Aortic Plaque Morphology and Vascular Events
A Follow-up Study in Patients With Ischemic Stroke
Background Atherosclerotic disease of the aortic arch has been found to be associated with the risk of ischemic stroke. We have shown that atherosclerotic plaques ≥4 mm in thickness in the ascending aorta and proximal arch detected by transesophageal echocardiography are a risk factor for ischemic stroke. The purpose of this study was to evaluate the impact, if any, of plaque morphology (ulceration, hypoechoic plaques or calcification) on the risk of subsequent vascular events.
Methods and Results We followed for a period of 2 to 4 years, a cohort of 334 patients 60 years or older who were consecutively admitted with brain infarction and who had transesophageal echocardiography. The risk of vascular events in patients with plaques in the aortic arch according to the presence of surface ulceration, calcifications, and sessile or mobile thrombus was estimated during a total of 788 person-years of follow-up. Hypoechoic plaques, calcifications, and ulceration were more frequently found in patients with plaques ≥4 mm as compared with those with plaques <4 mm. The presence of ulceration did not increase the relative risk of vascular events in patients with plaque ≥4 mm (the relative risk was 4.3 [P<.001] in those with ulceration and 5.7 [P<.001]) in those without ulceration. The lack of calcification did increase the risk of vascular events in patients with plaque ≥4 mm. The highest relative risk of events was found among the patients with noncalcified plaques (relative risk, 10.3; 95% confidence interval, 4.2 to 25.2; P<.001). The risk of events was systematically higher in patients without calcifications than in patients with calcifications regardless of what other morphological features were considered.
Conclusions In patients with brain infarction, the risk associated with aortic plaque thickness (≥4 mm) is markedly increased by the absence of plaque calcifications. These findings are important for the design of therapeutic trials in such patients.
Although the thoracic aorta has been recognized as a site of predilection for atheroma, atherosclerotic disease of the aortic arch was not regarded as a potential source of emboli until recently.1 2 3 4 5 6 7 8 The advent of transesophageal echocardiography has made possible the in vivo assessment of cardiac and vascular structures that could not have been studied by other diagnostic modalities.1 2 3 5 6 7 We7 and others2 5 8 have shown that protruding plaques in the aortic arch are a strong risk factor for ischemic stroke and for the overall vascular risk at follow-up.9 10 11 From these series, plaque thickness can be regarded as the most important factor. Other morphological parameters such as ulcerations, calcifications, and hypoechoic plaques have also been studied but generally were not matched with the information on plaque thickness.2 6 8 11 Stone et al14 and Di Tullio et al8 have suggested that transesophageal echocardiography (TEE)-detected ulcerations are more frequent in patients than in control subjects, this concuring with what we found at autopsy.4 In this study, we sought to evaluate the prognostic impact, if any, of the presence of ulceration, hypoechoic plaque, or calcification on the risk of subsequent vascular events.
The overall design of the French Study of Aortic Plaques in Stroke has been described elsewhere.7 9 Three hundred thirty-eight consecutively recruited patients with brain infarctions, all older than 60 years, were followed up for a mean of 2.3 years. Four patients were lost to follow-up and were therefore not considered in the analysis. Plaque thickness could not be assessed in 3 patients (0.9%), calcifications and ulceration in 14 patients (4.1%), and hypoechoic plaque in 17 patients (5.0%). Vascular risk factors including age, sex, tobacco smoking, diabetes, hypercholesterolemia, hypertension, history of myocardial infarction, and peripheral arterial disease were analyzed for each morphological feature. Vascular events included brain infarction defined as new focal symptoms lasting more than 48 hours, other vascular events such as retinal artery occlusion, myocardial infarction, peripheral embolism, bowel infarction, and death from a vascular cause including sudden death were considered. During the 754 person-years of follow-up, 98 vascular events were observed in 72 patients: 32 brain infarctions, 12 myocardial infarctions, 12 peripheral embolisms, and 42 vascular deaths.
Transesophageal Echocardiographic Assessment of the Aorta
Patients underwent TEE performed by trained cardiologists according to a standardized protocol that allowed an extensive evaluation of the thoracic aorta.7
Measurement of plaque thickness. Two-dimensional cross-sectional and longitudinal views of the different segments of the thoracic aorta were visualized with the ultrasound beam placed perpendicularly to the inner wall of the vessel.12 Plaque thickness measurements were done off-line on video-recorded tapes in the ascending aorta and proximal arch, according to a previously described methodology.7
Plaque morphology. The presence of disruption or marked irregularities of the plaque surface define ulceration (≥2 mm in depth and width). Focal increased echo density within the aortic plaque combined to a broad acoustic shadow define the presence of calcifications. The echocardiographic diagnosis of a hypoechoic plaque was described as a laminated or “layered” deposition along the involved intimal surface, with variable echogenicity sometimes with a thin border of relative echolucency along the margins of the thrombus. Hypoechoic plaques may be associated with mobile lesions suggesting a “debris” or a free-floating thrombus.3 13
Our previous reports showed a clear threshold effect of the risk of vascular event according to plaque thickness.7 9 We therefore dichotomized plaque thickness in the ascending aorta and proximal arch in plaques <4 mm and ≥4 mm. In a first step, the relative risk of vascular events was estimated for each morphological aspect considered separately (ie, ulceration, calcifications, hypoechoic plaques), taking into account variables that were shown to influence the risk in a Cox model such as age, sex, treatment, atrial fibrillation, and carotid stenosis.9 In a second step, we estimated the risk of the combination of plaque thickness with any other morphological abnormality. We decided to limit the combinations to two morphological features in order to ensure a significant power throughout the analyses and to limit the number of statistical tests. The data were analyzed with the use of SAS package.
