New advances in non-invasive imaging of the …...Third, the future of CEUS and three -dimensional...
Transcript of New advances in non-invasive imaging of the …...Third, the future of CEUS and three -dimensional...
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New Advances in Noninvasive Imaging of the Carotid Artery:
CIMT, Contrast-Enhanced Ultrasound, and Vasa Vasorum
Blai Coll, Vijay Nambi, and Steven B. Feinstein
Corresponding author:
Steven B. Feinstein
Professor of Medicine/Cardiology,
1015 Jelke,
1750 West Congress Parkway,
Rush University Medical Center,
Chicago, IL 60612, USA
e-mail: [email protected]
Abstract
Carotid ultrasound measurement of carotid intima-media thickness (C-IMT) and
detection of plaques is an useful method to better assess cardiovascular disease
risk status, especially in those at intermediate risk. We discuss the use C-IMT
and other emerging techniques such as contrast-enhanced carotid ultrasound
imaging in the evaluation of the carotid artery and its value in cardiovascular
disease.
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Keywords: Carotid intima-media thickness (CIMT); Contrast-enhanced
ultrasound (CEUS); Vasa vasorum; Atherosclerosis
Introduction
With the pan-epidemic of obesity, metabolic syndrome (MetSyn), and diabetes,
the worldwide cardiovascular risks of suffering a premature cardiovascular event
have increased significantly [1]. Current estimates state that in the United States
alone, there are approximately 44 million Americans diagnosed with MetSyn with
150 million worldwide. Based on a recent meta-analysis of the consequences of
MetSyn, it is notable that women have a one-third increase in death rates over
that of men [2]. And based on a review by Cowie et al. in 2006 [3], approximately
73 million Americans have diabetes or exhibit impaired fasting glucose. Clearly,
the MetSyn and diabetes significantly increase the risk for premature
cardiovascular morbidity and mortality.
Based on these data, it is imperative that we develop noninvasive imaging
systems capable of detecting and monitoring premature atherosclerosis in
populations. Therefore, it is reasonable to assume that the development of
advanced noninvasive technologies to detect surrogate markers of
atherosclerosis is a laudable public health initiative.
First, is a noninvasive, ultrasound-based system capable of detecting
systemic atherosclerosis an appropriate surrogate marker of disease? Arguably,
based on 24 years of clinical data, the widespread use of CIMT as a surrogate
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marker for detecting and monitoring atherosclerosis has stood the test of time
and clearly serves as a reliable surrogate marker in prospective population
studies [4].
Second, the discussion will focus on the added clinical value of contrast-
enhanced ultrasound (CEUS) for the following: 1) visualization of the entire
carotid artery vasculature, 2) enhancement of the near wall CIMT, and 3)
identification of the adventitial and intraplaque vasa vasorum. Importantly,
noninvasive detection of neovascularization within the vessel wall is associated
with premature atherosclerosis, a precursor to overt atheroslcerosis. The value of
using CEUS to detect and quantify preclinical disease is legion.
Third, the future of CEUS and three-dimensional (3D) volumetric,
ultrasound-based imaging will be discussed. It is anticipated that a 3D/four-
dimensional (4D) system can be devised to provide individualized assessment of
premature atherosclerosis versus assessment of relative risk in large population
studies. It is believed that a volumetric analysis approach is required because the
atherosclerosis process is eccentric and focal within the vasculature.
Therefore, the overall goal is to provide widely available, simple,
noninvasive, cost-effective technology to screen populations considered at risk
for coronary artery disease or described as “vulnerable” patients [5, 6].
