HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Figures Only All Versions of this Article: 2302020318v1 230/2/561    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kono, Y. Articles by Mattrey, R. F. Search for Related Content PubMed PubMed Citation Articles by Kono, Y. Articles by Mattrey, R. F.

Carotid Arteries: Contrast-enhanced US Angiography—Preliminary Clinical Experience¹

¹ From the Departments of Radiology (Y.K., S.P.P., C.B.S., B.G., W.W., R.F.M.) and Surgery (S.R.S.), University of California, San Diego Medical Center, 200 W Arbor Dr, Dept 8756, San Diego, CA 92103-8756. From the 1999 RSNA scientific assembly. Received April 1, 2002; revision requested June 13; final revision received March 4, 2003; accepted May 19. Address correspondence to Y.K. (e-mail: ykono@ucsd.edu).

	ABSTRACT

TOP ABSTRACT INTRODUCTION Materials and Methods Results Discussion REFERENCES

 
B-mode ultrasonographic (US) angiography enhanced with a microbubble-based US contrast agent (FS069) was evaluated in human subjects with carotid artery disease. Results at contrast material–enhanced US angiography and duplex US were compared with those at conventional angiography. Both US angiography and duplex US accurately depicted stenoses of 70% or more compared with those depicted at conventional angiography. The percentage diameter stenosis of the internal carotid artery measured at US angiography strongly correlated with that measured at conventional angiography (r = 0.988). The percentage area stenosis measured at US angiography strongly correlated with ex vivo measurements of the resected carotid plaque at magnetic resonance imaging (r = 0.979). US angiography depicted unsuspected wall irregularities, ulceration, and dissection.

© RSNA, 2003

Index terms: Carotid arteries, stenosis or obstruction, 172.721 • Carotid arteries, US, 172.12984, 172.12988 • Ultrasound (US), contrast media, 172.12984, 172.12988

	INTRODUCTION

TOP ABSTRACT INTRODUCTION Materials and Methods Results Discussion REFERENCES

 
Stroke is one of the leading causes of morbidity and mortality in the United States. Although atherosclerosis may affect the intracranial vessels themselves, 88% of patients with amaurosis fugax or hemispheric transient ischemic attacks have atherosclerotic disease at the carotid bifurcation (1). Results of the North American Symptomatic Carotid Endoarterectomy Trial, or NASCET (2); the European Carotid Surgery Trial, or ECST (3); and the Asymptomatic Carotid Study, or ECACAS (4) show the effectiveness of carotid endarterectomy for preventing stroke in patients with significant carotid stenosis.

Duplex ultrasonography (US) is the primary examination in patients considered for endarterectomy or suspected of having carotid artery disease. It is readily accessible, noninvasive, and relatively inexpensive. It was shown to be highly effective in the detection of flow-limiting disease (5) but has been limited in the depiction of the echogenicity of plaques and ulcerations (6,7), precise determination of the degree of stenosis (8–10), and differentiation of critical stenosis from complete occlusion when the Duplex US study is suboptimal (11,12).

Angiography is the reference standard for evaluation of the carotid arteries and is the only established diagnostic method capable of reliably differentiating highly stenosed from occluded vessels. However, because angiography outlines the luminal profile in limited angular projections and does not demonstrate the arterial wall or the plaque itself, it is unreliable in depicting ulceration (13,14). Furthermore, the results can cause under- or overestimation of the degree of stenosis (15). Moreover, the invasiveness of the technique adds risk, including stroke, making it impractical for the screening of asymptomatic patients or monitoring of disease progression (16).

Gray-scale US alone can be used reliably to assess intimal thickening and to determine whether carotid plaques are soft, mixed, or hard (17,18). However, it cannot be used reliably to detect plaque ulceration (18–20) or to directly assess luminal narrowing (21). In fact, the appearance of plaque surface at preoperative gray-scale US showed no correlation to intraoperative findings in a 270-patient multicenter study (18). We hoped that the addition of color and power Doppler imaging would provide an angiographic-like image to improve the assessment of the morphology of stenoses and plaque surface. The Doppler imaging techniques that overlay a functional image dependent on velocity provide less spatial resolution than does B-mode imaging. Doppler techniques are dependent on the angle of incidence; can be affected by velocity changes caused by plaque, stenoses, or tortuosity; and are highly dependent on instrument settings. These factors have reduced the consistency of Doppler imaging in the lumen and have limited its use to speeding up a duplex study and improving Doppler gate placement and angle correction. Results with color Doppler imaging may cause overestimation of the degree of stenosis by 10%–15% but are more accurate and reproducible than are measurements of the maximum velocity (22).

Results of US angiography with the standard B-mode technique were superior to those of US with Doppler techniques in precise delineation of the margins of the arterial lumen in an in vitro study with replicas of diseased human carotid arteries and in an in vivo study with a rabbit atherosclerotic model (23). B-mode technique allowed accurate depiction of intimal thickening, plaque, plaque size, ulceration, and degree of stenosis (23). The introduction of phase-inversion harmonic imaging has increased the sensitivity to contrast media and increased image contrast between vascular lumen and tissues (24). This contrast medium–specific imaging technique has allowed the visualization of agents not typically seen at standard B-mode imaging. FS069 (Optison; Mallinckrodt, St Louis, Mo) is a US contrast agent that is approved by the U.S. Food and Drug Administration for endocardial border delineation. The purpose of our study, therefore, was to evaluate B-mode US angiography enhanced with this contrast agent in human subjects with carotid artery disease.

