Symptomatic Carotid Artery Stenosis: Heterogeneity of Destabilizing Mechanisms?
To the Editor:
In a recent issue of Stroke, Stork and coworkers published their work on the relationship between the gross morphological characteristics of high-grade carotid artery thrombendarterectomy (TEA) specimens and the rate of cerebral microemboli in the ipsilateral middle cerebral artery measured preoperatively.1 They found a higher percentage of microemboli-positive patients (31% versus 13%, P=0.046) and a higher percentage of plaque ulcers (71% versus 47%, P=0.002) in the symptomatic group.1 In contrast, they did not confirm previous findings of a positive association between plaque ulceration or lumen thrombus and occurrence/rate of ipsilateral cerebral microemboli.1–4⇓⇓⇓ They concluded form their findings that small platelet aggregates or fibrin clots originating from a macroscopically intact plaque surface rather than thrombus formation caused by deep plaque surface defects are responsible for microemboli detectable downstream of a high-grade carotid stenosis.1
This very interesting study raised again the long-standing question after the correlation between any plaque-related morphological feature and clinical symptoms or surrogate markers of plaque instability (ie, cerebral microemboli) in high-grade carotid stenosis. The heterogeneity of the studies published thus far may be partially explained by the following reasons:
First, patient classification with respect to the presence of attributable clinical symptoms is sometimes difficult, because patients report their symptoms imprecisely, some symptoms are not definitely attributable to a single vascular territory alone or, alternatively, to an embolic pathogenesis, and others can pass unnoticed during sleep. Furthermore, in a single stroke patient several concurrent etiologies can be present. Additionally, it has been shown that in symptomatic patients different clinical presentations (ie, amaurosis fugax, hemispheric TIA, minor stroke) are associated with a substantially different future stroke risk.5 Presurgical drug treatment may also have an impact. Therefore, differences in study population characteristics can influence prevalences of pathoanatomic features derived from corresponding specimens.
Second, methodological problems also contribute to this issue. Different surgical techniques provide specimen with various quality for pathomorphological analyses. Longitudinal arteriotomy provides gross inspection of the vessel lumen intraoperatively by the surgeon but may disturb microscopic evaluation by dissecting the mostly eccentrically located atherosclerotic plaque. This can make it difficult to differentiate between spontaneous or artificial plaque fissuring. Intact pathoanatomy can be studied microscopically in specimen obtained from eversion TEA but, unfortunately, do not allow gross inspection. However, microscopic evaluation in transverse or longitudinal sections at 2- or 3-mm intervals throughout the entire plaque usually bears the risk of missing plaque erosions, fissures, or even small ulcerations. In contrast and also raised by the authors, nonblinded evaluation by the operating surgeon may harbor substantial bias.1
Third, there is some evidence that there might be a heterogeneity of biological mechanisms leading to symptom development. In previous series, the percentage of specimen derived from symptomatic patients without evidence of plaque surface disruption ranged from 29% to 52%.1,4⇓ In contrast, 18% to 50% of asymptomatic patients revealed plaque rupture. Furthermore, some authors reported the occurrence of intraluminal thrombus formation on a microscopically intact plaque surface.6 In the coronaries, Farb et al described thrombus formation on unruptured atherosclerotic plaques as a frequent histological substrate for acute coronary syndromes and defined these plaques as “eroded.”7 Nevertheless, the cellular and molecular mechanisms for this prothrombotic change of the visually intact intralesional endothelium remain unknown. Therefore, we believe that there is increasing evidence for plaque instability defined by clinical measures and/or microemboli detection without plaque surface disruption in atherosclerotic carotid artery disease, as it is hypothesized in the present study. Probably morphological or functional changes of the endothelium overlying the atherosclerotic plaque (ie, apoptotic cell death) need to be more elucidated using microemboli detection as a helpful surrogate marker and indicator of increased procoagulant activity of the atherosclerotic plaque.
- ↵Stork JL, Kimura K, Levi CR, Chambers BR, Abbott AL, Donnan GA. Source of microembolic signals in patients with high-grade carotid stenosis. Stroke. 2002; 33: 2014–2018.
- ↵Sitzer M, Muller W, Siebler M, Hort W, Kniemeyer HW, Jancke L, Steinmetz H. Plaque ulceration and lumen thrombus are the main sources of cerebral microemboli in high-grade internal carotid artery stenosis. Stroke. 1995; 26: 1231–1233.
- ↵Golledge J, Greenhalgh RM, Davies AH. The symptomatic carotid plaque. Stroke. 2000; 31: 774–781.
- ↵Carr S, Farb A, Pearce WH, Virmani R, Yao JS. Atherosclerotic plaque rupture in symptomatic carotid artery stenosis. J Vasc Surg. 1996; 23: 755–765;discussion 765–766.
- ↵Farb A, Burke AP, Tang AL, Liang TY, Mannan P, Smialek J, Virmani R. Coronary plaque erosion without rupture into a lipid core: a frequent cause of coronary thrombosis in sudden coronary death. Circulation. 1996; 93: 1354–1363.
We thank Drs Trotsdorf and Sitzer for their interest in our article and for their explanation of inconsistent results among studies correlating microemboli and plaque morphology.
Detection of microemboli is probably the strongest predictor of early postoperative stroke following carotid endarterectomy.1 As a surrogate marker of plaque instability and increased procoagulant activity, as suggested by Drs Trotsdorf and Sitzer, detection of microemboli may be an important predictor of stroke in patients with carotid stenosis. However, only after completion of ongoing cohort studies, for example the Asymptomatic Stenosis Embolus Detection Study,2 can we determine if microembolus detection is superior to symptom status and degree of stenosis for predicting stroke.
- ↵Levi CR, O’Malley HM, Fell G, Roberts AK, Hoare MC, Royle JP, Chan A, Beiles BC, Chambers BR, Bladin PF, Donnan GA. Transcranial Doppler detected cerebral microembolism following carotid endarterectomy: high microembolic signal loads predict postoperative cerebral ischaemia. Brain. 1997; 120: 621–629.