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Ποζιτρονιακή
Τομογραφία
και
μοριακή απεικόνιση
στην
καρδιολογία
Constantinos Anagnostopoulos M.D, Ph.D, FRCP, FRCR, FESCConstantinos Anagnostopoulos M.D, Ph.D, FRCP, FRCR, FESCInvestigator level B/ Associate Professor
Head, Nuclear Medicine DivisionHead, Nuclear Medicine Division
Clinical Research CentreClinical Research CentreBIOMEDICAL RESEARCH FOUNDATIONBIOMEDICAL RESEARCH FOUNDATION
ACADEMY OF ATHENSACADEMY OF ATHENS
Molecular Imaging Targets for Noninvasive Cardiac ImagingMolecular Imaging Targets for Noninvasive Cardiac Imaging
Angiogenesis
Metabolism
Autonomic Innervation
Microcirculation
Apoptosis
Extracell. Matrix
Atherosclerosis / Plaque Vulnerability
Stem Cell Migration
Transgene Expression
Why Molecular Cardiac Imaging?Why Molecular Cardiac Imaging?
••
Understand mechanisms Understand mechanisms
••
Early diagnosisEarly diagnosis
••
PrognosisPrognosis
••
Sophisticated treatment/personalisedSophisticated treatment/personalised
••
MonitoringMonitoring
Tools for molecular imaging with PET Tools for molecular imaging with PET
METABOLISM & PERFUSIONGlucose uptake 18F-FDG, 11C-glucose
Perfusion/blood flow
15O-H2
O, 13N-NH3/
Rubidium-82Oxygen consumption 15O-O2
,
11C-acetateFFA uptake & oxidation 18F-FTHA, 11C-palmitate
Amino acid uptake & protein synthesis 11C-MeAIB, 1111CC--methioninemethionineHypoxia
18F-fluoromiso, 18F-FETNIM
RECEPTOR FUNCTION/APUDDopamine system
1111CC--DOPA, DOPA, 1818FF--DOPA; DOPA; 1111CC--HTPHTPSomatostatin receptor
1818FF--fluorofluoro--octreotideoctreotideOTHER
Cortisol synthesis
1111CC--metomidatemetomidateThyroxin synthesis
124124IITT½½
1818F 109 minF 109 min1111C 20 minC 20 min1515O 2 minO 2 min
Thrombus
Rupture
vulnerable rupturednormal
Lipid core
Lipid core
Fibrouscap
FDG PET imaging of the coronary arteriesFDG PET imaging of the coronary arteries
Rogers IS et al. JACC Cardiovascular Imaging 2010
25 pts, mean age 57.9±
9y (72% male)10 ACS treated with PCI
15 with stable angina (5 underwent PCI and 10 ICA only )
Integrated Imaging of coronary anatomy and functionIntegrated Imaging of coronary anatomy and function
Brigham and Women’s Hospital-Harvard Medical School
CCS: 186
47 y old male, smoker, overweight, with borderline Hypertension and osteoarthritis
ml/min/gr
Interrelation between calcium score and MBFInterrelation between calcium score and MBF
0
0.5
1
1.5
2
2.5
3
3.5
1
MB
F (m
l/min
/g)
reststress
*
P <0.05 on pair-wise comparison
0 1-100 101-400 >400 vessel CAC score
136 consecutive patients without CAD (age 62 12 years, 68 % females) with normal myocardial perfusion using Rb-82 PET
Eur J Nucl Med MI 2009
CAD likelihood: 0.31±0.25
Assessment of endothelial functionAssessment of endothelial function
Cold pressor test
Prognostic value of CPT perfusion measurements
Group 1: patients with >/=40% increase in MBF Group 2, patients with >0 and <40% increases in MBFGroup 3, patients with decrease in MBF (</=0%)
72 patients risk factors for CAD but normal coronary angiography
Scindler TH et al J Am Coll Cardiol 2004
*CPT:cold pressor test
Prognostic Role of Myocardial Blood Flow Impairment in Prognostic Role of Myocardial Blood Flow Impairment in Idiopathic Left Ventricular Dysfunction Idiopathic Left Ventricular Dysfunction
D Neglia et al. Circulation. 2002
•67 pts (52 male, mean
age 52±12 years) with different degrees of idiopathic
LV systolic dysfunction: average LVEF 0.34±0.10;
range, 0.07 to 0.49)
•34 pts (51%) had no history of heart failure symptoms at enrollment
(NYHA class I)
CADCAD--LV dysfunction and LV dysfunction and heart failureheart failure
Prevalence of CAD in 13 randomized multicenter heart failure trials
Myocardial Perfusion and metabolism in the ischaemic Myocardial Perfusion and metabolism in the ischaemic myocardiummyocardium
Mild- moderate
ischaemia
Severe ischaemia
Recovery
Metabolism anaerobic oxidative
both anaerobic oxidative
Preferred substrate
glucose neither - necrosis
free fatty acid
After bypass
MRI
Pre-
bypass82Rb:Rubidium18F-FDG:Fluro-Deoxy-
Glucose
SOB, LVEF <35%
Altered myocardial fatty acid and glucose Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathymetabolism in idiopathic dilated cardiomyopathy
17 patients with IDCM (mean LVEF 27 ±
