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(Stroke. 1995;26:614-619.)
© 1995 American Heart Association, Inc.

Articles

Ultrasonographic Correlates of Carotid Atherosclerosis in Transient Ischemic Attack and Stroke

Arcangelo Iannuzzi, MD; Timothy Wilcosky, PhD; Michele Mercuri, MD, PhD; Paolo Rubba, MD; Fred A. Bryan, PhD M. Gene Bond, PhD

From the Institute of Internal Medicine and Metabolic Diseases, Medical School, Federico II University, Naples, Italy (A.I., P.R.); Research Triangle Institute, Research Triangle Park, NC (T.W., F.B.); and Division of Vascular Ultrasound Research, Bowman Gray School of Medicine, Winston-Salem, NC (M.M., M.G.B.).

Correspondence to Arcangelo Iannuzzi, MD, Institute of Internal Medicine and Metabolic Diseases, Medical School, Federico II University, Via S Pansini 5, 80131 Naples, Italy.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Atherosclerotic plaques in extracranial carotid arteries, particularly in the bifurcation of the common carotid and internal carotid arteries, may cause transient cerebral ischemia and stroke by lumen stenosis or plaque-related thromboembolism. B-mode ultrasound imaging has the capability of providing information on plaque thickness, characteristics, and location in carotid arteries.

Methods A retrospective analysis of 242 stroke and 336 transient ischemic attack (TIA) patients, recruited for the B-Scan Ultrasound Imaging Assessment Program, was performed to determine the ultrasonographic correlates of carotid atherosclerosis and acute cerebral ischemia. A matched case-control study design was used to compare brain hemispheres with ischemic lesions ("cases") to unaffected contralateral hemispheres ("controls") with regard to the presence and characteristics of carotid artery plaques.

Results The first set of analyses examined the association between the presence of carotid plaques ipsilateral to the brain lesion and the occurrence of stroke or TIA and showed an association with recent episodes of TIA and stroke (odds ratio [OR], 1.6; P=.03) but not with past episodes. In a subset (n=232) of patients with plaques in both carotid arteries and recent cerebral ischemic events, stroke was associated with ipsilateral carotid artery occlusion (P=.02). Lumen measurements at the site of the minimum residual lumen (MRL) diameter showed a significant association between a narrower lumen diameter in the carotid artery ipsilateral to case hemisphere and stroke (difference, 1.0 mm; P=.0003). TIA patients showed an association between both hypoechoic carotid plaques (OR, 3.0; P=.005) and the presence of longitudinal lesion motion (OR, 3.0; P=.02) with ipsilateral brain involvement. Plaque thickness at the MRL was positively correlated with both ipsilateral TIA (ipsilateral side, 4.4±0.15 mm; contralateral side, 3.9±0.16 mm; P=.007) and stroke (ipsilateral side, 4.2±0.23 mm; contralateral side, 3.3±0.21 mm; P=.0006).

Conclusions These data demonstrate significant relationships between carotid artery ultrasound plaque characteristics and ischemic cerebrovascular events. These findings encourage further prospective studies in asymptomatic subjects focused on echographic carotid plaque characteristics as predictors of subsequent TIA or stroke.

Key Words: atherosclerosis • carotid arteries • cerebral ischemia, transient • ultrasonics

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Extracranial atherosclerosis, particularly in the bifurcation of the common carotid and internal carotid arteries, is associated with transient ischemic attacks (TIAs) and stroke due to lumen stenosis and/or plaque rupture, with or without superimposed thrombosis.^{1 2} B-mode ultrasonic imaging provides structural detail of the vessel wall and atherosclerotic plaque.³ Neurological symptoms are associated with carotid plaques detected by real-time B-mode ultrasonography.⁴ Recently the severity and characteristics of asymptomatic carotid lesions estimated by B-mode ultrasonography have been closely related to the appearance of silent cerebral infarcts confirmed on magnetic resonance imaging.⁵ A critical and as yet an unanswered challenge is the in vivo identification of specific plaque characteristics (ie, site, size, morphology) that are predictive of future clinical outcomes.

The aim of this retrospective, case-control study was to determine the lesion characteristics associated with clinical events. A group of patients with TIA and/or stroke, randomized into the B-Scan Imaging Assessment Program, had bilateral carotid artery examination with high-resolution B-mode ultrasound, which evaluated plaque thickness, echogenicity, location, surface characteristics, and radial and longitudinal lesion motion.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects
The B-Scan Imaging Assessment Program included 1269 patients from five clinical centers (Bowman Gray School of Medicine, Winston-Salem, NC; Jefferson University Hospital, Philadelphia, Pa; the Miami Heart Institute, Miami, Fla; New England Deaconess Hospital, Boston, Mass; and the University of Rochester, Rochester, NY).

