From the Heart Institute, Good Samaritan Hospital, and University of
Southern California, Los Angeles (R.A.K.); University of Louisville (R.B.),
Louisville, Ky; Johns Hopkins University (E.M.), Baltimore, Md; Harvard
Medical School, Brigham and Women's Hospital (E.B.), Boston, Mass; and
the National Heart, Lung, and Blood Institute (L.R.), Bethesda, Md.
The meeting was chaired by Eugene Braunwald and cochaired by Roberto
Bolli, Eduardo Marban, and Robert A. Kloner and was coordinated by
Leslie Reinlib. Twenty participants represented a broad
spectrum of expertise: basic and clinical scientists, pathologists, and
surgeons. (A list of conference participants is provided in the
Appendix.)
The purpose of this article is to review some of the points made at the
workshop in regard to areas of general agreement and controversy and,
most importantly, to summarize the areas that need further research.
The following discussions briefly review the concepts of stunning,
hibernating, and preconditioning discussed at the workshop and some
additional material that has become available since the workshop.
Following each brief discussion are suggestions made by the
panel for future research directions.
Pathogenesis of Myocardial Stunning
Generation of ROS (Oxyradical Hypothesis)
The available evidence indicates that most or all of the ROS-mediated
injury responsible for stunning occurs in the initial moments of
reperfusion. For example, in the setting of a 15-minute
coronary occlusion in the dog, antioxidant therapies are
equally effective in alleviating myocardial stunning irrespective of
whether they are begun before ischemia or just prior to
reperfusion; however, antioxidant therapies begun 1 minute after
reperfusion are ineffective, indicating that the ROS important in
causing myocardial stunning are those produced immediately after
reflow.43 46 Thus, myocardial stunning can be
viewed in part as a form of ROS-mediated "reperfusion
injury."27 43 This concept may have significant
therapeutic implications because it suggests that antioxidant therapies
begun after the onset of ischemia could still be effective in
preventing postischemic dysfunction; however, a delay in
the implementation of such therapies until after reperfusion would
result in loss of efficacy.27 It is important to
stress, however, that none of the antioxidant therapies used thus far
has completely prevented myocardial stunning.27
On the basis of these observations, it seems reasonable to conclude
that the injury responsible for myocardial stunning consists of two
components: (1) a component that develops during ischemia
(ischemic injury) and is not responsive to antioxidant therapy
(no matter how vigorous or how early applied) and (2) a component that
develops after reperfusion (reperfusion injury) and can be mitigated by
early antioxidant therapy (Fig 1B
The exact source of ROS production in stunned
myocardium remains uncertain (Fig 1A
Availability of Activator Ca2+
Ca2+ Overload
Decreased Sensitivity of Myofilaments to Ca2+
If stunned myocardium is due to a decrease in
Ca2+ sensitivity, it is clear that this reduced
sensitivity can be overcome. A variety of inotropic agents can
stimulate the stunned myocardium to contract, and it is
clear that stunned myocardium manifests contractile
reserve.68 69 70 This is good news in the clinical
realm because it means that stunned myocardium can be
recruited to contract if needed.
Summary
The exact nature of the myofibrillar defect is an important area for
future investigation. It has been hypothesized that stunning is the
result of the activation of endogenous proteases that
attack the myofilaments and that the slow recovery of the stunned
myocardium is caused by the slow synthesis of new
contractile proteins to repair the damage.28 71
In particular, partial proteolysis of troponin I has been demonstrated
in globally stunned myocardium.66 The
impaired responsiveness of contractile filaments may also be caused by
oxidation of critical thiol groups, which could be quickly reversed on
normalization of the cellular redox state2 (Fig 1A
Repetitive Stunning Versus Hibernation
Effect of Age on Myocardial Stunning
Myocardial Stunning in Humans
One clinical situation in which stunning has been observed is that of
thrombolytic therapy. Several studies that measured
global and/or regional left ventricular function did not
observe initial dramatic improvement in function after
thrombolytic therapy. Improvement in
ventricular function occurred gradually over the course of
a few weeks.81 82 83 84 One
report85 suggested that stunned
myocardium could be recruited after
thrombolytic therapy with small boluses of inotropes.
These studies suggest that the ultimate return of cardiac function
cannot be determined immediately after reperfusion. Assessment of
function a few weeks after thrombolysis will provide a
clearer picture as to whether salvaged tissue has recovered.
Stunned myocardium has been described in patients
undergoing cardiac surgery. Despite the most modern cardioplegic
techniques, some postsurgical stunning is
common.86 87 88 89 Many patients require inotropic
support and pressors for hours to days after surgery, which eventually
can be weaned as the stunning abates.
Stunned myocardium occurs after exercise-induced
ischemia in patients. Persistent wall-motion abnormalities were
observed by echocardiography in patients with
severe multivessel coronary artery disease at a time when chest
pain and ST-segment deviations had resolved.90
Ambrosio et al91 observed that persistent
poststress regional wall-motion abnormalities were present at a
time when regional perfusion had recovered. This finding of a
flow-function dissociation is strong evidence in support of stunning as
the mechanism for this postexercise left ventricular
dysfunction. Fragasso et al92 showed that
diastolic abnormalities could persist in some patients for
a few days after an exercise test.
Angioplasty is a useful model for studying the heart's response to
transient episodes of brief ischemia. Brief coronary
occlusions (<60 seconds) induced at the time of angioplasty have been
associated with persistent abnormalities in ventricular
compliance.93 Sheiban et
al94 induced longer periods of coronary
artery occlusion (5 to 7 minutes) during angioplasty and observed that
recovery of regional wall motion required 24 to 36 hours. Recovery in
function was improved with calcium channel
blockade.94 These findings parallel the
experimental observations described in animal models of brief
coronary occlusion and reperfusion.
Stunning has been observed by echocardiography in
patients with unstable angina.95 In one
study,89 regional wall-motion abnormalities were
observed immediately after angina and for at least a few hours after
chest pain and ECG abnormalities had resolved.
An important clinical implication of stunning is that the phenomenon
may contribute to heart failure. Some have postulated that stunning may
play a role in ischemic cardiomyopathy.
However, the exact prevalence of this stunned myocardium in
humans is unknown because of the difficulty in distinguishing
myocardial stunning from other forms of reversible left
ventricular dysfunction, such as those caused by silent
ischemia and myocardial hibernation. A conclusive diagnosis of
myocardial stunning (as opposed to silent ischemia or
hibernation) requires simultaneous measurements of regional
myocardial perfusion and function, which are rarely
available.74 Even when available, techniques for
measuring regional perfusion in humans do not have sufficient
resolution to discern transmural gradients of myocardial perfusion.
This is a major limitation because subendocardial perfusion is the main
determinant of transmural contractile function. Another confounding
factor is that the coexistence of a subendocardial infarction with
subepicardial stunning could be mistaken for hibernation because
average transmural perfusion would be decreased.
The clinical situation is likely to be extremely complex, because
recurrent bouts of severe ischemia (frequently silent) could be
superimposed on a baseline of decreased perfusion, resulting in the
superimposition of repetitive stunning on a baseline state of chronic
hibernation.74 In many patients with a severe
coronary stenosis, the same myocardial region may
contain an admixture of subendocardial scar and subendocardial viable
myocardium in which stunning and hibernation can both
occur, either in close temporal proximity or even
simultaneously.74
Future Directions
Experimental Studies
1. To identify the precise myofilament lesion responsible for stunning,
the mechanism that produces this lesion, and the mechanism whereby this
lesion leads to impaired responsiveness to Ca2+
and to contractile dysfunction. Identification of the molecular basis
of myocardial stunning would not only advance our understanding of the
pathophysiology of ischemic heart disease but would also result
in better preventive therapies.
2. To elucidate the role of Ca2+ overload in the
genesis of myocardial stunning after regional ischemia
(completely reversible or partly reversible ischemia) in vivo
and after exercise-induced ischemia. If
Ca2+ overload is causally involved in stunning,
therapies aimed at preventing the rise in
[Ca2+] should be developed.
3. To identify the source(s) of the ROS responsible for stunning, the
relative contributions of different ROS to this phenomenon, and the
precise mechanism whereby a short burst of ROS production
results in prolonged depression of contractile function. Insights into
these issues may result in the development of more efficacious
antioxidant therapies.
4. To determine the mechanism of myocardial stunning after prolonged,
partly reversible regional ischemia (subendocardial infarction)
and after exercise-induced ischemia. The mechanism for stunning
in these settings is presently unknown.
5. To develop experimental models of repetitive stunning and chronic
hibernation. Use of these models should enable determination of whether
repetitive stunning can be a cause of chronic left
ventricular dysfunction mimicking hibernation and whether
hibernation, defined as a primary decrease in coronary flow,
does exist as a chronic condition.
6. To characterize the changes in gene regulation and receptor
expression and function associated with stunning. It is now clear that
brief, reversible ischemia has a significant effect on gene
expression that is likely to result in significant phenotypic changes,
particularly after repetitive bouts of ischemia. Given the fact
that most patients with coronary disease have recurrent
ischemic episodes, these studies would have great clinical
relevance.