Noninvasive, Ultrasound-Based Assessment of Cardiovascular Disease
Cardiovascular prevention is, in part, based on the identification of risk factors,
which includes serum cholesterol and blood pressure leading to an estimation of
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cardiovascular risk scores based on traditional scoring systems (ie, Framingham,
risk score, etc.). This process represents a uniform, validated and robust method
to classify high-risk and very low risk individuals. However, cardiovascular scores
do not clearly differentiate those individuals who are classified at intermediate
risk, and those subjects who will suffer a cardiovascular event in the future. The
need to further classify at-risk individuals is especially important because nearly
62% of patients who suffer from a coronary heart event present with no or a
single conventional risk factor [7]. Carotid ultrasound—measuring carotid intima-
media thickness (CIMT)—and the diagnoses of carotid plaques may provide
additional power to further identify those at-risk individuals. The measurement of
CIMT remains a well-established and accepted surrogate marker of
cardiovascular disease (CVD) [8]. It has been extensively studied in numerous
clinical trials [9] beginning with the initial description by Pignoli and Longo [10] in
1986 and currently accounts for the most extensive literature in the field of
atherosclerosis imaging.
The CIMT measurement directly correlates with pathology [11, 12] and is
indicative of the thickness of the arterial wall, and is precisely imaged using
ultrasound technology. In clinical studies, the CIMT measurement parallels the
significance of traditional cardiovascular risk factors, thus highlighting the utility
and consistency of using noninvasive measurements to assess risk factors
based on vessel wall biology. Over the years, clinical trials have provided
outcomes that support the role of CIMT measurements for predicting
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cardiovascular events (ie, the thicker the CIMT, the higher the rate of myocardial
infarction or stroke) [13].
The application of CIMT has become an accepted, reliable surrogate
marker for determination of atherosclerosis and is endorsed by the US Food and
Drug Administration (FDA) and by the European Agency for the Evaluation of
Medicinal Products. Today, CIMT measurements represent the preferred
technique for noninvasively assessing atherosclerosis in most clinical trial
studies, and clinical guidelines and scientific societies recommend the use of
carotid ultrasound to further assess cardiovascular status in selected populations
[14].
In low-to-intermediate cardiovascular risk groups, the presence of carotid
atherosclerosis has been studied. In a recently performed research study
(Unpublished data; Coll B. et al) the Spanish Society of Cardiology examined the
reclassification rate of low- to intermediate-risk individuals based on carotid
ultrasound imaging compared with the SCORE (Systemic Coronary Risk
Estimation) risk. In their study, 3778 volunteers were selected based on the
following criteria: no previous CVD, no diabetes mellitus, and SCORE risk low to
intermediate (< 5% probability to suffer from a fatal CVD in the following 10
years). From this group, 2354 healthy individuals were identified, and CIMT and
carotid plaques were identified along with clinical and laboratory data. The result
was that 37.4% of subjects revealed carotid atherosclerosis.
Using multivariate analyses, the variables that significantly related to the
presence of carotid atherosclerosis were age, male, and high blood pressure.
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Conversely, SCORE risk was not significantly related with carotid
atherosclerosis.
These results are consistent with the data published from earlier authors.
For example, Postley et al. [15] included 715 low-to-intermediate Framingham
risk subjects and reported a prevalence of carotid plaque at 32.8%. Age, male
gender, and dyslipidemia were among the significant related variables. Similarly,
in the Northern Manhattan Study, 1445 subjects were examined and the
prevalence of carotid plaques was 58%, although 459 (21%) of the participants
had previously suffered from a cardiovascular event [16].
Overall, there exists a significant dissociation between traditional risk
assessment and the observed presence of atherosclerosis as detected by
ultrasonography. Traditional risk assessment models (eg, Framingham, SCORE,
etc.) are designed to prospectively identify subjects who are at risk for suffering
from a premature cardiovascular event; these models were not based on the use
of surrogate markers of systemic atherosclerosis. However, subjects who are
identified with atherosclerosis based on noninvasive imaging techniques are at
an increased cardiovascular risk. Population-based studies have consistently
shown that the presence of carotid atherosclerosis served as an independent
variable in the prediction of cardiovascular events, coronary heart disease, and
stroke. Davidsson et al. [17] recently reported that the odds ratio of
cardiovascular events in subjects with a carotid plaque was 2.09 (CI, 1.05–4.16;
P = 0.03) in a multivariate analyses of 391 males from Sweden. Further, the
presence of carotid plaque was associated with a 2.9-fold (CI, 1.22–7.07)
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increased risk of cardiovascular events as noted in an observational study of 767
healthy Mediterranean subjects [18].