The target population was patients with signs and/or symptoms of carotid (n=1099) or peripheral (n=170) atherosclerotic disease who were scheduled for noninvasive testing and arteriography. Noninvasive testing included oculoplethysmography, periorbital Doppler flow analysis, spectral analysis of Doppler flow, and B-mode evaluation of the carotid arteries in patients with cerebrovascular symptoms in the carotid territory. Segmental Doppler pressures, pulse volume recordings, and B-mode evaluation of lower limb arteries were performed in patients with peripheral occlusive disease.

Among the 1099 patients with signs and/or symptoms indicating carotid artery disease, 1043 had a high-resolution B-mode carotid artery evaluation. A carotid endarterectomy procedure was performed in 478 patients. Cervical bruits were detected in 60% of the patients. The prevalence of cardiovascular risk factors was as follows: hypertension, 60%; cardiac disease, 53%; diabetes mellitus, 28%; current smoking, 42%; and previous smoking, 34%.⁶ The study population for the current analysis comprised the 549 patients with carotid artery disease who had a clinically diagnosed hemispheric ischemic stroke or TIA at any time before the B-mode evaluation. Of these patients, 61% were men with a mean age of 65 years (SD, 9.9 years), and 39% were women with a mean age of 64 years (SD, 10.6 years).

Patients were excluded if they had no previous stroke or TIA, stroke or TIA that was bilateral, stroke or TIA with undetermined hemispheric involvement, or brain stem involvement only. Thirteen patients were also excluded because their plaques at the site of the minimum residual lumen (MRL) were in the external carotid artery.

Clinical information was obtained by chart review of each patient's history and physical examination, including age, sex, history of hypertension, cardiac disease, diabetes mellitus, smoking habits, occurrence of cerebrovascular events, cerebrovascular symptoms, and medication for chronic conditions. Occurrence of TIA and stroke was categorized as recent (occurring 1 month before recruitment into the study) or past (occurring >1 month before).

B-Mode Ultrasound Imaging Method
A standardized B-mode ultrasound protocol was used to examine the extracranial carotid arteries. Training meetings were held for operators to standardize scanning and reading procedures.⁶ Ultrasound imaging was performed with the use of 7.5- and 10-MHz transducers (Biosound, Diasonics, Horizon Research Laboratory, and Picker). The protocol required an axial resolution of less than 0.5 mm at the focal point. Routine technical maintenance visits and phantom were used to ensure it throughout the study. B-scan images were performed and interpreted by operators who were unaware of history and physical findings of the patient. Eleven percent of the ultrasound scans were randomly assigned to a repeatability/variability study to evaluate within-reader and between-reader variation.⁷ Pulsed Doppler with spectral analysis was used to differentiate internal and external carotid arteries.

Carotid arteries were examined bilaterally at the levels of the common carotid, the bifurcation, and the internal carotid arteries from transverse and longitudinal orientations (ie, antero-oblique, lateral, and postero-oblique planes). Gain setting and continuous angling adjustments were used to optimize image quality.

Plaque was defined on the basis of accepted clinical standards, ie, as an arterial wall lesion that projected into the vessel lumen. The term "lesion width" used in this study refers to the arterial wall thickness at the site of plaque and was operationally defined as the distance between the lumen-intima and media-adventitia ultrasonic boundaries of the artery wall, which have been identified and validated as the lumen-intima and media-adventitia interfaces⁸ and are currently used in epidemiological studies and controlled clinical trials.⁹

Lumen diameter was defined operationally as the distance between the lumen-intima arterial wall boundaries. The MRL diameter on each side was identified, and the distance of this site from the flow divider separating the internal and external carotid arteries was determined.

Measurements of lesion width and lumen diameter were made at plaque sites, at the MRL, and at the reference point, ie, 6 mm above the flow divider, in the internal carotid artery. Lumen diameter was also measured at a standard location 15 mm below the flow divider, in the common carotid artery (Figure).⁷ Surface characteristics of the wall were qualitatively assessed as being smooth (a continuous boundary), irregular (an uneven, pitted boundary), or pocketed (a craterlike defect with sharp margins). Also, the ultrasonic reflectivity, ie, gray scale intensity of lesions (echogenicity) was assessed qualitatively as being on average either low (ie, bloodlike echogenicity), intermediate, or high (ie, intensely bright echogenicity). Radial wall motion, defined as changes in vessel diameter during the cardiac cycle, was qualitatively assessed as being present or absent both proximal and distal to the MRL site. Longitudinal plaque motion was evaluated (ie, present or absent) at the MRL site and defined as an apparent distal shift of the plaque axis.