8%) and 12 normal controls underwent dynamic PET to assess myocardial glucose utilization (MGU) with 11C-Glucose and
myocardial fatty acid utilization (MFAU) + myocardial fatty acid
oxidation (MFAO) using 11C-Palmitate
VG Davila-Roman et al. J Am Coll Cardiol 2002
uptake 1 mechanism
NA concentration at the myocyte membrane
Myocyte hyperstimulation
Hypertrophy, remodellingDisturbed intracellular Ca2+ handling ApoptosisArrhythmias
Neuronal function and chronic Heart FailureNeuronal function and chronic Heart FailureReduced noradrenaline clearance because of
a) low cardiac output+
b) Sympathetic nerves of the
failing myocardium release more NA and remove it less efficiently
by reuptake
1111C hydroxyephedrine (HED) PET in combination with flow and C hydroxyephedrine (HED) PET in combination with flow and metabolsim imagingmetabolsim imaging
Prediction of ARrhythmic Events with Positron Emission Tomography
Aim: to investigate the clinical utility of assessing regional sympathetic nerve function and its role as a risk factor for sudden cardiac death
200 patients with ischemic LV dysfunction
Monitoring the effect of Stem cell therapy
Before 6 months 18 months
Angiogenesis in REGENERATE-IHD Study Flow
6-M FU 12-M FUBone marrowAspiration
1d 5d 6d-5d 0 6M 12M
CT/MRINOGA mapping
Time line for Angiogenesis study
2d 3d 4d
G-CSF
LV angio/
PECT/CT angiogenesis
PET/CT
7d
ECHOIM/IC injection
ECHOLV angio /
NOGA mapping
PET/CT angiogenesis
CT/MRI
PET/CT
-1d
PET/CT Angiogenesis study
PET/CT Perfusion study
IM Intramyocardial; IC Intracoronary
Imaging angiogenesis with FImaging angiogenesis with F--1818--galacto RGDgalacto RGD
Arginine-glycine-aspartate (RGD)-binding
αv
β3
-integrin
THANK YOU
Hibernation and Hibernation and heart failureheart failure
Cell death
CVR
CVR
MyocardialIschaemia(Daily life and silent)
Repetitive Ischaemia andStunning
Functional hibernation Revascularisation Early recovery offunction
Structural hibernationRevascularisation Slow recovery of
function
TIME
Cell death
CVR
Cell de-differentiation(Glycogen increase with loss of
contractile proteins etc)
Enzyme induction
Perfusion intact
Perfusion FDG+
Metabolic adaptations
Protein Abnormalities
Altered geneexpression/transcription
FDG -
TIME
Imaging Fatty Acid MetabolismImaging Fatty Acid Metabolism
PET with 13NPET with 13N--ammonia and 18Fammonia and 18F--FDG in the assessment of myocardial FDG in the assessment of myocardial perfusion and metabolism in patients with recent AMI and perfusion and metabolism in patients with recent AMI and
intracoronary stem cell injectionintracoronary stem cell injection
15 patients were randomly assigned to 3 groups based on different treatments Group A: bone marrow-derived stem cells; Group B: peripheral blood-derived stem
cells; group C: standard therapy alone
Castellani M et al. J Nucl Med 2010
Imaging appoptosis with PET tarcersImaging appoptosis with PET tarcers
Adrenoreceptor density assessed by PETAdrenoreceptor density assessed by PET
CGP 12177: Non-selective adrenoreceptor antagonist
Choudhury L
Heart 1996; 75:50-54
•Lower Myocardial Perfusion Reserve Is Associated With Decreased Regional Left Ventricular Function in Asymptomatic Participants of the Multi-Ethnic Study of Atherosclerosis (MESA) B D Rosen et al Circulation 2006
•Among an asymptomatic multiethnic American cohort (MESA), Decreased Regional Left Ventricular Function is an
independent
predictor beyond traditional risk factors and global
LV assessment for incident heart failure and atherosclerotic
cardiovascular
events
(R T Yan et al J Am. Coll Cardiol 2011)
•
Assessment of total integrated Vasodilator capacityAssessment of total integrated Vasodilator capacity
Vascular Smooth muscles+
endothelium
Coronary Vasodilator Reserve vs. coronary stenosis
C. Anagnostopoulos et al Eur J Nucl Med MI 2008
Di Carli et al Circulation 1995
Hybrid imaging in Stem cell therapy post MI
Courtesy F. BengelFrom C.Anagnostopoulos et al. Non Invasive Imaging of myocardial
ischaemia-Springer Verlag
51 patients with HCM and normal coronary arteries
f/u8.1±2.1 years (range, 2.2 to 11.1)
35 patients were stable (NYHA class I or II),16 patients had an unfavorable outcome: 9 died from cardiovascular causes, 1 developed recurrent sustained VT implantation of a cardioverter–
