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JACC Vol . 16. No . 2
August 1990A86-8
Editorial Comment
Wanted : Dead or Alive - The
Search for Markers of
Myocardial Viability*
RICHARD A. GOLDSTEIN, MD, FACC
Houston, Texas
For more than 25 years cardiologists have sought a method
for the accurate determination of myocardial viability to
evaluate and guide treatment in patients with acute infarction. Recently this search has been expanded to include
assessment of viability in patients with chronically ischemic
or "hibernating" myocardium that may be present long after
the initial insult has occurred, Although these two situations
share many characteristics, the requirements for an acceptable technique to define them may be considerably different .
In an acute, evolving infarction the method should be simple
and rapidly acquired, allow monitoring and access to the
patient, have results available within minutes of completion
and permit frequent repetition to allow monitoring of therapy . In chronic ischemia, rime is not as critical . Patients are
usually in stable condition and decisions about treatment
need not be immediate . Ideally the procedure would also be
applicable to patients with heart failure, in whom it could
help distinguish recoverable forms of myopathy from irreversibly damaged muscle.
E eetrocardioseaphle (ECG) estimates of Infarct size . In
the 1970s; the major test to estimate the extent of myocardial
necrosis was the sum of ST segment elevation from multiple
sites (1-4) . The rationale was simple: the higher the ST
segment elevation, the larger the zone of ischemic injury . If
the height of the ST segments was lowered, less myocardium
would become necrotic. The clinical use of nitroglycerin
during acute infarction was primarily based on studies that
measured benefit by alterations in ST segment elevation
(2,4) . However, it was subsequently recognized that, at best,
this approach was limited in the presence of conduction
abnormalities . hypertrophy or certain drugs independent of
any effect on ischemia. The theoretic relation between ST
'Editorials published in J
.-al of chic Amrrirnn College j C+rcinloxv
reflect the views ergot auf er, and do not -wily represent the views of
JACC or the American College orCaNtology .
From the Department of Nuclear Cardiulogy . !!niversity of Texas Medial School a1 Houston . Houston . Texas .
Address for reprints ; Richard A. Goldstein . MD. Associate tronssor of
Medicine . Director. Nuclear Cardiology . University of Texas Medical School
at Hr-star
. Room 1 .146.6431 Fannin Street. Houston . Texas 77030.
=?1990 by the American College of Cardiology
segment measurements and the size of the igjured region was
critically evaluated by Fozzard and DasGupta (5) with the
conclusion that "inferences from the extent or magnitude of
ST changes overlying an area of ischemia may be misleading
and ST segment mapping should not be used as an independent measure of ischemia ."
Binchendal reci iati s of infarct size. Sabel et al . (6) proposed that infarct size could be determined with the use 4:f
myocardial creatine kinase (CK) enzymes by integrating the
area under the curve generated from multiple, frequent
enzyme measurements. Although this approach is suitable
for controlled studies with large numbers of patients, it
provides little information for therapy in the acute stage of
infarction or management of patients with chronic ischemia .
The introduction of thrombolytic agents to the treatment
regimen further complicates the measurement (7) .
Ventricular function . Regional abnormalities in left ventricular wall motion occur within seconds of the onset of
ischemia . After reperfusion it may take 7 to 10 days before
viable tissue recovers function (8). Therefore, the presence
of regional dysfunction does not by itself indicate irreversible disease . In chronic ischemia the ability to increase left
ventricular ejection fraction after isotropic stimulation predicts a good prognosis in patients with coronary artery
disease (9) . Similarly, lessening of regional wall motion
abnormalities after nitroglycerin administration also prevides presumptive evidence for viability.
Radlauelide amassment of viabYYy. Radionuclide imag.
ing allows visualization of normal and abnormal myocardium
on the basis of alterations in perfusion, metabolism or
function. Medically useful radionuclides can be separated on
their mode of decay into two groups: single photon or
positron emittors . Single photon emittors (thallium-201,
technetium-99!n) release gamma photons that leave the
tissue in a random direction. Regional activity cannot be
accurately quantitated because of attenuation of activity
from overlying tissue and the effects of scatter from photons
outside the area of interest. Positron tracers (carbon-11,
fluorine-18, nitrogen . 13, rubidium-82) decay by the emission
of a positron, a particle that has the mass of an electron but
a positive rather than a negative charge . After traveling a few
millimeters in tissue, the positron collides with an electron
and releases two high energy photons that go 180° apart .
Tracer activity can be localized and quantified using coincidence detection so that the activity is accepted only when
each of file two paired detectors records the photons .