View larger version (18K): [in this window] [in a new window]   Figure 1. Schematic representation of the type of measurements performed by B-mode ultrasound imaging of the carotid artery.

Statistical Analysis
The first set of analyses examined the association between the presence of plaques and the occurrence of stroke or TIA using four outcome variables: (1) recent stroke, ie, hemispheric strokes that occurred within 1 month from the ultrasound examination; (2) stroke at any time, ie, recent plus past strokes (patients with bilateral strokes resulting from episodes that occurred in contralateral hemispheres at different times were excluded); (3) recent TIA, ie, TIA within the past month; and (4) TIA at any time, ie, recent plus past TIAs.

A subsequent analysis focused on the large subset of patients with bilateral plaques and recent cerebrovascular ischemic events and examined plaque characteristics in relation to ipsilateral events. Only patients who had a hemispheric stroke or TIA within the month preceding the B-scan evaluation and who also had plaques in both the left and right carotid arteries were included in this analysis. Among the 232 patients who met these criteria, 73 had stroke and 171 had TIA. Twelve of these patients had both stroke and TIA, which were ipsilateral in all but one patient.

A matched case-control design was used to compare clinically affected brain hemispheres ("cases") with unaffected contralateral hemispheres ("controls") with regard to the presence and characteristics of carotid artery plaques. A case hemisphere was considered exposed if the ipsilateral carotid artery had the characteristic of interest; if the carotid artery ipsilateral to the control hemisphere had the characteristic, the control hemisphere was considered exposed. Odds ratios (ORs)¹⁰ were used to determine the strength of the association, and the McNemar ² test was used to determine the nominal statistical significance.¹¹ All tests were two-sided, and P<.05 was considered statistically significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Of the 536 patients in these analyses, 242 had a history of stroke, and 336 had a history of TIA (42 had both). The majority of ischemic events (110 of the strokes and 273 of the TIAs) occurred within the month before examination.

Most patients had bilateral plaques detected by ultrasound. However, Table 1 shows that among patients with unilateral plaques who had TIAs within the month before the examination, the prevalence of carotid artery lesions on the same side as the brain damage was 70% higher than the prevalence in the contralateral carotid artery (P=.04). When we combined patients who had a recent stroke or TIA, a similar difference was observed, with plaques 60% more frequent in the ipsilateral carotid than in the contralateral artery (P=.03) (Table 1).

View this table: [in this window] [in a new window]   Table 1. Presence of Plaques in the Carotid Arteries in Patients With Recent Stroke or Transient Ischemic Attack

When the analysis was expanded to include those with ischemic events at any time in the past, differences between ipsilateral and contralateral arteries regarding the presence or absence of lesions were no longer statistically significant. The large subset of patients with a hemispheric stroke or TIA in the month preceding the B-scan evaluation and who had plaques in both the left and right carotid arteries was analyzed separately. Patients who experienced a recent stroke had a higher prevalence of occlusion in the ipsilateral carotid arteries (P=.02) (Table 2), but no difference was present in plaque motion or plaque characteristics. In these patients lesion thickness (the sum of near and far wall thickness) at the MRL was 0.94 mm larger on the ipsilateral side compared with the contralateral side (ipsilateral side, 4.2±0.23 mm [mean±SEM]; contralateral side, 3.3±0.21 mm; P=.0006) and 0.42 mm larger at the reference point (ipsilateral side, 1.7±0.25 mm; contralateral side, 1.3±0.24 mm; P=.05). Residual lumen diameter was 1.01 mm narrower at the MRL on the ipsilateral side (ipsilateral side, 3.6±0.23 mm; contralateral side, 4.6±0.27 mm; P=.0003) and 0.55 mm narrower at the reference point (ipsilateral side, 5.1±0.28 mm; contralateral side, 5.6±0.23 mm; P=.02). There was no difference in lumen diameters between ipsilateral and contralateral sides at the standard location.

