early atherosclerosis imaging: role of different non-invasive
TRANSCRIPT
“Early atherosclerosis imaging:
role of different non-invasive modalities -
Magnetic resonance imaging”
Ali Yilmaz Division of Cardiology
Robert-Bosch-Krankenhaus Stuttgart / Germany
ESC Congress 2012 – Munich:
Disclosure of conflict of interest:
I have no financial relationships to disclose
- and -
I “will” discuss off label use and/or investigational use of Gd-based
and USPIO-based compounds in my presentation.
Non-invasive molecular imaging tools (in comparison):
Camici et al, Eur Heart J 2012;33:1309-1317
Carotid atherosclerotic plaque morphology:
Features associated with plaque disruption
• Intra-plaque hemorrhage
• Large necrotic cores
• Thin overlying fibrous caps
• Plaque neovasculature
• Inflammatory cell infiltrate C. Yuan, SCMR meeting 2011
High-spatial-resolution, multi-parametric, multi-contrast in vivo MRI:
Bright-blood TOF:
• Intact fibrous cap =
continuous hypo-
intense band against
the bright lumen
• Discontinuity of hypo-
intense band and
irregular surface
suggest ruptured
plaque
Black-blood T2W:
• Hypo-intense signal
suggests lipid-rich
necrotic core due to
high content of
cholesterol
• Hyper-intense signal
indicates presence of
inflammation
Contrast-
enhanced
T1W:
• Hyper-intense
signal indicates
presence of
inflammation
T1W (without
contrast):
• Discontinuity of
hypo-intense
band and
irregular
surface
suggest
ruptured
plaque
Chu et al, JACC Cardiovasc Imaging 2009;2:883-896
High-spatial-resolution, multi-parametric, multi-contrast in vivo MRI:
Chu et al, JACC Cardiovasc Imaging 2009;2:883-896
Loose matrix Lipid-rich
necrotic core
Intra-plaque
hemorrhage
Thin fibrous-cap
rupture
CASCADE = Computer-Aided System for Cardiovascular Disease Evaluation (to
generate component outlines)
CASCADE FC = additional algorithm to collect fibrous cap length, depth, and area
MEPPS = Morphology Enhanced Probability maPS (to generate an automated map of
the plaque)
Accuracy of multi-parametric MRI for identifying LRNC and intra-plaque hemorrhage in human carotid plaques:
Yuan et al, Circulation 2001;104:2051-2056
Overview MRI weightings and plaque classification:
Multi-parametric MRI weightings:
Multi-parametric MRI-based plaque classification:
Saba et al, Atherosclerosis 2012;220:294-309
Prevalence of type VI unstable plaques = plaques with surface irregularities, hemorrhage and thrombus
METHODS:
• 32 consecutive patients (22 male; mean age 71.7 ± 11.9 years) with
– cryptogenic stroke and
– non-stenosing (50%) eccentric carotid plaques.
• Other causes of stroke were excluded by
– brain MRI, duplex sonography,
– ECG, Holter monitoring, TTE / TEE, and
– laboratory investigations.
• All patients received multi-parametric MRI at 3-T using surface coils and parallel imaging techniques.
• Prevalence of AHA type VI plaque (= unstable plaque with surface irregularities, hemorrhage and thrombus) was determined in both carotid arteries (on the basis of previously published MRI criteria).
Freilinger et al, JACC Cardiovasc Imaging 2012;5:397-405
Freilinger et al, JACC Cardiovasc Imaging 2012;5:397-405
Documented plaque rupture in a patient ...
3D-TOF T2W Pre-contrast T1W Post-contrast T1W
Ba
se
lin
e
10
mo
nth
s la
ter
Chu et al, Circulation 2006;113:e660-e661
Natural course of human carotid artery plaques?
Kwee et al, PLoS ONE 2012;7:e42472
Limitations of multi-parametric MRI-based plaque imaging:
• Significant technical limitations (suboptimal reproducibility) for its wide clinical applicability beside CE-MRA.
• Need for dedicated MR-hardware (3.0-T) and MR-sequences.
• Multi-parametric MRI with longer duration of the MR examination.
• In the large majority of institutions: surgical and/or endovascular treatment for carotid atherosclerosis are still performed based on stenosis degree alone without taking into account histological considerations.
Visualization of coronary wall atherosclerosis?
