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Nuklearmedizinische Klinik im Klinikum rechts
der Isar der Technischen Universität München
Cardiovascular Molecular Imaging since 2004
M. Schwaiger,
Technische Universität München Germany
Symposium on Multimodality Cardiovascular
Molecular Imaging SNM Molecular Imaging Center
of Excellence Natcher Auditorium NIH Bethesda,
Maryland April 30 1. May 2009
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Molecular Imaging

• Visualisation of Biologic Processes
• Non-invasive
• Targeting
• Quantification
• Multimodality

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Cardiac Imaging
Multimodal Spectrum of Information

• Visualization of Anatomy and Tissue Structure
• CT Density, MR Relaxation Characteristics
• Measurement of Physiologic Function
• Perfusion , Hemodynamic Performance
• Quantitation of Protein Expression
• Receptor Ligands, Enzyme-Substrate
• Determination of Protein Function / Interaction
• Transport, Metabolism, Signaling, Cell
  Interaction
• Assessment of Gene Expression
• Reporter Gene Imaging

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From Tracers to System Characterization
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From Cancer to Plaque
Involvement of ECM Proteinase Capacity
Cell migration.phagocytic capacityCell Adhesion,
Macrophages
Inflamed Atherosclerotic Plaque Proteom
Platelet Control Fibrin,Thrombogenicity
Enhanced Angiogenesis
Endothelial dysfunction Endothelial Activation,
Flow dynamics
Programmed cell death, Apopt0sis
Life style Environment Risk Factors
Genetic Risk
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Development of Imaging Technologies
Multimodality
PET-CT
PET
MR-PET
PET
MRI
LN-MRI
Diffusion MRI
MRI
Clinical practice
Interventional Ultrasound
Ultrasound
Ultrasound
X-rays
X-rays
CT
MSCT
MSCT
X-rays and CT
1900
1920
1940
1960
1970
1980
1985
1990
1995
2000
2001
2002
2003
2004
2005
2006
2007
2008
Diaphanoscopy
Fibre optic
FRI
BLI
HR-FRI
Lifetime FRI
Macroscopic reflectance
Optical development
DOT
FMT
FPT
FMT-CT
FMT-MRI
Tomography
Microendoscopy
MPM
Confocal
OCT,OFDI
Epifluorescence
Bright field
Bright field
Microscopy
Weissleder R, Pittet MJ et al, Nature 2008,
580-589.
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Cardiac Imaging Modalities

• Spatial and temporal resolution
• Sensitivity
• 4D data acquisition, dual gating
• Coregistration, reconstruction
• Simultaneous multi-energy,-channel, -frequency
  -spectral imaging as well as multimodality
  imaging
• Quantitation, modelling

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PET/MR Perfusion

• ASL Results

• 15OWater Results

Pichler et al. University Tübingen, Germany
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In-vivo optical imaging continuum in discovery
Imaging depth
1mm
1cm
10cm
0.1mm
Established methods
Revolutionary emerging methods
MESOSCOPIC TOMOGRAPHY
PLATE READING / MICROSCOPY
MACROSCOPIC TOMOGRAPHY
CELL
INSECT/FISH
SMALL ANIMAL
CLINICAL
(confocal, 2p)
HYBRID FMT-XCT MULTI-SPECTRAL OPTOACOUSTIC
TOMOGRAPHY (MSOT)
Resolution
1mm
100mm
0.1mm
1mm
Institute for Biological Medical Imaging (IBMI)
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Intravascular Detector Systems (Radiation,Optical
, Acoustic,MR)
Fatty Deposits
Inflammatory Cells
? Detector
Radiotracers
W.Strauss 2009
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Molecular Probe Development
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Clinical Need (Translational Culture)
Diagnostic and Prognostic Validation (Sponsor)
Reimbursement ( Acceptance)
Training ( Cooperation of Professional Groups)
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Clinical Need

• Early Diagnosis and Risk Assessment in CAD
• Quantitative flow reserve, vascular imaging,
  combination in-vivo/in-vitro markers
• Prognostic Phenotyping of Heart Failure
• Cardiac function. remodeling, inflammation.
  tissue energetics, innervation
• Management of Arrhythmic Patients
• Localisation of focus, risk of SD,
  selection for ICD and CRT, guidance of ablation
• Selection and Monitoring of Therapy
• Individual risk profiles, target
  identification, visualization of cell migration
  and survival, development of surrogate end points