Thallium-201 perfusiommlistribition studies . Thallium201 is a diffusible cation that is taken up by myocardial tissue
in proportion to flow (10). Initial images are therefore an
index of perfusion . Over the next several hours thallium
equilibrates (redistributes) in the myocardium and reflects
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activity in the potassium pool that requires a functioning cell
membrane (11,12). Thus, delayed images that demonstrate
resolution of perfusion defects can be used to assess tissue
viability. In acute myocardial infarction, thallium scans can be
used to document perfusion deficits (13) . However. the redistribution images cannot be performed until decisions about
interventions have been made . Thallium-201 is also constrained by a long half-life (73 h) that decreases the allowable
dose and precludes restudy during the acute process.
In hibernating myocardium the filling in of stress-induced
perfusion defects on redistribution (late) images is taken as a
measure of viability. The sensitivity is improved if redistribution images are obtained 24 h later (14) . However . recent
studies (15,16) have shown that between 38% and 58% of
thallium defects that am interpreted as showing scar are
viable as judged by uptake of 2-fluoro-2-deoxyglu .ose (F1)G)
by position emission tomographic (PET) imaging . A recently
presented study (17) suggests that the diagnostic accuracy of
thalliumfordetermiring viability is enhanced by the addition
of a second injection of the tracer if the defect persists on a
4 h redistribution image .
Idarct-inld tracers, Technetium-99m pyrophosphate and
indium-I l 1-labeled myosin antibody localize regions of myocardial necrosis (18). Unfortunately, images obtained with
these tracers do not b :come positive until several hours after
irreversible changes have occurred and the tracers require time
for delivery to the damaged tissue . Sequential scanning with
thallium-201 (perfusion) can be followed by an infarct-avid
tracer (necrosis) so that the difference is related to hypoperfused, viable myocardium . Problems with scatter and variable
attenuation, as well as the discrepancy between thallium studies and FDG, suggest that this approach may be of limited
value .
Positron emitters. Positron-emitting isotopes include carbon-I I, oxygen-15, nitrogen-13 . fluorine-I8 and rubidium-82 .
The first four tracers can be incorporated into virtually any
important physiologic or pharmacologic moiety, thus allowing metabolic imaging. Most studies of myocardial viability
have utilized FDG, a nonmetabolizable analogue of glucose .
The uptake and phosphorylation of FDG requires a viable
cell . Schelbert and his colleagues (19 .20) have demonstrated
that myocardial viability can be identified by the uptake of
FDG in hypoperfused myocardium . Patients with areas of
glucose uptake are much more likely to recover regional left
ventricular function after revascularization than are patients
without areas of glucose uptake . FDG is well suited to the
evaluation of patients suspected of having residual viable
myocardium after infarction . However, it is not practical for
patients with acute infarction because of the time needed to
complete the imaging sequence . The study requires at [east
1 .5 h and includes an attenuation scan (15 to 20 min) .
perfusion image (15 to 20 min) and time for uptake of FDG
(approximately 45 min followed by a II) to 15 min acquisition) . The synthesis o1 tracer also requires either a fully
GOLDSTEIN
ECITORIAL COMMENT
487
automated cyclotron and chemical synthesis or an in-house
physicist and chemist to avoid further delays.
Other metabolic tracer, Several other metabolic tracers
have been proposed as indexes of viability including carbonII palmitate, carbon-11 acetate and carbon-II pyruvate .
Carbon-I I paimitate is a medium-chained fatty acid analogue
that is taken up by the heart and converted to fatty aryl COA,
which leaves the myocardium only by being oxidized
(21 .22) . The rate of clearance of tracer is therefore related to
the rate of fatty oxidation . However, some carbon-I I palmitale leaves the cell before being activated, especially during
ischemia, which readers this measurement less reliable (23).
Recovery of normal clearance seems to predict recovery of
regional function in experimental studies. Like FDG, this
approach would only be practica' for the postinfarction
evaluation of viability.
Carbon-1 I acetate is rapidly oxidized by the myocardium
and reflects the state of oxidative metabolism (24). Initial
studies suggest that it too may be useful in assessing viability in
hibernating tissue following infarction . Carbon-I I pyruvate is
taken up and metabolized by aerobic tissue but accumulates as
lactate in areas of ischemia (25). Pyruvate metabolism is
complicates by the potential for multiple routes of conversion
in addition to lactate including transamination .
Rub ldlunr-82- Rubidium-82 is a short-lived (half-life 75 s)
generator-produced diffusible cation that, like thallium and
potassium, is taken up by the myocardium in proportion to
flow (26) . Because it is generator produced, tracer can be
made available 24 h a day without the need of any additional
synthetic process . In experimental studies the tracer remains
in viable tissue for the imaging period but leaks out of
irreversibly injured myocardium presumably because of
damage to the membrane (27,28). The entire imaging sequence including an attenuation scan takes <30 min, making
it possible to get information rapidly about myocardial
perfusion )arterial patency) and possibly viability (29). Further studies are needed to determine whether this approach
is a reliable indicator of myocardial viability in patients .
