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Inflammation & Imaging
Ahmed Tawakol, MDCo-Director Cardiac MR PET CT Program
Massachusetts General HospitalHarvard Medical School
Disclosures
• Research Grants:– Genentech, Takeda, Actelion
• Consulting– Actelion, Amgen, Astra Zeneca, Takeda
Maddox et al. JAMA 2014
Non-Obstructive Plaques:
an Important Locus of Plaque Rupture
1-yr MI Risk
Falk et al. Circulation 1995
68%
18%
14%
<50%
50-70%
>70%
% Stenosis
% Cases N
Culprit Plaques:
Caused Insignificant Stenosis
Within 6 Mo Prior to Rupture
Non-Obstructive CAD Assoc w
Nearly 5-fold Increased 1-yr MI Risk
1) Stenosis evaluation • inadequate for plaque evaluation and risk
stratification.
2) Evaluation of wall composition and biology • may provide important insights.
3) Achieved via • combination of molecular and structural imaging.
Imaging Atherosclerosis
Oncology: Demonstrated Clinical Utility of Combined
Biological and Structural Imaging
• Combined molecular and structural imaging (PET-CT) more accurate than structural imaging alone (CT or MR) for tumor staging and localization – Lardinois NEJM 2003, – Antoch, JAMA. 2003
• Transformed Oncology practice and clinical trials
• Prompted wide proliferation of PET/CT
Inflammation: A Central Player
From: Libby P. Nature 2002
Tarkin, Joshi, Rudd Nature CV 2014
Inflammation: Many Targets
FDG-PET Accumulation:
Measure of Tissue’s Glycolytic Rate
Rudd et al JACC 2010
FDG Uptake By Macrophages:
Important in Tumor Imaging
Kubota et al JNM 1994
Macrophage Glycolysis
Increased after M1 Activation
M1
M2-or No Rx
Rodriguez-Prados et al J Immunol 2010
Inflammation and Metabolism in an
Atherosclerotic Environment
Tawakol et al ATVB 2015
normoxia hypoxia
Gly
coly
tic F
lux
Inflammation and Metabolism in an
Atherosclerotic Environment
Tawakol et al ATVB 2015
normoxia hypoxia
Gly
coly
tic F
lux
Pro
-Infla
mm
ator
y A
ctiv
ity
Inflammation and Metabolism in an
Atherosclerotic Environment
Tawakol et al ATVB 2015
Glycolytic FluxP
ro-In
flam
mat
ory
Act
ivat
ion
(TN
F al
pha
pg/m
l)
Gly
coly
tic F
lux
Pro
-Infla
mm
ator
y A
ctiv
ity
normoxia hypoxia
FDG Uptake
Linked to Pro-Inflammatory Activation
Satomi et al JNM 2013
PET-CT
Axia
lC
oro
na
l
1.41.2
1.31.0
MeasuredROI
Values
2.5
2.2
2.0
1.2
Whole Vessel
Most Diseased Segment
(MDS)
Mean
Value
Max
Value
2.2
2.0
1.5
1.0
1.4
1.3
2.5
2.2
2.0
1.2
2.5
2.2
2.0
Whole Vessel
TBR
1.77
MDS
TBR
2.23
Axial measurements every 5 mm
1.5
cm
Imaging Endpoints
Arterial FDG Uptake Relates to
Plaque Inflammation
Figueroa Circ CV Imaging 2011
CT PET/CT PET/CT
L
Histopathology
coronal coronal axial axial
R=0.70,p<0.001
FDG uptake (TBR)
Macrophage DensityTawakol JACC 2006
R=0.8,p<0.005
MA Font et at,
Frontiers in Bioscience 2009
Multi-group Confirmation
r = 0.45, P = 0.22
r = 0.77, P = 0.01
: r = 0.67, P = 0.03
: r = 0.67, P = 0.03 M
. Græ
be et al.E
ur J Vasc Endovasc S
urg 2009
R=0.64P<0.001
Taqueti et al Circ Imaging 2014
Arterial FDG Uptake: Relationship to Cardiac