7. To elucidate the mechanism for the increased susceptibility of aged
myocardium to stunning and to characterize the
pathophysiology and pathogenesis of stunning in senescent hearts.
Human Studies
1. To elucidate the pathogenesis of stunning, particularly with regard
to the role of myofilament dysfunction and oxidative stress. Little or
nothing is known regarding the mechanism of stunning in patients. These
studies should translate experimental findings to the clinical arena by
testing in humans the pathogenetic hypotheses developed in animal
models.
2. To develop better methods for the diagnosis of stunning in humans,
including the development of diagnostic techniques that can
rapidly distinguish stunning from necrosis after cardiac surgery and
after revascularization for acute myocardial
infarction. In these situations, such a distinction is essential for
selecting the proper management of patients with severe left
ventricular dysfunction or cardiogenic shock. Better
diagnostic methods that can distinguish stunning from
hibernation would also help to define the prevalence, natural history,
and clinical importance of these two conditions; ideally, these
diagnostic methods should be accurate, relatively
inexpensive, and broadly available.
3. To define the natural history of disease progression, especially in
the case of repetitive and exercise-induced stunning. Longitudinal
follow-up of patients with these syndromes, coupled with serial
measurements of regional myocardial function and perfusion, could
elucidate whether recurrent or exercise-induced ischemia can
result in persistent impairment of ventricular function
simulating hibernation.
4. To develop efficacious treatments that can prevent or alleviate
myocardial stunning. For the most part, the information acquired in
experimental settings regarding the treatment and prevention of
myocardial stunning has not yet been translated into clinically
applicable therapies. Treatments aimed specifically at preventing
myocardial stunning have not been developed in patients. These studies
should clarify the usefulness of agents shown to be effective in
experimental models (eg, antioxidants,
adenosine,96 97 98
KATP channel openers,99
Ca2+
antagonists,6 100 101 102 and
angiotensin-converting enzyme
inhibitors103 104 ) as preventive
measures against myocardial stunning in such clinical settings as acute
infarction with early revascularization, unstable
angina, bypass surgery, and cardiac transplantation. Agents that are
given during ischemia or at the time of reperfusion might
prevent stunning. Other agents (infusion of inotropes) may improve
function of the myocardium once it has been stunned; such
therapy may be temporary and lasts only as long as the inotrope is
infused. Inotropes given to myocardium that appears stunned
may worsen ischemia in other areas of the heart if reperfusion
or revascularization has not been complete.
Clinical Observations
Time Course of Recovery of Hibernating Myocardium
Nienaber et al117 observed improvements in left
ventricular function after PTCA. They studied the effect of
PTCA using PET scanning and two-dimensional
echocardiography before PTCA, within 72 hours of
revascularization, and late (67 to 68 days) after
PTCA. Early postangioplasty images showed improvements in regional
perfusion assessed by 13N-ammonia PET imaging.
This was not accompanied by an early improvement in wall motion.
However, segmental wall motion markedly improved on the late
echocardiogram. This study suggested that although hibernating
myocardium did recover function after
revascularization, such recovery was not
necessarily immediate. Baker et al123 described
the case of a patient who had evidence of hibernating
myocardium due to compression of the coronary
arteries by a ventricular pseudoaneurysm. Severe
left ventricular dysfunction was documented by both
radionuclide ventriculography and echocardiography.
Thallium tomography revealed a perfusion defect in the anterior and
anteroapical distribution of the left ventricle. After repair of the
pseudoaneurysm and relief of compression on the
coronary arteries, both regional and global function gradually
returned toward normal over a 10-week period. One year after repair,
thallium imaging showed normal perfusion and
echocardiography showed normal function.
Thus, the recovery time of hibernating myocardium after
revascularization has been variable. Immediate
recovery of function might indicate that hibernation was acute, slow
recovery over days to weeks might suggest subacute hibernation, and
very slow recovery (months to years) might suggest that the hibernation
was chronic.124 Recovery time could be dependent
on a number of factors, including duration of ischemia,
severity of ischemia, degree of
revascularization (complete versus partial), and
amount of myocyte dedifferentiation within the hibernating zone.
Recovery that occurs over days to weeks after
revascularization of a hibernating segment might
represent stunning. Recovery that occurs over a longer time
period might represent the regeneration of myofibrils and
repair of structural alterations that occurred during the chronic
hibernating phase.
Studies described above and many others123 124 125 126 127 128 129 130 131 132 133 134
support the concept of hibernating myocardium as originally
defined. However, one limitation of these clinical studies is that in
general they do not track reduced flow and reduced function in a
chronic manner, that is, at multiple time points before
revascularization. Usually, they describe an acute
"snapshot" view of the heart before
revascularization. The terms "chronic flow
reduction" and "chronic wall-motion abnormality" are often used
in the description of hibernation, but it is not clear whether the
wall-motion abnormalities and reductions of flow are truly chronic in
all cases. Also, several PET studies in patients with left
ventricular dysfunction observed relatively normal regional
coronary blood flow in hibernating
segments.135 136 137 138 Other groups have observed
normal oxidative metabolism in these regions, suggesting
that oxygen delivery to hibernating segments actually may be
normal.139 One area of active debate is whether
hibernating myocardium in patients truly is characterized
by reduced flow or normal flow with reduced coronary
vasodilator reserve. Some of this debate may be related to the wide
variation in what is reported as "normal" coronary flow in
humans.
Detecting Hibernating Myocardium
Other, more commonly available methods, notably thallium
redistribution scintigraphy and dobutamine
stress echocardiography, will probably turn out to
have similar predictive accuracies.144 145
Thallium redistribution scintigraphy relies on the
reasoning that coronary perfusion, although decreased, persists
in the hibernating region; furthermore, the hibernating cells maintain
membrane integrity and ion homeostasis so that they can accumulate the
thallium. Tissue that does not accumulate thallium even with prolonged
redistribution or after a secondary thallium infusion is not likely to
be viable.146 147
Dobutamine stress echocardiography
assesses the contractile function of various myocardial segments. A
region of the heart that functions poorly at baseline may not respond
to dobutamine infusion at all (in which case it is
nonviable) or may improve or worsen its contractility
with the pressor challenge. Myocardium whose function
improves with low-level dobutamine infusion but
deteriorates with high-level infusion can be expected to improve with
revascularization.148 149 If
this indeed reflects the prototypical response of hibernating
myocardium (as is commonly assumed), then hibernating
myocardium retains both viability and the ability to
respond to inotropic challenges.150 151
More invasive approaches (eg, tissue sampling) are impractical
clinically but yield additional clues as to the nature of the
adaptation. Human hibernating myocardium has a distinctive
histological appearance with myolysis, glycogen
accumulation, and increased interstitial fibrosis (Fig 3
Variable Chronicity of Hibernation
The Concept of Metabolic Adaptation
Canty161 pointed out that hibernating
myocardium was characterized by a downregulation of
regional myocardial oxygen consumption. He stated that "a key point
is that the presence of both reductions in regional resting flow and
oxygen consumption distinguish this adaptation from stunned
myocardium."161 162 163
Hibernation Versus Repetitive Stunning
Future Directions
Given these considerations, the members of the workshop recommended
that future effort be concentrated on two areas. The first is to
correct the deficiency of appropriate animal models for hibernating
myocardium. Although it is recognized that no single animal
model may be appropriate to address all of the questions relevant to
hibernation, desirable features of such models include the
following:
1. Validation of the model by generally accepted clinical criteria for
hibernating myocardium: PET verification of increased
glycolytic precursor uptake relative to blood flow, responsiveness to
dobutamine, verification of the characteristic
histological features, and demonstration of
reversibility with reflow.166
2. Exploration of the roles of multivessel disease and/or superimposed
atherosclerosis in hibernation. This recommendation
reflects the growing recognition that coronary
atherosclerosis may have functional consequences that
transcend those attributable solely to simple flow limitation.
3. Generation of appropriate small animal models of hibernation with
high reproducibility.
4. Development of cellular models of hibernation. Such models could be
used to investigate the pathogenesis of the
histological lesions, including dedifferentiation, and
of the metabolic adaptation, notably the switch from
aerobic to anaerobic metabolism.
The second area deemed worthy of further focused study was in the
clinical arena, in which several crucial issues regarding natural
history and treatment remain to be explored. The following questions
were highlighted as worthy subjects for future investigation:
1. What is the natural history of hibernating myocardium?
Clinical studies are needed that look at more than just a snapshot view
of perfusion and function at one time point before
revascularization. Regional function, regional
perfusion, and regional viability at multiple time points before
revascularization are necessary to answer the
question of whether segments of the ventricle truly hibernate as
originally conceptualized.
2. What are the most effective (and most cost-effective)
diagnostic and therapeutic strategies? Might medical
therapy be a viable alternative to mechanical
revascularization in some patients?
3. What is the relationship of hibernating myocardium to
heart failure?167 Does hibernating
myocardium commonly underlie ischemic
cardiomyopathy? How many segments of hibernating
myocardium must be revascularized to substantially improve
myocardial function?
4. Is there any benefit of revascularization of
hibernating myocardium independent of the functional
improvement?