Gerretsen et al, PLoS ONE 2010;5:e12998
X-ray CA bSSFP coronary MRA MR-CVW
Res. 0.98 x 0.98 x 3 mm Res. 0.78 x 0.78 x 2 mm
„Molecular“ imaging targets in the atherosclerotic plaque:
Camici et al, Eur Heart J 2012;33:1309-1317
Molecular imaging agents (mostly preclinical):
McAteer et al, Atherosclerosis 2010;209:18-27
Molecular targets in pre-clinical studies:
Small paramagnetic (Gd):
• Type 1 collagen
• Fibrin
• Elastin
• DNA
• MMP
Gd nanoparticles:
• Macrophage scavenger receptor
• Ox-LDL
• Integrins
Superparamagnetic iron-oxide NPs:
• Macrophage content
• Macrophage scavenger receptor
• Ox-LDL
• Apoptosis
• VCAM-1
Superparamagnetic microparticles:
• VCAM-1
• P-Selectin
• Activated platelets
D. Sosnovik, SCMR meeting 2012
Clinical studies with molecular/cellular targets?
METHODS:
• 47 patients with
– carotid stenosis 40% on duplex ultrasonography and
– intraplaque accumulation of USPIO on MRI at baseline
• USPIO compound = Sinerem (intravenous infusion of 2.6 mg/kg BW).
• Random assignment in a balanced, double-blind manner to
– either 10 mg atorvastatin daily or
– 80 mg atorvastatin daily
for 12 weeks.
• Multi-contrast imaging of both the left and right internal carotid artery before USPIO infusion and 36 h after infusion with a 1.5-T scanner.
• Primary end point = change from baseline in signal intensity (SI) on USPIO-enhanced MRI in carotid plaque at 6 and 12 weeks.
Tang et al, J Am Coll Cardiol 2009;53:2039-50
Tang et al, J Am Coll Cardiol 2009;53:2039-50
Pre-USPIO 36h post-USPIO
Baselin
e
6 w
eeks
12 w
eeks
Human monocyte-targeting using SPIO (ex vivo):
Co
ntr
ol
SP
IO (
Reso
vis
t)
200x 1000x
Human macrophage-targeting using SPIO (ex vivo):
Co
ntr
ol
SP
IO (
Reso
vis
t)
0h 24h
In vivo imaging of macrophages using USPIO in humans?
Cin
e-C
MR
(L
A)
Baseline (pre-FH) 6h post FH 24h post FH 48h post FH 96h post FH 3months post FH
T2-S
E-C
MR
(L
A)
T1-L
GE
-CM
R (
LA
)
Yilmaz et al, Circulation 2012; in press
Take home messages:
• Multi-parametric MRI allows a non-invasive assessment of human plaque morphology and subsequent classification of human carotid plaques (with detection of type VI unstable plaques).
• Classification of carotid plaques based on multi-parametric MRI goes beyond the standard luminographic approach based on CE-MRA and seems to have additional prognostic and possibly therapeutic value.
• There are still some technical limitations to overcome in order to suggest a wider and more intensive use of multi-parametric MRI for plaque imaging.
• MRI for visualization of coronary plaques is still far away from routine clinical use.
• Molecular atherosclerosis imaging approaches – in particular based on USPIO-based imaging agents – are promising, but not yet clinically established.
Thank you for your attention!
Ali Yilmaz, MD
Head, Group Molecular Imaging and Cardiomyopathies
Division of Cardiology
Robert-Bosch-Krankenhaus
Auerbachstr. 110
70376 Stuttgart
► www.rbk.de/herzbildgebung
MR sequence parameters:
Plaque features in „symptomatic patients“:
Moderate stenosis
(peak velocity
125-230 cm/sec)
Mild stenosis
(peak velocity
<125 cm/sec)
p value
Prevalence of intraplaque hemorrhage
48.7 % 19.7 % p = 0.002
Prevalence of a thin and/or ruptured
fibrous cap 61.5 % 36.1 % p = 0.013
Lipid-rich necrotic
core percentage 12.3 % 6.8 % p = 0.042
Fibrous tissue percentage
82.7 % 88.4 % p = 0.024
Kwee et al, Stroke 2010;41:1389-1393
Major results:
• Symptomatic pts. with moderate stenosis have a higher prevalence of complicated plaques than pts. with mild stenosis.
• Increasing age was positively associated with intraplaque hemorrhage.
• Statin use was negatively associated with complicated plaque features.
Tang et al, J Am Coll Cardiol 2009;53:2039-50
Pre-USPIO 36h post-USPIO
Baselin
e
12 w
eeks