With regard to the categorical increments in IMT, a measured CIMT
difference of 0.1 mm, corrected for age and gender, yielded a 10% to 15%
increase in future cardiovascular events and an increased stroke risk of 13% to
18% [4]. Further, sensitivity, specificity, and receiver operating characteristic
curves are consistently enhanced after carotid ultrasound results are
incorporated into the equation [19].
Recently, a major new finding was reported by Nambi et al. [20•], in which
the authors correlated cardiovascular events to CIMT and carotid plaque from the
ARIC (Atherosclerosis Risk i Communities) database. The authors commented
on the predictive role of carotid ultrasound (CIMT and plaque) from a serial
analysis of 13,145 healthy subjects. In this study, there were 1812 cardiovascular
events reported over a mean follow-up of 15 years. Area under the curve
significantly increased following the addition of CIMT and plaque when added to
the conventional risk factors. Moreover, the authors cited a significant
improvement in the net reclassification index when using carotid ultrasound
(21.7% of participants in the intermediate-risk group were correctly reclassified).
CEUS Imaging, CIMT, and Intraplaque/Adventitial Vasa Vasorum
Ultrasound contrast agents (UCAs) are intravascular indicators that serve as
near perfect acoustic reflectors. As a class, UCAs are micron-sized, air-filled
spheres composed of a thin shell (generally lipid or protein) and a relatively
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nondiffusible gas; Albunex (Mallinckrodt Medical, St. Louis, MO), the first
commercial UCA, was approved by the FDA in 1994. Currently, UCAs are
clinically indicated in a variety of ultrasound applications for cardiac imaging in
the United States and for body imaging globally.
CEUS imaging, when used for vascular applications, enhances the vessel
lumen and, consequently, provides complete visualization of the carotid artery
vasculature, luminal surfaces, near and far IMT, and adventital and intraplaque
angiogenesis (vasa vasorum).
CEUS: near wall CIMT
Initially described in 2004, CEUS provided a reliable and precise measurement of
the near wall CIMT compared with CIMT measurements performed without the
use of UCAs [21].
The historic focus on the quantification of IMT from the far wall of the
common carotid artery was deliberate and based on utilitarian issues surrounding
technique and acoustics [22, 23]. Although the far wall measurement of the
common carotid remains the most reliable measurement, systemic
atherosclerosis is not uniquely confined to a specific domain. Despite the higher
prevalence of atherosclerosis on the near and distal carotid walls, there are
inherent acoustic and technical explanations for the difficulties encountered in
acoustically defining the near wall of the common carotid artery. In fact, in the
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2004 report by Macioch et al. [21], the near wall of the common carotid artery
wall measured 20% thicker than that of the far wall; these findings are consistent
with the histology report by Wong et al. in 1993 [11].
CEUS: vasa vasorum
The first clinical description of the carotid artery vasa vasorum using CEUS was
reported in 2004 [24]. These initial dramatic images were subsequently validated
using histology specimens [25•]. The CEUS method for detecting carotid artery
angiogenesis was subsequently corroborated by independent groups [26–28].
These reports provided evidence that the use of CEUS is a practical,
noninvasive, cost-effective method to identify the neovascularization in patients
who are considered “at risk.”
In support of measuring neovascularization with CEUS methods, Fleiner
et al. [29] published an important article in which they described
neovascularization (vasa vasorum) noting that these changes were harbingers of
systemic atherosclerosis, which appear to predate incremental changes in CIMT.
From their work: “… findings indicate that there is an association among
intraplaque hemorrhage, an increase in the size of the necrotic core, and lesion
instability in coronary plaques.” And “…a hyperplastic network of vasa vasorum
constitutes an early sign of symptomatic atherosclerosis; importantly, these
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changes were observed to precede the development of increased intima-media-
thickness.”