Risk Factors
Kim et al Circulation Imaging 2010
Arterial Inflammation Predicts
Subsequent Plaque Progression
Abdelbaky et al Circ Imaging 2013
Baseline Inflammation (by PET) Precedes Subsequent Local Plaque Calcification (by CT)
Rel
ativ
e FD
G U
ptak
e
CTCTPET
Baseline2-yr
Follow-up
Changes in Arterial Inflammation Predict Plaque
Progression: Wall thickness by MR
Early Changes in Inflammation (by PET) Predict Long-Term Changes in Wall Thickness, (by MRI)
Fayad et al Lancet 2011; Tawakol et al ESC 2012
Decreased Increased
6M Change in TBR
Cha
nge
in W
all T
hick
ness
ove
r 24
Mo
PET
1
MR
1
6M
24M
BeginRX
PET
2
MR
2
Figueroa et al JACC Imaging 2013
Arterial FDG Signal Predicts
Risk of Subsequent CVD Events
Risk Categories NRI[95% bootstrap CI]
Events correctly
reclassified
Non-events
correctly
reclassified
< 10% risk
10-20% risk
> 20% risk
29.44%
[13.45,48.42]
12.20% 17.24%
Carotid FDG Uptake
Predicts Early Stroke Recurrence
Marnane et al. Annals of Neurology 2012
Human Treatment Studies
• FDG PET/CT arterial imaging– Widely employed to test effects of therapy– Over a dozen MCTs
• 4 drug classes – Both PET/CT data and outcomes data.– How predictive are PET/CT imaging results?
LaRosa et a NEJM 2005
Hi vs Low-Dose Atorva
PET/CT Imaging Trial Clinical Endpoint Trial
Tawakol et al JACC 2013
Non-Pharmacologic LDL Lowering:
ApheresisA
rt In
flam
mat
ion
(TB
R)
LDL
Van Wijk et al JACC 2014
Pre Post
P=0.03 R=0.71P=0.01
Art
Infla
mm
atio
n (T
BR
)
Response To Therapy: Pioglitazone
Mizoguchi et al JACC CV Imaging 2011
Pio Glimepiride
PET/CT Imaging Trial Clinical Endpoint Trials
Nis
sen
et a
l JA
MA
200
7E
rdm
ann
et a
l JA
CC
200
7
Cha
nge
in P
ET
Sig
nal
Effect of the CETP Antagonist Dalcetrapib
Fayad et al Lancet 2011
PET/CT Imaging Trial Clinical Endpoint Trials
Schwartz et al , NEJM 2012
N=15,871
Effect of LPPLA2 Inhibition on
Arterial FDG Uptake
O’D
onog
hue
et a
l JAM
A. 2
014
The
STA
BIL
ITY
In
ve
stig
ato
rs.
N E
ng
l J M
ed
20
14
.
Tawakol et al JACC 2014
PET/CT Imaging Trial Clinical Endpoint Trials
N=13,026
N=15,828
Arterial Inflammation is Increased in HIV
Subramanian et al JAMA 2012
Aortic Inflammation is Associated with
High Risk Coronary Plaques
Tawakol et al JAIDS 2014
Aortic TBR
< Median Value
> Median Value
High-Risk
Coronary Plaque Morphology
Low Attenuation Low Attenuation and Positive Remodeling
% S
ubje
cts
with
Hig
h-R
isk
Cor
onar
y P
laqu
es
Atherosclerotic mechanisms
may have important
components that exist outside
the vessel wall
Think outside of the vessel wall…
Multi-Tissue Assessment in Systemic Disease:
Bone Marrow, Splenic, Arterial Axis in Mice
Dutta et al Nature 2012
…and subsequent
aortic plaque inflammation
… increase in splenic granulocyte macrophage
progenitors (GMPs)
MI (LAD Ligation)Triggers b3AR-mediated
progenitor cell release frombone marrow
Dutta et al Nature 2012
MI
Arterial Inflammation
Dutta et al Nature 2012
MI
Arterial Inflammation
Does this axis exist in humans?