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The insecticide target in the PSST subunit of
complex I Franz Schuler and John E Casida Pest
Manag Sci, 57932-940 (2001)
Insecticides
The mitrochondrial electrontransport chain
Complex I inhibitors have been used as
insecticides and miticides for more than 150
years and as fish poisons for a much longer
period.
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F-18 BMS747158-02
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Dynamic Rb-82 PET-CT for Quantification of
Myocardial Blood Flow
Rb Flow vs Microspheres
Dog Model of Myocardial Ischemia
Lautamäki et al, EJNMMI 2009
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DCE MR Coronary Imaging
stent
stent
LAD
3 days post AMI
LCX
3 months post AMI
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Molecular Mechanisms of CoronaryAtherosclerosis
and Thrombosis
FDG
Choudhury RP, Fuster V, Fayad ZA. Nat Rev Drug
Discov. 2004 Nov3(11)913-25.
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Inflammatory Aortic AneurysmF-18-FDG PET/CT
CT-Angiography
Pat, ?, 65 Jahre
CT-Angiography
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18F-FDG PET/CT of the culprit artery after
inferior AMIAcute RCA occlusion, previous LAD
stenting
Myocardial uptake supressed by low carbohydrate,
high fat diet
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Molecular Mechanisms of CoronaryAtherosclerosis
and Thrombosis
Choudhury RP, Fuster V, Fayad ZA. Nat Rev Drug
Discov. 2004 Nov3(11)913-25.
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Carotid Atherosclerotic Lesion Angiogenesis
Marker (F-18 RGD)
Beer et al. TUM
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Vascular imaging

• Coronary calcification adds diagnostic and
  prognostic information to management of CAD
  patients
• Numerous markers of inflammation are currently
  investigated wit varying translational potential
• Molecular imaging of coronary disease remains
  challenging because of object size, motion,
  biological contrast as well as dynamic nature of
  disease process
• Diagnostic approach towards the early detection
  of vulnerable plaques is not defined yet
  (validation/cost efficiency)
• Combination of in-vitro and in-vivo biomarkers is
  highly attractive for monitoring of preventive
  drug regimens

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Phenotyping of Ischemic Heart Failure
Nuclear FDG
MRI Gd-DTPA
Klein et al, Circulation
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PET/CT Myocardial Viability
NH3
Viability
FDG
Regional Analysis - Normal 77 Mismatch 23
Scar 0 The coronaries
show calcifications above 400 HU in yellow.
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Imaging of Cardiac Repair F-18-gRGD in Patient
with Myocardial Infarction (2 weeks after AMI
with successful reperfusion)
13N-ammonia
DeMRI
18F-gRGD
4-chamber view
2-chamber view
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CMR in Myocarditis
Cooper et al, New England Journal of Medicine,
2009, 1533
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Molecular Imaging of Heart Failure

• Multimodality imaging combines highly accurate
  functional assessment with biologic information
• Clinical impact only defined for viability
  evaluation
• Cardiac metabolism is target of new drug
  development, which may benefit from targeted
  metabolic imaging
• MRI provides clinical DCE signal for inflammatory
  processes

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Molecular Imaging

• Application in arrhymthic patients
• Definition of risk for SD
• Selection of ICD patients
• Prediction of CRT success

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Integration von PET/CT und LV-Mapping
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Regional Alterations of Sympathetic Innervationin
HF
Polar Maps
SA
HLA
100
0
13N-Ammonia
VLA
11C-HED Innervation
13N-Ammonia Blood Flow
10/min
0/min
11C-HED
C-11 hydroxyephedrine PET
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Molecular imaging of patients at risk for
arrhythmia

• Morphological imaging is helpful for the
  identification of structural abnormalities
• Multimodal imaging information can be fed into
  modern guiding systems for stereotactic ablation
• Neuronal imaging results are associated with
  incidence of SD in heart failure
• Prospective trials will address incremental
  prognostic value of molecular imaging

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Imaging Cell Transplantation
MRI
PET
124I- i.v.
Donor cells
124I-
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Monitoring Cell Therapy with Reporter Gene Imaging
Longitudinal Measurements
PET (I-124 /13NH3)
MRI (T2)
Day 1
Day 3
Day 7
Days after cell transplantation
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Molecular Tracking of Cell therapy
Gheysens, Molecular Imaging of Cell- and
Gene-based Therapies, 2009, 44
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The last 5 years, what is next?

• Molecular Imaging developed successfully
  providing tools for experimental research during
  last 5 years
• Molecular imaging in the heart can benefit from
  oncology, since most imaging targets are not
  specific to cardiovascular tissue
• Clinical applications lack behind, because of
  regulatory issues and limited funding for large
  trials evaluating molecular imaging procedures
• Cardiac imaging is currently dominated by
  non-invasive CTA following established strategies
  and turfs
• Interdisciplinary training and communication are
  required to accelerate the translational process
  of innovative approaches