Myocardial viability

and cardiac innervation

Jeroen J Bax

Dept of Cardiology

Leiden Univ Medical Center

The Netherlands

Nice ETP course, may 2010

Heart failure

2 issues major importance

• Myocardial viability

• Cardiac innervation

Viability assessment

Why is it needed?

• Which technique?

• What can we predict?

Ischemic LV Dysfunction

Epidemiology

• USA:

5-6 million pts with CHF500.000 new cases per year>1 million hospitalizations per year

20 30 40 LVEF (%)

mortality

Risk of surgery is high

Ischemic LV Dysfunction

Current Therapies

• Medical therapy

- long term prognosis poor

• Revascularization

- high risk

• Heart transplantation

- Limited nr of donor hearts

• Cardiac Resynchronization

- LV dyssynchrony not always present

Ischemic LV Dysfunction

ΔLVEF post-revascularization

30%

EF

58%

EF

12%

EF

N=355 pts with

LVEF <35%

Schinkel et al. AJC 2004

Ischemic LV Dysfunction

• Clinical goal:

-identify patients with viable tissue

-with potential to recover function

-to justify enhanced surgical risk

Incidence of Viability

FDG Imaging

N=110 pts

LVEF <35%

46%

Nonviable

54%

Viable

Schinkel et al. Heart 2002

Viability assessment

• Why is it needed?

Which technique?

• What can we predict?

• What additional information is needed?

Features vs techniques

• Metabolism (glucose, FFA’s): FDG, BMIPP

• Intact cellmembrane: Tl-201

• Intact mitochondria: Tc-99m

• Intact perfusion: Tl-201, Tc-99m, MCE

• Contractile reserve: stress echo/MRI

• Scar tissue: contrast-enhanced CMR

FDG imaging:

the tracer

Pirich C et al. 1999

Techniques, FDG

• FDG: marker of glucose utilization

Hypoperfused myocardium with FDG uptake = viable

Maddahi et al. J Nucl Med 1994

FDG Imaging

Tissue Characterization

Contraction Perfusion FDG uptake

Viable

Viable

Scar

N/

N N

Normal Stunned Mismatch Scar

PET Imaging

Tissue Characterization

Schwaiger M. 2005

Thallium-201

• Early uptake is perfusion

• Late uptake is cellmembrane integrity

• Protocols:

– stress-redistribution-reinjection

– rest-redistribution

Thallium-201 rest-redistribution

Tc-99m labeled agents

• Retention depends upon:

– perfusion, cellmembrane integrity

– intact mitochondria

• Protocols:

– resting image (with gating)

– with nitrates to enhance uptake

NTG

NTG

SHORT AXIS VLA

Resting Tc-99m MIBI,

Nitrate Enhanced

Courtesy A Cuocolo

Rest

Nitrates

Dobutamine Echo / MRI

• Akinetic but viable tissue

– Can have contractile reserve

• During dobutamine infusion

– Contraction improves

– And can be visualized by echo/MRI

rest low-dose post-revasc

Courtesy JH Cornel

Dobutamine Echo

• Low-dose dobutamine

• Viability detection

Rest LDD

Chronic LV Dysfunction - MRI

Delayed hyperenhancement

Contrast-enhanced MRI

• DE = myocardial necrosis

• Resolution allows assessement of

– transmural extent of necrosis

MRI – DE, transmurality

Viability assessment

• Why is it needed?

• Which technique?

What can we predict?

• What additional information is needed?

Viability assessment

What can we predict?

– Improvement of

• Regional LV function

• Global LV function

• Exercise capacity

• Reverse remodeling

• Prognosis

.... after revascularization

What’s in the literature?

N=105 studies, 3003 pts

84

69

8271

0

20

40

60

80

100

Sens Spec NPV PPV

perc

enta

ge

Improvement of Regional LV Function

50

60

70

80

90

100

0 10 20 30 40 50 60 70 80 90 100

Specificity (%)

Sen

sit

ivit

y (

%)

95% Confidence

Intervals

Dobutamine Echo 41 st./1421 pts

FDG PET 20 st./598 pts

Tc-99m 25 st./721 pts

Tl-201 40 st./1119 pts

MRI 13 st./420 pts

Prediction of Functional Recovery

After Revascularization

The extent of viable myocardium on FDG imaging

predicts the improvement in LVEF post-revascularization

Bax et al. JNM 2001

Nr of viable segments

Prediction of OutcomeGlobal LV function

sens spec

0

20

40

60

80

percentage

EEC

Multicenter

FDG PET

Study

n=178 pts

LVEF 39±14%

82 improved

LVEF >5%

Gerber et al. EHJ 2001

Prediction of OutcomeExercise capacity

<5% 5-17% >17%

Increasing extent of FDG PET mismatch

0

2

4

6

METS

DiCarli et al. Circ 1995

NS

(Reverse) remodelingn=35 pts, FDG PET imaging

40

60

80

100

Bax et al. 2006

viable nonviable

EDVI (ml/m2)

Pre-CABG

Post-CABG

<0.01

<0.01

7

2017 17

0

10

20

30

40

50

Revasc Med Revasc Med

Eve

nt

rate

(%

)

Viable + Viable -

Prognostic Value

Event Rate vs Viability

Data based on 20 studies (n=2362 pts)

n=377 n=572 n=342 n=458

Conclusions

• Ischemic heart failure is / will be the largest problem in clinical cardiology

• Viability assessment is mandatory to predict outcome / risk stratification

Heart failure

2 issues major importance

• Myocardial viability

• Cardiac innervation

Presynaptic Sympathetic Innervation of the Heart

MIBG (Adreview) visualizes

-cardiac innervation

-cardiac denervation

-behaves as norepinephrine

-tracer is internalized by pre-synaptic nerve endings

Tracing Presynaptic Sympathetic

Innervation by MIBG Imaging

MIBG

MIBG

MIBGMIBG

MIBG

CARDIOMYOCYTE

MIBG

MIBG

BLOOD

SYMPATHETIC

NERVE TERMINAL

MIBG

Uptake-1

NOREPINEPHRINE

123I-

METAIODOBENZYL-

GUANIDINE (MIBG)