	Materials and Methods

TOP ABSTRACT INTRODUCTION Materials and Methods Results Discussion REFERENCES

 
Patients
This study was performed within the guidelines of the institutional review board, and informed consent was provided by each patient. Twenty consecutive patients with abnormal duplex US scans (stenosis of internal carotid artery of 70% or more), who would probably be advised to undergo conventional angiography or who were scheduled for endoarterectomy, were enrolled in the study of a physician-sponsored investigational new drug as an off-label use of FS069. The U.S. Food and Drug Administration and the institutional Human Subjects Committee approved the study. Fourteen male and six female patients (age range, 48–80 years; mean age, 64 years) agreed to participate. Ten patients had undergone conventional angiography before or after US angiography and were included for statistical analysis. All patients underwent duplex US before US angiography. Three patients underwent duplex US at an outside institution, and the results were not available for analysis. The endarterectomy specimens from five patients were studied ex vivo; two of them were also studied at conventional angiography. Two patients underwent magnetic resonance (MR) angiography. The US angiographic data from five patients were used only to test the feasibility of this technique (eg, opacification of vessels, duration of enhancement, side effects) but not for comparison with other imaging modalities.

Duplex US Study
All duplex US examinations were performed in our institution by one of the sonographers in the Department of Radiology as part of regular service. The velocity threshold is shown in Table 1. The full capability of the US machines (Sonoline Elegra, Siemens Ultrasound, Issaquah, Wash; or HDI 5000, ATL, Philips Medical Systems, Bothell, Wash), including color Doppler and power Doppler, was normally used in addition to duplex Doppler measurement, but each sonographer decided if they needed color or power Doppler. Retrospectively, 13 (76%) of the 17 duplex US studies were performed with color or power Doppler, and four (24%) were performed with duplex US without color or power Doppler.

The US contrast agent was administered through a 20-gauge peripheral intravenous catheter in multiple bolus injections of 0.5–1.0 mL, followed by a saline flush. None of the patients received more than the maximum total allowable dose of 8.7 mL.

US Imaging
The machine used for the contrast-enhanced US study (Sonoline Elegra; Siemens Ultrasound) was operated with version 4.3 software, which allows phase-inversion harmonic imaging with the 7.5-MHz linear transducer. The central transmit frequency was set between 3.3 and 7.2 MHz.

Instrument settings were optimized as would be done for standard B-mode imaging by adjusting the field of view, gain, and placement of the focal zone. The minimum power setting that allowed for adequate signal-to-noise ratio was used to minimize bubble destruction; the setting was typically 25%–40% of the maximum allowed with the scanner. Imaging began before the contrast medium was administered and continued until arterial filling became incomplete (decreased contrast medium concentration after 1–2 minutes). The carotid arteries were imaged by means of sweeping the transducer across the vessel in the long and short axes during the peak enhancement phase, which lasted 1–2 minutes. In five (25%) of the 20 patients, contrast-enhanced Doppler tracings were obtained at or just distal to the detected stenosis. Images of the vessel filled with contrast medium were obtained digitally for archival use, and the entire study was videorecorded on an S-VHS tape. Imaging in all patients was performed by one of two authors (Y.K., R.F.M.), who were blinded to findings at conventional angiography and duplex US.

Vital signs—including blood pressure, heart rate, respiratory rate, and body temperature—were monitored, and serial neurologic and electrocardiographic examinations were performed before and after administration of contrast material. The total dose of FS069 to image both carotid arteries was 6.9 mL ± 1.8. The carotid arteries were completely filled with contrast medium (0.5–1.0 mL). Acoustic power varied from 10% to 100% (mechanical index, 0.3–1.3). The duration of clinically useful enhancement varied from 1 to 2 minutes. No clinically important change—systolic blood pressure change of more than 20 mm Hg, diastolic blood pressure change of more than 20 mm Hg, pulse rate change of more than 15 beats per minute, temperature change of more than 1.5°C (2.7°F)—was seen in any of these measurements, and there were no complaints from patients during the examination. Findings at neurologic imaging and electrocardiography were interpreted as showing no clinically important changes.

Data Collection
The degree of stenosis was measured on conventional and US angiograms wherever stenoses were detected with the NASCET criteria. The diameter at the point of stenosis (A) and that at the distal end of normal-appearing vessels (B) were measured, and the percentage stenosis was calculated as 100 · (B - A)/B. Independently, one observer (Y.K.) analyzed US data, and another observer (S.P.P.) analyzed conventional data. Both internal carotid arteries in each patient were evaluated.

Stenosis of 70% or more measured at conventional angiography requires surgical intervention for symptomatic patients (2); therefore, the patients in this study were divided into those with stenosis of less than 70% and those with stenosis of 70% or more measured at conventional angiography. The estimate of stenosis from the duplex US study was determined by means of correlation of peak velocity to established criteria currently used at our institution (Table 1). The accuracy of duplex US and US angiographic measurements to help division of stenoses into the five categories shown in Table 1 was also compared with the degree of stenosis measured at conventional angiography.

Ex Vivo MR Imaging of Plaques
At endarterectomy in five patients in the current study, the plaque was embedded in gelatin within a small cylinder immediately after its removal. High-spatial-resolution three-dimensional gradient-echo MR imaging (repetition time msec/echo time msec of 11.1/4.3, flip angle of 15°, section thickness of 0.6 mm, field of view of 210 mm, matrix of 256 x 256, two signals acquired) of the plaque was performed with a small (1.5-inch [3.8-cm]) receiver surface coil. The isotropic three-dimensional data set was then processed with multiplanar reconstruction to obtain true cross-sectional images of the carotid plaque. The cross-sectional percentage area stenosis was measured at the point of maximal stenosis. The outer diameter of the vessel (C) and remaining patent lumen (D) were outlined by one observer on US scans (Y.K.) and by another observer on MR images (S.P.P.). Both observers calculated the percentage stenosis as 100 · (C/D)/C.

