Clin. Cardiol.
14, 708-712 (1991)
The Stunned and Hibernating Myocardium: A Brief Review
c. RICHARDCONTI, M.D.
Division of Cardiology, Department of Medicine, University of Florida College of Medicine, Gainesville, Florida, USA
Summary: Definitions: Stunned myocardium is viable
myocardium salvaged by coronary reperfusion that exhibits
prolonged postischemic dysfunction after reperfusion.
Hihernuting myocardium is ischemic myocardium supplied
by a narrowed coronary artery in which ischemic cells
remain viable but contraction is chronically depressed.
Clinical evidence: Stunned myocardium has been identi-
fied in the following patient groups: (1) thrombolysis or
percutaneous transluminal coronary angiography (PTCA)
i n patients with acute evolving infarction; (2) unstable
angina; (3) exercise-induced angina; (4) coronary artery
spasm; ( 5 ) platelet aggregation or transient thrombosis of a
coronary artery; (6) PTCA for chronic myocardial ische-
mia; and (7) immediately following coronary artery bypass
graft (CABG). Evidence of hibernating myocardium (LV
dysfunction) is found in the patient with severe coronary
artery stenosis, even in asymptomatic patients at rest.
Stunned myocardium returns to normal after a prolonged
period of time (hours to weeks). Hibernating myocardium
returns to normal function rather quickly if the cause is
removed.
Differentiation: Stunned myocardium can be differenti-
ated from hibernating myocardium by three clinical param-
eters, namely, LV wall motion, myocardial perfusion, and
myocardial metabolism. Stunned myocardium has abnor-
mal wall motion that tends to normalize in response to
Address fnr Reprints:
C. Richard Conti. M.D.
PiiliiiBeach Heafl Association
Eminent Scholar (Cardiology)
Chief. Division of Cardiology
BOX5-277, JHMHC
Gninesville, FL 326 10, USA
Received: July 22, 1991
Accepted: July 22, 1991
inotropes and postextrasystolic potentiation. Perfusion is
adequate and metabolism is also adequate. Hibernating
myocardium also has abnormal wall motion, which nor-
malizes after nitrates, inotropes, post extrasystolic potenti-
ation (PESP), PTCA, or CABG. Myocardial perfusion is
reduced but can be reversed with PTCA or CABG and
metabolism is adequate.
Key words: stunned myocardium, hibernating myocardi-
um, left ventricular dysfunction
Introduction
Most of this review will deal with the stunned myocardi-
um since the animal models and the human representation
are more easily studied than the models of hibernating
m yocardi um.
The word stunned is derived from the Latin extonrrw
meaning to thunder, from the old English stunian meiin-
ing to crash, and from the old French esfoner meaning to
resound. Synonyms include rendering senseless, knocking
unconscious, and dazing.
Kloner defined the stunned myocardium as a viable
myocardium that has been salvaged by coronary reperfu-
sion, yet exhibits prolonged but transient postischemic dys-
function, lasting hours to days.'
Animal Evidence for Stunned Myocardium
Most have used the IS minute coronary artery occlusion
to investigate stunning. Numerous observations have been
made. These include the following:
1. Depression of contractile function for 6 hours after
reflow2
2. Prolonged diastolic relaxation time3
3. Depressed levels of adenosine triphosphate (ATP) up
to 72 hours4
4. Nonnal myocytes as viewed by light microscopys
 C. R. Conti: Stunned and hibernating myocardium
5. Reversible mitochondria1 changes of unknown sig-
niftcance as viewed by electron microscopy’
6. Stimulation of the ventricle to contract with several
inolropes including dopamine, isoproterenol, epin-
ephrine, calcium, hydralazine, and postextrasystolic
potentiationb
Mechanisms of Stunned Myocardium
There probably is no single mechanism that results in
myocardial stunning but several should be considered:
1. Abiiormal energy utilization
2. Prtduction of oxygen-derived free radicals
3. Abnormal calcium flux
4. White cell accumulation in previously ischemic tissue
5 . Microvascular abnormalities
6 . A combination of all of these
Greenfield and Swain’ have shown experimentally in
animals after a IS-minute occlusion followed by reperfu-
sion that there is a disruption of energy utilization rather
than abnormal energy production. They found a decrease
in niyocxrdial creatine kinase (CK) plus a decrease in
adenosine diphosphate which is necessary for maximal
creatine kinase activity in the animals studied.
