Cardiología Nuclear:

Evaluación de la inervación adrenérgica.

Papel de la gammagrafía con MIBG-I123 en el

manejo de pacientes con insuficiencia cardiaca.

Claudio Tinoco Mesquita

Claudio Tinoco Mesquita

Universidade Federal Fluminense

Professor de Medicina Clinica

Jefe Servicio Medicina Nuclear

Hospital Pró-Cardíaco

Jefe Servicio Medicina Nuclear

Cardiólogo y Medico Nuclear

Inervación Cardíaca

Autonomic

Innervation

of the Heart

Properties of Cardiac Autonomic System

Sympathetic System Parasympathetic System

Origin Intermediate horn of T3-T6 Brain stem via Vagus nerve

Distribution Atria and ventricles Predominantly in atria

Receptors Adrenoceptors: 1, 2 ,1, 2

Muscarinic receptors

Neurotransmitters Norepinephrine (major) Acetylcholine

Effects

Heart rate : Mainly 1, also some 2

Cardiac output

Contractility : Mainly 1, also some 2 (atria also)

Conduction : 1

Coronaries Dilation (2); constriction () Dilation

Lautamäki, Tipre, Bengel. Eur J Nucl Med Mol Imaging 2007;34:S74-S85.

Tyrosine

Dopa

Dopamine

Norepinephrine

PRESYNAPSE

POSTSYNAPSE

Axon

Myocyte

NE NE NE

NE

SYNAPTIC

CLEFT

1 1 2

NE

NE NE NE

NE Uptake 1

NE NE

Uptake 2

NE release into

synaptic space

Post synaptic receptors

G G

AC AMP cAMP

Vesicles

Sympathetic Neuron Synapse

NE

Norepinephrine Synaptic Cleft

Clearance

Uptake 1 Neuronal

92%

Uptake 2 Non-neuronal

4%

Circulation Spill Over

4%

Inervación en

la Falla Cardiaca

Down-Regulation

Norepinephrine Neuronal Transporter (NET)

Gene do NET: Braço longo do Cromossomo 16 (16q12.2)

HF

↑NE

↑ PKC

↓ NET

NE enzyme

oxidation

Increase in oxygen free

radicals production

↓ density NET Free radicals

bind to NET

NET Dysfunction

Chronic Heart Failure:

Increase in Autonomic Tonus and Reduction in

Receptor Density

123I-MIBG

Molecular Structures of Norepinephrine (NE), Guanethidine, and 123I-MIBG

No need to withdraw heart

failure medication for MIBG

Imaging.

123I-MIBG

MIBG IMAGING Parameters Assessed

Global cardiac uptake of tracer (planar, delayed images)

Heart/mediastinal ratio. 2.2 0.3 (<1.6 is 2 SD below normal mean).

Global washout (planar, from initial to delayed images)

Measures ability of myocardium to retain MIBG.

Normal pts: 10% 9%. Higher values correlate with disease, such as CHF. (>27%: dramatically increased mortality).

Regional uptake of tracer (SPECT)

Heterogeneous uptake may indicate regional denervation, i.e, autonomic imbalance, and possibly increased susceptibility to arrhythmia.

Hattori N, Schwaiger M. Eur J Nucl Med 2000;27:1-6. Flotats and Carrió. J Nucl Cardiol 2004; 11:587-602.

Ogita H, et al. Heart 2001; 86:656-660.

H/M ratio = 2.24

WO = 10.64

H/M ratio = 1.29

WO = 23.35

NORMAL ABNORMAL

LATE MIBG AND REST SESTAMIBI SPECT IMAGES

Potential Clinical Uses of MIBG

Congestive Heart Failure Prognosis

Assess response to standard medical therapy

Identify pts who would benefit from mechanical interventions (CRT, LVAD, Transplant)

Cardiac Arrhythmias Assess risk for sudden cardiac death

Better identify patients who would benefit from ICD

Assess patients with primary arrhythmias

Monitor recovery & complications post Cardiac Transplant

Assess patients with Ischemic Heart Disease Increased sensitivity to detect disease

Ischemic memory

Identify higher risk patients with Diabetes Mellitus

Assess toxic effects of Chemotherapy

MIBG en la Falla Cardíaca

Decrease in retention of MIBG:

Increase in Washout

123I-MIBG Imaging and Prognosis

in CHF/LV Dysfunction

0

20

40

60

80

100

120

0 5 10 15 20 25

ELAPSED TIME IN MONTHS

SURVIVAL RATE

(%)

H/M > 120%

H/M < 120%

p< 0.001

Merlet P et al. J Nucl M ed 1992.

90 pts. with CHF and EF < 45%

H/M 4 hrs after injection

123I-MIBG Imaging for Risk of Major Cardiac Event (Retrospective European Multicenter Study)

Agostini et al. Jacobson. Eur J Nucl Med Mol Imaging. 2008;35: 535-546.