Statistical Analysis
Measurements of percentage diameter stenosis in all regions at conventional angiography and those at US angiography were correlated with the Pearson correlation coefficient. Agreement was determined with Bland-Altman analysis (bias plot analysis).

Measurements of percentage area stenosis at ex vivo MR imaging and those at US angiography were correlated with the Pearson correlation coefficient. Agreement was determined with Bland-Altman analysis. The paired Student t test was used to compare the mean peak velocities at precontrast duplex US with those at postcontrast duplex US. A P value of less than .05 was considered to indicate a statistically significant difference.

	Results

TOP ABSTRACT INTRODUCTION Materials and Methods Results Discussion REFERENCES

 
Longitudinal and transverse cross-sectional US images were obtained within the 1–2-minute diagnostic window, although complete intense filling was only observed during the peak bolus phase. US angiograms clearly displayed the outer and inner luminal margins of the vessel (Fig 1), which allowed precise assessment of the arterial wall, including intimal thickening, plaques, and ulcerations.

View larger version (82K): [in this window] [in a new window]   Figure 1a. Images in a 69-year-old male patient with a history of transischemic attack. (a) Precontrast US angiogram in right common carotid artery shows calcified (arrows) and noncalcified (arrowheads) plaque. (b) Postcontrast US angiogram obtained after injection of 0.5 mL of FS069 shows complete luminal enhancement. Soft plaque (arrowheads) along the posterior wall is well visualized. Also note the noncalcified component (arrows) of the calcified plaque along the anterior wall that was not detected in a. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery. (c) Conventional angiogram depicts the right common carotid artery (superior artery is on the left side, and inferior artery is on the right side). Gray scale is inverted to emphasize the similarity of this image and the contrast-enhanced US angiogram. This image was interpreted as showing focal kinking, which was actually intimal thickening.

View larger version (91K): [in this window] [in a new window]   Figure 1b. Images in a 69-year-old male patient with a history of transischemic attack. (a) Precontrast US angiogram in right common carotid artery shows calcified (arrows) and noncalcified (arrowheads) plaque. (b) Postcontrast US angiogram obtained after injection of 0.5 mL of FS069 shows complete luminal enhancement. Soft plaque (arrowheads) along the posterior wall is well visualized. Also note the noncalcified component (arrows) of the calcified plaque along the anterior wall that was not detected in a. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery. (c) Conventional angiogram depicts the right common carotid artery (superior artery is on the left side, and inferior artery is on the right side). Gray scale is inverted to emphasize the similarity of this image and the contrast-enhanced US angiogram. This image was interpreted as showing focal kinking, which was actually intimal thickening.

View larger version (44K): [in this window] [in a new window]   Figure 1c. Images in a 69-year-old male patient with a history of transischemic attack. (a) Precontrast US angiogram in right common carotid artery shows calcified (arrows) and noncalcified (arrowheads) plaque. (b) Postcontrast US angiogram obtained after injection of 0.5 mL of FS069 shows complete luminal enhancement. Soft plaque (arrowheads) along the posterior wall is well visualized. Also note the noncalcified component (arrows) of the calcified plaque along the anterior wall that was not detected in a. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery. (c) Conventional angiogram depicts the right common carotid artery (superior artery is on the left side, and inferior artery is on the right side). Gray scale is inverted to emphasize the similarity of this image and the contrast-enhanced US angiogram. This image was interpreted as showing focal kinking, which was actually intimal thickening.

View larger version (27K): [in this window] [in a new window]   Figure 2. Bland-Altman plots of the percentage diameter stenosis measured on US angiograms and conventional (X-ray) angiograms. Most of the data points lie within the 95% CI, which indicates strong agreement between results with the two methods.

US angiograms depicted ulceration in five patients, which were also depicted on the conventional angiograms in three patients (Fig 3). In the other two patients, conventional angiograms did not depict an ulcer. In none of these cases did the duplex US image depict any abnormality other than the stenosis. In one patient, the US angiogram depicted a dissection as a thin channel of microbubbles flowing parallel to the true lumen within the false lumen, which was probably thrombosed. This dissection, which was also depicted on the conventional angiogram, was not detected on the duplex US image (Fig 4); instead, a long soft plaque was depicted.

View larger version (106K): [in this window] [in a new window]   Figure 3a. Images in a 79-year-old male patient with a history of cerebrovascular disease. (a-c) US angiograms show ulceration (arrow in a and c) in a thick soft plaque involving the anterior and posterior wall of the bulb that narrowed the origin of both the internal and external carotid arteries. (d) Conventional angiogram (superior artery is on the left side, and inferior artery is on the right side) shows ulceration (arrow). Gray scale is inverted. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery.

View larger version (109K): [in this window] [in a new window]   Figure 3b. Images in a 79-year-old male patient with a history of cerebrovascular disease. (a-c) US angiograms show ulceration (arrow in a and c) in a thick soft plaque involving the anterior and posterior wall of the bulb that narrowed the origin of both the internal and external carotid arteries. (d) Conventional angiogram (superior artery is on the left side, and inferior artery is on the right side) shows ulceration (arrow). Gray scale is inverted. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery.