Hematopoietic Activation: Relates to Pro-
Inflammatory Gene Activation in Leucocytes
Emami et al JACC Imaging 2015
AC
S
AC
S
AC
SS
tabl
e C
AD
Sta
ble
Sta
ble
Bone Marrow Spleen
Dutta et al Nature 2012
MI
Arterial Inflammation
Does Hematopoietic tissue activity predict CVD Risk?
Hematopoietic Tissue Activity Correlate w Arterial
Activity in Individuals without known Athero
Emami et al JACC Imaging 2015
Splenic Activity Predicts Subsequent CVD
Emami et al JACC Imaging 2015
Splenic Activity Predicts Subsequent CVD
Emami et al JACC Imaging 2015
Sub-Cutaneous
Adipose Tissue
FDG Uptake
Marincheva et al, JACC 2011
FDG Uptake
Aortic Valve Calcification
AS Progression (ECHO)
Mice Humans
Hara et al Circulation 2014
FDG-PET/CT: Characterization of Inflammation in DVT
Neutrophil Depleted
DV
T F
DG
Sig
na
l
ControlMice
3210
*
How could we use
inflammation imaging clinically
today?
Clinical Imaging
Blankstein JACC 2014 Saby et al JACC 2013
Increases sensitivity of modified Duke criteria
Predictive of Death/VT
Serrazin et al JACC 2012
Improved detection
SarcoidosisProsthetic Valve
Endocarditis Device Infection
Future uses:
• Moderate to severe carotid stenosis– Risk stratification to guide treatment
• Chronic Coronary Atherosclerosis– Fine-tune risk– Allocation of treatments
• New treatments will be available– Mounting costs and side effects
• Need to improve ability to allocate treatments– Think like oncologists
– Follow response to expensive/toxic treatments– Switch course when drugs are not working
• Venous Thromboembolism– Predict post thrombotic syndrome– Identify young clots susceptible to thrombolysis
Coronaries?
Culprit Coronary Lesions
Have Higher Arterial FDG Uptake
Rogers et al JACC CV Imaging 2010
Culprit LesionACS
Stable SyndromeNew Stent
Stable SyndromeOld Stent
18F NaF Imaging of Micro-calcification
Localizes to culprit lesionsFar less background uptake than FDG
• Unclear mechanism leading to its uptake in culprit• Unclear If its modifiable by therapy• Unclear If provides additional prognostic info above CAC
Joshi et al, Lancet 2014
NAF UPTAKE IS NOT CELL-SPECIFIC
Irkle A and Vesey A, Newby DE, et al, Rudd JHF and Davenport A, Nature Communications 2015 In Press 2015
Technological Advances
Development of New Tracers
TSPO Imaging
Pugliese et al JACC 2010
Elmaleh et al PNAS 2006
Ado Receptor Imaging
Tahara et al Nature Medicine 2014
Manose Receptor
Imaging
Ga DOTATATE
Courtesy of James Rudd
PET/MR
Acknowledgements
MGH CV Imaging Team• Amr Abdelbaky, MD• Hamed Emami, MD• Amparo Figueroa, MD• Brian Ghoshhajra, MD• Amorina Ishai, MD• Philip Joseph, MD• Udo Hoffmann, MD• Hoey Chyi Lim, BA• Megan Macnabb , BA• Thomas Neilan, MD• Parmanand Singh, MD• Sharath Subramaninan, MD• Richard Takx, MD
Key Collaborators
• Lisardo Bosca, MD• Ciprian Catana, MD• Marcelo DiCarli, MD• Michael E Farkouh MD• Zahi A Fayad PhD• Henry Gewirtz, MD• Michael Jaff, DO• Farouc Jaffer, MD, PhD• Peter Ganz, MD• Stephen Grinspoon, MD• Linda Hemphill, MD• Priscilla Hsue, MD• Janet Lo, MD• Matthias Nahrendorf, MD• Jagat Narula, MD• Miguel Pampaloni, MD• Roger Pitman, MD• James HF Rudd MD PhD• Bruce Rosen, MD, PhD• Marielle Scherer-Crosbie, MD• Lisa Shin, PhD• David Sosnovik, MD• Quinh Truong, MD