Fluorine-18 8aoromlwnidazale . The study by Shelton et
al . (30) in this issue of the Journal presents a novel approach
to the differentiation of hypoxk and normal myocardium
using the positron-emitting tracer fluorine-IS fluoromisonidazole. Extraction of the tracer occurs in hypoperfused
areas early after occlusion but is minimal at 6 or 24 h,
suggesting that the agent may be useful in separating reversible from irreversibly injured necrotic tissue. Unfortunately,
histochemical or pathologic validation, or both, was not
performed to further support the hypothesis .
if fluorine-18 fluoromisonidazole is proved to provide an
accurate way of delineating hypoxic viable myocardium,
how will it be employed clinically? The tracer takes 30 to 45
min to prepare . Imaging of fluorine-IS fluoromisonidazole in
this study was performed over 45 min and followed the
acquisition of an attenuation scan, blood pool scan and
488
GOLDSTEIN
EDITORIAL COMMENT
perfusion scan . In the setting of acute infarction an imaging
procedure that requires up to 2 h from the time the patient is
initially seen for evaluation is too long to be practical. An
additional limitation of this approach is the 108 min half-life
of fluorine-18, which precludes a repeat study for several
hours to monitor the effect of treatment. It is more likely that
this approach could be used to determine the presence of
hibernating myocardium in patients with previous infarction,
in whom the issue is whether revascularization of the region
could restore function . Future studies should include comparisons with FDG and histologic findings to determine th6
relative merits of the two tracers.
Conclusions. At the present time FDG seems to be the
most accepted indicator of viable, ischemic myocardium . In
the future, imaging with other tracers or magnetic resonance
imaging may supplant it for use in chronic ischemia . In acute
myocardial infarction there is currently no accurate way of
determining the extent of reversibly injured myocardium .
The search for a standard continues .
References
1 . Mamko PR. Bmunwald E . Modification or myocardial infarct size after
coronary occlusion . .Ann Intern Med 1973:79 :720-33 .
2. Myers RW . SchererjL. Goldstein RA . Goldstein RE. Kent KM, Epstein
SE, Effects of nitroglycerin and nitroglycerin-methoxamine during acute
myocardial ischcmia in dogs with preexisting mullivesscl coronary occlusive disease. Circulation 1975 :51:632-40.
3. Reid PR, Taylor DR, Kelly DT, et al . Myocnrdial.irf'u ctextension detected
by precordiat ST-segment mappirit . N Eng11 Med 1974290:121-8.
4. Come PC, Flaherty JT, Heard MG, et al . Reversal by phenylephrine of the
beneficial effects of intravenous nitroglycerin in patients with acute
myocardial infarction. N Engl J Med 1975 :293:1003-7 .
5. Fozzard HA, DacGupla DS . ST-segmen potentials and mapping. Circulation 1976 :54:53}7 .
6. Sobel BE, Shell WE. Serum enzyme determinations in The diagnosis and
assessment of myocardial infarction . Circulation 1972:45:471-81 .
7 . Blanke H, you Hardenberg D . Cohen M. et al. Patterns of creatine kinese
release during acute myocmdial infarction after nonsurgical reperfusion :
comparison with conventional treatment and correlation with infarct size .
J Am Coll Cardiol 1904 ;3 :675-g0 .
8. RedutoLA.SmallingRW,FreundDC.GouldKL .Intracuronaryinfusion
or streptokinase in patients with acute myocardial infarction : effect of
repedhsion on left ventricular performance . Am 1 Cardiol 1981 :48:403-9.
9. Next . RW, Cohn LH, Collins 11 . Wynne J, Halmsn L. Cohn PF.
Inotropic contractile reserve : a useful predictor of increased 5 year
survival and improved postoperative left ventricular function of patients
with coronary sorry disease and reduced ejection fraction . Am J Cardiol
1952 :5039-44.
10 . Mean JA. Becuer LC. Quantitative relationship between global IeS
ventricular Thallium uptake and blood flow : effects of proprnolol . ouabain. dipyridamote- and coronary artery occlusion . J Nutt Med 198627:
641-52.
11, Guldhaber SZ, Newell 1B, Alpert NM. Andrews E. Pothosl GM . Ingwall
IS. Effects of isckamiodike insult on myocordial thallium-201 occumulaNon. Cucalation 1983:67:778-86 .
