Caner Et Al-1998-Clinical Cardiology

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Clin. Cardiol. 21, 235-242 (1998)

Reviews

Are Technetium-99m-Labeled Myocardial P e h s i o n Agents Adequate

for

Detection

of

Myocardial Viability?

BRAY CANER,

M.D., AND

GEORGE

. BELLER,.D.

Nuclear Cardiology Laboratory, Card iovascularDivision, Department

of

Medicine, University

of

Virginia, Health Sciences Center,

Charlottesville,Virginia,

USA

Summary:Th e noninvasive assessm ent of myocardial via-

bility

in

patients with coronary artery disease and depressed

left ventricular function has proven clinically useful for iden-

tifying those patients with ischemic cardiomyopathy who

benefit most from coronary revascularization. Thallium-201

(201T1) maging at rest has been the radionuc lide im aging

technique most often utilized for distinguishing viable my-

ocardium from scar. However, new technetium-99m (99mTc)

perfusion agents such

as

wmTc-sestamibiand 99 1Tc-tetrofos-

min have em erged as alternatives to "IT1 for imaging of re-

gional myocardial perfusion. Whether these new agents,

which have better physical properties for imaging with a

gamm a camera than 201T1, re valid for use in assessing my-

ocardial viability is still uncertain. Recent clinical studies

have demonstrated that these agents, when imaged using

quantitative SPECT, can identify patients with m yocardial

hibemation w ho exhibit improved regional systolic function

following revascularization. Experimental laboratory stud-

ies have shown that the uptake of 99m Tc-sestamibi nd 99mTc-

tetrofosmin in ischemic myocardium is only slightly lower

than the uptake of

201T1.

hes e 99mTc-labeled gents remain

bound intracellularly in mitochondria of viable m yocytes un-

der conditions of myocardial stunning and short-term hiber-

nation. producing severe myocardial asynergy. With respect

to determination of viability, the inferior wall region is at

times problema tic since attenuation of 99mTc-sestamibi nd

99mTc-tetrofosmin s greatest in this area . Dem onstration of

preserved systolic thickening on ECG-gated S PE CT images

is indicative of viability in the instance

of

decreased regional

Address

for

reprints:

George A. Beller.

M.D.

Chief., Cardiovascular Division

Department

of

Medicine

HSC

Box 158

University

of

Virginia Health Sciences Center

Charlottesville. VA 22908, USA

Received: October 2 , 1997

Accepted: October 2 . I997

99mTc ounts due to attenuation and

not

scar. A dministration

of nitrates prior to tracer injection improv es the sensitivity

for identifying viable myocardial segmen ts using rest imag-

ing with 99 1Tc-sestamibi r 99mTc-tetrofosmin.

Thus, it appears that the new 99mTcperfusion imaging

agents can be successfully employed for the determination of

myocardial viability

in

the setting of severe regional dysfunc-

tion and chronic coronary artery disease. The greater the my@

cardial uptake of these agents in the resting state, the greater

the probability of improved systolic function after coronary

revascularization.

Key words:technetium-99m-sestamibi 99mTc), 9mTc-tetro-

fosmin, thallium-20 1, radionuclide imaging, myocardial per-

fusion imaging, coronary artery disease, left ventricular dys-

function

Introduction

The topic of myocardial viability has been the subject of in-

tense discussion in the fields of modem cardiology and nucle-

ar medicine.]- Over the last decade, it has been realized that

left

ventricular (LV) dysfunction in coronary artery disease

(CAD) is not always irreversible, and that a marked improve-

ment in regional and global function can be observed after

successful revascularization in some patients. Suc h patients

with reversible LV dysfunction have either hibernating or

stunned myocardium. The differentiationof such viable from

nonviable myocardium is therefore highly relevant in patients

who are being considered for revascularization. It is well

known that the cardiac event rate with C AD with LV dysfunc-

tion and presence of viability detected by thallium-201 (20'T1)

and positron emission tomography (PET) in patients who are

treated med ically is higher than the event rate in patients with

compa rable viability w ho under went revascularization.I2, 3

Moreover, many patients who dem onstrate viability associat-

ed with severe

LV

dysfunction may still be candidates for

revascularization rather than for cardiac transplantation.