Fleiner et al. [29] examined carotid, renal, and iliac arteries from autopsies
of 49 subjects, of which approximately half died of CVDs while the “control” group
died of unrelated causes. In the cardiovascular subgroup, two distinct findings
were observed: 1) presence of ectopic intraplaque neovascularization, and 2)
hyperplasia of adventitial vasa vasorum. The authors noted that ectopic
neovascularization reflected an adaptive response of the arterial wall to an
increased nutritional demand and occurs in the course of intima thickening. The
authors concluded that the presence of a hyperplastic network of vasa vasorum
differentiated symptomatic and asymptomatic patients.
In addition to the work of Fleiner et al. [29], Moreno and Fuster [30] and
Dunmore et al. [31] noted that adventitial vasa vasorum (neovascularization)
discriminates between active versus nonactive (vulnerable) plaques in
symptomatic versus asymptomatic subjects. The presence of these angiogenic
vessels was observed in all systemic arteries, which included the aorta,
coronaries, carotids, and the femoral arteries. Moreno and Fuster [30] concluded
that “… pathologic neovascularization of the vessel wall is a consistent feature of
atherosclerotic plaque development and progression of the disease.”
Dunmore et al. [31] a vascular surgeon, commented: “…Symptomatic
carotid plaques contain abnormal, immature microvessels similar to those found
in tumors and healing wounds. Such vessels could contribute to plaque instability
by acting as sites of vascular leakage by inflammatory cell recruitment....”.
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Jeziorska and Woolley [32] noted the presence of initial, diffuse
neovascularization at each stage of atherosclerotic plaque formation. Their
conclusions were based on an examination of 191 carotid endarterectomy
specimens. The tissue specimens were divided into six categories, types I
through VI, based on degree of atherosclerotic progression, with type I lesions
being the earliest and type VI lesions being the most advanced. Noting that
conventional staining procedures typically underestimated the extent of
neovascularization, they employed staining of monoclonal antibodies to CD31,
CD34, and von Willebrand factor to provide “… an ultra-sensitive technique with
which to visualize blood vessels in early atherosclerotic lesions…”. The authors
concluded that “...new microvessels are a prominent feature of even the early
developmental stages of atherosclerosis.”
And most recently, there appears to be a paradigm change in thinking of
plaque “vulnerability” as reflected in the comments by Shalhoub et al. [33] in their
review article. The authors stated the following: “…2D CEUS presents the
possibility of imaging plaque microvasculature, a proven hallmark of
vulnerability.”
Historically, pathologists, physiologists, and surgeons have long
recognized the association of angiogenesis and plaque. In a seminal paper from
1984, Barger et al. [34] noted that in 1938 Winternitz described “…presence of
rich vascular channels surrounding and penetrating sclerotic lesions.”
Subsequently, Barger et al. [34] published a manuscript in which they
noted that if the coronary arteries were free of atherosclerosis the adventitial
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vasa vasorum vessels were minimally present, whereas in areas with
atherosclerosis the pattern of vasa vasorum was “strikingly different” and was
associated with the presence of “a dense plexus of microvessels … suggesting
marked neovascularization.”.
Kumamoto M. et al [35] concluded that the regions of coronary
atherosclerotic injury are especially rich in vasa vasorum and thus that
neovascularization may play “a fundamental role in the pathogenesis of the
atherosclerotic process and its sequelae”
Further, Barger et al. [34] noted that minimal neovascularization showed in
cases of little or no evidence of atherosclerosis, whereas specimens with a
greater proportion of neovascularization “invariably showed atherosclerotic
changes.” Barger et al. observed that the most striking feature of the heavily
neovascularized areas “was the involvement of the inner media or intima/plaque
locations by microvessels.”
Experimental animal models of atherosclerosis reflect the concept that
angiogenesis is intimately involved in the pathophysiology of atherosclerosis and
present as “outside-to-inside” genesis of atherosclerosis. Heistad and Armstrong
[36] described a five- to sixfold increase in blood flow via vasa vasorum in the
coronary intima and media in diet-induced atherosclerotic monkeys compared
with nonhypercholesterolemic monkeys. And Moulten [37] and Wilson et al. [38]
reported on the development of experimental animal models designed to test the
hypothesis that angiogenesis is associated with the atherosclerosis process.