View larger version (107K): [in this window] [in a new window]   Figure 3c. Images in a 79-year-old male patient with a history of cerebrovascular disease. (a-c) US angiograms show ulceration (arrow in a and c) in a thick soft plaque involving the anterior and posterior wall of the bulb that narrowed the origin of both the internal and external carotid arteries. (d) Conventional angiogram (superior artery is on the left side, and inferior artery is on the right side) shows ulceration (arrow). Gray scale is inverted. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery.

View larger version (107K): [in this window] [in a new window]   Figure 3d. Images in a 79-year-old male patient with a history of cerebrovascular disease. (a-c) US angiograms show ulceration (arrow in a and c) in a thick soft plaque involving the anterior and posterior wall of the bulb that narrowed the origin of both the internal and external carotid arteries. (d) Conventional angiogram (superior artery is on the left side, and inferior artery is on the right side) shows ulceration (arrow). Gray scale is inverted. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery.

View larger version (113K): [in this window] [in a new window]   Figure 4a. Images obtained in the right internal carotid artery in a 67-year-old male patient with a history of cerebrovascular disease. (a) US angiogram depicts a dissection as a thin channel of microbubbles (arrows) flowing parallel to the true lumen within the false lumen, which is probably thrombosed. (b) Conventional angiogram (superior artery is on top, and inferior artery is on the bottom). Gray scale is inverted. Dissection (arrows) is depicted. Dissection was not detected on the duplex US image (not shown).

View larger version (111K): [in this window] [in a new window]   Figure 4b. Images obtained in the right internal carotid artery in a 67-year-old male patient with a history of cerebrovascular disease. (a) US angiogram depicts a dissection as a thin channel of microbubbles (arrows) flowing parallel to the true lumen within the false lumen, which is probably thrombosed. (b) Conventional angiogram (superior artery is on top, and inferior artery is on the bottom). Gray scale is inverted. Dissection (arrows) is depicted. Dissection was not detected on the duplex US image (not shown).

View larger version (133K): [in this window] [in a new window]   Figure 5a. Transverse images in a 72-year-old male patient with intermittent symptoms of transient ischemic attack. (a-f) Serial US angiograms were obtained in the carotid artery from the common carotid artery (a) to the normal portion of the distal carotid artery (f). The carotid artery is depicted with a long noncalcified plaque (arrow in b-e) that causes eccentric stenosis of the internal carotid artery (arrowhead in b). (g) Conventional angiogram (superior artery is on top, and inferior artery is on the bottom) shows a severe stenosis (arrow) in the internal carotid artery. This two-dimensional projection along the long axis of the eccentric stenosis shows that the degree of stenosis is overestimated. Gray scale is inverted. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery. (h-m) Corresponding ex vivo high-spatial-resolution MR images depict the plaque seen in a-f. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery.

View larger version (133K): [in this window] [in a new window]   Figure 5b. Transverse images in a 72-year-old male patient with intermittent symptoms of transient ischemic attack. (a-f) Serial US angiograms were obtained in the carotid artery from the common carotid artery (a) to the normal portion of the distal carotid artery (f). The carotid artery is depicted with a long noncalcified plaque (arrow in b-e) that causes eccentric stenosis of the internal carotid artery (arrowhead in b). (g) Conventional angiogram (superior artery is on top, and inferior artery is on the bottom) shows a severe stenosis (arrow) in the internal carotid artery. This two-dimensional projection along the long axis of the eccentric stenosis shows that the degree of stenosis is overestimated. Gray scale is inverted. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery. (h-m) Corresponding ex vivo high-spatial-resolution MR images depict the plaque seen in a-f. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery.

View larger version (136K): [in this window] [in a new window]   Figure 5c. Transverse images in a 72-year-old male patient with intermittent symptoms of transient ischemic attack. (a-f) Serial US angiograms were obtained in the carotid artery from the common carotid artery (a) to the normal portion of the distal carotid artery (f). The carotid artery is depicted with a long noncalcified plaque (arrow in b-e) that causes eccentric stenosis of the internal carotid artery (arrowhead in b). (g) Conventional angiogram (superior artery is on top, and inferior artery is on the bottom) shows a severe stenosis (arrow) in the internal carotid artery. This two-dimensional projection along the long axis of the eccentric stenosis shows that the degree of stenosis is overestimated. Gray scale is inverted. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery. (h-m) Corresponding ex vivo high-spatial-resolution MR images depict the plaque seen in a-f. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery.

View larger version (137K): [in this window] [in a new window]   Figure 5d. Transverse images in a 72-year-old male patient with intermittent symptoms of transient ischemic attack. (a-f) Serial US angiograms were obtained in the carotid artery from the common carotid artery (a) to the normal portion of the distal carotid artery (f). The carotid artery is depicted with a long noncalcified plaque (arrow in b-e) that causes eccentric stenosis of the internal carotid artery (arrowhead in b). (g) Conventional angiogram (superior artery is on top, and inferior artery is on the bottom) shows a severe stenosis (arrow) in the internal carotid artery. This two-dimensional projection along the long axis of the eccentric stenosis shows that the degree of stenosis is overestimated. Gray scale is inverted. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery. (h-m) Corresponding ex vivo high-spatial-resolution MR images depict the plaque seen in a-f. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery.