To

date, several noninvasive approaches have been used to

distinguish viable from nonviable myocardium. These include

nuclear cardiology techniques [single-photon emission com -

puted tomography (SPE CT) and PET], dobutamine echocar-

diography, and recently magnetic resonance imaging (MRI).


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236

Clin. Cardiol. Vol. 2 1 April 1998

Nuclear cardiology techniques permit the detectionof residu-

al perfusion, cell membrane integrity, and metabolic activity n

the myocardium. With dobutamine echocardiography, in-

otropic reserve in viable myocardium through catecholamine

stimulation can be assessed. The standard of reference for de-

tecting the presence of viable but ischemic myocardium in a

dysfunctional myocardial region is enhanced myocardial

function following revascularizationor evidence of preserved

glucose uptake by PET or SPECT.14.

5

Positron emission

tomography is not readily available in most institutions, and

postoperative assessment of viability is not helpful for the

preoperative decision-making process. For clinical practice,

therefore, SPECT has emerged as the most frequently used

technique for viability assessment in patients with CAD and

reduced LV function. For SPECT imaging, 201T1 nd tech-

netium-99m (99mTc)-sestamibire the most commonly used

radiopharmaceuticals.Recently, other 99mTc-labeled yocar-

dial perfusion agents such as wmTc-tetrofosmin,wmTc-tebor-

oxime, 99mTc-furifosmin,nd 99mTc-N-NOETave been in-

troduced to the clinical practice or are under investigation.

The role of

201Tl

or viability assessment has been intense-

ly studied, and it has gained wide acceptance as a suitable

viability agent for use with SPECT or planar imaging.Ib-l8 t

has a positive value of 70-75% for predicting improvement n

regional function after revascularization.Only approximately

20% of segments with


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B. Caner and G.A. Beller: Assessment of myocardial viability

237

solely dependent on regional blood flow but also on myocar-

dial cell viability. It was also shown that if wY lTc-sestamibi

was idministered early after reperfusion and imaging was per-

formed soon afterward, the degree of salvage could

be

signifi-

cantly overestimated and infarct size could

be

underestimated

because wmTc-sestamibi ptake may

be

more related tohyper-

emic flow than

to

cellularretention.'y

Clinical studies are in good agreement with the obser-

vations in the experimen tal laboratory. Gibbon s

e t d 3 ( )

eport-

ed that yy 'Tc-sestamibi allows fo r the quantification of the

amount of hypoperfused m yocardium at risk

in

acute myocar-

dial infarction (MI), and the defect size on I1'Tc-sestamibi

images taken 6 to 14days after MI corr elated well with the late

resting LV ejection fraction. Leavitt

etu/.3.

eported an inter-

esting case in which stunned myocardium was successfully

identified by OnlTc -sestamibi ptake

12

h after thrombolytic

therapy in an akinetic region detected

on

contrast ventrjculog-

raphy. After coronary artery bypass graft (CABG) surgery,

follow-up ' Tc-sestamibi scintigraph y showed normal per-

fusion and radionuclide ventriculography demonstrated nor-

mal LV function, demo nstrating that ylllTc-sestam ibi fter

myocardial reperfusion could detect stunned myocardium and

therehy facilitate the decision-making process.

Thus,

both experimental and clinical studies have shown

the validity of wlnTc-sestamibi

s

a viabiliry marker wh en ad-

ministered at an appropriate time during the course of evolv-

ing ischem ic injury in the setting of stunned myo cardium .

Technetium-99m-Sestamibiand

Viability Assessment

in Chronic Coronary Artery Disease

The issue of whether ylllTc-sestamibi maging at rest can

be accurately employed for assessment

of

viability in patients

with CA D and severe

LV

dysfunction is

not

yet entirely re-

solved. The uptake of 9yn1Tc-sestamibit rest after an intra-

venous injection might be expected to demon strate a perfu-

sion defect consequent to the low-flow state that does not

reflect the amount of viable but underperfused m yocardium.

