Aortic Root Dilatation in Patients With Spontaneous Cervical Artery Dissection
Background Spontaneous cervical artery dissections are a relatively common cause of ischemic stroke in young adults. Their mechanism is unknown, though it is generally assumed that an underlying minor form of extracellular matrix defect could exist. The present study tested the hypothesis that aortic and cardiac morphological abnormalities usually seen in patients with heritable connective diseases are more frequent in patients with spontaneous cervical artery dissections than in patients without such dissections.
Methods and Results We performed a case-control study of 28 case patients with spontaneous cervical artery dissection and 84 control subjects with an ischemic stroke not due to cervical artery dissection. Control subjects were matched to case patients for age (±5 years), sex, and year of hospitalization. The aortic root was more frequently enlarged (ie, diameter >34 mm) in case patients (56%) than in control subjects (15%). Mitral valve prolapse, mitral valve dystrophy, and aortic valve dystrophy were more frequent in case patients than in control subjects. In multivariate analyses, aortic diameter >34 mm was the only variable associated with an increased risk of spontaneous cervical artery dissection (odds ratio, 14.2; 95% CI, 3.2 to 63.6; P<.001).
Conclusions These results suggest that aortic root diameter enlargement is associated with an increased risk of spontaneous cervical artery dissection. This finding is consistent with the idea that a generalized defect of the extracellular matrix is present in patients with spontaneous cervical artery dissection.
Cervical artery dissection accounts for up to 20% of strokes in young adults.1 An underlying arterial wall disease is often suspected, particularly in spontaneous cervical artery dissection (SCAD), and indeed, a few cases have been reported in patients with heritable connective tissue disorders such as Marfan's syndrome, Ehlers-Danlos syndrome, pseudoxanthoma elasticum, and polycystic kidney disease.2 3 4 These diseases are also frequently associated with aortic and valvular abnormalities that are considered markers of the extracellular matrix defect.5 In patients with SCAD, typical heritable connective tissue disorders are rarely found, but a minor form of a general extracellular matrix defect might nevertheless exist. An important argument supporting this hypothesis would be an association between SCAD and the valvular and aortic morphological abnormalities usually seen in general extracellular matrix defect. The purpose of the present study was to compare cardiac and aortic morphology in patients with SCAD and in control subjects.
We studied 28 patients (10 men and 18 women; mean age, 45.5±7.9 years) with SCAD who were admitted consecutively in our department from November 1992 through February 1995. Cervical artery dissections were all confirmed by duplex scanning and MRI or angiography. Clinically, none of the case patients had any skin, joint, eye, or skeletal abnormalities suggesting a heritable connective tissue disorder. Each case patient was matched for age (±5 years) and sex to 3 control subjects hospitalized during the same year for an ischemic stroke not due to arterial dissection and randomly selected from our stroke files.
All case patients and control subjects had two-dimensional transthoracic echocardiography followed by a transesophageal echocardiography. M-mode tracings were obtained under two-dimensional guidance. Measurements were made perpendicularly in the long axis of the aorta by use of the leading-edge technique at the level of the valve leaflets.6 Up to three cycles of the aortic diameter were marked on stop-framed images, measured, and averaged by use of calipers. Transesophageal echocardiography was performed according to a previously described methodology.7 We used commercially available imaging systems (VingMed CFM 700, CFM 800, and Acuson XP128) with 5-MHz biplane and multiplane probes. Mitral valve prolapse was diagnosed by excursion of one or both mitral leaflets superior to the plane of the mitral annulus in the parasternal long-axis view on transthoracic two-dimensional echocardiography.8 Atrial septal aneurysm was defined as a redundant, hypermobile atrial septum usually involving the entire septum or located in the region of the fossa ovalis. The criteria for diagnosis of aneurysmal atrial septum included a base width ≥15 mm and an excursion beyond the plane of the atrial septum or phasic excursion during the cardiorespiratory cycle of ≥15 mm.9 Tricuspid valve prolapse diagnosis was based on the demonstration of superior movement or arcing of one or more of the tricuspid leaflets above the plane of the tricuspid annulus in the apical four-chamber view.10 Valve thicknesses were measured off-line on stop-framed transesophageal echocardiography images. Mitral valve dystrophy was described as present when the thickness of the middle part of the anterior mitral leaflet was >3 mm.11 Aortic valve dystrophy was recognized as a cusp thickness >2 mm, measured in the middle region between the free edge and the annulus.12 The echocardiograms were analyzed off-line by two experienced observers without knowledge of the clinical status of the patient. The two reviewers (A.C. and N.L.) reached a consensus by a joint review of the echocardiograms. For technical reasons, aortic diameter was not available for one case patient and four control subjects.