View larger version (135K): [in this window] [in a new window]   Figure 5e. Transverse images in a 72-year-old male patient with intermittent symptoms of transient ischemic attack. (a-f) Serial US angiograms were obtained in the carotid artery from the common carotid artery (a) to the normal portion of the distal carotid artery (f). The carotid artery is depicted with a long noncalcified plaque (arrow in b-e) that causes eccentric stenosis of the internal carotid artery (arrowhead in b). (g) Conventional angiogram (superior artery is on top, and inferior artery is on the bottom) shows a severe stenosis (arrow) in the internal carotid artery. This two-dimensional projection along the long axis of the eccentric stenosis shows that the degree of stenosis is overestimated. Gray scale is inverted. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery. (h-m) Corresponding ex vivo high-spatial-resolution MR images depict the plaque seen in a-f. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery.

View larger version (134K): [in this window] [in a new window]   Figure 5f. Transverse images in a 72-year-old male patient with intermittent symptoms of transient ischemic attack. (a-f) Serial US angiograms were obtained in the carotid artery from the common carotid artery (a) to the normal portion of the distal carotid artery (f). The carotid artery is depicted with a long noncalcified plaque (arrow in b-e) that causes eccentric stenosis of the internal carotid artery (arrowhead in b). (g) Conventional angiogram (superior artery is on top, and inferior artery is on the bottom) shows a severe stenosis (arrow) in the internal carotid artery. This two-dimensional projection along the long axis of the eccentric stenosis shows that the degree of stenosis is overestimated. Gray scale is inverted. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery. (h-m) Corresponding ex vivo high-spatial-resolution MR images depict the plaque seen in a-f. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery.

View larger version (83K): [in this window] [in a new window]   Figure 5g. Transverse images in a 72-year-old male patient with intermittent symptoms of transient ischemic attack. (a-f) Serial US angiograms were obtained in the carotid artery from the common carotid artery (a) to the normal portion of the distal carotid artery (f). The carotid artery is depicted with a long noncalcified plaque (arrow in b-e) that causes eccentric stenosis of the internal carotid artery (arrowhead in b). (g) Conventional angiogram (superior artery is on top, and inferior artery is on the bottom) shows a severe stenosis (arrow) in the internal carotid artery. This two-dimensional projection along the long axis of the eccentric stenosis shows that the degree of stenosis is overestimated. Gray scale is inverted. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery. (h-m) Corresponding ex vivo high-spatial-resolution MR images depict the plaque seen in a-f. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery.

View larger version (107K): [in this window] [in a new window]   Figure 5h. Transverse images in a 72-year-old male patient with intermittent symptoms of transient ischemic attack. (a-f) Serial US angiograms were obtained in the carotid artery from the common carotid artery (a) to the normal portion of the distal carotid artery (f). The carotid artery is depicted with a long noncalcified plaque (arrow in b-e) that causes eccentric stenosis of the internal carotid artery (arrowhead in b). (g) Conventional angiogram (superior artery is on top, and inferior artery is on the bottom) shows a severe stenosis (arrow) in the internal carotid artery. This two-dimensional projection along the long axis of the eccentric stenosis shows that the degree of stenosis is overestimated. Gray scale is inverted. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery. (h-m) Corresponding ex vivo high-spatial-resolution MR images depict the plaque seen in a-f. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery.

View larger version (145K): [in this window] [in a new window]   Figure 5i. Transverse images in a 72-year-old male patient with intermittent symptoms of transient ischemic attack. (a-f) Serial US angiograms were obtained in the carotid artery from the common carotid artery (a) to the normal portion of the distal carotid artery (f). The carotid artery is depicted with a long noncalcified plaque (arrow in b-e) that causes eccentric stenosis of the internal carotid artery (arrowhead in b). (g) Conventional angiogram (superior artery is on top, and inferior artery is on the bottom) shows a severe stenosis (arrow) in the internal carotid artery. This two-dimensional projection along the long axis of the eccentric stenosis shows that the degree of stenosis is overestimated. Gray scale is inverted. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery. (h-m) Corresponding ex vivo high-spatial-resolution MR images depict the plaque seen in a-f. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery.

View larger version (147K): [in this window] [in a new window]   Figure 5j. Transverse images in a 72-year-old male patient with intermittent symptoms of transient ischemic attack. (a-f) Serial US angiograms were obtained in the carotid artery from the common carotid artery (a) to the normal portion of the distal carotid artery (f). The carotid artery is depicted with a long noncalcified plaque (arrow in b-e) that causes eccentric stenosis of the internal carotid artery (arrowhead in b). (g) Conventional angiogram (superior artery is on top, and inferior artery is on the bottom) shows a severe stenosis (arrow) in the internal carotid artery. This two-dimensional projection along the long axis of the eccentric stenosis shows that the degree of stenosis is overestimated. Gray scale is inverted. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery. (h-m) Corresponding ex vivo high-spatial-resolution MR images depict the plaque seen in a-f. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery.

View larger version (140K): [in this window] [in a new window]   Figure 5k. Transverse images in a 72-year-old male patient with intermittent symptoms of transient ischemic attack. (a-f) Serial US angiograms were obtained in the carotid artery from the common carotid artery (a) to the normal portion of the distal carotid artery (f). The carotid artery is depicted with a long noncalcified plaque (arrow in b-e) that causes eccentric stenosis of the internal carotid artery (arrowhead in b). (g) Conventional angiogram (superior artery is on top, and inferior artery is on the bottom) shows a severe stenosis (arrow) in the internal carotid artery. This two-dimensional projection along the long axis of the eccentric stenosis shows that the degree of stenosis is overestimated. Gray scale is inverted. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery. (h-m) Corresponding ex vivo high-spatial-resolution MR images depict the plaque seen in a-f. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery.

