Bedeutung der

Ultraschallkontrastmittel im
angiologischen Alltag:
Heute und in Zukunft

Daniel Staub
Angiologie
Universittsspital Basel
staubd@uhbs.ch
12. Unionstagung 9. November 2011 SGUM-Jahresversammlung
Ultraschall Med 2011;Epub Aug 26
Overview
Principles of contrast-enhanced ultrasound (CEUS)

CEUS of the carotid artery

Vasa vasorum and plaque neovascularization

CEUS of the abdominal aorta

CEUS of the kidney / transplanted kidney

Future applications of CEUS and Conclusions
Ultrasound Contrast Agent
Microscopic bubbles
Either freeze dried
or in suspension
1-5 x 10
8
bubbles / ml
2 8 m
Size the bubbles
are smaller than the
diameter of the smallest
human blood vessels.
Gas they contain a low
solubility, non-toxic gas,
not normally present in the
body.
Coating they have
a surfactant or polymer
shell to prevent them
dissolving or coalescing.
Feinstein SB, Staub D J Nucl Cardiol 2010;17:206
Lindner JR Nat Rev Drug Discov 2004;3:527
Why ultrasound contrast agents improve ultrasound scans?
There is a large difference in density and compressibility between the
gas-filled bubbles and the surrounding liquid (blood).
Consequently bubbles produce much
stronger echoes than blood cells.
Optimal intravascular tracer
5 m
8 m
Bubbles also produce echoes which are non-linear, i.e. at different frequencies
from the incoming wave.
Tissue echo
Bubble echo
Incoming frequency
frequency frequency
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Incoming frequency
harmonics
This makes it easier to distinguish bubble echoes from those from tissue which are
normally at the same frequency as the incoming wave.
Contrast-specific ultrasound modes: Harmonic-Imaging, Pulsinversion-Imaging, etc.
Lindner JR Nat Rev Drug Discov 2004;3:527
CEUS: Application
Venous access
Venflon (20G)
Ultrasound contrast agent:
SonoVue (second generation) 4.8ml
CEUS: Application
0.5ml-1.0ml bolus
followed by flow rate 1ml/min
1.0ml -2.4ml bolus
followed by 10ml NaCl 0.9% flush
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Time
1min 2min 3min 4min 5min 6min
Bolus iv.
bolus bolus bolus
Perfusor iv. (VueJect)
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Time
1min 2min 3min 4min 5min 6min
bolus
continuous flow
CEUS: Equipment and Settings
Broadband transducer: Linear array 9 to 3 MHz or Curved array 5 to 1 MHz
Harmonic-Imaging, Pulsinversion-Imaging, Powermodulation
Low-MI (0.06-0.20), Gain 80%, Low dynamic range, displace focus zone
Contrast time, loop recording (DICOM) initial 10-40 sec, shorter clips at 1-3 min
Contrast-specific
ultrasond mode
B-mode ultrasound
CEUS: Safety
Senior R Eur J Echocardiogr 2009;10:194
Not nephrotoxic, no interaction with the thyroid gland

Incidence of severe hypersensitivity reactions is lower than with X-ray agents

Life threatening anaphylactoid reactions < 0.002%

Caution: severe coronary artery disease and pulmonary hypertension

Relative contraindication: unstable ischaemic heart disease < 7 days
EFSUMB Guidelines Ultraschall Med 2011
Enhancment of the carotid lumen
Delineation of the endovascular border
Plaque ulcerations
CEUS of the Carotid Artery
Intra-luminal Plaque
IMT
Feinstein SB, Staub D J Nucl Cardiol 2010;17:106
68-year-old man with carotid bruit who has coronary artery disease and no
cerebrovascular event. Standard ultrasound revealed high-grade carotid stenosis

CEUS of the Carotid Artery
B-mode ultrasound CEUS
Staub D AJR Am J Roentgenol 2012;198:W1
CEUS of the Carotid Artery
61-year-old man with symptomatic microembolic retinal ischemia. Standard
ultrasound revealed calcified carotid stenosis.