There are certain limits to the benefits of preconditioning. The
protection afforded by brief episodes of ischemia is transient
and dissipates after 1 to 2 hours of reperfusion. In addition, if the
duration of prolonged ischemia is very long (>90 minutes in
some models), then the benefits of preconditioning are
lost.170 Of note is the observation that in some
studies using rabbits, dogs, and rats, the benefits of preconditioning
reappear when the interval between preconditioning ischemia and
the prolonged ischemic episode is extended to 24 to 72
hours.171 172 173 174 A signature of preconditioned
myocardium in the canine model is slowed ATP depletion and
lactate accumulation during the sustained episode of
ischemia.175 This characteristic of
slowed energy utilization by preconditioned tissue may be related to
the mechanism whereby ischemic preconditioning delays cell
death. Murry et al175 pointed out that
preconditioned tissue also exhibits a high creatine phosphate
concentration, more intracellular glucose, less glycogen, and a smaller
adenine nucleotide pool, contains more K+, and is somewhat
edematous.
Although the definition of ischemic preconditioning was
initially used to describe reduction in myocardial necrosis by brief
episodes of preceding ischemia, the definition was extended to
include protection against
arrhythmias176 177 and
postischemic left ventricular dysfunction
(stunning).178 179 However, the efficacy of
ischemic preconditioning in reducing arrhythmias and
stunning has not been as consistent as its ability to reduce
necrosis. Furthermore, it is unknown whether the protection afforded by
preconditioning against arrhythmia and stunning is mediated by
the same mechanism that mediates its protection against lethal cell
injury.180 181
Another term that has appeared in the literature related to
preconditioning is "pharmacological
preconditioning."182 183 This term refers to
the ability of pharmacological agents given before coronary
occlusion to reduce myocardial infarct size by stimulating the second
messenger pathways thought to be involved in preconditioning, but
without inducing ischemia. Examples of pharmacological
preconditioning include administration of adenosine
A1 agonists and KATP
channel openers. These agents have also been referred to as
"preconditioning mimetics."169
Mechanism of Preconditioning
Role of Protein Kinase C
A schematic of the cell signaling pathways followed during
preconditioning is shown in Fig 4
Similar findings were observed in a model of isolated rabbit
cardiomyocytes developed by Armstrong et
al.195 196 They assessed myocyte injury as the
rate of development of osmotic fragility during prolonged
ischemic pelleting of cells incubated under oil. Protection of
the cells was induced, after a brief ischemic
preincubation,195 196 by adenosine,
adenosine receptor agonists, bradykinin,
angiotensin, and phenylephrine. Protection also
occurred when the cells were preincubated with the phorbol ester PMA
and the PKC activator ingenol. In addition,
adenosine receptor antagonists, adenosine
deaminase, and selective PKC inhibitors blocked the benefit
of ischemic preconditioning.
Other Cellular Mediators
There is, however, controversy regarding virtually all aspects of the
proposed cellular mediators of preconditioning downstream from the
initial stimulation of G proteincoupled receptors. For example,
Przyklenk et al199 200 concluded that activation
of 5'-nucleotidase is not required to elicit cardioprotection, whereas
Ovize and colleagues201 reported that
pharmacological inhibition of tyrosine kinase limited infarct size in
control myocardium but failed to block the protective
effects of preconditioning. Similarly, Shipolini et
al202 failed to confirm the concept that
Na+-H+ exchange might play
a role in preconditioning-induced protection.
Arguments For and Against the Role of PKC
Although these observations in the canine and porcine models argue
against the role of PKC in ischemic preconditioning,
interpretation of both pharmacological and biochemical results may be
confounded by limitations in methodology; ie, few PKC
inhibitors are selective for PKC alone, and if only one of
the 12 isoenzymes of PKC identified to date is important in eliciting
protection, measurement of total PKC activity may not reflect the
subtle alterations in the subcellular distribution of the one crucial
isoenzyme. It is even possible that unidentified receptors may exist in
dog or pig that enter the signal transduction pathway downstream of
PKC, bypassing it. Quantitative assessment of the activity and
distribution of PKC isoenzymes in response to both pharmacological
manipulation and ischemic preconditioning per se may be
required to resolve this controversy conclusively. In this regard,
recent studies have documented isoform-selective translocation of PKC
in response to preconditioning stimuli,206 207 208
in some instances with no change in total PKC
activity.206 Isoform-selective translocation of
PKC-
Another emerging concept that may be relevant to the mechanism of
ischemic preconditioning is that protein phosphatase inhibition
appears to protect isolated rabbit cardiomyocytes even when
added late in the prolonged ischemic
phase.210
Role of Potassium Channels
However, not all studies have implicated KATP
channels in preconditioning. Some studies in rabbit hearts, isolated
rabbit cardiomyocytes, and rats have not confirmed the
importance of KATP channels in
preconditioning.215 216 217 A recent
study218 suggested that the
KATP channel blocker glibenclamide, which is
often used in these models, must be administered well before the
coronary occlusion to block the effect of preconditioning.
Although an initial hypothesis was that stimulation of
KATP channels might work by shortening the action
potential duration and slowing the utilization of ATP, not all studies
have documented a shortening of the action potential, and the
mitochondrial KATP channels possibly play a
role.
The exact final effector mechanisms of preconditioning remain to be
elucidated. We do not know what factors exactly explain the resistance
to ischemia after preconditioning ischemia. The slowed
rate of ATP fall observed in preconditioned tissue could be a
consequence rather than a mechanism of preconditioning. If it is a
mechanism, why is it transient, only lasting for 10 to 20 minutes
during ischemia? It remains to be determined whether the
protection is due to preservation of energy stores. Alternatively, the
brief episodes of ischemia might limit production of
oxidants during a subsequent long ischemia, resulting in
protection of membranes. Considerable work is needed to better define
the end-effector mechanism of ischemic preconditioning.
Second Window
Stunning Versus Preconditioning
Therefore, although brief periods of ischemia induce both
stunning and preconditioning, the two phenomena can be dissociated, and
preconditioning is not due to simply reduced contractile function of
stunned myocardium.
Clinical Evidence for Preconditioning
Repeated coronary artery occlusions in the course of PTCA may
simulate the preconditioning phenomenon. Several clinical studies have
observed progressive decreases in chest pain, ST-segment elevation, and
lactate production on subsequent compared with first 60- to
90-second intracoronary balloon
inflation.239 240 The potassium channel blocker
glibenclamide can prevent the beneficial effects of repeated balloon
angioplasty. Adenosine can mimic the protective
effect,241 whereas adenosine
antagonists block it,242 243 findings
that parallel experimental observations in the animal laboratory. Some
studies that assessed collateral flow showed no evidence of recruitment
during sequential balloon inflations,239 although
one study240 did report that in about half of the
patients, there was recruitment.
A number of clinical studies have shown that preinfarct angina may
confer benefit in acute myocardial infarction, including smaller
infarct size assessed by enzymes or ECG, better in-hospital survival,
less in-hospital heart failure and shock, better left
ventricular function, and lower rate of
arrhythmia.244 245 246 In the recent TIMI 9
trial,247 preinfarction angina reduced the
combined end point of 30-day mortality, heart failure, and recurrent
myocardial infarction, but only when the preinfarct angina occurred
within 24 hours of infarction. Ishihara et al248
showed that patients with prodromal angina within 24 hours of
infarction had an improved 5-year survival. Although ischemic
preconditioning is one potential mechanism whereby preinfarct angina
confers benefits to infarct patients, other potential mechanisms
include earlier and more complete thrombolysis, which
has been observed in one study249 and may imply a
preconditioning-like effect on the vasculature, and the development of
intramural collaterals that are not detected by coronary
angiography.
Patients with coronary artery disease have been observed to
exercise longer before developing angina and may develop less angina
and ischemia during a second exercise test compared with a
first test when these tests are separated by a brief rest
period.250 251 The clinical observation of the
"warm-up" phenomenon may represent one aspect of
preconditioning in humans.
Mentzer252 and colleagues have applied the
pharmacological preconditioning concept to patients undergoing open
heart surgery. Placebo and various doses of adenosine (100
µmol/L, 1 mmol/L, 2 mmol/L, and a 2 mmol/L plus a
6-minute 140 µg · kg-1 ·
min-1 pretreatment infusion) were administered
to patients before cardiopulmonary bypass. Patients were
hemodynamically monitored before, during, and after
dosing, before being placed on cardiopulmonary bypass, after
weaning from bypass, and then for 24 hours.
Transesophageal echocardiography
was performed before bypass, after bypass, and during the postoperative
stay. The results showed that adenosine was safe and well
tolerated in the doses used. The patients receiving high-dose
adenosine required significantly less or no vasoactive drugs
during the first 24 hours after heart surgery and had improved average
regional wall motion by echocardiography. This is
one of the first trials to apply pharmacological preconditioning
directly to humans to try to improve outcomes. There have been
anecdotal reports of actually inducing ischemic preconditioning
(by transiently clamping a coronary artery and then
reperfusing) before minimally invasive directed coronary artery
bypass.