Przyklenk and Kloner,8 Myers,9 and Grosslo and co-
workers have reported that cytotoxic oxygen-derived free
radicals (e.g., hydroxide and superoxide anion) are associ-
ated with stunning and free radical scavengers attenuate
the sluniied myocardium.
The hypothesis that stunning is due to altered calcium
flux, that is, calcium entry after reperfusion, is supported
by the observation that nifedipine given 30 minutes after
reperfusion restores myocardial function toward normal. I
Conflicting data are reported relating to white cell accu-
mulation i n previously ischemic tissue which results in mi-
crovascular plugging after reperfusion. Both of these can
decrease blood flow (the low retlow phenomenon) to pre-
viously ischemic myocardium and can also be a possible
extracellular source of oxygen-derived free radicals.”,
Tilmanns et nl. showed that there was altered capillary
permeability and red and white cell clumping in the animal
model of stunned myocardium suggesting abnormalities at
the microvascular level as a possible cause for stunning.”
Clinical Evidence for Stunned Myocardium
Nunicrous observations have been made following
thronibolysis or percutaneous transluminal coronary
angiogrophy (PTCA) in patients with evolving acute
myocardial infarction. Prolonged recovery of myocardial
function has also been noted in patients with unstable angi-
na. folltwing exercise-induced angina, following PTCA
for chronic myocardial ischemia, and following coronary
artery bypass graft surgery. In this latter example, a stun-
709
ned myocardium is implied since patients often require
long-term inotropic support after cardiopulmonary bypass.
Anderson,14 Stack,15 and RedutoI6 and their colleagues
have shown clearly that following thrombolysis for acute
myocardial infarction there is gradual continued improve-
ment of ventricular function weeks after successful reper-
fusion. This gradual improvement was not seen in patients
whose infarct-related artery was not reperfused.
In the unstable angina patients, Nixon,I7 Satler,I8 and
colleagues have shown convincing cardiac echo evidence
of temporary ventricular dysfunction during angina-free
periods. They have also shown that isoproterenol improves
contraction of these “stunned myocardium” analogous to
results in animals.
Robertson and colleaguesI9 have also shown cardiac
echo evidence of regional wall motion abnormalities 30
minutes after exercise, particularly in patients with multi-
vessel disease. Camici et a/.,*” using positron emission
tomography (PET) studies, have also shown prolonged
alteration in metabolism using fluorodeoxyglucose (i.e.,
decreased myocardial uptake of glucose).
Further clinical evidence for a stunned myocardium
comes from Wijns and colleagues,21who evaluated dias-
tolic abnormalities of the ventricle and showed marked
decrease in compliance during balloon occlusion and
reduced compliance up to 15 minutes after repetitive
PTCA.
The Hibernating Myocardium
Hibernate derives from the Latin hibernus meaning win-
try. To hibernate is to spend a period, either seasonal or
diurnal in a state of deep sleep, especially one marked by
a distinct lowering of metabolism and body temperature. A
second definition is “a state of death-like sleep.”
Rahimtoola?? defined hibernating myocardium as ische-
mic myocardium (that is supplied by narrowed coronary
artery) in which cells remain viable but contraction is
chronically depressed. The depressed contractile function
reduces oxygen demand, which presumably protects these
myocytes.
Keller and Cannon?’ reported a model of hibernating
myocardium using isolated perfused rat heart by using
graded reductions in coronary artery pressure. Table I sum-
marizes their observations. They demonstrated significant
reductions in myocardial oxygen consumption and con-
tractile performance that returned to control when coro-
nary artery pressures were returned to baseline.
With modest decrease in coronary perfusion pressure
these changes were associated with a decrease in myocar-
dial creatine phosphate but no lactate production or change
in myocardial pH or adenosine triphosphate (ATP).
With further reduction in coronary perfusion pressure,
creatine phosphate decreased further, myocardial lactate
production increased, myocardial pH decreased, and ATP
decreased. These observations suggest that traditional
710 Clin. Cardiol. Vol. 14, September 1991

TArjt,F, I Hibernating myocardiumf4

Myocardial
Contractile creatine Lactate Myocardial Myocardial
MVO:, function phosphate production PH ATP
Modest 1 1 1 0 0 0
I CPP
Moderute 1 I 11 T I 1
ICPP
“Isolated perfused rat heart model.