View larger version (150K): [in this window] [in a new window]   Figure 5l. Transverse images in a 72-year-old male patient with intermittent symptoms of transient ischemic attack. (a-f) Serial US angiograms were obtained in the carotid artery from the common carotid artery (a) to the normal portion of the distal carotid artery (f). The carotid artery is depicted with a long noncalcified plaque (arrow in b-e) that causes eccentric stenosis of the internal carotid artery (arrowhead in b). (g) Conventional angiogram (superior artery is on top, and inferior artery is on the bottom) shows a severe stenosis (arrow) in the internal carotid artery. This two-dimensional projection along the long axis of the eccentric stenosis shows that the degree of stenosis is overestimated. Gray scale is inverted. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery. (h-m) Corresponding ex vivo high-spatial-resolution MR images depict the plaque seen in a-f. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery.

View larger version (142K): [in this window] [in a new window]   Figure 5m. Transverse images in a 72-year-old male patient with intermittent symptoms of transient ischemic attack. (a-f) Serial US angiograms were obtained in the carotid artery from the common carotid artery (a) to the normal portion of the distal carotid artery (f). The carotid artery is depicted with a long noncalcified plaque (arrow in b-e) that causes eccentric stenosis of the internal carotid artery (arrowhead in b). (g) Conventional angiogram (superior artery is on top, and inferior artery is on the bottom) shows a severe stenosis (arrow) in the internal carotid artery. This two-dimensional projection along the long axis of the eccentric stenosis shows that the degree of stenosis is overestimated. Gray scale is inverted. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery. (h-m) Corresponding ex vivo high-spatial-resolution MR images depict the plaque seen in a-f. CCA = common carotid artery, ECA = external carotid artery, ICA = internal carotid artery.

View larger version (26K): [in this window] [in a new window]   Figure 6. Bland-Altman plots of the percentage area stenosis determined at US angiography and ex vivo MR imaging of the plaque. Most of the data points lie within the 95% CI, which indicates strong agreement between findings with the two methods.

	Discussion

TOP ABSTRACT INTRODUCTION Materials and Methods Results Discussion REFERENCES

Color and power Doppler imaging provide angiographic-like images of the carotid arteries that help delineate the lumen but are limited by low temporal or spatial resolution, angle dependence, and susceptibility to artifacts. We showed in vitro and in an animal model that gray-scale filling of vessels with contrast medium is more reliable and more accurate than is filling of vessels with Doppler signal, as the latter relies on flow (23). Although Doppler imaging is reasonable in a number of situations, flow and structure do not overlap in conditions when flow is turbulent or disturbed by plaque or clot or when vascular tortuosity is present. Furthermore, regions of slow or small volume flow, as in very tight stenoses and long narrow channels, may be invisible at Doppler imaging but will be depicted at contrast-enhanced B-mode harmonic imaging, as was the case in one of the subjects with dissection in the current study. Contrast-enhanced B-mode harmonic images clearly depicted ulcerations and a recanalized channel that were not detected on Doppler US images, which may have been affected by turbulence, flow disturbance, or slow flow. Furthermore, B-mode images are more reproducible than are Doppler images because they are not dependent on the angle of incidence and technical parameters for optimal filling of vessels with color (23). Phase-inversion harmonic B-mode imaging is superior to standard B-mode imaging because of increased contrast between the vascular lumen and surrounding tissues and the demonstration of turbulent flow (24). By using replicas of actual diseased human carotid arteries, we showed that the direct measurement of vessel stenosis was accurate with contrast-enhanced B-mode US (r = 0.94) and was poor with duplex US (r = 0.42) (23) and that direct measurement was insensitive to flow alterations that may be caused by ipsilateral or contralateral carotid artery stenoses (24).

Although B-mode techniques for contrast-enhanced US are not affected by artifacts such as blooming of color or power Doppler, they show acoustic shadowing or attenuation if large doses are used. The 0.5- and 1.0-mL bolus injections used in the current study filled the carotid arteries without shadowing or attenuation. Although use of lower acoustic power is preferable to minimize bubble destruction (28), we needed to use higher acoustic pressure in large patients and when the plane of imaging placed the vessel at greater depths.

Findings in the current study confirm that contrast-enhanced gray-scale US with phase-inversion harmonic imaging fills the carotid arteries with echoes and highlights plaques in human subjects. The ability to visualize the entire lumen allowed accurate depiction of stenoses, with percentage stenosis values that were highly correlated with those at conventional angiography (r = 0.988). Furthermore, because US images also show the outer wall, the full thickness of the plaque is displayed, which allows accurate monitoring of disease regression or progression (23). The ability to depict the outer and inner margins in the transverse plane allowed the measurement of percentage area reduction at the point of maximal narrowing. Percentage area narrowing values should be more reliable than the percentage diameter stenosis because they were measured at the point of interest rather than at the distal vessel, where findings may or may not be normal. Furthermore, because stenoses can be eccentric, they should be more accurately measured on two-dimensional projections, as was demonstrated in plaque on ex vivo MR images (Fig 5). Given the high contrast between the lumen and vessel wall, image segmentation may allow automated analysis and three-dimensional display, as well as more reliable comparison of follow-up images.

