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University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
Antti Saraste, MD, PhDCardiologist, Associate Professor
Turku PET Centre and Heart CenterTurku University Hospital and University of Turku
Helsinborg 21.5.2015
Hybrid PET/CT Cardiac Imaging
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
Detection of coronary artery disease by PET-CT hybrid imaging
Hybrid device:PET/SPECT + 64-rowCT
Comprehensive evaluation of anatomy and functionGaemperli,Saraste,Knuuti. Eur Heart J Cardiovasc Imaging 2012
15-O-water PETAdenosine stressCTA
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
RCA
LAD
LCX64-row CT
Prospective gating
Radiation dose: 3-5 mSv
Non-invasive coronary CT angiography:Exclusion of obstructive CAD
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
ACCURACY Trial – Multi-Center Study in 230 subjects, 16 sites
Sens. Spec. PPV NPV Prevalence
PER PATIENT
> 50% Stenosis 95% 83% 64% 99% 24%
> 70% Stenosis 94% 83% 48% 99% 14%
PER VESSEL
> 50% Stenosis 84% 90% 51% 99% 10%
> 70% Stenosis 84% 92% 36% 99% 4%
Budoff et al, JACC 2008
.
Multi Center Trials
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
Hulten E J Am Coll Cardiol 2013
Increased utilization of diagnostic tests/ invasive coronary angiography after CTA
Meta-analysis of CCTA in
chest pain in the ED
UC = Usual care
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
Challenges for CT angiographyIrregular heart rate and extensive calcifications Overestimation of stenosis
Schroeder EHJ 2008, Taylor JACC 2010
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
Challenges for coronary angiography:Anatomy vs. Functional Significance
Angiographic Diameter Stenosis (%)
Pres
sure
-der
ived
FFR
0 20 40 60 80 1000.0
0.2
0.4
0.6
0.8
1.0
N = 2334
Wijns, de Bruyne, Vanhoenacker, JNC 2007;93:856-61
FFR = Fractional flow reserve –invasive measurement of the
pressure gradient during adenosine infusion
Hybrid imaging?
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
Tonino et al. FAME
Impact of functional significance on prognosis after PCI
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
Revascularization and ischemic burden
Circulation 2003; 107: 2899–2906
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
PET: Accuracy in the detection of significant CAD
Saraste and Knuuti, J Nucl Cardiol 2012
McArdle, J Am Coll Cardiol 2013
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
PET flow quantification = measurement of myocardial perfusion in absolute terms (ml/g/min)
Dynamic imagingKinetic modelingMBF in ml/g/min
Technical improvements• Count rate performance
• Data handling• Computing power
Moody et al J Nucl Cardiol 2015
Combination withclinical protocols
SPECT
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
Analysis of PET 15-O-water study
Carimas TM free software developed in Turku PET Centre
Software packagesfor myocardial flow
quantification:
- Cardiac Vuer- Munich Heart
- PMOD- FlowQuant- Carimas- Syngo
- Hoquto- QPET
- UW-QPP- ImagenQ
- Corridor 4DM
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
The cross-comparisonbiplots of 10 software packages
When using1-TCM, the agreementby any SW is good
Complexmathematicalmodeling, accuratemeasurement of tracer input and myocardial activity
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
PET Tracers for Perfusion Quantifiaction
Absolute flow (ml/g/min)
Trac
er u
ptak
e
0
1
2
3
4
5
6
0 1 2 3 4 5 6
18F-flurpiridaz
15O-water
13N-ammonia
82Rb
99mTc-SPECTtracers
(Nekolla Circulation 2009)
(Lortie EJNMMI 2007, Lautamäki EJNMMI 2009, El Fakhri JNM 2009)
Saraste and Knuuti, J Nucl Cardiol 2012
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
New F-18 labeled PET perfusion tracer (Flurpiridaz)
Nekolla et al. Circulation 2009Berman et al. JACC 2013
Good kinetics, image quality and safety
3C-model
Phase III trial
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
What is normal myocardial blood flow ?
0
1
2
3
4
5
6
0 1 2 3 4 5 6
Absolute flow (ml/g/min)
Mea
sure
d/m
odel
led
flow
Abnormal
Normal
Absolute flow
Tracer uptake
Rangein absoluteflow image
Rangein tracer uptake
Stress
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre Heart Centre
Optimal MBF cut-off for the detection of significant epicardial CAD? 330 patients with
suspected CAD and O-15 water
PET(Turku, Amsterdam,
Uppsala)
ICA +FFR in all
intermediate (30-90%) stenoses
116 with obstructive CAD
Optimal cutoff for O-15-waterStress MBF <2.3 ml/g/minCFR <2.5
Danad et al JACC 2014
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre Heart Centre
0 20 40 60 80 100
Danad et al JACC 2014
Accuracy of quantitative PET perfusion
Absolute flow is as good as flow reserve
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre Heart Centre
Accuracy of quantitative PET perfusion
High negative predictive valueDanad et al JACC 2014
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre Turku PET Centre, Finland
Case RECase 1
LAD
LCX
RCA
CT Acquisition: • Premedication: Metoprolol 12 mg i.v.