defibrillator and 6 had progression to NYHA functional class III
or IV
Coronary Microvascular Dysfunction and Prognosis in Coronary Microvascular Dysfunction and Prognosis in Hypertrophic CardiomyopathyHypertrophic Cardiomyopathy
Camici PG et al N Eng J Med 2003
PET/CT for imaging of atherosclerosisPET/CT for imaging of atherosclerosis
Rudd et al Circulation. 2002;105:2708-2711
Same views as above depicting an asymptomatic carotid stenosis
PET, contrast CT, and PET/CT images in the sagittal plane, from a 63-year-old man who had experienced 2 episodes of left-sided hemiparesis
Hybrid imaging in Stem cell therapy post MI
Courtesy F. BengelFrom C
Anagnostopoulos et al
Non Invasive Imaging of myocardial
ischaemia-Springer Verlag
Relationship between perfusion and metabolismRelationship between perfusion and metabolism
Myocardial infarct
Comparison of non invasive imaging techniques for assessment of myocadial viability/hibernation
Schinkel et al Curr Probl Cardiol 2007
Coronary Vasodilator Reserve vs. coronary stenosis
C. Anagnostopoulos et al Eur J Nucl Med MI 2008
Di Carli et al Circulation 1995
HK
Fatty AcidsC11-Palmitate
F18-FTHA (heptadecanoid acid)
Mitochondria
Glycogen Glucose-6-phosphate Pyruvate Lactate
F-18 FDG, C-11 GlucoseGlucose
PFK IIII G3PDH
ATP
ADP
TC A
CO2
Acyl-CoA Acetyl-CoA
-oxidation
PET tracers of myocardial metabolism
AcetateC-11 Acetate
PDH
Fatty Acyl CoA
Fatty Acyl CoA
+Carnitine
C-11 Lactate
Courtesy of P Camici, Hammersmith, Hospital, ICSM Courtesy of P Camici, Hammersmith, Hospital, ICSM
-3
-2
-1
0
1
2
3
Mean+2 SD
-2 SD
0 1 2 3 4 5Diff
in M
BF (M
icro
sphe
res-
PET)
(mL.g-
1.min
-1)
Average MBF by Microspheres and PET (mL.g-1.min-1)
Agreement between PET and microspheresAgreement between PET and microspheres
Mean Difference -0.11±0.36 mL·g-1·min-1
J Nucl Med 2002; 43: 1031-1040
PET: Molecular imaging of metabolic pathwaysPET: Molecular imaging of metabolic pathways
F-18 FTHAO-15 oxygen
C-11 LactateF-18
TCA=tricarbocyclic acid
Similarities of [Similarities of [1111C]epinephrine (EPI)C]epinephrine (EPI)
and [and [1111C]hydroxyephedrine (HED) using PETC]hydroxyephedrine (HED) using PET
Münch G
et al. Circulation;2000; 101:516-5
Assessment of presynaptic
sympathetic neuronal function
Myocardial Energetics and EfficiencyMyocardial Energetics and Efficiency••
The heart relies almost exclusively on the aerobic oxidation of The heart relies almost exclusively on the aerobic oxidation of
substrates for generation of energysubstrates for generation of energy
••
There is close coupling between myocardial oxygen consumption There is close coupling between myocardial oxygen consumption
(MVO(MVO22
) and the main determinants of systolic function: heart ) and the main determinants of systolic function: heart
rate, contractile state, and wall stressrate, contractile state, and wall stress
••
Only part of the energy invested is converted to external powerOnly part of the energy invested is converted to external power
••
The ratio of useful energy produced (ie, stroke work [SW]) to The ratio of useful energy produced (ie, stroke work [SW]) to
oxygen consumed is defined as mechanical efficiencyoxygen consumed is defined as mechanical efficiency
Myocardial Energetics and EfficiencyMyocardial Energetics and Efficiency
••
In pathophysiological disease states, such as In pathophysiological disease states, such as heart failure, mechanical efficiency is heart failure, mechanical efficiency is reducedreduced
••
Increased energy expenditure relative to Increased energy expenditure relative to work contributes to progression of the work contributes to progression of the disease disease
••
Quantification of efficiency of the heart to Quantification of efficiency of the heart to study disease processes and monitor study disease processes and monitor interventions interventions
RV
LV
Cardiac oxidative Cardiac oxidative metabolism:metabolism:
[[1111C]Acetate PETC]Acetate PET
Kmono
Kmono
Effect of CRT on global LV efficiency Effect of CRT on global LV efficiency
Ukkonen et al Circulation 2003
Rest
WMI=SWI x HR/kmono
WMI: work metabolic index
KnuutiKnuuti
••
PET sensitive etc..PET sensitive etc..