Severe calcifications hindered our ability to fully visualize the lumen in two lesions. However, the presence of contrast medium did not preclude the ability to measure flow velocity. In fact, the presence of contrast material increased the Doppler signal, as has been shown by others (29).

Preclinical observations (23) in rabbits with a different contrast agent (AF0150, Imagent; IMCOR, division of Photogen Technologies, San Diego, Calif) that demonstrated the superiority of vascular B-mode US compared with all Doppler imaging techniques encouraged us to conduct this study in human subjects. We believe that the results reported herein are not unique to FS069. Since most of the new generation of microbubble-based US contrast agents contain perfluorocarbon, the performance of all these agents should be similar to that of FS069 by providing optimal imaging for several minutes. We anticipate that most of these agents will also be well tolerated, as was observed with FS069 in prior studies (30) and in the current study.

Limitations of our study include the small number of patients; the data are encouraging but they must be validated in a larger number of patients. On the basis of our estimates, the misclassification rate for US angiography is approximately 16%. The corresponding error rate for duplex US was 36%. With 200 subjects, we would have 80% power for a two-sided test ( = .05) to detect a 10% reduction in misclassification rate with US angiography versus that with Doppler US (26% vs 36%). Clearly, this sample will also yield sufficient power if the error rate with US angiography is even lower than 28%, as we observed with our data.

In summary, results with US angiography of the carotid arteries with B-mode phase-inversion harmonic imaging were comparable to those with conventional angiography and ex vivo MR imaging in this small group of patients. US angiography provided accurate depiction of carotid stenoses, plaques, and ulcerations in this preliminary study and allowed the calculation of percentage area stenosis. With US angiography, the high correlation with results at conventional angiography, consistent display of intraluminal detail, and lack of added risk combined with the advantages of US warrant further clinical development.

	ACKNOWLEDGMENTS

 
We thank Loki Natarajan, PhD, assistant adjunct professor of Division of Biostatistics, Department of Family and Preventive Medicine, University of California, San Diego, for her help regarding statistical data analysis. We also thank Mallinckrodt for providing the contrast agent.

	FOOTNOTES

 
Author contributions: Guarantors of integrity of entire study, Y.K., R.F.M.; study concepts/design, Y.K., R.F.M.; literature research, Y.K.; clinical studies, Y.K., S.P.P., C.B.S., S.R.S., B.G., W.W., R.F.M.; data acquisition and analysis/interpretation, Y.K., S.P.P.; statistical analysis, Y.K., R.F.M.; manuscript preparation, Y.K.; manuscript definition of intellectual content, editing, and revision/review, Y.K., R.F.M.; manuscript final version approval, all authors

	REFERENCES

TOP ABSTRACT INTRODUCTION Materials and Methods Results Discussion REFERENCES

 