Future Directions
Mechanism of Preconditioning
1. There is a need to develop models allowing assessment of
intracellular signaling pathways in preconditioning and determination
of the final effector(s). These models will require multidisciplinary
approaches and should be designed to help resolve the roles of
suggested signaling pathways, including but not limited to PKC,
5'-nucleotidase, adenosine A3 receptors,
and KATP channels. Small-animal models (ie,
rabbit) may rely on PKC-dependent signaling, whereas large animals
(dog, pig) may rely on KATP and other mechanisms
that may be independent of PKC.
2. There is a need to clarify the mechanism of the second window (or
late phase) of ischemic preconditioning. Very little is known
regarding the mechanism of the second window.
3. Because it is unknown which mechanisms are most important in humans,
it would be prudent to include whole animal models of both small and
large animals. Isolated myocyte models in humans and in large and small
animals should also be developed.
Biology of Preconditioning
1. Ascertain whether metabolic changes (such as slower
rate of ATP degradation and attenuation of acidosis) and improvement in
cell volume regulation are mere markers of preconditioning or are
necessary for protection.
2. Determine whether preconditioning is effective or altered in aged
and diseased hearts.
3. Establish the long-term consequences of preconditioning on left
ventricular remodeling, infarct expansion, and
survival.
4. Elucidate the properties of the "second window of protection,"
particularly in large-animal models.
5. Determine whether preconditioning exerts a beneficial effect on
arrhythmias and the vasculature, including the recent concept
that a preconditioned vessel may be more amenable to
thrombolysis.
Clinical Studies of Preconditioning
*Participated in workshop; elected not to participate in preparation of
manuscript.
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241.
Leesar MA, Stoddard M, Ahmed M, Broadbent J, Bolli R.
Preconditioning of human myocardium with adenosine
during coronary angioplasty. Circulation. 1997;95:25002507.
242.
Tomai F, Crea F, Gaspardone A, Versaci F, De Paulis R,
Polisca P, Chiariello L, Gioffre PA. Effects of
A1 adenosine receptor blockade by
bamiphylline on ischaemic preconditioning during coronary
angioplasty. Eur Heart J. 1996;17:846853.
243.
Claeys MJ, Vrints CJ, Bosmans JM, Concraads VM, Snoeck
JP. Aminophylline inhibits adaptation to ischemia during
angioplasty: role of adenosine in ischaemic preconditioning.
Eur Heart J. 1996;17:539544.
244.
Kloner RA, Shook T, Przyklenk K, Davis VG, Junio L,
Matthews RV, Burstein S, Gibson M, Poole WK, Cannon CP, McCabe C,
Braunwald E, for TIMI Investigators. Previous angina alters in-hospital
outcome in TIMI 4: a clinical correlate to preconditioning?
Circulation. 1995;91:3747.
245.
Ottani F, Galvani M, Ferrini D, Sorbello F, Limonetti
P, Pantoli D, Rusticali F. Prodromal angina limits infarct size: a role
for ischemic preconditioning. Circulation. 1995;21:291297.
246.
Anzai T, Yoshikawa T, Asakura Y, Abe S, Meguno T,
Akaishi M, Mitamura H, Handa S, Ogawa S. Effect on short-term prognosis
and left ventricular function of angina pectoris prior to
first Q-wave anterior wall acute myocardial infarction. Am J
Cardiol. 1994;74:755759.[Medline]
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Kloner RA, Shook T, Antman EM, Cannon CP, Przyklenk K,
McCabe CH, Braunwald E, TIMI 9 Investigators. A prospective
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© 1998 American Heart Association, Inc.
Special Reports
Medical and Cellular Implications of Stunning, Hibernation, and Preconditioning
An NHLBI Workshop
Key Words: stunning, myocardial hibernation preconditioning ischemia infarction
![]()
Introduction
Top
Introduction
Myocardial Stunning
Hibernating Myocardium
Preconditioning
Summary
Appendix
References
On July 23, 1996,
the National Heart, Lung, and Blood Institute sponsored a workshop in
Columbia, Md, entitled "The Medical and Cellular Implications of
Myocardial Stunning, Hibernation, and Preconditioning." The goals of
this workshop were to identify and discuss the areas of agreement and
controversy regarding these important phenomena and in particular to
identify areas of future research for each. One aspect of these goals
included determination of the mechanisms of these phenomena. Stunning
is a form of prolonged contractile dysfunction that occurs after relief
of a discrete episode or episodes of ischemia; hibernation is a
form of prolonged contractile dysfunction associated with ongoing low
blood flow, although controversy exists as to whether absolute blood
flow or coronary reserve is reduced and whether it may
represent repetitive bouts of stunning. Preconditioning is a
cardioprotective mechanism in which the heart is exposed to a
controlled, short period of sublethal ischemia that attenuates
cellular damage from a subsequent prolonged lethal episode of
ischemia. Research efforts have not yet provided a clear
understanding of all aspects of these conditions. The workshop
presented the current state of both basic science knowledge and
clinical knowledge of these disorders, promoted discussions between
basic and clinical scientists, and identified likely mechanisms and new
directions for research.
![]()
Myocardial Stunning
Top
Introduction
Myocardial Stunning
Hibernating Myocardium
Preconditioning
Summary
Appendix
References
The Protean Nature of Myocardial Stunning
Myocardial stunning is a general term that describes the
mechanical dysfunction that persists after reperfusion despite the
absence of irreversible damage and despite return of normal or
near-normal perfusion.1 2 This phenomenon was
first described by Heyndrickx et al3 in 1975 in
conscious dogs undergoing brief coronary occlusions. One of the
major problems in formulating a unifying
pathophysiological and pathogenetic paradigm for
myocardial stunning is that this phenomenon occurs in a wide variety of
settings that differ from one another in several major
respects.2 Indeed, myocardial stunning might be
regarded not as a single entity but instead as a phenomenon. At the
experimental level, the available observations can be grouped into six
categories2 : (1) stunning after a single,
completely reversible episode of regional ischemia in vivo (eg,
a coronary occlusion <20 minutes in the dog), as originally
described by Heyndrickx et al3 4 5 6 ; (2) stunning
after multiple, completely reversible episodes of regional
ischemia in vivo (eg, repeated 5- or 10-minute coronary
occlusions in the dog)7 8 9 10 11 ; (3) stunning after a
partly reversible (no necrosis) plus partly irreversible (some areas of
necrosis) episode of regional ischemia in vivo (eg, a
coronary occlusion >20 minutes but <3 hours in the
dog)12 13 (this category may be relevant to
patients who receive thrombolysis or angioplasty for
acute myocardial infarction and then demonstrate delayed recovery of
function of the salvaged tissue); (4) stunning after global
ischemia in vitro (isolated heart
preparations)14 15 16 17 18 19 ; (5) stunning after global
ischemia in vivo (cardioplegic
arrest)20 21 22 23 ; and (6) stunning after
exercise-induced ischemia (high-flow
ischemia).24 25 26 Because of the
heterogeneity of these settings, it is possible that
findings developed in one setting may not be applicable to
another.2 Thus, an important, unresolved issue is
whether all forms of stunning share a common pathogenesis.
Myocardial stunning is probably a multifactorial process that
involves complex sequences of cellular perturbations and the
interaction of multiple pathogenetic mechanisms.2
The most plausible hypotheses regarding the pathogenesis of myocardial
stunning are the oxyradical hypothesis and the calcium hypothesis. The
oxyradical hypothesis postulates that stunning is caused by oxidant
stress secondary to the generation of ROS.2 27 In
a very broad sense, the calcium hypothesis postulates that stunning is
the result of a disturbance of cellular calcium
homeostasis.2 28 29 As pointed out
previously,2 these theories are not mutually
exclusive and probably represent different facets of the same
pathophysiological process. A unifying hypothesis
for the pathogenesis of myocardial stunning is proposed in Fig 1A
.

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Figure 1. A, Illustration of the proposed pathogenesis of
postischemic myocardial dysfunction. This proposal
integrates and reconciles different mechanisms into a unifying
pathogenetic hypothesis. Transient reversible ischemia followed
by reperfusion could result in increased production of
superoxide radicals ( ·O2-) through
several mechanisms, including the following: (1) increased activity of
xanthine oxides; (2) activation of neutrophils; (3) activation of the
arachidonate cascade; (4) accumulation of reducing
equivalents during oxygen deprivation; (5) derangements of
the mitochondrial electron transport system resulting in increased
univalent reduction of oxygen; and (6) autoxidation of
catecholamines and other substances. Superoxide dismutase
(SOD) dismutates ·O2- to hydrogen
peroxide (H2O2); in the presence of catalytic
iron, ·O2- and
H2O2 interact in a Haber-Weiss reaction to
generate the hydroxyl radical (·OH).