PLANAR IMAGINGHMR = 2.2

SPECT IMAGING

123-I Metaiodobenzylguanidine (123-I MIBG) Imaging

Normal MIBG uptake

MIBG planar imaging

LVEF 33%

HMR 2.06 HMR 1.01

LVEF 21%

Prognostic Value of Cardiac 123-I MIBG Imaging

Merlet P, et al. J Nucl Med. 1999

H/M ratio >1.20

H/M ratio ≤1.20

Cardiac 123-I MIBG Imaging for Risk Stratification of Patients with HF

Two-year cardiac event rate for subjects with LVEF ≤35% and LVEF 36-49%, stratified accordingto H/M ratio

Agostini D, et al. EJNMMI 2008

41

ADreView Myocardial Imaging for

Risk Evaluation in Heart Failure

42

961 HF failure patients; NYHA II 83%, class III 17%

Ischemic HF 66%, non-ischemic HF 34%

LVEF ≤35%, mean 27% (range 5-35%)

MIBG planar scan; H/M ratio:

H/M ratio ≥1.6 – low risk

H/M ratio <1.6 – high risk

ADreView Myocardial Imaging for

Risk Evaluation in Heart Failure

43

Primary end points

HF Progression

Arrhythmic Event

Cardiac Death

Total

Patients # having a first event

163 subjects

(68%)

50 subjects

(21%)

24 subjects

(10%)

237

(25%)

ADMIRE-HF primary endpoints

44

237 cardiac events

AdreView: additional prognostic value for adverse cardiac event risk

Event rates vs HM ratioA

CE

Cu

mu

lati

ve in

cid

en

ce (

%)

Months

H/M ratio <1.60

H/M ratio ≥1.60

0

10

20

30

40p<0.0001

201 subjects 25 events

760 subjects

212 events

147%

0 6 12 18 24

45

AdreView: proven prognostic value for heart failure progression

HF progression vs H/M ratio

0

10

20

30

0 6 12 18 24 Months

H/M ratio <1.60

H/M ratio ≥1.60

0

10

20

30p=0.001

760 subjects

154 HF progression

201 subjects

22 HF progression

HF

pro

gre

ss

ion

Cu

mu

lati

ve

in

cid

en

ce

(%

)

176 patients HF progression

46

Cardiac death vs H/M ratio53 patients cardiac death

Time (months)

Su

rviv

al p

rob

ab

ilit

y (

%)

*p=0.002 vs H/M ratio≥1.60

H/M ratio≥1.60: 2-year event-free survival 98%

H/M ratio<1.60: 2-year event-free survival 89%

201 subjects2 cardiac deaths

760 subjects

51 cardiac deaths

NPV 98% for cardiac death

47

Comparison of AdreView vs.

current risk-stratifiers

LVEF (Left Ventricular Ejection Fraction)

BNP (B-Type Natriuretic Peptide)

48

Event rate vs LVEFCut-off value LVEF = 30%

LVEF 30% threshold does risk-stratify

AC

EC

um

ula

tive

in

cid

en

ce

(%

)

Months

LVEF<30%

LVEF≥30%

0

10

20

30

40p<0.0001

50

0 6 12 18 24

471 subjects

83 events

490 subjects

154 events

49

AC

EC

um

ula

tive

in

cid

en

ce

(%

)

Months

LVEF<30%, H/M<1.60*

LVEF<30%, H/M≥1.60*

0

10

20

30

40 *p=0.0004

†p=0.024

50

LVEF≥30%, H/M≥1.60†

LVEF≥30%, H/M<1.60†

H/M ratio 1.6 threshold provides incremental prognostic information

over LVEF 30% threshold

Event rate vs LVEF and H/M ratio

0 6 12 18 24

120 subjects

13 events

81 subjects

12 events

351 subjects

70 events

409 subjects

142 events

LVEF 30% cut-off value and H/M ratio 1.6

50

0

10

20

30

40

50

0 6 12 18 24

AC

EC

um

ula

tive in

cid

en

ce (

%)

BNP>140 ng/l

BNP≤140 ng/l

0

10

20

30

40p<0.0001

50

Months

Event rate vs BNP

BNP 140 ng/l threshold does risk-stratify

BNP 140 ng/l cut-off value

463 subjects

155 events

463 subjects

75 events

51

0

10

20

30

40

50

0 6 12 18 24

AC

EC

um

ula

tive

in

cid

en

ce

(%

) BNP>140 ng/l, H/M<1.60*

BNP>140 ng/l, H/M≥1.60*

0

10

20

30

40

*p=0.004

†p=0.041

50

BNP≤140 ng/l, H/M<1.60†

BNP≤140 ng/l, H/M≥1.60†

Months

Event rate vs BNP and H/M ratioBNP 140 ng/l cut-off value and H/M ratio 1.6

H/M ratio 1.6 threshold provides incremental prognostic information over BNP 140 ng/l

406 subjects

146 events

326 subjects

60 events

57 subjects

9 events

137 subjects

15 events

52

Conclusions

• Cardiac innervation (MIBG, Adreview) can be used for risk stratification in HF patients

• Predicts HF progression and cardiac death

• Is incremental over LVEF and BNP