1. Eisenberg RL, Nemzek WR, Moore WS, Mani RL. Relationship of transient ischemic attack and angiographically demonstrable lesions of carotid artery. Stroke 1977; 8:483-486.[Abstract/Free Full Text]
2. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991; 325:445-453.[Abstract]
3. European Carotid Surgery Trialists’ Collaborative Group. MRC European carotid surgery trial: interim results for symptomatic patients with severe (70–99%) or with mild (0–20%) carotid stenosis. Lancet 1991; 337:1235-1243.[CrossRef][Medline]
4. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995; 273:1421-1428.[Abstract]
5. Moneta GL, Edwards JM, Chitwood RW, et al. Correlation of North American Symptomatic Carotid Endarterectomy Trial (NASCET) angiographic definition of 70% to 99% internal carotid artery stenosis with duplex scanning. J Vasc Surg 1993; 17:152-159.[CrossRef][Medline]
6. Widder B, Paulat K, Hackspacher J, et al. Morphologic characterization of carotid artery stenoses by ultrasound duplex scanning. Ultrasound Med Biol 1990; 16:349-354.[CrossRef][Medline]
7. Young N, Soo YS, Fischer P. Comparison of duplex ultrasound with angiography in assessment of carotid bifurcation disease. Australas Radiol 1992; 36:54-58.[Medline]
8. Hood DB, Mattos MA, Mansour A, et al. Prospective evaluation of new duplex criteria to identify 70% internal carotid artery stenosis. J Vasc Surg 1996; 23:256-262.
9. van Everdingen KJ, van der Grond J, Kappelle LJ. Overestimation of a stenosis in the internal carotid artery by duplex sonography caused by an increase in volume flow. J Vasc Surg 1998; 27:479-485.[Medline]
10. Grant EG, Duerinckx AJ, El Saden AM, et al. Ability to use duplex US to quantify internal carotid arterial stenoses: fact or fiction? Radiology 2000; 214:247-252.[Abstract/Free Full Text]
11. AbuRahama AF, Pollack JA, Robinson PA, Mullins D. The reliability of color duplex ultrasound in diagnosing total carotid artery occlusion. Am J Surg 1997; 174:185-187.[CrossRef][Medline]
12. Bornstein NM, Beloev ZG, Norris JW. The limitation of diagnosis of carotid occlusion by Doppler ultrasound. Ann Surg 1988; 207:315-317.[Medline]
13. van Damme H, Vivario M. Pathologic aspects of carotid plaques: surgical and clinical significance. Int Angiol 1993; 12:299-311.[Medline]
14. Edwards JH, Kricheff II, Riles T, Imparato A. Angiographically undetected ulceration of the carotid bifurcation as a cause of embolic stroke. Radiology 1979; 132:369-373.[Abstract]
15. Alexandrov AV, Bladin CF, Maggisano R, Norris JW. Measuring carotid stenosis: time for a reappraisal. Stroke 1993; 24:1292-1296.[Abstract/Free Full Text]
16. Harley JD, Haynor DR. Angiography. In: Zeirler RE, eds. Surgical management of cerebrovascular disease. New York, NY: McGraw-Hill, 1995; 221-236.
17. Feeley TM, Leen EJ, Colgan MP, Moore DJ, Hourihane DO, Shanik GD. Histologic characteristics of carotid artery plaque. J Vasc Surg 1991; 13:719-724.[CrossRef][Medline]
18. ECPSG (European Carotid Plaque Study Group). Carotid artery composition: relationship to clinical presentation and ultrasound B-mode imaging. Eur J Endovasc Surg 1995; 10:23-30.
19. O’Leary DH, Holen J, Ricotta JJ, Roe S, Schenk EA. Carotid bifurcation disease: prediction of ulceration with B-mode US. Radiology 1987; 162:523-525.[Abstract/Free Full Text]
20. Barry R, Pienaar C, Nel CJC. Accuracy of B-mode ultrasonography in detecting carotid artery plaque hemorrhage and ulceration. Ann Vasc Surg 1990; 4:466-470.[Medline]
21. Delcker A, Diener HC. 3D ultrasound measurement of atherosclerotic plaque volume in carotid arteries. Bildgebung 1994; 61:116-121.[Medline]
22. Arbeille P, Bouin-Pineau MH, Herault S. Accuracy of the main Doppler methods for evaluating the degree of carotid stenoses (continuous wave, pulsed wave, and color Doppler). Ultrasound Med Biol 1999; 25:65-73.[CrossRef][Medline]
23. Sirlin CB, Lee YZ, Girard MS, et al. Contrast-enhanced B-mode US angiography in the assessment of experimental in vivo and in vitro atherosclerotic disease. Acad Radiol 2001; 8:162-172.[CrossRef][Medline]
24. Sirlin CB, Coley B, Mattrey RF. The vascular space. In: Thomsen HS, Muller R, Mattrey RF, eds. Trends in contrast media. Medical radiology: diagnostic imaging and radiation oncology series. New York, NY: Springer, 1999; 355-365.
25. de Jong N, Ten Cate FJ, Lancee CT, Roelandt JR, Bom N. Principles and recent developments in ultrasound contrast agents. Ultrasonics 1991; 29:324-330.[CrossRef][Medline]
26. Girard MS, Mattrey RF, Baker KG, Peterson T, Deiranieh LH, Steinbach GC. Comparison of standard and second harmonic B-mode sonography in the detection of renal infarction with ultrasound contrast in a rabbit model. J Ultrasound Med 2000; 19:185-192.[Abstract]
27. Steinbach GC. Contrast-specific instrumentation and its potential applications. In: Thomsen HS, Muller R, Mattrey RF, eds. Trends in contrast media. Medical radiology: diagnostic imaging and radiation oncology series. New York, NY: Springer, 1999; 321-332.
28. Wible JH, Jr, Wojdyla JK, Hughes MS, Brandenburger GH. Effects of transducer frequency and output power on the ultrasonographic contrast produced by Optison using fundamental and harmonic imaging techniques. J Ultrasound Med 1999; 18:753-762.[Abstract]
29. Gutberlet M, Venz S, Zendel W, Hosten N, Felix R. Do ultrasonic contrast agents artificially increase maximum Doppler shift? in vivo study of human common carotid arteries. J Ultrasound Med 1998; 17:97-102.[Abstract]
30. Cohen JL, Cheirif J, Segar DS, et al. Improved left ventricular endocardial border delineation and opacification with OPTISON (FS069), a new echocardiographic contrast agent: results of a phase III multicenter trial. Am Coll Cardiol 1998; 32:746-752.[Abstract/Free Full Text]

This article has been cited by other articles:

				M. Magnoni, S. Coli, M. M. Marrocco-Trischitta, G. Melisurgo, D. De Dominicis, D. Cianflone, R. Chiesa, S. B. Feinstein, and A. Maseri Contrast-enhanced ultrasound imaging of periadventitial vasa vasorum in human carotid arteries Eur J Echocardiogr, August 29, 2008; (2008) jen221v1. [Abstract] [Full Text] [PDF]

				S. Coli, M. Magnoni, G. Sangiorgi, M. M. Marrocco-Trischitta, G. Melisurgo, A. Mauriello, L. Spagnoli, R. Chiesa, D. Cianflone, and A. Maseri Contrast-enhanced ultrasound imaging of intraplaque neovascularization in carotid arteries correlation with histology and plaque echogenicity. J. Am. Coll. Cardiol., July 15, 2008; 52(3): 223 - 230. [Abstract] [Full Text] [PDF]

				R. M. Kwee, R. J. van Oostenbrugge, L. Hofstra, G. J. Teule, J.M.A. van Engelshoven, W. H. Mess, and M. E. Kooi Identifying vulnerable carotid plaques by noninvasive imaging Neurology, June 10, 2008; 70(24_Part_2): 2401 - 2409. [Abstract] [Full Text] [PDF]

T. Holscher, J.A. Sattin, R. Raman, W. Wilkening, C.V. Fanale, S.E. Olson, R.F. Mattrey, and P.D. Lyden Real-Time Cerebral Angiography: Sensitivity of a New Contrast-Specific Ultrasound Technique AJNR Am. J. Neuroradiol., April 1, 2007; 28(4): 635 - 639. [Abstract] [Full Text] [PDF]