B-mode ultrasound
CEUS
Carotid Stenosis
Sub-occlusive stenosis
Occlusion
Follow-up after carotid stenting
Re-stenosis
Clevert DA Eur J Radiol 2011;80:68 Clevert DA Clin Hemorheol Microcirc 2011;48:199
Carotid Dissection
Clevert DA Eur J Radiol 2011;80:68
Arterio-venous Fistula
Clevert DA Ultraschall Med 2010;31:610 Clevert DA Eur J Radiol 2011;80:68
Carotid-jugular arterio-venous fistula
CEUS is recommended for the following indications:
Differentiation between total carotid occlusion and
residual flow in tight stenoses by contrast enhanced
Doppler or CEUS. Recommendation Level: B;3
Improvement of lumen delineation in technically difficult
carotid arteries. Recommendation Level: B;3
Improving the detection of dissection of the common and
internal carotid arteries, vertebral artery and aorta.
Recommendation Level: C;3

Ultraschall Med 2011;Epub Aug 26
Carotid Plaque Characterization
Plaque on B-mode ultrasound
c-IMT
Intra-luminal Plaque
A 63-year old female subject who has no cardiovascular disease but has
high lipids: B-mode ultrasound reveals hypoechogenic plaque at the origin of
the internal carotid artery.
SonoVue 2.4ml iv.
Staub D AJR Am J Roentgenol 2012;198:W1
Vasa Vasorum and
Plaque Neovascularization
SonoVue 2.4ml iv.
CEUS imaging illustrates intraplaque neovascularization with moving bubbles
which reach the plaque core
Staub D AJR Am J Roentgenol 2012;198:W1
Factors known to promote unstable plaque
Eyding J, Staub D Ultraschall Med 2011;32:267
Mechanisms of Vessel Wall
Neovascularization in Atherosclerosis
Doyle B, Caplice N JACC 2007;49:2073
Normal
Atherosclerosis
Pro-Angiogenic Growth
Factor Expression
Vascular SMC
Macrophages
Leukocytes
Platelets
Endothelium
Extracellular matrix
VEGF
PDGF
FGF
HGF
Hypoxia (HIF)
Inflammation
Oxidative stress
Hypertension
Nicotin
Stimuli
Sources
Factors
Upregulation
Neovascularization and Plaque Instability
Contribution of neovascularization to
plaque growth and plaque instability
Delivery of inflammatory cells
and mediators
Delivery of oxygen and
metabolic substrates
Delivery of lipid
Inflammation
Vascular leakage
Intraplaque hemorrhage
Plaque rupture and thrombosis
Doyle B, Caplice N JACC 2007;49:2073
Neovascularization in
Vulnerable Plaques / Patients
Dunmore BJ J Vasc Surg 2007;45:155
(n=13)
(n=15)
p < 0.001
Neovascularization and
Cardiovascular Outcome
816 patients underwent CEA with histology
Clinical follow-up 3 years
Vascular event in 24% (vascular death, stroke, MI)
Intraplaque vessel density
Plaque hemorrhage
Multivariate, HR
1.5 (1.1-2.2)
Multivariate, HR
2.2 (1.2-3.8)
Hellings WE Circulation 2010;121:1941
No/minor
Moderate/heavy Moderate/heavy
No/minor
Histology (CD31 and CD34)
after CEA
Intraplaque Neovascularization:
CEUS and Histology
Intraplaque neovascularization
quantification on CEUS
Staub D JACC Cardiovasc Imaging 2010;3:761
Intraplaque Neovascularization:
CEUS and Histology
Coli S JACC 2008;52:223
p=0.005
Neovascularization on CEUS
Hoogi A AJR Am J Roentgenol 2011;196:431
Vasa Vasorum on CEUS
in a Swine Model of Atherosclerosis
5 weeks 12 weeks 43 weeks
Schinkel AFL, Staub D Eur J Echocardiogr 2010;11:659
Vasa Vasorum on CEUS
in a Swine Model of Atherosclerosis
Schinkel AFL, Staub D Eur J Echocardiogr 2010;11:659
Neovascularization on CEUS in
Atherosclerotic Carotid Lesions
Standard and CEUS in 175 patients with 293 carotid lesions
Standard Ultrasound:
Degree of stenosis
maximal lesion thickness
Plaque echogenicity (Class I-IV)
Staub D Radiology 2011;258:618
Neovascularization on CEUS in
Atherosclerotic Carotid Lesions
Standard and CEUS in 175 patients with 293 carotid lesions
Neovascularization
on CEUS:
Grade 1 (absent)
Grade 2 (moderate)
Grade 3 (extensive)
Staub D Radiology 2011;258:618
Severity
Stenosis < 50% 226 (77%)
Stenosis 50-69% 49 (17%)
Stenosis 70% 18 (6%)
Maximal lesion thickness (mm)* 2.70.9 (1.3 to 7.9)
Echogenicity
Class I 30 (10%)
Class II 99 (34%)
Class III 111 (38%)
Class IV 53 (18%)
Neovascularization
Grade 1 178 (61%)
Grade 2 96 (33%)
Grade 3 19 (6%)
Characteristics on Standard and CEUS in
Atherosclerotic Carotid Lesions (n=293)
Staub D Radiology 2011;258:618
Neovascularization on CEUS
is Correlated with Lesion Severity
p=0.008 by chi-square for trend p<0.001 by chi-square for trend
Staub D Radiology 2011;258:618
Neovascularization on CEUS
is Correlated with Lesion Echogenicity
p<0.001 by chi-square for trend
Neovascularization
is correlated with
features of plaque instability
(echolucency)
Staub D Radiology 2011;258:618
Neovascularization on Carotid CEUS
and Clinical Symptoms
A 68-year old female subject who has right sided amaurosis fugax:
B-mode ultrasound reveals a plaque at the origin of the right ICA.
Following an iv. bolus injection of 2.4 ml of SonoVue, the CEUS reveals
intraplaque neovascularization and vasa vasorum at the base of the plaque
Staub D AJR Am J Roentgenol 2012;198:W1
Staub D Stroke 2010;41:41
Standard carotid ultrasound and CEUS in 147 patients
Intraplaque
neovascularization:
grade 1 (absent)
grade 2 (present)
Clinical data
cardiovascular risk factors
cardiovascular events:
myocardial infarction,
Stroke/TIA
Optison or Definity 2.0ml iv.
Neovascularization on Carotid CEUS
and Clinical Symptoms
Baseline Characteristics (n=147)
Cardiovascular risk factors
Age, years 6411
Male gender 89 (61%)
Diabetes mellitus 45 (31%)
Hypertension 100 (68%)
Smoker 68 (46%)
LDL, mg/dL 8743
Clinical history
Myocardial infarction 22 (15%)
TIA/Stroke 17 (12%)
Cardiovascular events 37 (25%)
Staub D Stroke 2010;41:41
Carotid Ultrasound Imaging and
Cardiovascular Events
Staub D Stroke 2010;41:41
31%
38%
8%
20%
0
5
10
15
20
25
30
35
40
45
50
Plaque Intra-plaque Neovascularization
Grade 2
%