290 CHF pts. In 6 European Centers during 10 yr. period.

MCE: Cardiac death, transplant, potentially fatal arrhythmia (including ICD discharge)

18 studies, 1755 patients

Cardiac death

Cardiac

events (cardiac death, MI, transplant, HF hospitalization)

MBG Washout MIBG and Mortality

MIBG diminuído esteve associado a 10X maior mortalidade

MIBG, BNP and Adverse events

MIBG

UFF & Pro-Cardiaco

B1-adrenoreceptor polymorphisms in heart

failure patients and its relationship to

cardiac I123-MIBG and carvedilol

treatment response

ET. Mesquita1, SM. Miranda1, S D. Moscavitch1, SB. Pereira1, RA. Freitas1, JC. De

Azevedo2, LR. Messias1, RC. Rodrigues1, GS. Ribeiro1, CT. Mesquita2

-20%

-10%

0%

10%

20%

30%

Ser49Ser Ser49Gly ou Gly49Gly

Washout 49Gly xSer49Ser.

Interleukin 1β levels correlate with MIBG

and exercise parameters, in heart failure? Messias L, Miranda S, Mesquita CT, et al.

Arq Bras Cardiol, in press

MIBG en Arritmias

What Causes Sudden Cardiac Death in CHF?

Of CHF deaths: 50% are sudden and unexpected (6-9x general population)

Presumption: mostly VT/VF, but increasing % from bradyarrhythmias and EMD

Medical therapy for CHF may be lessening disposition to VT/VF

PATHOPHYSIOLOGY

Myocardial ischemia

Action potential prolongation/dispersion of repolarization

Disruption of K, Na, Ca channels

Altered conduction

Inexcitable barriers and tissue discontinuities

Genetic predisposition

Altered neurohormonal signaling

RAAS activation

Autonomic abnormalities : Global disruption, regional heterogeneities of sympathetic

innervation

Tomaselli, Zipes. Circ Res 2004; 95: 754-63.

RELATIONSHIP OF MIBG AND HRV

VARIABLES TO ICD DISCHARGES

0

100

200

300

400

500

600

700

800

900

1 1,1 1,2 1,3 1,4 1,5 1,6 1,7 1,8 1,9 2 2,1

EARLY HMR

(lf)

ICD Discharge NO ICD Discharge

Group II

Group I

Group IV

Group III

(lf) = 443

HMR = 1.54

Arora R et al Travin MI . J Nucl Cardiol 2003;10:121-31.

*

* p = 0.03 compared with Group IV

54 patients with ICD

Predicting the Need for ICD with MIBG, BNP and LVEF

Nagahara D, Nakata et al. . J Nucl Med 2008; 49: 225-

233.

Jacobson AF. Presented at American College of Cardiology 58th Annual

Scientific Session, March 29-31, 2009, Orlando, Florida.

Senior R et al., Circulation 2009; 120. Presented at AHA

2009

25% of pts.

123I-MIBG H/M Improves Risk Stratification Beyond the Seattle Heart Failure Model

Ketchum E, Jacobson A, Caldwell J, Senior R, Cerqueira M, Thomas G, Agostini D, Narula J, Levy W. J Nucl Cardiol 2012, in press

961 ADMIRE-HF patients

Tomographic MIBG Assessing Regional Abnormalities

ICD PATIENT: NO SHOCK

LATE MIBG AND REST SESTAMIBI SPECT IMAGES

ICD PATIENT: SHOCK

LATE MIBG AND REST SESTAMIBI SPECT IMAGES

MIBG Image Findings in Relation to

Occurrence of ICD Discharges

0

5

10

15

20

25

30

35

40

45

123I-MIBG 123I- MIBG/99mTc-Sestamibi

Defect Score Mismatch Score

ICD + ICD - CONTROLS

0

0,5

1

1,5

2

2,5

3

HMR

n = 10 7 2 10 7 2 10 7 2

1.45 1.68 1.92 41.3

8.6

18.0

7.5 3.4 0

p < 0.05

p < 0.05

p < 0.05

Arora R et al Travin MI . J Nucl Cardiol 2003;10:121-31.

Sympathetic Denervation Assessed with 123I-MIBG Imaging

Predicts Ventricular Arrhythmias in ICD Patients

Boogers et al. Bax. J Am Coll Cardiol 2010; 55; 2769-77.

116 patients with CHF referred for ICD therapy

Difference in appropriate ICD therapy: Late MIBG SSS > 26 vs. SSS < 26

What SPECT Parameters Should be Measured?

Summed score

Would we expect parameters useful for perfusion imaging to also work for

autonomic imaging?

Caution! Different from perfusion imaging in that uptake of the entire

myocardium is often abnormal.

Heterogeneity measure of some type

Maximum – minimum

Spread function

MIBG/Perfusion Mismatch

Severity

Area

Distribution

123I-mIBG PARAMETERS:

High HMR

Low W.O.

High negative predictive value for

lethal arrhythmias and SCD

Thanks

Dr. Mark Travin

http://www.huap.uff.br/medicinanuclear/