H2O2 can also generate ·OH in the
absence of ·O2- through a Fenton
reaction provided that other substances (such as ascorbate) reduce Fe
(III) to Fe (II). ·O2- and ·OH attack
proteins and polyunsaturated fatty acids, causing enzyme inactivation
and lipid peroxidation, respectively. In the setting of reversible
ischemia, the intensity of this damage is not sufficient to
cause cell death but is sufficient to produce dysfunction of key
cellular organelles. Postulated targets of free radical damage include
the following: (1) the sarcolemma, with consequent loss of selective
permeability, impairment of calcium-stimulated ATPase activity and
calcium transport out of the cell, and impairment of the
Na+-K+-ATPase activity; the net result of these
perturbations would be increased transsarcolemmal calcium influx and
cellular calcium overload; (2) the sarcoplasmic reticulum, with
consequent impairment of calcium-stimulated ATPase activity and calcium
transport; this would result in decreased calcium sequestration (which
would contribute to increase free cytosolic calcium) and decreased
calcium release during systole (which would cause
excitation-contraction uncoupling); and (3) other structures, such as
the extracellular collagen matrix (with consequent loss of mechanical
coupling) or the contractile proteins (with consequent decreased
responsiveness to calcium); for example, free radicals could oxidize
thiol groups in myofilaments, causing impaired Ca2+
sensitivity. At the same time, reversible ischemia/reperfusion
could cause cellular Na+ overload due to (1) inhibition of
sarcolemmal Na+-K+-ATPase and (2) acidosis and
Na+-H+ exchange. This could further exaggerate
calcium overload via increased Na+-Ca2+
exchange. An increase in free cytosolic calcium would activate
protein kinases, phospholipases, and other degradative enzymes and
further exacerbate the injury to the aforementioned key subcellular
structures (sarcolemma, sarcoplasmic reticulum, and contractile
proteins). Thus, calcium overload could serve to amplify the damage
initiated by oxygen radicals. In addition, calcium overload could in
itself impair contractile performance and contribute to
mechanical dysfunction. It is also possible that the increase in free
cytosolic calcium could increase oxyradical production by
promoting the conversion of xanthine dehydrogenase to xanthine oxidase.
The ultimate consequence of this complex series of perturbations is a
reversible depression of contractility. Reproduced with
permission of the American Heart Association from Bolli
(Circulation. 1990;82:723738). B, Possible components
of postischemic dysfunction. Myocardial stunning probably
arises from the additive effects of a reperfusion-induced pathology
(identified, as least in part, by the fraction [dark shading] of the
contractile deficit, which can be restored through the use of an
antioxidant intervention given transiently at the time of reperfusion)
and a second component (light shading), which incorporates the
ischemic pathology from which the heart is slowly recovering,
together with any additional reperfusion-induced component that is not
amenable to the chosen intervention. Reproduced with permission, Hearse
DG. Stunning: a radical review. In: Opie LH, ed. Stunning,
Hibernation, and Calcium in Myocardial Ischemia and Reperfusion.
Boston, Mass: Kluwer Academic Press; 1992:1055.
It is now generally accepted that ROS play an important role in
the pathogenesis of myocardial stunning in the following experimental
settings (as reviewed in Reference 2727 ): (1) after a single, completely
reversible episode of regional ischemia in
vivo30 31 32 ; (2) after multiple, completely
reversible episodes of regional ischemia in
vivo9 33 ; (3) after global ischemia in
vitro18 19 34 35 36 ; and (4) after global
ischemia in vivo.20 21 22 23 For example, in
the first setting (coronary occlusion <20 minutes),
alleviation of stunning by antioxidant therapies has been reproducibly
observed by several independent laboratories in a variety of animal
models and species.37 Similar protective effects
of antioxidants have subsequently been demonstrated in conscious
animals.33 38 39 At the time of this writing, at
least 22 full-length articles have been published that have examined
the effect of antioxidants on myocardial stunning after a 15-minute
coronary occlusion; all of these articles (except those that
used superoxide dismutase alone40 41 42 or catalase
alone40 ) have reported a protective effect of
antioxidants against stunning.37 Furthermore,
generation of ROS in stunned myocardium has been
demonstrated directly by both spin
trapping9 39 43 44 45 46 47 and aromatic
hydroxylation48 techniques, and attenuation of
ROS generation has repeatedly been shown to result in attenuation of
contractile dysfunction.9 39 43 45 46 A role of
ROS in the genesis of myocardial stunning can now be regarded as a
proven hypothesis. Nevertheless, it remains unclear whether ROS play a
role in all settings of stunning. There is presently no evidence
that they contribute to exercise-induced postischemic
dysfunction.49 Data regarding the effects of
antioxidants on myocardial stunning after a prolonged (>20 but <180
minutes) ischemic insult, causing some subendocardial
infarction and adjacent areas of stunning, are conflicting (reviewed in
Reference 3737 ); thus, the role of ROS in this setting is uncertain.
).27 50 Judging
from the effects of antioxidants, the reperfusion injury component
appears to be larger than the ischemic injury
component.27
), but two points are
clear: (1) neutrophils do not contribute to stunning after
reversible ischemia in vivo,51 52 and (2)
xanthine oxidase is not necessary for ROS to be generated in sufficient
quantities to induce stunning, because ROS also participate in the
genesis of postischemic dysfunction in xanthine
oxidasedeficient species.33 42 53 The exact
mechanism whereby ROS depress contractile function remains to be
determined (Fig 1A
). The number of potential molecular targets is vast
because ROS can attack nonspecifically virtually all cellular
components. ROS have been shown to interfere with a number of ion
transport mechanisms in the sarcolemma, including
Ca2+ ATPase,54 55
Na+-K+ATPase,56
and the Na+-Ca2+
exchanger,57 that would result in increased
transsarcolemmal Ca2+ influx and cellular
Ca2+ overload. Transient exposure to ROS has also
been found to decrease the responsiveness of myofilaments to
Ca2+58 and to impair the function of sarcoplasmic
reticulum.59 Investigation of the manner in which
ROS perturb Ca2+ homeostasis and/or
Ca2+ responsiveness is important not only because
it should elucidate the pathogenesis of stunning but also because it
may reconcile the oxyradical and Ca2+ hypotheses
of stunning into one pathogenic mechanism (Fig 1A
).
In the setting of global ischemia in vitro, myocardial
stunning is not caused by decreased availability of
activator Ca2+. Measurements of free
cytosolic [Ca2+] (using gated NMR, aequorin, or
fura 2) in this setting have shown the Ca2+
transients to be normal or even increased in stunned
myocardium.15 60 61 Although
Ca2+ transport has been found to be impaired in
sarcoplasmic reticulum isolated from an in vivo model of stunned
myocardium,62 no data are available
regarding Ca2+ transients in stunned
myocardium in vivo because there is currently no technique
that enables measurements of free cytosolic
[Ca2+] in this situation.
On the other hand, there is considerable evidence that a transient
Ca2+ overload during the early phase of
reperfusion contributes to the pathogenesis of myocardial stunning
after global ischemia in vitro14 17 28 60
(Fig 1A
). Indirect evidence indicates that Ca2+
overload also contributes to postischemic dysfunction after
regional ischemia in vivo,63 but direct
demonstration of this concept is still lacking. The mechanism whereby
Ca2+ overload causes contractile dysfunction
remains unknown.
Studies in models of stunning after global ischemia in
vitro14 15 and in ventricular
trabeculae isolated from these
models61 have concluded that the alteration
responsible for the contractile dysfunction consists of a decrease both
in the maximal Ca2+-activated force and
the sensitivity of myofilaments to Ca2+. A
decrease in Ca2+ sensitivity of myofilaments has
not been observed consistently in all models of global
ischemia in vitro, however.60 Studies in
single myocytes obtained from a porcine model of myocardial stunning
caused by reversible ischemia in vivo have demonstrated that
the Ca2+ sensitivity of tension was markedly
decreased with no resolvable change in maximal
tension.64 Interestingly, this decrease in
Ca2+ sensitivity occurs after reperfusion, not
during ischemia, further supporting the notion that stunned
myocardium is a manifestation of reperfusion
injury.65 This decrease in
Ca2+ sensitivity of tension appears to be due at
least in part to alterations in the cardiac troponin regulatory
complex.66 The loss of Ca2+
sensitivity, however, is not a universal feature of stunned
myocardium in this porcine model, because it was observed
after a severe ischemic insult but not after milder
insults.67 Nevertheless, cells from such
"mildly" ischemic regions do display abnormally slow
cross-bridge cycling, indicative of myofilament
injury.67
It appears that one of the lesions responsible for myocardial
stunning after global ischemia in vitro and regional reversible
ischemia in vivo is an alteration of the contractile proteins
resulting in decreased responsiveness of the contractile machinery to
Ca2+ (Fig 1A
), so that for any given
Ca2+ transient, the myocardium
generates less force. In this sense, myocardial stunning could be
viewed as a disturbance of myofilament function. However, it is
not yet clear whether or not myofilament alterations are a general
feature of all forms of stunning.
).