HR 60/min
• Acquisition: Prospective step-and-shoot protocol 750 mA, 120 kV
• Contrast: Iomeron 400mg/ml 90 ml
• Radiation dose 8 mSv
>50%
>50%
IM
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
5 10 15
Adenosine
0 20 25 30
PET
H2O
Time (min)
CT scanPET scanTracer injectionContrast injection
Scou
tsC
alci
um s
core
CTA CTA
C
Stre
ss p
erfu
sion
Cardiac CTA + PET perfusion protocol
PET- 64 row CT
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
Carimas TM free software developed by Turku PET Centre Nesterov et al EJNMMI 2009
Fusion of CTA and PET perfusion ?
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre Turku PET Centre, Finland
Case RECTA and O15-water stress perfusion image fusionCase 1
PET Acquisition: • Injected Dose: 1100 MBq O-15-water
• Stress: Adenosine 140 µg/min/kg for 6.5 min
• Acquisition: Dynamic 4.5 min
• Radiation dose 0.9 mSv
Anterior view Posterior view
2.3 ml/g/min
Evaluation of haemodynamic significance of stenoses
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
LAD
LCX
Invasive angiographyTurku PET Centre, Finland
Case RECase 1
Left coronary artery RCA
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
Hybrid PET/CT for CAD diagnosis
Kajander et al Circulation 2010
Sensitivity (%)
Specificity (%) PPV (%) NPV (%) Accuracy (%)
MDCT 75 95 76 94 91PET 94 93 77 98 93MDCT-PET hybrid 95 99 96 99 98
0102030405060708090
100
Figure 2b: Vessel Analysis against ICA+FFR
MDCT
PET
MDCT-PET hybrid
107 patients with intermediate probability of CADTurku PET Centre, Finland
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
Challenges and solutions of perfusion imaging
Challenge Solution
Balanced 3 vessel disease Hybrid imaging/quantitationMultivessel disease Hybrid imaging/quantitationLM disease Hybrid imagingAnatomical location Hybrid imagingNon-obstructive CAD Hybrid imagingMicrovascular disease Hybrid imaging/quantitation
Impact of hybrid imaging in clinical practice ?
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
Advantages of hybrid imaging: Detection of multivessel disease
0 100 %6040 0 3.5 ml/g/min2.51.520 80 1 3
Absolute scale (0-3.5 ml/g/min)Relative scale
Adenosine stress O15-water PET perfusion
52-year old female, atypical chest pain
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
Diffusely reduced stress MBF and 3-vessel obstructive CAD
LADRCA
LCX
CTA + Adenosine stress O15-water PET perfusion
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre Heart Centre
Ziadi MC, et al J Nucl Cardiol 2012.
Example: Different severity of ischemia after quantification with 82Rb PET
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre Heart Centre
Relative analysis vs. quantification in patients with multivessel disease
Kajander S et al Circ Cardiovasc Im 2011
- Balanced 3-VD missed in 2 (2%) patients- Underestimated in 13 (12%) other patients
Regional analysis in patients with intermediate likelihood of CAD, n=104
PET perfusion with O15-waterduring adenosine stress
24 patients with multivessel CAD (QCA and FFR)
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
Advantages of hybrid imaging: Localization of culprit vessel
Ischemia in theRCA territory
Small LCX
Posterior view
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
Incremental prognostic value of hybrid CTA-perfusion
MSCT - MPI -
MSCT - MPI +MSCT + MPI -
MSCT + MPI +
Van Werkhoven J Am Coll Cardiol 2009
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
No plaque on CTA
Plaque on CTA
Chow ATVB 2014
Baseline statin therapy and non-obstructive CAD on coronary CTA
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
Advantages of hybrid imaging: Differentiation of epicardial and microvascular dysfunction
65-y old male, risk factors for CAD (smoking, family history), atypical chest pain, >2 mm ST-depression
anterior posterior
Fusion image of 3D coronary anatomy (CTA) and O15-water PET perfusion during adenosine stress
2.3ml/g/min
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
Hybrid imaging: Differentation of Epicardial and microvascular disease
Rest flow: ~ 0.9 ml/g/min
Stress flow: ~ 1.6 ml/g/min
3.5 ml/g/min
0 ml/g/min
CFR = 1.8
O15-water PET during adenosine stress
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre Heart Centre
Circulation 2011
2783 patients with suspected CAD, Rb82 rest-stress PET
>2.0
<1.5
Ischemia (% of LV)
CFR
Prognostic implications of CFR
CFR
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
Implementation of hybrid imaging ?
