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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..