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Recently, Schinkel et al. [39•] reported on the experimentally induced femoral
wall angiogenesis in the Rapacz familial hypercholesterolemic swine model.
The initial CEUS report that described neovascularization within the
carotid plaque provided an opportunity to define intraplaque perfusion in an in
vivo setting using real-time ultrasound systems coupled with unparalleled spatial
and temporal image resolution and without ionizing radiation. Uniquely, CEUS
imaging can be performed at the bedside, using current commercial equipment,
without incurring ionizing radiation and remains cost-effective for screening at-
risk populations. The ability to provide bedside documentation of a vessel wall
neovascularization permits initiation of treatment for an inflamed vessel wall,
which represents a “vulnerable” plaque.
Conclusions
Although there is substantial clinical validation of the use of carotid artery (CIMT)
as a surrogate marker for systemic atherosclerosis in populations, there is a
need to provide a volumetric analysis of the entire vascular bed to provide a total
“plaque burden” for populations and, specifically, for an individual subject.
Total plaque burden within the carotid artery would constitute an
improvement in accuracy for detecting and monitoring systemic atherosclerosis
[40]. The basis for applying a volumetric approach to plaque detection and
angiogenesis is supported by several recent articles in which the authors
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described measurement of the carotid plaque area as superior compared with
the CIMT for detecting significant disease based on a clinical outcome study [41].
Therefore, based on the development of newer, real-time 3D/4D
ultrasound technologies, it is possible to provide a total volumetric analysis of
both the CIMT as well as the angiogenesis associated with the vessel wall.
It is anticipated that with the continued ultrasound technology
developments of miniaturization and image automation, quantification of
preclinical atherosclerosis in at-risk populations will prove to provide life-saving
events while maintaining cost-effectiveness for a wide cross-section of the
community.
Disclosure
Dr. Steven B. Feinstein has been a speaker for Abbott, Takeda, and General
Electric. Blai Coll received speaker honorarium from Novartis, Astra and Abbott.
Vijay Nambi received research support collaboration with General Electric and
speaker honorarium from the American Heart Association.
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as:
• Of importance
•• Of major importance
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1. Hossain P, Kawar B, El Nahas M: Obesity and diabetes in the developing
world--a growing challenge. N Engl J Med 2007, 356:213–215.
2. Gami AS, Witt BJ, Howard DE, et al.: Metabolic syndrome and risk of
incident cardiovascular events and death: a systematic review and meta-analysis
of longitudinal studies. J Am Coll Cardiol 2007, 49:403–414.
3. Cowie CC, Rust KF, Byrd-Holt DD, et al.: Prevalence of diabetes and
impaired fasting glucose in adults in the U.S. population: National Health And
Nutrition Examination Survey 1999-2002. Diabetes Care 2006, 29:1263–1268.
4. Lorenz MW, Markus HS, Bots ML, et al.: Prediction of clinical
cardiovascular events with carotid intima-media thickness: a systematic review
and meta-analysis. Circulation 2007, 115:459–467.
5. Casscells W, Naghavi M, Willerson JT: Vulnerable atherosclerotic plaque:
a multifocal disease. Circulation 2003, 107:2072–2075.
6. Naghavi M, Falk E, Hecht HS, et al.: From vulnerable plaque to vulnerable
patient--Part III: Executive summary of the Screening for Heart Attack Prevention
and Education (SHAPE) Task Force report. Am J Cardiol 2006, 98:2H–15H.
7. Khot UN, Khot MB, Bajzer CT, et al.: Prevalence of conventional risk
factors in patients with coronary heart disease. JAMA 2003, 290:898–904.
8. Espeland MA, O'Leary DH, Terry JG, et al.: Carotid intimal-media
thickness as a surrogate for cardiovascular disease events in trials of HMG-CoA
reductase inhibitors. Curr Control Trials Cardiovasc Med 2005, 6:3.
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9. Hurst RT, Ng DW, Kendall C, Khandheria B: Clinical use of carotid intima-
media thickness: review of the literature. J Am Soc Echocardiogr 2007, 20:907–
914.