Ahhrc.viurions: ATP = adenosine triphosphate; CPP = coronary perfursion pressure; MVO;?=myocardial oxygen consumption.
Based on data from Ref. 23.

markers of myocardial ischemia need not be present in the
“hibemating” myocardium but oxygen delivery may be an
important determinant of myocardial function in this
model of decreased coronary perfusion pressure.
Clinical Evidence for Hibernating Myocardium
Several observations have been made suggesting the
presence of a hibernating myocardium in humans:24.25
I . Reversal of chronic ventricular asynergy by nitrates,
postextrasystolic potentiation, inotropes, exercise,
and revascularization.
2. There is some correlation with the severity of coro-
nary artery disease and the presence or absence of
coronary artery collaterals.
3. There is some correlation with quantitated (histolog-
ic) myocardial loss (e.g., if‘ nitrates are given and
there is only 10% cell death there will be reversible
function of the ventricle. In contrast, if 50% of the
cells are dead there will be little reversible function.
4. Reversal of a thallium perfusion defect in akinetic
myocardium following coronary artery bypass sur-
gery.
Summary of Difference Between Stunned and
Hibernating Myocardium
Table I1 outlines some differences between stunned,
hibernating, and infarcted myocardium. The stunned
myocardium occurs after ischemia and after reperfusion.
Hibernating myocardium occurs during ischemia. The
clinical causes of stunned myocardium include episodes
of severe ischemia due to either exercise, PTCA occlusion,
coronary artery spasm, platelet aggregation, or transient
thrombosis of a coronary artery. In contrast, the clinical
cause of hibernating myocardium is severe coronary artery
stenosis even under resting conditions.
Stunned myocardium returns to normal after a pro-
longed period of time (hours to weeks). In contrast, hiber-
nating myocardium has an indefinite delay, but returns to
normal function rather quickly if the cause is removed.
A clinical example of the stunned myocardium is the
reperfused evolving myocardial infarction. The clinical
example of the hibernating myocardium is LV dysfunction
prior to CABG or PTCA compared with normalized func-
tion following CABG or PTCA.
As summarized in Table 111, one can clinically differen-
tiate stunned from hibernating myocardium using three
parameters (i.e., wall motion, perfusion, and metabolism).

II Some differences between stunned, hibernating, and infarcted myocardium

TABLE
Return of
Condition of Time of Clinical myocardial Clinical
myocardium occurrence cause function example
Stunned After Discrete episodes Prolonged Reperfused
ischemia of severe ischemia delay evolving MI
and e.g., exercise, spasm,
reperfusion platelet aggregation,
transient thrombosis
Hi beriiatiiig During Patent but severe Indefinite LV function
ischemia coronary artery delay prior to
stenosis CABG or PTCA
1n farcted After Coronary artery No recovery Failure of
ischemia occlusion reperfusion
 S. P. Karas et al.: Restenosis after coronary angioplasty
l'rapadil, an inhibitor of PDGF-induced cellular prolif-
eration, has been shown to reduce intimal thickness fol-
lowing balloon injury in the atherosclerotic rabbit.ImIn-
sulin-like growth factor-I (IGF-I) acts synergistically with
PDGF to promote smooth muscle cell replication in
vitrO,.VJ.111 Production and release of IGF- 1 by smooth mus-
cle cells is regulated by growth hormone. Angiopeptin is a
synthetic analog of somatostatin which blocks the release
of growlh hormone by the pituitary. Pretreatment of rats
and rabbits with this compound was found to greatly inhibit
vascular smooth muscle proliferation following denuda-
tion of the carotid arteries.'". Its effects on human
restenosis are currently under investigation at Georgetown
University.
Hypertrophy of the vascular muscle layers seen in hy-
pertension may be mediated by the local production of an-
giotensin 11.102 Local angiotensin systems may also be in-
volved in the myoproliferative response to vascular injury.
Studies have clearly shown a reduction in intimal thickness
following carotid injury in rats treated with the angiotensin
converting enzyme inhibitor ~ilazapril.~" A multicenter
clinicill study in patients following PTCA is currently in
progress at European and U.S. enters, including our own.
