor precipitating event appears to be essential.2,3,23 The necessity of this association could explain why sCAD is a relatively rare disease and why recurrent dissection are exceptional.
In conclusion, carotid arteries, but not aorta and RA, displayed abnormal elastic properties in sCAD patients. Higher stiffness of carotid wall material and circumferential wall stress could increase the risk of dissection in these patients.
This study received financial support from Institut National de la Santé et de la Recherche Médicale (INSERM), Journées de Neurologie de Langue Française (JNLF), and Hôpital Sainte-Anne, Paris. We are deeply indebted to Isabelle Gautier for her technical assistance. All persons mentioned have seen and approved mention of their names in the article.
- Received January 23, 2004.
- Revision received May 21, 2004.
- Accepted May 26, 2004.
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