A major unresolved issue that has important
pathophysiological and clinical implications is
whether repetitive episodes of myocardial stunning can account for at
least some of the clinical manifestations of so-called myocardial
hibernation (ie, the syndrome of reversible ventricular
dysfunction thought to be secondary to a primary deficit of
coronary flow and initially referred to as "chronic
stunning").1 Animal studies have shown that
repeated brief bouts of ischemia have a cumulative effect on
contractility, such that the duration and severity of
myocardial stunning greatly exceed those induced by a single
ischemic episode.7 9 25 33 72 73 If
regional perfusion is not measured simultaneously with
regional contractile function, the protracted but ultimately reversible
dysfunction associated with repetitive stunning may mimic myocardial
hibernation.74 With repetitive stunning, regional
perfusion should recover while function remains depressed. With
hibernation, as originally conceived, regional perfusion should be
depressed and function should be depressed. Clinically, it is well
known that many patients with coronary artery disease
experience recurrent episodes of ischemia in the same
territory, which may occur on a daily basis, so that the
myocardium may remain reversibly depressed for extended
periods of time. It is therefore possible that in some clinical cases
in which reversible left ventricular dysfunction is thought
to be secondary to hibernation, the depression of
contractility is in fact secondary to repetitive
episodes of stunning.74
In response to brief ischemia, myocardium from
senescent animals is more susceptible to myocardial stunning and
Ca2+ overload than that of young
animals.75 76 The mechanism for this increased
sensitivity to stunning and impaired ability to maintain
Ca2+ homeostasis is uncertain and may be related
to the accumulation of Ca2+ in the cytosol and
nucleus, resulting in DNA nicking associated with endonuclease
activation.77 Whether these changes impair the
synthesis of new contractile proteins to repair damaged myofilaments
during the recovery phase of stunning is unknown and requires further
investigation.
Myocardial stunning undoubtedly occurs in patients with
coronary artery disease in a variety of situations in which the
myocardium is exposed to transient ischemia, such
as unstable angina, exercise-induced ischemia, acute myocardial
infarction with early reperfusion, open heart surgery, and cardiac
transplantation (as reviewed in References 74 and 7874 78 80).
The members of the workshop identified a number of crucial areas
for future investigation that can be grouped into two broad categories:
experimental studies and clinical studies.
There is a need to integrate further the oxyradical and calcium
hypotheses of myocardial stunning and also to augment understanding of
the long-term consequences of brief ischemic episodes that
cause stunning. Therefore, in experimental models, it will be important
to accomplish the following:
There is a need to transfer experimental concepts to the clinical
setting. Therefore, in human studies it will be important to accomplish
the following:
![]()
Hibernating Myocardium
Top
Introduction
Myocardial Stunning
Hibernating Myocardium
Preconditioning
Summary
Appendix
References
The Concept of Hibernation
There is a subset of patients in whom left ventricular
function improves significantly after coronary
revascularization
procedures.105 106 Such improvement can occur
even in patients with chronic stable angina in whom there was no
evidence of active ischemia at the time of
revascularization. The functional improvement
cannot simply be due to prevention of ongoing necrosis. These clinical
observations have led to the concept that myocardium may
adapt to chronic ischemia by decreasing its
contractility, matching the reduced perfusion with
reduced energy demand and thereby preserving viability (Fig 2A
). If the ischemia is relieved,
the myocardium regains normal
contractility. From the earliest days of
coronary artery bypass grafting, it was reported that impaired
ventricular function was improved by
operation.107 108 In l974, in studies at Brigham
and Women's Hospital, Horn et al109 pointed out
that in patients with coronary artery disease and chronic
asynergy, epinephrine infusion improved impaired regional wall
motion. Postextrasystolic
potentiation110 and
exercise111 also induced increases in
contractility. Diamond et al112
stated in 1978 that "reports of sometimes dramatic improvement
in segmental left ventricular function following
coronary bypass surgery, although not universal, leaves the
clear implication that ischemic noninfarcted
myocardium can exist in a state of function(al)
hibernation." Rahimtoola105 106 aptly referred
to hibernating myocardium as the persistently impaired
function of viable myocardium in the setting of reduced
coronary blood flow. In clinical studies, he observed
progressive improvement in left ventricular wall-motion
abnormalities after coronary artery bypass grafting in the
absence of transmural necrosis. The concept of hibernating
myocardium113 114 115 has stimulated
extensive clinical and basic investigation.

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Figure 2. Schematic showing two potential routes of
hibernation.
There are numerous clinical studies that support the concept of
hibernating myocardium. These studies show that left
ventricular wall-motion abnormalities in patients with
chronic angina were reversed by successful
revascularization.107 108 116 117 118
In a classic case report, Rahimtoola105 reported
a patient with single-vessel coronary artery disease (occluded
left anterior descending artery) who had a left ventricular
ejection fraction of 37% and a large anteroapical region of akinesis
on ventriculography. There had been no history of myocardial
infarction. After administration of nitroglycerin, the
regional wall-motion abnormality improved substantially. Eight months
after coronary artery bypass surgery, the vein graft was
patent, the regional wall-motion abnormality had fully resolved, and
the ejection fraction had risen to 76%. Rankin et
al119 showed that 34% of patients with chronic
stable angina had improvement in left ventricular function
after coronary artery bypass surgery. From 7 to 14 days after
operation, there was an increase in global ejection fraction from 53%
to 71%. Tillisch et al120 showed with PET that
they could identify areas of reduced perfusion that were
metabolically active. After surgical
revascularization, the majority of these segments
recovered function. Cohen et al121 identified 12
patients with severe wall-motion abnormalities who had evidence of
reversible ischemia and had improvements in global as well as
regional wall motion immediately after PTCA.
The time course of recovery of hibernating myocardium
after revascularization has been variable. One
study by Topol et al122 described nearly
immediate improvement in regional wall-motion abnormalities after
coronary artery bypass surgery. They used
transesophageal echocardiography at
the time of cardiac surgery to track changes in left
ventricular function. Of 152 analyzed segments,
there was an immediate improvement in systolic wall thickening
from a prerevascularization value of 43% to a
value of 52% (P<.001) after
revascularization. As noted above, Cohen et
al121 also observed immediate recovery of
function after PTCA.
Clinical experience has led to acceptance of the idea that
hibernation is not only a "real" phenomenon but that it is also of
compelling practical significance, at least in a subset of patients
with critical coronary lesions. Much effort has gone into
developing strategies to assess myocardial viability with a view to
identifying those patients who are most likely to benefit from
aggressive
revascularization.140 PET has
led the way in this regard and has provided insight into the
pathophysiology of the adaptation.141 142 In some
studies, hibernating myocardium exhibits a characteristic
switch from aerobic to anaerobic metabolism, as
gauged by enhanced fluorodeoxyglucose uptake in the face of reduced
blood flow detected by PET. Such myocardial segments tend to recover
function after
revascularization.143
).134 152 153 154 It
has been suggested that these histopathological changes may
represent a dedifferentiation of the
myocytes.153 When advanced, such changes indicate
a poor prognosis for recovery even with adequate
revascularization.154

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Figure 3. Light and electron microscopy of chronic
hibernating myocardium. a and b, Light micrographs of
moderately (a) and severely (b) altered myocardial areas. Red stain
represents glycogen, which fills the myolytic cytosol. Note the
more abundant glycogen stores in the severely affected cells and the
accompanying increase in extracellular space (ES) in b. (Magnification
x675.) c and d, Corresponding electron micrographs showing detailed
structural remodeling in a moderately (c) and a severely (d) myolytic
cardiomyocyte (CM). Glycogen (gl) is abundant; sarcomeres
(sm) are present at the cell periphery; mitochondria (m) vary in
size and shape (some are very small; arrows); the heterochromatin is
uniformly distributed in the nucleus (n); and sarcoplasmic reticulum is
virtually absent. These are characteristics of dedifferentiation. (a,
magnification x8.820; b, x7.650.) Reproduced with permission from M.
Borgers, Janssen Research Foundation, Beerse, Belgium.
The original clinical descriptions of hibernating
myocardium were based on the long-term recovery of function
after revascularization (assessed several weeks or
months after coronary artery bypass
grafting).105 106 More recently, the variable
chronicity of hibernation has been
highlighted,117 122 leading to the hypothesis
that the longer the ischemia, the slower the subsequent
recovery.155 Virtually all the animal models of
hibernation have investigated the myocardial response to acute,
low-grade ischemia,105 156 157 a
situation that may or may not have common clinical correlates. The
observation period is limited to several hours or days at most. In such
models, there is a downregulation of contractile function roughly
commensurate with the decrease in flow. Stunning generally ensues on
the relief of the ischemia, complicating the interpretation of
the recovery time course.158 Such acute
compensation to low-grade ischemia is not universally observed
and, when it does occur, appears to be operative over a very limited
perfusion range.105 Nevertheless, the
pathophysiology of such acute low-flow ischemia is
consistent with the teleological notion that hibernating
myocardium can downregulate its function (and thus its
energy demand) so as to offset the otherwise lethal consequences of
limited perfusion (Fig 2A
).
There is debate as to whether the hibernating
myocardium is truly ischemic or not. Some of this
debate hinges on the definition of ischemia itself. If one
defines the abnormality of contractility as a crucial
component of the definition of ischemia, then hibernating
tissue would be considered by some to be truly ischemic.