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Yes Non
p=0.037
p=0.038
Univariate and Multivariate Analysis
Cardiovascular Events
OR (95%CI) p-Value
Univariate analysis
Presence of Plaque 4.5 (1.3-15.5) 0.019
Intraplaque Neovascularization
Grade 2
2.5 (1.1-6.1) 0.034
Multivariate analysis
Presence of Plaque * 2.1 (0.5-8.9) NS
Intraplaque Neovascularization
Grade 2*
4.0 (1.3-12.6) 0.017
*adjusted for age, gender, and cardiovascular risk factors

Staub D Stroke 2010;41:41
Quantification of Intra-plaque
Neovascularization
Shalhoub J Eur J Vasc Endovasc Surg 2010;39:381
CEUS in Symptomatic and Asymptomatic
Carotid Stenosis
SonoVue 1.5ml iv.
Variable Symptomatic
Group (n=35)
Asymptomatic
Group (n=69)
P Value
Contrast
enhancement
28 (80) 21(30) <0.001
Enhanced intensity
in plaque (dB)
13.9 6.4 8.8 5.2 <0.001
Ratio 0.54 0.23 0.33 0.19 <0.001
Xiong L Radiology 2009;251:583
Late Phase CEUS
Inflammation within Carotid Plaque
Owen DR Radiology 2010;255:638
Late Phase CEUS
Inflammation within Carotid Plaque
Shalhoub J Stroke 2011;Epub Sep 29
Identification of Vulnerable Plaque
61-year-old man with several cardiovascular risk factors (smoking, arterial
hypertension, and high lipids). He is asymptomatic and has high-grade stenosis
of the internal carotid artery.
One week after carotid ultrasound was performed, patient had recurrent TIA.
Subsequently, he underwent urgent left carotid endarterectomy.
Staub D AJR Am J Roentgenol 2012;198:W1
Analysis of Carotid Lesions
73-year-old woman with arterial hypertension and high lipids. She has
symptomatic (dysarthria and left-sided central facial palsy) high grade stenosis.
She underwent carotid endarterectomy that revealed plaque
with large superimposed thrombus formation.
Staub D AJR Am J Roentgenol 2012;198:W1
30-year-old man who developed recurrent episodes of pain over past 2 months
that was located at right side of neck (region of carotid bifurcation). Pain was
constant, sometimes irradiating to ipsilateral ear and generally dissolved within
few days to course of ibuprofen.
Clinical course together with findings on standard and CEUS suggest diagnosis
of idiopathic carotidynia.
Analysis of Carotid Lesions
Staub D AJR Am J Roentgenol 2012;198:W1
A 35-year-old woman with a 5-year history of fatigue and low-grade fever. Six
months before admission, she had pain in the neck and in the infrascapular
region. Examination of the neck disclosed bilateral carotid murmurs.
Laboratory examination: Lc 21.7109/L; ESR 120 mm/h; CRP 76.4 mg/L.