Several studies

I 9-l 1

have reported that ' Tc-sestamibi

underestimates myocardial viability in chronic CA D. Using

planar scintigraphy

in

20 patients with CAD and LV dys-

function, Cuocolo eral. comp ared the results of'OiTI rest/

reinjection with those of 'Tc-sestamibi and conclud ed that

99mTc-sestamibi as primarily a perfusion agent and not a vi-

ability agent. They did not use quantitative m ethods to assess

y')lnTc-sestamibi ptake; a visual five-point grading system

was used instead. Moreover, 'Tc-sestamibi uptake was

compared with that of2()'T I edreinjec tion, and did not cor-

relate directly with the recovery of contrac tile function. Mau -

rea

r t

t r / . 2 0 eported a case of chronic CAD

in

which the pre-

operative 201TIeinjection study correctly identified the

presence of viable myoca rdium in regions w here yylllTc-ses-

tamihi images show ed irreversible perfusion defects; thus,

*O1TI

ut not yylnTc-sestamibi ccurately predicted functional

recovery after revascularization.

No

quantitation fo r y')nlTc-

sestamibi uptake was done and planar scintigraphy was per-

formed for imaging. Maublant

et

reported SPECT

y9111Tc-sestamibiesults

in

25

patients with

LV

dysfunction

and postrevascularization recovery and concluded that

as

long as some residual y9 mTc-sestamibiptake wa s present,

viable myocardium was also present. A visual analysis was

used for scoring yylnT c-sestamibi ptake, and the sensitivity

and yxcificity of yymTc-sestamibi or viability assessment

were 8 3 and 79%, respectively.

QuantitationofTechnetium-9mn-Sestamibi Uptake

Previou s studies with 20iTl howed that myocardial viabili-

ty may be related not only

to

defect reversibility from stress to

rest but also to the amount

of

*"TI uptake quantitated at re-

distribution or after reinjection. I

'

o Similarly, several studies

using quantification of I1'Tc-sestamibi uptake at rest were

performed for viability determination with variable results.

Som e reports indicate the inability to define

a

threshold for

wlnTc-sestamibi uptake which could reliably distinguish vi-

able from nonviable In a limited number of

patients (n

= 14),

Marzullo etnl.21 ompared 99mTc-sestamibi

uptake on planar images with postrevascularization functional

recovery and reported that even with quantitative techniques,

w'nTc-sestamibi provided limited information

on

viability.

Technetium-99m-sestamibi

ensitivity and specificity

in

the

detection of postvascularization recovery of function w ere 8 3

and 7

1

, respectively. Sawada ern/.** ompared the results of

yynlTc-sestamibi PEC T with those

of

PET. It was shown that

y9 1Tc-sestamibiefects, either moderate (50-59%

of

peak ac-

tivity)

or

severe ( 4 0 f peak activity), frequently had evi-

dence of viability by PET. Moreo ver,

no

significant difference

was found in mean wmT c-sestamibi ctivity

in

viable and non-

viable myocardium segments. Altehoefer et

a/.*4

demon-

strated that in 80%

of

severe

(<

30%), 48%

of

moderate

(3

1

SO%), and 3 I C of mild

(>SO%)

peak activity, defects shown

by 9y111Tc-sestamibiere nonv iable on the basis of PET.

On the other hand, there are some reports indicating the

usefulness of quantitative *InTc-sestamibi imaging for viabil-

ity assessmen t.*3,~4.3s.s' ilsizian

eta/ 23

eported that wlllTc-

sestamib i significantly undere stimated viability on the basis of

201T1 nd PET, but the identification of viable myocardium

could be greatly enhanced with yymTc-sestamibiwhen the

severity of decrease in yyn'Tc-sestamibiuptake within irre-

versible defects was considered, or when an additional redis-

tribution image was acquired 4 h after the rest injection. With

an additional redistribution image, the concordance between

201T1 nd yyrnTc-sestamibi tudies was increased from 70

to

82%.

When 4 0 % of normal activity was considered as the

evidence for nonviability, then the overall concordance be-

tween

*()IT1

nd lTc-sestamibi uptake increascd

to

93%.

Udelson

et n1 32

ompared the regional activities of2(j1T1nd

wnlTc-sestamibi or predicting functional recovery after rest-

ing injec tion in31 patients. They ind icated that regional activ-

ities of both agents

as

assessed by quantitative analysis were

similar in reversibly dysfunctional myocardium 172

f 1 1

vs.75 ? 9% of peak activity for 201T1 nd 'Tc-sestamibi, re-

spectively) and both agents comparably predicted postopera-


4/8

Clin. C ardiol. Vol. 21, April 1998

90

80.

70-

60-

.

50-

P

f 40-

30.