However, if one defines ischemia as a reduction in blood flow
severe enough to induce anaerobic metabolism,
then hibernating tissue may not be truly ischemic, because
there is evidence that hibernating myocardium has undergone
a metabolic adaptation. Examples supporting the
metabolic adaptation or metabolic
"downregulation" theory of hibernating myocardium come
from experimental studies. Animal models of short-term hibernation have
shown that after placement of a partial coronary artery
stenosis, there is a decrease in contractile function that
correlates with a reduction in flow.156 157 159
Myocardial creatine phosphate content decreases during the first few
minutes of ischemia induced by partial occlusion but then
returns toward normal within 60 to 85
minutes.157 159 Fedele et
al160 showed that within 5 minutes after
placement of a partial stenosis in an animal model of acute
hibernation (in which necrosis did not occur), there was a significant
reduction in anterior interventricular vein pH. However, by
180 minutes after stenosis placement, the pH had recovered to
normal. In the same study, lactate consumption reversed to lactate
production at 5 minutes after stenosis but then
recovered toward lactate consumption by 120 minutes after
stenosis. Thus, in the setting of ongoing hypoperfusion and
contractile dysfunction, the myocardium remained viable and
no longer appeared to be metabolically
anaerobic. These experimental findings differ somewhat from
PET studies in humans, which in some cases have shown increased
fluorodeoxyglucose uptake in decreased zones of perfusion, suggesting
continued anaerobic metabolism.
Longer-term models of coronary stenosis have
yielded results that suggest a fundamentally different mechanism for
hibernation.73 The central concept here is as
follows: chronic coronary artery stenosis acts
primarily to limit coronary reserve, not to decrease resting
blood flow.136 Episodes of spontaneous excitement
and exercise then lead to repetitive cycles of ischemia
precipitated by increased demand in the setting of limited flow
reserve. When the ischemia is relieved, the
myocardium remains dysfunctional despite having normal
basal perfusion; essentially, it is chronically
stunned.164 165 These observations have led to
the proposal that hibernation is the result of repetitive cycles of
ischemia and reperfusion (Fig 2B
). In this view, cumulative
stunning, not downregulation of function to counter chronic low-grade
ischemia, leads to the distinctive phenotype of
hibernating myocardium.73 149 There
was considerable discussion related to this area at the workshop, and
there were differences of opinion. Some investigators pointed out that
there are a wealth of clinical examples and series of patients in which
there is evidence of reduced blood flow at rest associated with
regional dysfunction, both of which improve after
revascularization. It is possible that there are
subsets of patients who exhibit true hibernating (with reduced flow),
some who exhibit repetitive stunning, and possibly some who exhibit
both.74 145 This is clearly an area that will
require additional research.
The basic biology of hibernation is less understood than either of
the other conditions, ie, stunning and preconditioning; there is no
universally accepted animal model, and thus the fundamental mechanisms
remain largely unexplained. The situation here is exactly the opposite
to that with stunning and preconditioning, both of which were
laboratory-based discoveries that subsequently found clinical
application. Hibernation, instead, is a clinical phenomenon of
potentially immense importance that has proven difficult to study at
the basic level.
![]()
Preconditioning
Top
Introduction
Myocardial Stunning
Hibernating Myocardium
Preconditioning
Summary
Appendix
References
Biology of Preconditioning
The term preconditioning was applied to the observation made in
1986 by Murry et al168 that canine
myocardium subjected to four brief episodes of
ischemia and reperfusion would tolerate a more prolonged
episode of ischemia better than myocardium not
previously exposed to ischemia. Since that seminal observation
in dogs, brief episodes of preconditioning ischemia
consistently have been shown to reduce the size of
experimentally induced myocardial infarction in rats, rabbits, pigs,
and other species. Data from clinical studies suggest that
preconditioning probably occurs in humans.169
There is general agreement that other than early reperfusion,
preconditioning is the strongest form of in vivo protection against
myocardial ischemic injury.
Determination of the exact mechanism of ischemic
preconditioning is important because if the mechanism can be
elucidated, then better therapies (preconditioning mimetics) may be
developed to treat a host of ischemic syndromes.
Downey and colleagues184 185 186 187 have proposed
that in the rabbit, the mechanism of preconditioning involves
stimulation of adenosine, bradykinin, and opioid receptors,
which all couple through phospholipases to activate PKC, which
then phosphorylates an unknown effector. Specifically, it
was initially proposed that translocation of PKC from the cytosol
(where it was inactive) to cellular membranes (where it became
activated) constituted the memory for preconditioning.
, as
proposed by Downey. Adenosine receptors couple to
Gi protein, which stimulates phospholipase
(probably phospholipase D)188 ; this in turn
degrades membrane phospholipids to phosphatidic acid, which is
converted to DAGs; the latter then activates PKC, which
eventually phosphorylates some unknown effector, perhaps
the sarcolemmal KATP channel. Once the
KATP channel is activated,
K+ exits the cells acting as a regional
"cardioplegic"; the duration of action potential shortens, reducing
energy demand. Studies supporting these hypotheses come from a series
of experiments showing that in some models, antagonists of
these various steps can block preconditioning, whereas agonists could
mimic preconditioning.184 185 186 187 For example, the
adenosine A1 receptor agonist
R(-)N6(2-phenylisopropyl)-adenosine (PIA) reduced infarct
size in the rabbit model in several
laboratories.184 189 The adenosine
antagonist 8-p-sulfophenyl theophylline (SPT) blocked
preconditioning.184 PKC blockers such as
staurosporine, chelerythrine, and polymixin prevented
preconditioning in rabbit hearts,185 and
calphostin C blocked it in the rat heart.190
Isolated rabbit hearts were protected by direct activators
of PKC such as phorbol esters and DAGs. Recent studies suggested that
free radicals, which directly stimulate phospholipases in cells, also
contribute to triggering preconditioning in the rabbit
model.191 192 193 Evidence also suggests that at
least one tyrosine kinase that also may be involved in the mechanism of
preconditioning exists downstream from PKC in the rabbit
heart.194

View larger version (22K):
[in a new window]
Figure 4. Overall flow chart for the signal transduction
system of preconditioning in the rabbit heart. Note that tyrosine
kinase may also activate mitogen-activated protein
kinase, causing expression of stress proteins and the second window of
protection. PLC=phospholipase C; PLD=phospholipase D; PKC=protein
kinase C; MAP=mitogen activated protein kinase. Reproduced with
permission from J. Downey, University of South Alabama, Mobile.
Although activation and translocation of PKC is perhaps the most
popular and attractive theory to explain infarct size reduction with
preconditioning, there are other hypotheses that have been put forward.
One of these, advocated by Kitakaze and
colleagues,197 involves activation of
5'-nucleotidase, the enzyme responsible for
dephosphorylation of AMP to form adenosine,
which would then be protective. A second, alternate hypothesis is that
calcium influx during the preconditioning stimulus, perhaps via
Na+-H+ and
Na+-Ca2+ exchange, is
important in eliciting cardioprotection.198
Without doubt, the most hotly debated potential mediator of
preconditioning is PKC. Evidence in support of the PKC hypothesis was
largely derived from administration of PKC agonists and
antagonists in the rabbit and rat models. However, PKC
inhibitors failed to attenuate preconditioning in the
dog203 and pig,204 205
whereas brief preischemic infusion of PMA did not limit
infarct size in the porcine heart.204 When
biochemical quantitation as well as fluorescence confocal
microscopy was used, PKC translocation was not observed during brief
episodes of preconditioning ischemia in the canine
heart.203 However, translocation was observed
with longer coronary occlusions and with PMA injections.
was observed in isolated rat hearts
(immunohistochemistry208 ), of PKC-
and -
in
isolated rat neonatal
cardiomyocytes,207 and of PKC-
and
-
with no change in the subcellular distribution of total PKC
activity in conscious rabbits (Western
immunoblotting),206 suggesting
that the mechanism of preconditioning might involve selective
activation of one or few isozymes. However, even the conclusive
identification of isoform-selective PKC translocation may be unable to
definitively resolve the controversy because the isoform-specific
antibodies often used in these studies are limited by their inability
to distinguish whether the isoform is active or
inactive.209
A final proposed mediator of infarct-size reduction is the
ATP-sensitive potassium channel (KATP).