10. Pignoli P, Longo T: Ultrasound evaluation of atherosclerosis.
Methodological problems and technological developments. Eur Surg Res 1986,
18:238–253.
11. Wong M, Edelstein J, Wollman J, Bond MG: Ultrasonic-pathological
comparison of the human arterial wall. Verification of intima-media thickness.
Arterioscler Thromb 1993, 13:482–486.
12. Gamble G, Beaumont B, Smith H, et al.: B-mode ultrasound images of the
carotid artery wall: correlation of ultrasound with histological measurements.
Atherosclerosis 1993, 102:163–173.
13. O'Leary DH, Polak JF, Kronmal RA, et al.: Carotid-artery intima and media
thickness as a risk factor for myocardial infarction and stroke in older adults.
Cardiovascular Health Study Collaborative Research Group. N Engl J Med 1999,
340:14–22.
14. Stein JH, Korcarz CE, Hurst RT, et al.: Use of carotid ultrasound to identify
subclinical vascular disease and evaluate cardiovascular disease risk: a
consensus statement from the American Society of Echocardiography Carotid
Intima-Media Thickness Task Force. Endorsed by the Society for Vascular
Medicine. J Am Soc Echocardiogr 2008, 21:93–111; quiz 189–190.
15. Postley JE, Perez A, Wong ND, Gardin JM: Prevalence and distribution of
sub-clinical atherosclerosis by screening vascular ultrasound in low and
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intermediate risk adults: the New York physicians study. J Am Soc Echocardiogr
2009, 22:1145–1151.
16. Rundek T, Arif H, Boden-Albala B, et al.: Carotid plaque, a subclinical
precursor of vascular events: the Northern Manhattan Study. Neurology 2008,
70:1200–1207.
17. Davidsson L, Fagerberg B, Bergstrom G, Schmidt C: Ultrasound-assessed
plaque occurrence in the carotid and femoral arteries are independent predictors
of cardiovascular events in middle-aged men during 10 years of follow-up.
Atherosclerosis 2009, 209:469–473.
18. Griffin M, Nicolaides A, Tyllis T, et al.: Carotid and femoral arterial wall
changes and the prevalence of clinical cardiovascular disease. Vasc Med 2009,
14:227–232.
19. Folsom AR, Kronmal RA, Detrano RC, et al.: Coronary artery calcification
compared with carotid intima-media thickness in the prediction of cardiovascular
disease incidence: the Multi-Ethnic Study of Atherosclerosis (MESA). Arch Intern
Med 2008, 168:1333–1339.
20.• Nambi V, Chambless L, Folsom AR, et al.: Carotid intima-media thickness
and presence or absence of plaque improves prediction of coronary heart
disease risk: the ARIC (Atherosclerosis Risk In Communities) study. J Am Coll
Cardiol 2010, 55:1600–1607.
This recent manuscript detailed 15-year cardiovascular outcome data for the
cohort. The results provided evidence that the combined use of CIMT and carotid
plaque serve as powerful predictors for cardiovascular outcomes. In fact, when
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these were used in tandem, the ability to reclassify "at risk" was statistically and
clinically significantly improved over traditional risk factor utilization.
21. Macioch JE, Katsamakis CD, Robin J, et al.: Effect of contrast
enhancement on measurement of carotid artery intimal medial thickness. Vasc
Med 2004, 9:7–12.
22. Montauban van Swijndregt AD, De Lange EE, De Groot E, Ackerstaff RG:
An in vivo evaluation of the reproducibility of intima-media thickness
measurements of the carotid artery segments using B-mode ultrasound.
Ultrasound Med Biol 1999, 25:323–330.
23. Montauban van Swijndregt AD, The SH, Gussenhoven EJ, et al.: An in
vitro evaluation of the line pattern of the near and far walls of carotid arteries
using B-mode ultrasound. Ultrasound Med Biol 1996, 22:1007–1015.
24. Feinstein SB: The powerful microbubble: from bench to bedside, from
intravascular indicator to therapeutic delivery system, and beyond. Am J Physiol
Heart Circ Physiol 2004, 287:H450–H457.