Plaques ≥4 mm in thickness in the ascending aorta and proximal arch were present in 45 patients (13.4%), ulceration in 71 (21.9%), plaque calcifications in 128 patients (39.8%), and hypoechoic plaques in 29 (9.0%). Patients with morphological abnormalities were significantly older and had a higher prevalence of peripheral arterial disease than those without those abnormalities. Patients with plaques ≥4 mm or with hypoechoic plaques were more frequently smokers than those with plaques <4 mm. There was no other significant difference with regard to the distribution of vascular risk factors (sex, diabetes, hypercholesterolemia, hypertension, history of myocardial infarction) in patients with or without morphological plaque abnormalities.
All morphological abnormalities were more frequent in patients with plaques ≥4 mm than in those with plaques <4 mm, respectively; 79.6% and 12.9% for ulceration (P<.001), 76.2% and 34.4% for calcifications (P<.001), and 60.5% and 1.1% for hypoechoic plaques (P<.001). In a Cox model, the relative risk of vascular events was significantly increased for thickness, ulceration, and thrombus but not for calcifications (Table 1⇓) or mobile debris (11.4 and 9.5 per 100 person-years, respectively).
The relative risks of vascular events for combinations of morphological abnormalities are shown in Table 2⇓. The highest risk was observed in the absence of plaque calcifications (relative risk, 10.3, 95% confidence interval 4.2 to 25.2, P<.001). As shown in the Figure⇓, the relative risk of vascular events was higher in patients without plaque calcifications than in patients with calcifications, regardless of what other morphological features were considered.
The present prospective study confirms that plaques ≥4 mm in the ascending aorta and proximal arch impart a high risk of subsequent vascular events. Furthermore, in patients with plaques ≥4 mm, the lack of calcification imparts a much higher risk of recurrent events (relative risk, 10.3). Combination of thickness and ulceration or thickness and hypoechoic plaque was not predictive of a higher risk when compared with plaque thickness alone. In fact, noncalcified plaques were systematically associated with a higher risk of vascular event when combined to any of the other morphological features, ulceration, or hypoechoic plaques.
The current study is the first one in which such morphological analysis of aortic plaques was systematically performed. Case-control studies, using autopsy material4 and TEE,8 14 have shown a significant association between ulcerated plaques in the aortic arch and the risk of ischemic stroke. However, in the present follow-up study, TEE-detected plaque ulcerations had no additive prognostic value when we considered plaques ≥4 mm. In addition, none of the previous studies have evaluated the risk associated with each morphological plaque feature (mobile lesions,2 3 8 presence of calcification15 16 17 ) compared with plaque thickness measurement.
The reason noncalcified plaques ≥4 mm in the ascending aorta and proximal arch were associated with a very high risk of vascular events at follow-up (incidence rate, 63.4 per 100 person-years) remains to be elucidated. Our results suggest that vulnerable aortic arch plaques are rather those ≥4 mm thick, which are noncalcified and hypoechoic. The noncalcified plaques are probably the lipid-laden plaques, which have been shown to be unstable in the coronary arteries and prone to rupture and thrombosis.18
A major limitation of morphological analysis of aortic plaques is the lack of pathological correlation between plaque morphology analyzed with ultrasound and at histology. Toyoda et al16 and more recently Laperche et al17 have reported results suggesting that TEE had the potential to detect complicated atherosclerotic lesions in the thoracic aorta more accurately than did plain radiography,16 computed tomography,16 or angiography.16 17 Finally, because of relatively small numbers, we could not evaluate specifically the risk associated with superimposed mobile lesions or with the combination of three or four morphological features.
New approaches, including three-dimensional TEE, ultrasonic tissue characterization,19 20 and magnetic resonance imaging21 as well as pathological correlations18 may help recognize vulnerable aortic arch plaques and their natural history. Our findings, if confirmed, would be of interest from a clinical point of view because they could help to define a group of patients at very high risk of vascular events. These results also may be important for the design of therapeutic trials in such patients.
In patients with brain infarction, the risk associated with aortic plaque thickness (≥4 mm) is markedly increased by the absence of plaque calcifications.
This study was supported by grants from the Institut National de la Santé et de la Recherche Médicale (CNEP 92CN23) and from the Direction de la Recherche Clinique de l’Assistance Publique-Hôpitaux de Paris (n°922601).
Presented in part at the 67th Scientific Sessions of the American Heart Association, Dallas, November 14-17, 1994 and the 69th Scientific Sessions of the American Heart Association, New-Orleans, La, November 10-13, 1996.
- Received July 9, 1997.
- Revision received September 26, 1997.
- Accepted September 30, 1997.
- Copyright © 1997 by American Heart Association
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