All potential pharmacologic treatments for restenosis
are limited by the difficulty in maintaining a high con-
centration of the drug at the desired site of activity for an
extended period of time without systemic toxicity. Meth-
ods hilvl! been devised to deliver agents directly to in-
jured vascular segments. Perforated balloon catheters have
been uscd to inject high concentrations of heparin into
the arterial wall without significant vascular tra~ ma. " '~
Genetically modified endothelial cells have been success-
fully implanted onto vascular grafts"Mand onto the de-
nuded luminal surface of porcine iliac arteries.'O5 Recent-
ly, recombinant genes were successfully transferred
directly into endothelial cells and myocytes by introducing
a retroviral vector to the vessel wall through a catheter.lo5
Using this technology, recombinant genes could be de-
livered to the arterial wall during PTCA and induce pro-
longed It~calproduction of antithrombotic or antiprolifer-
ative suhstances in order to inhibit restenosis.Io6Stents
are being developed which may store and slowly release
high concentrations of inhibitory agents locally over an ex-
tended pcriod of time. A recent study investigated the ef-
fect of heparin bonding on the development of neointimal
proliferation after placement of a tantalum stent in porcine
carotid arteries.
New Devices
The development of new techniques in the treatment
of coronary artery disease has offered new hope that the lu-
minal diameter could be restored without inducing myoin-
timal proliferation.
797
Since events during angioplasty appear to influence the
later development of restenosis, much of the research on
new devices has been focused on improving the luminal di-
ameter and geometry at the time of PTCA.
The use of coronary artery stents may be one way to op-
timize final lesion morphology. Initial animal studies
showed minimal restenosis associated with placement of an
intracoronary stent.Ios Studies in humans have shown
restenosis rates of about 20% following placement of a
Palmaz-Schatz stent. l1(] One needs to be aware, howev-
er, that reports of restenosis rates following stent place-
ment vary considerably depending on the definition of
restenosis used. For example, in the same group of patients
studied 2 4 months after placement of a Palmaz-Schatz.
stent, Ellis found that 20% had restenosis as defined as a
>50% stenosis at the site of the stent.l"'When restenosis
was defined as a decrease in luminal diameter of >0.72
mm, the rate of restenosis was 50%. Although relatively
fewer patients undergoing stent placement developed sig-
nificant lesions, half of them showed significant intimal
proliferation. In a recently published study of the self-ex-
panding Wallstent, Sermys et al. reported a restenosis rate
of 33%, based on a change of ~ 0 . 7 2mm in minimal lumi-
nal diameter.'ll The restenosis rate was 13% when defined
as a stenosis of >50%. These data suggest that perhaps
the benefit of stent placement may be due to stretching of
the vessel and thus optimizing luminal diameter, rather
than by limiting the degree of intimal proliferation. Our
studies in swineBoand those of others in humans'". have
confirmed this suspicion. Results from our swine model in-
dicate that the luminal diameter was significantly greater
following stent placement compared with the diameter
after balloon dilatation. Furthermore, the long-term loss
in luminal diameter with stents was comparable to that
seen following the use of other modalities.
Using atherectomy devices, atherosclerotic plaque can
be shaved from the luminal surface and subsequently re-
moved from the body.'13 Cenain features of atherectomy
led to expectations that this technique might be associated
with less intimal reaction and restenosis than balloon an-
gioplasty. Atherectomy usually results in a smooth, wide-
ly patent vessel, often with a residual stenosis of <10%."3
Because the device improves luminal diameter by cutting
and removal of tissue, the vessel sustains minimal stretch.
Since atherectomy almost invariably removes portions of
the media, elimination of such potential sources of smooth
muscle proliferation may reduce the risk of restenosis.
Simpson reported overall restenosis rates of 24% following
atherectomy of de novo lesions in native coronary arter-
ies.I13 He observed, however, higher rates of restenosis in
patients with vessels <3.0 mm (33%) and in those with
ostial lesions (46%). Others have found restenosis rates
following atherectomy of de novo native lesions to be
>30%, a figure comparable to those reported following
balloon angi~plasty."~. I l 5 Data from atherectomy reports
indicate even higher rates of restenosis in patients under-
going atherectomy of restenotic lesions or lesions in saphe-
713 Clin. Cardiol. Vol. 14, September 1991
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