View this table: [in this window] [in a new window]   Table 2. Presence of Occlusion in the Carotid Arteries in Patients With Bilateral Carotid Lesions Who Experienced a Recent Stroke or Transient Ischemic Attack

Proximal and distal radial motion was a common feature of almost all carotids examined. In patients with recent TIAs, radial arterial motion distal to the lesion was less frequent (P=.01) in the ipsilateral compared with the contralateral carotid arteries (Table 3). Longitudinal lesion motion was present in approximately 37% of the examinations, was positively associated with thicker lesions at the MRL, and was more prevalent in the ipsilateral artery of patients with recent TIAs (P=.02) (Table 3). Low lesion reflectivity compared with combined moderate and high reflectivity was significantly associated with recent TIAs (P=.005), as were irregular plaque surfaces (P=.03) compared with combined smooth and pocketed surfaces (Table 4). In these patients lesions were thicker both at the MRL (ipsilateral side, 4.4±0.15 mm; contralateral side, 3.9±0.16 mm; P=.007) and at the reference point (ipsilateral side, 2.4±0.18 mm; contralateral side, 1.9±0.17 mm; P=.004) when comparing the ipsilateral artery with the contralateral asymptomatic side. Furthermore, the residual lumen diameter was smaller on the ipsilateral side at the reference point (ipsilateral side, 4.9±0.16 mm; contralateral side, 5.3±0.15 mm; P=.02), while no statistically significant difference in residual lumen diameters at the MRL was observed (ipsilateral side, 3.8±0.23 mm; contralateral side, 4.0±0.16 mm).

View this table: [in this window] [in a new window]   Table 3. Plaque Motion1 in Patients With Bilateral Carotid Lesions Who Experienced a Recent Transient Ischemic Attack

View this table: [in this window] [in a new window]   Table 4. Plaque Characteristics in Patients With Bilateral Carotid Lesions Who Experienced a Recent Transient Ischemic Attack

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
A critical question is why some carotid plaques result in clinical sequelae while others remain asymptomatic. There is conflicting evidence about the importance of lumen stenosis in predicting ischemic events. Lennihan et al,¹² in a retrospective review of 200 consecutive endarterectomies, demonstrated that patients with stenosis less than 75% were more likely than those with stenosis greater than 75% to have ischemic symptoms ipsilateral to endarterectomy. On the other hand, Imparato et al¹³ reported that 82% of patients with focal symptoms had stenosis greater than 70% on the ipsilateral side, while only 53% of patients with focal symptoms had stenoses greater than 70% on the contralateral asymptomatic side. Also, studies performed with duplex ultrasonography have produced different findings. Leahy et al¹⁴ found no difference when comparing percent carotid artery stenosis between symptomatic and asymptomatic sides. In contrast, Dempsey et al¹⁵ suggested that percent stenosis is an independent predictor of ipsilateral stroke. These discrepancies may be explained by the different definitions for asymptomatic sides. Our analytic model evaluated the differences in the prevalence of both ipsilateral and contralateral carotid plaques in patients with hemispheric TIA or strokes. Our approach allows internal comparisons and resembles a study of identical twins. This model provides a perfect matching for genetic determinants as well as cardiovascular risk factors. By controlling for these determinants of stroke and TIA through matching, the study investigates the atherosclerotic determinants of brain lesions. Because these ischemic outcomes are fairly rare in the general population, ORs can be interpreted as relative risk.¹⁶ In our experience the majority of the patients had bilateral plaques; however, in the small number of patients with monolateral plaques, these were more likely to be ipsilateral to the recent ischemic event. The large subgroup of patients with recent stroke or TIA and bilateral carotid plaques was used to determine the differences in plaque characteristics between ipsilateral symptomatic side and contralateral asymptomatic side. A higher prevalence of carotid occlusion ipsilateral to signs and symptoms of a recent stroke was found. These data indicate that a sudden thrombotic occlusion may be the cause of stroke under these circumstances.

This study has demonstrated that ipsilateral longitudinal plaque motion is associated with prevalent TIA; however, there was no such difference in stroke patients. This apparent plaque movement could represent the effect of pressure variability during the cardiac cycle on the boundary interfaces between the plaque and other arterial wall tunics. Atherosclerotic lesions produce angiogenic factors that induce proliferation and penetration of adventitial vasa vasorum through the tunica media into the base of plaques.¹⁷ This phenomenon, similar in many respects to the initial steps in wound healing, is thought to be beneficial by providing oxygen, nutrients, and leukocytes to damaged tissues and also by providing conduits for removing metabolic products from these areas. However, longitudinal plaque movement may also cause a shearing effect at the base of lesions, resulting in damage and rupture of vasa vasorum and producing hemorrhage within the lesion as well as exacerbating tissue ischemia and necrosis, with a consequent plaque instability.