Low probability (<15%)
Secondary prevention / Medical therapy
Revascularization and medical therapy
Primary prevention
Intermediate probability (15-85%)
High probability (>85%)
ICA to confirm disease and final decision of revascularization (if necessary with help of FFR)
Ischemia +CAD +
Ischemia -CAD +
CT angiography to detect disease and localize stenoses
Stress imaging (ischemia)
CAD - CAD +
Symptomatic patients with suspected CAD
Estimation of pretest probability of CAD using clinical history and exercise ECG when available
Hyb
rid im
agin
g
Knuuti and Saraste Eur Heart J 2013
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
Benefits vs. incremental radiation dose ?Cost effectiveness ? Order of anatomy/functional ?Clinical implementation ?
Duration Radiation, mSvPerfusion CT
SPECT rest and stress imaging 3-4 h 12 -SPECT/CAC rest and stress imaging 3-4 h 12 1SPECT/CTA rest and stress imaging 3-4 h 12 3-5PET/CTA stress and rest imaging 1 h 2-5 3-5SPECT/CTA stress only imaging 1.5 h 6 3-5PET/CTA stress only imaging (quantification) 0.5 h 1-3 3-5
Invasive Coronary Angiography 2.3 – 22.7 (mean 7) mSv
Open questions with hybrid imaging:
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
Molecular imaging of myocardial responses to injury
Kiugel et al. Mol Im Biol 2014
3 integrin
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
18F-Galacto-RGD PET of human MI
DeMRI13N-ammonia 18F-gRGD
4-ch
2-ch
Makowski Eur Heart J 2008
Relationship to functional recovery ?
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
PET imaging of coronary atherosclerosis and rupture prone plaque ?
Biomarker
PET
AnatomyTurku PET Centre
MDCT
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
Clinical nuclear imaging of atherosclerotic plaque inflammation by 18F-FDG PET-CT
Rudd Circulation 2002
FDG accumulation detected in carotid artery plaquesof patients with acute stroke
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
Vascular 18F-FDG uptake associated with future vascular events
932 cancer patients with prior 18F-FDG PET studyMean of TBRs in aorta, carotid and iliac arteries
Roeminger JNM 2009Vascular event in 15 patients
Prospective trials in non-cancer patients (HRP)
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
Dual gated 18F-FDG PET/CT of coronary arteries in ACS patients
20 ACS patientsDual-gated FDG PET+ CTA
3 ± 2 days after onset of symptoms5 before PCI, 15 after PCI
Myocardial uptake suppressed by low carbohydrate diet + fasting
19 sufficient for analysis
79% of patients visual coronary FDG uptake
Hoppela et al (abstract) ICNC 2011
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
New PET tracers for atherosclerotic plaque imaging
Hellberg, Saraste et al. EAS 2013 (abstract)
[18F] CholineHE stain Autoradiography
AB
[18F] galacto-RGDHE stain Autoradiography
Laitinen, Saraste et al. Circ Cardiovasc Imaging 2009
Silvola, Saraste et al., ATVB 2011
[18F] EF5HE stain Autoradiography
Silvoa et al., manuscript
[18F] Siglec-9
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre
Summary: Hybrid PET/CT Cardiac Imaging
CTA: Exclusion of CADFlow quantification with perfusion PETHybrid imaging: Evaluation of both coronary anatomy and ischemia
Functional significance of intermediate stenosisLocalization of culprit vesselDetection of multivessel diseaseNon-obstructive diseaseMicrovascular disease
University of Turku • Åbo Akademi University • Turku University HospitalTurku PET Centre Heart Centre
Turku PET Centre Juhani Knuuti, Anne Roivainen, Miikka Tarkia, Virva Saunavaara, Pirjo Nuutila, Riikka Lautamäki, Tommi Kokki, Chunlei Han, Sergei Nesterov, Mika Teräs, Sami Kajander, Tommi Noponen, Olof Solin, Matti Haavisto, Sauli Uotila, Antti Varis, Johanna Silvola, Sanna Hellberg, Max Kiugel, Suvi Puolakkainen, Erika Hoppela, Teemu Maaniitty, Iida Soukka, Valtteri Uusitalo, Xiang Guo-Li, Anu Autio
Acknowledgements
Turku Univeristy Hospital, Cardiac Surgery Timo Savunen, Tommi Vähäsilta, ChristofferStark, Ville-Veikko Hynninen
Turku University Hospital, Heart CenterMikko Pietilä, Juhani Airaksinen, Heikki Ukkonen, Ville Kytö, Marjatta Strandberg
University of Turku, Forensic MedicineProf. Pekka Saukko
University of Eastern Finland, Seppo Ylä-Herttuala, Markku Laakso