25.• Shah F, Balan P, Weinberg M, et al.: Contrast-enhanced ultrasound
imaging of atherosclerotic carotid plaque neovascularization: a new surrogate
marker of atherosclerosis? Vasc Med 2007, 12:291–297.
This manuscript correlated and quantified the association of contrast-enhanced
visualization of intraplaque vasa vasorum and histologic-based
neovascularization. This histologic validation supported the earlier reported
clinical observations on the subject of carotid artery angiogenesis.
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26. Vicenzini E, Giannoni MF, Puccinelli F, et al.: Detection of carotid
adventitial vasa vasorum and plaque vascularization with ultrasound cadence
contrast pulse sequencing technique and echo-contrast agent. Stroke 2007,
38:2841–2843.
27. Coli S, Magnoni M, Sangiorgi G, et al.: Contrast-enhanced ultrasound
imaging of intraplaque neovascularization in carotid arteries: correlation with
histology and plaque echogenicity. J Am Coll Cardiol 2008, 52:223–230.
28. Xiong L, Deng YB, Zhu Y, et al.: Correlation of carotid plaque
neovascularization detected by using contrast-enhanced US with clinical
symptoms. Radiology 2009, 251:583–589.
29. Fleiner M, Kummer M, Mirlacher M, et al.: Arterial neovascularization and
inflammation in vulnerable patients: early and late signs of symptomatic
atherosclerosis. Circulation 2004, 110:2843–2850.
30. Moreno PR, Fuster V: New aspects in the pathogenesis of diabetic
atherothrombosis. J Am Coll Cardiol 2004, 44:2293–2300.
31. Dunmore BJ, McCarthy MJ, Naylor AR, Brindle NP: Carotid plaque
instability and ischemic symptoms are linked to immaturity of microvessels within
plaques. J Vasc Surg 2007, 45:155–159.
32. Jeziorska M, Woolley DE: Neovascularization in early atherosclerotic
lesions of human carotid arteries: its potential contribution to plaque
development. Hum Pathol 1999, 30:919–925.
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33. Shalhoub J, Owen DR, Gauthier T, et al.: The use of contrast enhanced
ultrasound in carotid arterial disease. Eur J Vasc Endovasc Surg 2010, 39:381–
387.
34. Barger AC, Beeuwkes R 3rd, Lainey LL, Silverman KJ: Hypothesis: vasa
vasorum and neovascularization of human coronary arteries. A possible role in
the pathophysiology of atherosclerosis. N Engl J Med 1984, 310:175–177.
35. Kumamoto M, Nakashima Y, Sueishi K: Intimal neovascularization in
human coronary atherosclerosis: its origin and pathophysiological significance.
Hum Pathol 1995, 26:450–456.
36. Heistad DD, Armstrong ML: Blood flow through vasa vasorum of coronary
arteries in atherosclerotic monkeys. Arteriosclerosis 1986, 6:326–331.
37. Moulton KS: Plaque angiogenesis and atherosclerosis. Curr Atheroscler
Rep 2001, 3:225–233.
38. Wilson SH, Herrmann J, Lerman LO, et al.: Simvastatin preserves the
structure of coronary adventitial vasa vasorum in experimental
hypercholesterolemia independent of lipid lowering. Circulation 2002, 105:415–
418.
39.• Schinkel AF, Krueger CG, Tellez A, et al.: Contrast-enhanced ultrasound
for imaging vasa vasorum: comparison with histopathology in a swine model of
atherosclerosis. Eur J Echocardiogr 2010 Apr 12 [Epub ahead of print].
doi:10.1039/ejechocard/jeq048
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In this recent publication, the authors provided a new experimental model for the
in vivo assessment of atherosclerosis using the Rapacz familial
hypercholesterolemic swine model.
40. Ainsworth CD, Blake CC, Tamayo A, et al.: 3D ultrasound measurement
of change in carotid plaque volume: a tool for rapid evaluation of new therapies.
Stroke 2005, 36:1904–1909.
41. Shai I, Spence JD, Schwarzfuchs D, et al.: Dietary intervention to reverse
carotid atherosclerosis. Circulation 2010, 121:1200–1208.