20

10-

O

238

100

90

40

30

20

10

0

o

\

O\

0

s

0

\,

0

4

\ o

c

oo ,* -

88

'\,

a

r=-0.79,

0

' \a?

p=6.4e-7 t

5n nn

Mildly reduced viability

7 0 -

60 -

' 50-

P

n

i i

40-

s

30

20

Normal Redistribution Fixed

\ o

'o

\

\

o', 0 0

O \ 0

\\O 0

0 ,

-

0

:0

8 '

FIG. Comparisonof201T1nd 9'mTc-sestamibiuptake in patients

with

normal or

mildly

reduced viability by zolTlscintigraphic crite-

ria. Open bars indicate initial rest 201T1ptake; hatched bars, delayed

rest 201TIuptake; solid bars, 99mTc-sestamibiptake. Reprinted from

Ref. No. 35with permission.

tive function al recovery. If

60%

of peak activity was consid-

ered as a threshold cutoff point, the positive and negative pre-

dictive values for functional recovery after revascularization

were80and 96%, espectively, for 99mTc-sestamibind 75 and

92%, respectively, for

201Tl.

v erextractio n of 9 9 m T ~ - ~ e ~ -

tamibi at low flow rates, redistribution

of

99mTc-sestamibi

al-

though slight) over time, and better imaging resolution of

wmTc-sestamibi elated to the superior physical characteris-

tics of 99mT~ver 201T1 ere all proposed as explanations for

the com parability

of

wmTc-sestamibiwith 201Tl.

Kauffman

et ~ 1 ~ ~

onfirmed the findings of Udelson

et ~ 1 ~ ~

Using quantitative SPEC T in

25

patients with

LV

dysfunction,

rest-delayed 201T1 ptake and rest 99mTc-sestamibiuptake

were compared. M yocardial segments were classified as ei-

ther normal, a m ild reduction in viability (defined as delayed

uptake 50 ),

or a severe reduction in via-

bility (defined as delayed

201Tl

ptake

40%) .

Mild and se-

g r0

101 r=-0.78:

O w

p=2.5e-6

On f;n

-- .--

(A) MlBl of max (n

=

25) (B) Re1PET flow (n=

26)

FIG. Percent fibrosis detected by biopsy specimens versus 99mTc-

sestamibi uptake

(A)

and

versus relative myocardial blood

flow

de-

tected by PET

(B).

Note the significant inverse linear relationship

between

Y9r11Tc-sestamibiptake and presence

of

fibrosis. Reprinted

from

Ref. No.

34

with permission.

100

Severely reduced viability

70

6on1

U

40

30

20

10

0

Redistribution Fixed

FIG. Comparison

of

'TI and 9ymTc-sestamibi

ptake in patients

with a severe reduction in viability by 201TI cintigraphic criteria.

Open

bars

indicate

initial

rest

201Tl

ptake; hatched bars, delayed rest

201T1ptake; solid bars, 99mTc-sestamibiptake. Reprinted

from

Rel:

No. 35 with permission.

vere defec ts were furthe r classified as fixed o r having rest2011 1

redistribution.

As

shown in Figures

1

and

2,

ptake of

2017 1

and 99mTc-sestamibi ere comparable

in

segments with both

mildly and sev erely reduced viability. Sciagra etdSeported

similar results indicating he importance of quantitation for V I-

ability assessment. They studied

44

patients and pointed

out

the possibility to identify

a

cutoff point that differentiates hi-

bernating from fibrotic myocardium. A significant difference

was foun d in percent severity between the defects in territories

with postvascularization functional recovery and those in ter-

ritories with unchanged dysfunction. In a m ore recent study

using quantitative SPECT , Maes

et

~ 1 ~ ~eported that l~LJmT c-

sestamibi reflects not only flow but also m yocardial viability.

A significant inverse linear relationship was found between

99mTc-sestamibi ptake and the amount

of

fibrotic tissue from

myocardial biopsy specimens obtained at the time

of

surgery

(Fig. 3). Moreover, significantly higher 99'nTc-sestamibi al-

ues were found in patients with improved ejection fraction at 3

months following revascularization compared with those who

did not improve

(76*

13% vs.

53

&

22 )

(Fig.

4).

When using

postrevascularization ecovery as the standard of reference for

90

80

70

6

4

fi

30

50

0

=

20

10

0

t-test: p

=

0.00416

8

Improvement

No

mprovement

FIG.4

Technetium-99m-sestbi

uptake values in patients

show

ing improvement of regionalejection fraction after revascularizatioii

and in those without improvement. Reprinted from Ref. No. 34with

permission.