Of interest are the data concerning plaque echogenicity.¹⁸ In this study hypoechoic plaques showed a strong association with recent TIA. Langsfeld et al¹⁹ focused on the importance of plaque echogenicity and found that the more echolucent plaques were associated with more symptoms than the denser echogenic plaques. Weinberger et al²⁰ suggested that plaque evolution associated with intraplaque hemorrhage is more important than degree of stenosis in determining ipsilateral symptoms. In vitro studies have demonstrated that B-mode ultrasound imaging is a valid and reliable system to differentiate between normal and atherosclerotic walls.^{8 21} In addition, with the use of densitometric analyses it is possible to predict with high confidence the histological diagnosis of atherosclerotic plaques and to differentiate between fibrous and complicated plaques. However, under controlled experimental conditions B-mode ultrasound has not been shown to be reliable in identifying specific histological components of the complicated plaques, ie, necrosis, cholesterol crystals, and minerals.²¹ While this study confirms the association between hypoechoic plaques and TIA, it also emphasizes the necessity of further studies that address the relevance of plaque tissue characterization in predicting acute events.

It is difficult to draw definitive conclusions from the association between irregular plaque surface and recent TIAs. In fact, irregular plaque surfaces have never been shown to be reliably detected by ultrasound. Ricotta et al²² showed that compared with angiography, sensitivity and specificity in detecting plaque ulceration with ultrasound are .72 and .32, respectively. O'Leary et al⁷ also demonstrated poor inter-reader reproducibility in detecting surface ulceration. TIA and stroke patients with bilateral plaques had thicker ipsilateral lesions. Other studies demonstrated that plaque thickness correlates with intraplaque hemorrhage, atheronecrosis, thrombosis, and surface irregularity, suggesting that the thicker the lesion, the more frequent the plaque complications.^{23 24} These data are in agreement with those of Glagov and Zarins² in that "regardless of extent of involvement, critical lumen narrowing and plaque complications are the significant determinants of clinical severity rather than percentage of stenosis." The Cardiovascular Health Study has recently shown that the history of stroke is better predicted by wall thickness than percent diameter stenosis.²⁵ However, in a prospective study of asymptomatic patients with cervical bruits, Roederer et al²⁶ found a significant increase of internal carotid stenosis, documented by Doppler analysis, in patients who developed symptoms. In a 6-year serial clinical and Doppler evaluation, Bornstein and Norris²⁷ found the majority of ischemic cerebral events in patients with carotid stenosis progressing to occlusion.

In our study TIA patients had even more marked differences in lesion thickness between ipsilateral and contralateral arteries at the reference point, ie, 6 mm distal to the flow divider, than at the site of the MRL. Furthermore, while patients with stroke had a highly significant difference in MRL diameters, those with previous TIA did not demonstrate differences in MRL diameters. The lesions of TIA patients are thicker and of greater extent, while in stroke patients the reduction of MRL seems to be more important. Despite methodological differences, these data are in agreement with those of Dempsey et al,¹⁵ who found that plaque thickness was an independent predictor of TIA, whereas percent lumen stenosis was an independent predictor of stroke.

The accuracy of ultrasound measurements is confirmed by the study of Ricotta et al,²² in which lesion thickness measured by B-mode ultrasound correlated with plaque thickness measured from endarterectomy specimens, although it was underestimated by 19%. In this same study ultrasound was superior to angiography for quantifying atherosclerotic plaque thickness. On the other hand, angiography²² and Doppler frequency shift analysis²⁸ were more reliable indicators of percent stenosis. However, the debate is still open regarding defining the superiority of angiography²⁹ or duplex scanning³⁰ in quantitatively measuring the degree of stenosis.

In conclusion, the main objective of our study was to identify the B-mode ultrasound characteristics of likely symptomatic and asymptomatic carotid lesions. The results suggest that the features more strongly associated with stroke were either the occlusion of the ipsilateral carotid artery or wider lesions and smaller MRL diameter. The features that were more consistently associated with TIAs were low echogenicity of carotid plaques, thicker plaques, and presence of longitudinal motion. These findings encourage further prospective studies that use carotid ultrasound imaging and focus on plaque characteristics and thickness measurements. These studies are required to improve our ability to predict the occurrence of cerebrovascular ischemic events in the presence of carotid plaques.

	Acknowledgments

 
This study was supported by a grant awarded by the International Atherosclerosis Society and by a research and development grant from the Division of Vascular Ultrasound Research (DVUR), Bowman Gray School of Medicine (Dr Iannuzzi). Dr Iannuzzi is a visiting research fellow at the DVUR. The authors are grateful to Rosanna Scala for secretarial assistance in the preparation of the manuscript.

Received June 24, 1994; revision received January 19, 1995; accepted January 19, 1995.

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