12 . Beller GA. Watson DD, Ackell P . Pohost G . Time course of thallium-201
JACC Vol. 16. No. 2
August 1990:486-8
redistribution after transient myocardial ischemla . Circulation 1980 ;61 :
791-7 .
13. Wackers FJ . Sokole Ell . Samson G . et al . Value and limitations of
Thallium-201 scintigesphy in the acute phase of myocardial udardan.
N East J Mcd 1976:295 :1-5.
14. Kiat H. Be-, DS . Maddahi J- et al . Late reversibility of tomographie
myocardial thallium-201 defects: an accurate marker of myocardial via .
bility . J Am Cog Cardiol 1988:12:1456-63 .
15. Bnmken R. Schwaiger M, Graver-McKay M, Phelps ME, Tdliscb 1,
Schelben HR . Positron emission tomography detects tissue metabolic
activity in myocardial segments with persistent thallium perfusion defats. J Am Coll Conduct 1987;10;557-67.
16. Tamaki N, Yonekum Y . Yamashita K, et al . Relation of left ventricular
perfusi and wall motion with metabolic activity in persistent defects on
thallium-201 tomography in healed myocardial infarction . Am I Cordial
193862 :202-8 .
17. Dilsizian V, Swain J, Dextms R, Almagor Y, Boom R . Prediction of
viable myocardium by thallium reinjection at rest after stressredistribution imaging : a pre- and pose-revascularizalion study (abile) .
Circulation 1989;SOlsuppl 11):11-366.
18. Willerson IT. Parkey RW, Baste Fl . Lewis SE, Cor6en J, Buja LM .
Pethophysiologic considerations and clinicopatloraical correlates or
technelium-99m pyrophosphate myocardial scintigraphy . Semin Noel
Mod 1950:5 :54-69.
19. Tillisch J, Brushes R . Marshall R, at al . Reversibility of cardiac Wall .
motion abnormalities predicted by positron toologaphy . N Bunt I Met,
1986:314:881-8 .
20 . Bmnken R, Tilpsch J, Schwaiger M, et al . Regional perfusion, glucose
metabolism . and wall motion in patients with chronic electrocardiogmpbic Q wave infarctions : evidence for persistence of viable tissue in
some itdarcl regions by positron emission tomography. Circulation 1966;
73:951-63.
21 . Goldstein RA, Klein MS. Welch Mr. .Snhel BE . External .--at Of
myocardial metabolism with C-I I peck :: : : :e in vivo. I Noel Med 1910¢1:
342-8.
22. Saturn HR. Sulelbert HR, NyjaO A, et al. C-11 labeled palmittc acid for
the noninvasive evaluation of rcgioeal myocardial fatty acid metabolism
th positroncomlmtedtomography . I LR. Kinetics of C-Il psjnritie acid is
acutely ischeeric myocardium . Am Heart 1 1982 :103:548-61.
23. Fax KAA. Abendschein DR. Ambes HD, Sobel BE. Bergmann SR .
Efflux of metabolized and nom metabolized fatty acid from canine myocardium. Cue Res 1995 :57:232-43.
24. Brown M, Marshall DR . Suhel BE, Bergmann SR . Iklineation of myocardial oxygen utilization with carbon-11 labeled acetale . Circulation
1987 :76:687-96 .
25. Goldstein RA, Klein MS . Sobel BE. Detection of myocardial ischemia
prior to infarction based on accumulation of labeled pymvate . J Nuct Med
198011 :1101-4.
26 . Gold stein RA, Mullani NA, Fisher D1, Marani SK, Gould KL, O'Brien
HA. Myocardial perfusion with mbidium-82.11. The effects of metabolic
and pharnrcologic interventions . J Noel Med 1983 :24:907-15 .
wi
27 . Goldstein RA . Kinetics of mbidium-82 after coronary occlusion ad
reperfosion : assessment of potency and viability in openc!tested dogs .
J Clin Invest 1995 :75:1131-7.
28. Goldstein RA. Rubidium-82 kinetics after coronary occlusion : temporal
relation of net myocardial accumulation and viability in openchested
dogs . I Nucl Med 1986;27:1456-61 .
29. Goldstein RA. Mullani NA . Wing WH, el al. Positron imaging of
myocardial infarctico with mbidium-82. J Nuct Mad 1986:27:1824-9.
30. Shelton ME, Dance CS. Hweng D-R, Hneeeeo P . Welch Mr . Bergmann
SR . In vivo delineation of myocardial hypoxia during coronary occlusion
using fluorine. l8 luommisonidezok and positron emission lomography: a
potential approach for identification ofjeopardired myocardium . J Am
Coll Cardiol 1990;16:477-85.