(n

=

13) (n = 10)


5/8

B . Caner and G.A. Beller: Assessment of myocardial viability 239

viability, an optimal threshold of

50%

for wmTc-sestamibiwas

identified, with positive and negative predictive values of 82

and

78%,

respectively.

In

an interesting study of 37 patients who underwent revas-

cularization, Soufer

et~ 1 ~ ~

pecifically addressed the regional

distribution of wmTc-sestamibi/PETdiscordance and found

that discordant wmTc-sestamibi onviable segments were pre-

dominantly

in

the inferior wall. It was thought that attenuation

artifacts were less likely to explain all of the discordance de-

tected in the inferior wall, since all of the defects were severe

(500/0of normal up-

take) in patients with LV dysfunction was 9

1

.

Technetium-99m-teboroxime s a perfusion agent that is

chemically different from gY lTc-sestamibind is rarely em-

ployed in the clinical setting. It has high early myocardial ex-

traction, rapid blood clearance, and rapid myocardial wash-

out. It has been suggested that the differential washout of

99mTc-teboroximemore rapid washout from normal area

than from ischemic zone) may be helpful in viability detec-

t i ~ n . ~ * - ~ ~

evertheless, this agent is most suitable for assess-

ment of myocardial flow with dipyridamole or adenosine

stress.Technetium-99m-furifosminand 99mTc-N-NOET re

new agents, and no data on their ability to assess myocardial

viability

in

the clinical setting are a ~ a i l a b l e . ~ ~ , ~ *

Recently, new high-energy collimators and SPECT gamma

cameras with an abilityof imaging5 I 1 keV photon of I8F-flu-

orodeoxyglucose (FDG) have been introduced into clinical

practice. It seems quite useful

in

routine clinical practice to


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240

Clin. Cardiol. Vol.

21,

April 1998

comb ine perfusion imagin g with 'Tc-labeled myo cardial

agents, with m etabolic informa tion using

FDG

SPECT.79

Conclusions

Several conclusions can

be

drawn: F irst,

in

the setting of

stunned myocardium , ' Tc-sestamibi functions

as

a reliable

marker for viability assessment; second, in the setting of hiber-

nating myo cardium , 99g'11Tc-sestamibiay underestimate via-

bility when PET and postrevascularization functional recov-

ery arc used as standards of reference. There are several

limitations to the stu dies, concludin g that wmTc-sestamibiwas

a poor marker for viability assessment in hibernation. These

include the fact that 1 ) the number of patients studied was

generally small;

(2)

planar scintigraphy was used instead of

SPECT;

( 3 )

quantitation of 99mTc-sestamibi ptake was sel-

dom used and, instead, visual interpretation was employ ed;

(4)

in

some stud ies, the reference standard for myqcard ial viabili-

ty assessment, such

as

postrevascularization functional im-

provement

or

PET, was lacking; and

(5)

no late im ages of

lllTc-sestamibin which som e redistribution could have been

detected were acquired.

Approaches

to

maximize the ability of 99n1Tc-sestamibio

detect viable myocardium are as follows:

I )

quantitation of

qrllTc-sestamibi ptake in the defect regions;

(2)

administra-

tion of nitra te before o l)mTc-sestamibi njection; (3) electro-

cardiographic gating for determination of residual myocar-

dial

thickening;

(4)

acquisition of additional redistribution

' illTc-sestamibi images after the initial rest image; and (5)

correction of I Tc-sestamibi images for attenuation to get

more accurate measurement of regional activity.

Finally, a major reason to consider wm Tc-sestamibiover

?')IT1

or viability determination is its advantage

of

having

technetium

as

the radiolabel. Based

on

the better image quali-

ty, L)yrllTc-sestamibiounts will be m ore efficient than 201T1

counts amo ng the relatively thinned, poorly contractile hiber-

nating segments. This is particularly true

in

obese and female

patients. Further data derived from a larger numb er

of

patients

are required for definite determination of w hether 99mTc-ses-

tamibi can, indeed, provide information comparable to 201T1

for distinguishing viable from nonviable myocardium. Simi-

larly. more studie s must be performed

to

determine the worth

of

some

of

the new 9yn1Tc-labeled yocardial imaging agents

for viability assessm ent.

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