Analysis of carotid lesions
The detection of contrast agent microbubbles within the vascular thickening as a
marker of neovascularization is consistent with the initial inflammatory phase of
Takayasu arteritis.
Magnoni M Circ Cardiovasc Imaging 2011;4:e1
CEUS is recommended for the following indications:
Evaluation of carotid plaque neovascularization.
Recommendation Level: B;1b
Ultraschall Med 2011;Epub Aug 26
CEUS of the Abdominal Aorta
Abdominal aortic aneurysm (AAA)
Delineation of the aortic lumen
Detection of the main branching arteries
Aortic dissections
Aortic rupture
Schuster H Ultraschall Med 2009;30:528
Chronic Periaortitis
Vaglio A Lancet 2006;367:241
56-year-old man with chronic
abdominal pain
low back pain
weight loss of 6kg
CRP 12 mg/l, ESR 19 mm/1h
Chronic Periaortitis
CEUS at baseline CEUS at follow-up after
3 months of prednisone therapy
Greenhalgh RM NEJM 2008;358: 494
Endoleaks after EVAR
CEUS after EVAR
Endoleak Type 2
CEUS versus CT (7 Studies, 288 Patients):
Sensitivity 98% und Specificity 88%
Mirza TA Eur J Vasc Endovasc Surg 2010;39:418
Detection and Characterization of Endoleaks
with Quantitative Perfusion Analysis
CEUS with quantitative perfusion analysis
compared with CT Angiography:
Sensitivity 99% und Specificity 93%
Jung EM Ultraschall Med 2010;31:564
CEUS is recommended for the following indications:
Detection of aortic wall rupture. Recommendation Level: B;3
As additional tool in the characterization of
suspected inflammatory AAA. Recommendation Level: B;3
Detection and characterization of endoleaks after AAA
repair. Recommendation Level: A;1a
Follow-up of AAA endoleak. Recommendation Level: A;1a
Ultraschall Med 2011;Epub Aug 26
Renal Perfusion on CEUS
Renal Ischaemia on CEUS
Renal infarction Renal parenchymal ischaemia
in transplanted kidney
CEUS is recommended for the following indications:
Suspected vascular disorder, including renal
infarction and cortical necrosis.
Recommendation Level: A;1a
Ultraschall Med 2011;Epub Aug 26
Future applications of carotid CEUS imaging
Risk stratification of plaque/stenosis (vulnerable patient)
Monitoring of therapeutic intervention
Prospective studies with quantitative and 3D analysis of
intraplaque neovascularization are needed


Feinstein SB, Staub D J Nucl Cardiol 2010;17:106
Quantitative perfusion imaging
Peripheral skeletal muscle
microcirculation in patients
with PAD and diabetes mellitus
Duerschmied D Diab Res Clin Pract 2008
Weber MA, Krix M Invest Radiol 2011
Lindner JR JACC Cardiovasc Imaging 2008

Arrival time parametric imaging
to detect acute rejection of
kidney grafts
Fischer T Ultraschall Med 2007

Future applications of CEUS imaging
Molecular ultrasound imaging
(targeted contrast agent,
e.g.
v

3
-integrin-targeted, targeted to
growth factor receptors, ICAM-1, VCAM-1)

Schinkel AF J Nucl Cardiol 2010;17:897
Villanueva FS J Nucl Cardiol 2008;15:576
Kaufmann BA Cardiovascular Research 2009;83:617
Future applications of CEUS imaging
Future applications of CEUS imaging
Ultrasound-directed, site-specific therapies with
microbubbles for drug and gene delivery
(e.g. antiangiogenic therapy, thrombolytic therapy)
Bekeredjian R Ultraschall Med 2006;27:134
Conclusions
CEUS imaging of arteries (carotid artery / aorta):
Enhancement of the artery lumen

Improvement of lumen delineation (plaque, ulceration)

Occlusion/stenosis

Dissection

Vessel wall rupture

Fistula

Detection and follow-up of endoleaks after EVAR
Conclusions
CEUS imaging of vessel wall (Plaque):
Real-time visualization and quantification of the
microcirculation

Vasa vasorum and intra-plaque neovascularization
(Identification of vulnerable plaque/patients)

Vessel wall inflammation (vaskulitis, periaortitis,
inflammatory AAA)


CEUS imaging of parenchymal organ

Evaluation of renal perfusion

Renal infarction, cortical necrosis

Splenic infarction

Staub D JACC Cardiovasc Imaging 2010;3:761
Thank you!