Inflammation & Imaging

Ahmed Tawakol, MDCo-Director Cardiac MR PET CT Program

Massachusetts General Hospital

Harvard 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

-In

flam

mato

ry

Activity

Inflammation and Metabolism in an

Atherosclerotic Environment

Tawakol et al ATVB 2015

Glycolytic FluxP

ro-I

nfla

mm

ato

ry A

ctiva

tio

n(T

NF

alp

ha p

g/m

l)

Gly

coly

tic F

lux

Pro

-In

flam

mato

ry

Activity

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 Density

Tawakol JACC 2006

R=0.8,

p<0.005

MA

Fo

nt e

t at,

Fro

ntie

rs in

Bio

scie

nce 2

00

9

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. G

ræb

e e

t al.

Eu

r J V

asc E

nd

ova

sc S

urg

20

09

R=0.64

P<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)

Rela

tive F

DG

Upta

ke

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

Change in W

all

Thic

kness o

ver

24 M

o

PET

1

MR

1

6M

24M

Begin

RX

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 Inflam

mation

(TB

R)

LDL

Van Wijk et al JACC 2014

Pre Post

P=0.03R=0.71

P=0.01

Art

Inflam

mation (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

al JA

MA

20

07

Erd

mann

et

al JA

CC

2007

Change 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

onoghue e

t al JA

MA

. 2014

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 H

igh-R

isk

Coro

nary

Pla

ques

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 from

bone 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

table

CA

D

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

Control

Mice

3

2

1

0

*

How could we use

inflammation imaging clinically

today?

Clinical Imaging

Blankstein JACC 2014 Saby et al JACC 2013

Increases sensitivity of

modified Duke criteriaPredictive 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 Lesion

ACS

Stable Syndrome

New StentStable Syndrome

Old Stent

18F NaF Imaging of Micro-calcification

Localizes to culprit lesions

Far 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