The association between aortic root diameter or cardiac morphological abnormalities and risk of SCAD was expressed in terms of odds ratio (OR) obtained through conditional logistic regression with multiple controls per case. ORs adjusted for age and sex were first estimated for each morphological variable separately. Variables significantly associated with SCAD were then entered together into the same model, and a stepwise backward procedure was applied.
The mean aortic root diameter (SD) was 33.3 mm (5.3 mm) in case patients and 29.8 mm (4.7 mm) in control subjects (P=.002, Mann-Whitney U test). The Figure⇓ shows the relative frequency distribution of aortic diameter among case patients and control subjects. In control subjects, aortic diameter distribution had a bell-shape pattern, whereas in case patients, the distribution was characterized by an excess of subjects with high values of aortic diameter. Because of this heterogeneous distribution, we decided, for comparison between case patients and control subjects, to stratify aortic diameter by quartiles. Comparison by quartiles showed that the most dramatic difference between case patients and control subjects was for the highest quartile: 56% of the case patients had an aortic diameter >34 mm, compared with 15% in control subjects. Estimation of the risk of SCAD showed a clear threshold effect between the first three quartiles of aortic diameter and the highest quartile (Table⇓). We therefore used this cutpoint (ie, >34 mm and ≤34 mm) in further multivariate analyses.
Aortic and mitral valve dystrophy and mitral valve prolapse were significantly more prevalent in case patients than in control subjects (Table⇑). When aortic root diameter and valvular morphological abnormalities were taken into account in the same model, aortic root diameter >34 mm remained the only variable associated with an increased risk of SCAD (OR=14.2; 95% CI, 3.2 to 63.6; P<.001).
To the best of our knowledge, this is the first study to show that patients with SCAD have an enlarged aortic root compared with matched control subjects. This difference was due to a high proportion of case patients with a large aortic root diameter in comparison with control subjects. We also found that mitral and aortic valve dystrophy and mitral valve prolapse were more frequent in patients with SCAD. When all variables associated with SCAD were included in the same model, the only significant variable associated with the risk of SCAD was a large aortic root diameter. Selection biases are rather unlikely in this study: recruitment of case patients was consecutive, control subjects were randomly selected, and a transesophageal echocardiography is systematically performed in our stroke patients.
Aortic dilatation is a hallmark lesion of Marfan's syndrome and other diseases of the extracellular matrix that are known to be associated with a higher risk of spontaneous cervical artery dissections.5 Because a complete syndromic pattern was never observed in the present study, the aortic root dilatation observed in case patients reinforces the concept of a predisposing minor form of heritable connective tissue disorder in patients with SCAD. Additional evidence of generalized extracellular matrix involvement was the increased frequency of aortic and mitral valve dystrophy and mitral valve prolapse, which are known to occur more frequently in patients with connective tissue disorders.5 13
The reason why aortic enlargement seems to be present only in a group of patients with SCAD remains to be elucidated. The suspected extracellular matrix involvement might be more pronounced or more generalized in this subgroup of patients, who might therefore be an appropriate target group to further investigate the nature of the connective tissue disorders involved in SCAD. These future studies should also take into account other indirect signs, such as ultrastructural abnormalities of collagen and elastic fibers in skin biopsies.14 Finally, when feasible on a large scale, a genetic approach to detecting such underlying conditions might prove the most rewarding, although a recent study failed to show any evidence of this.15
These results suggest that aortic root enlargement is associated with an increased risk of SCAD. This finding supports the idea that a generalized defect of the extracellular matrix is present in patients with SCAD.
The authors are grateful to Dr Annick Alpérovitch for her thoughtful comments.
- Received February 27, 1997.
- Revision received March 17, 1997.
- Accepted March 18, 1997.
- Copyright © 1997 by American Heart Association
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