Specifically, Gross and colleagues211 212 have
shown that the KATP channel is important for
preconditioning in the canine model. Intravenous
glibenclamide, a KATP channel
antagonist, given either before or after a single 5-minute
period of ischemic preconditioning, abolished the protective
effect afforded by preconditioning in reducing infarct size in the
canine model.211 The nonsulfonylurea
KATP channel blocker sodium 5-hydroxydecanoate
(5-HD) antagonized the protective effect of preconditioning without
affecting infarct size in nonpreconditioned
hearts.212 These investigators have also shown
that a number of KATP channel openers
(nicorandil, pinacidil, and bimakalin) are capable of mimicking the
effects of ischemic preconditioning. Activation of a variety of
receptors (adenosine, acetylcholine, bradykinin, and others)
that can mimic the cardioprotective effects of ischemic
preconditioning may involve the KATP channel,
because glibenclamide and 5-HD were shown to block the cardioprotective
effects of these agents.213 214
The second window of protection was described by Yellon and
Baxter219 and Kuzuya et
al172 as enhanced tolerance to lethal
ischemia 24 hours after a preconditioning stimulus of brief
repetitive episodes of ischemia.219 The
phenomenon of late reappearance of the protective effect of
preconditioning has been observed in open chest rabbit and dog and
chronically instrumented conscious rabbit and
rat.172 219 220 221 Recent work suggests that the
delayed anti-infarct effect of preconditioning may extend over a period
of 1 to 3 days, unlike the early period of protection by classic
preconditioning, which is lost within a few
hours.222 The mechanism of the delayed effect of
preconditioning is under investigation. The time delay may allow
activation of genes and expression of new proteins that could play a
role in the late protection. It is unlikely that expression of new
proteins plays a role in the early protection after ischemic
preconditioning. It is possible that an entirely different set of
triggers and signaling pathways is important to the second window. Some
of the mechanism that are being studied include expression of heat
shock protein (HSP70), alterations in the activity of superoxide
dismutase, induction of inducible nitric oxide synthase, and
involvement of PKC.221 223 224 225 Recently, Bolli
et al showed that brief episodes of ischemic preconditioning
can protect the porcine and rabbit heart from an episode of stunning 24
hours or more after the preconditioning
episode226 and that this protection is triggered
by the generation of oxyradicals227 and nitric
oxide.228 In addition, they demonstrated that in
the conscious rabbit, the delayed protection against infarction is also
triggered by the generation of nitric oxide during the initial
preconditioning ischemia.229 This
"second window" of protection against infarction is not, however,
seen in the pig model.230
Stunning and preconditioning have similarities in that both
phenomena involve brief episodes of ischemia followed by
reperfusion. One initial thought regarding the mechanism of
preconditioning was that the myocardium, having been
stunned by a brief period of ischemia, would have reduced
contractility and hence reduced oxygen demand,
rendering it more resistant to subsequent ischemia.
This concept turned out to be incorrect. First, the myocardial oxygen
demand of stunned myocardium has not been reduced in most
studies.231 Also, Murry et
al232 studied the temporal relationship between
preconditioning and stunning. They observed that one 15-minute
coronary occlusion separated by 5 minutes of reperfusion
markedly reduced infarct size induced by a 40-minute occlusion. If the
reperfusion phase between the brief preconditioning ischemia
and 40-minute occlusion was extended to 120 minutes, the
myocardium remained severely stunned after the brief
ischemia, but the myocardial infarct size plotted against
collateral flow returned toward nonpreconditioned
values. In another study, Matsuda et al233 showed
that dobutamine could be used to reverse stunning induced
by four 5-minute coronary occlusions in the dog model but that
reversing stunning did not prevent preconditioning. Conversely, as
already described in regional models of coronary
occlusion/reperfusion, classic ischemic preconditioning does
not reduce acute stunning.159
The most direct evidence that human myocardium can be
preconditioned comes from studies performed in isolated, cultured human
cardiomyocytes subjected to simulated ischemia and
reperfusion. Ikonomidis et al234 showed that
prior brief episodes of ischemia improved survival when
cultured human cardiac myocytes were exposed to 90 minutes of sustained
ischemia. Studies of human myocardium obtained at
the time of cardiac surgery have demonstrated better preservation of
ATP during 10-minute periods of aortic cross-clamp fibrillation when
hearts were exposed to prior 3-minute episodes of
ischemia.235 In addition, in the same
model, it has recently been shown that troponin release is
significantly attenuated in patients who had been preconditioned
previously.236 Studies using human cardiac muscle
(atrial trabeculae) confirm findings in the animal
laboratory with respect to initiation of preconditioning with
hypoxia and the adenosine A1
agonist rPIA.237 Furthermore, the signaling
pathways in human cardiac muscle appear to involve PKC, with supporting
evidence for the role of the KATP channel as a
positive end effector.238
The members of the workshop suggested studies within three general
areas: mechanism of preconditioning, the biology of preconditioning,
and clinical studies.
If preconditioning mimetic pharmaceuticals are going to be
developed for the clinical treatment of ischemia, then it is
crucial to learn the mechanisms of preconditioning.
There is a need to characterize further the short-term and
long-term "biology" of preconditioning. With the use of large- and
small-animal models and cell-based models, studies should be
specifically designed to accomplish the following:
There is a need for well-designed clinical trials to test
ischemic preconditioning agonists (or mimetics) such as
adenosine, A1 and
A3 agonists, and/or KATP
channel openers, administered either acutely before an ischemic
event or 24 hours before planned ischemia (mimicking the second
window of protection). Suggested clinical arenas for studies should
include (1) angioplasty (a useful setting for initial screening of
potential mimetics), (2) coronary artery bypass grafting and
other open heart surgery, (3) minimally invasive directed
coronary artery bypass (MIDCAB), (4) preconditioning of a donor
transplant heart, and (5) unstable and stable angina.
![]()
Summary
Top
Introduction
Myocardial Stunning
Hibernating Myocardium
Preconditioning
Summary
Appendix
References
During the last 15 years, the concepts of stunning, hibernating,
and preconditioning have emerged as new phenomena that relate to
myocardial ischemia/reperfusion. Stunning and hibernation have
the potential to contribute to heart failure, and clinicians are
becoming increasingly aware of these phenomena. In particular,
preconditioning has the potential to lead to new therapies for a
variety of ischemic syndromes. The participants at this NHLBI
workshop strove to consider numerous factors in producing a list of
promising yet practical opportunities to advance our understanding of
these ischemic conditions. The recommendations emerging from
the workshop are designed as a guide to the NHLBI's Heart Research
Program in planning support of studies addressing stunning,
hibernation, and preconditioning and their roles in ischemia,
heart failure, and arrhythmia. It is hoped that future efforts
in this area will ultimately improve the national
cardiovascular health.
![]()
Appendix
Top
Introduction
Myocardial Stunning
Hibernating Myocardium
Preconditioning
Summary
Appendix
References
Participants in the Workshop
Eugene Braunwald, MD, Workshop Chairman, Brigham and Women's
Hospital, Harvard Medical School, Boston, Mass; Leslie J. Reinlib, PhD,
Workshop Coordinator, National Heart, Lung, and Blood Institute,
Bethesda, Md; Roberto Bolli, MD, Workshop Co-Chairman, University of
Louisville, Louisville, Ky; Robert A. Kloner, MD, PhD, Workshop
Co-Chairman, University of Southern California, Good Samaritan
Hospital, Los Angeles; Eduardo Marban, MD, PhD, Workshop
Co-Chairman, Johns Hopkins University, Baltimore, Md; Robert O. Bonow,
MD, Northwestern University Medical School, Chicago, Ill; Marcel
Borgers, PhD, Janssen Research Foundation, Beerse, Belgium; James
Downey, PhD, University of South Alabama, Mobile; Harvey Feigenbaum,
MD, Indiana University, Indianapolis; Charles Ganote, MD, Quillen
College of Medicine, Johnson City, Tenn; Garrett Gross, PhD, Medical
College of Wisconsin, Milwaukee; Robert Jennings, MD, Duke University
Medical Center, Durham, NC; Sidney Levitsky, MD, Harvard Medical
School, Boston, Mass; James D. McCully, PhD, Harvard Medical School,
Boston, Mass; Robert Mentzer, Jr, MD, University of Kentucky Medical
Center, Lexington; William P. Miller, MD, University of Wisconsin,
Madison; Karin Przyklenk, PhD, Good Samaritan Hospital, Los Angeles,
Calif; Shahbudin Rahimtoola, MD,* University of Southern California,
Los Angeles; Stephen Vatner, MD, Allegheny University of the Health
Sciences, Pittsburgh, Pa; and Derek Yellon, DSc, HonMRCP, FESC, The
Hatter Institute, University College London Hospital and Medical
School, London, United Kingdom.
![]()
Selected Abbreviations and Acronyms
DAG
=
diacylglycerol
PET
=
positron emission tomography
PKC
=
protein kinase C
PMA
=
phorbol myristate acetate
PTCA
=
percutaneous transluminal coronary angioplasty
ROS
=
reactive oxygen species
![]()
Footnotes
A list of workshop participants appears in the Appendix. Correspondence to Robert A. Kloner, MD, PhD, Heart Institute Research Laboratory, Good Samaritan Hospital, 1225 Wilshire Blvd, Los Angeles, CA 90017.
![]()
References
Top
Introduction
Myocardial Stunning
Hibernating Myocardium
Preconditioning
Summary
Appendix
References
1.
Braunwald E, Kloner RA. The stunned
myocardium: prolonged, postischemic
ventricular dysfunction. Circulation. 1982;66:11461149.
and
in the heart of
conscious rabbits without subcellular redistribution of total protein
kinase C activity. Circ Res.. 1997;81:404414.
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R. A. Kloner and R. B. Jennings Consequences of Brief Ischemia: Stunning, Preconditioning, and Their Clinical Implications: Part 1 Circulation, December 11, 2001; 104(24): 2981 - 2989. [Abstract] [Full Text] [PDF] |
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P. Abete, N. Ferrara, F. Cacciatore, E. Sagnelli, M. Manzi, V. Carnovale, C. Calabrese, D. de Santis, G. Testa, G. Longobardi, et al. High level of physical activity preserves the cardioprotective effect of preinfarction angina in elderly patients J. Am. Coll. Cardiol., November 1, 2001; 38(5): 1357 - 1365. [Abstract] [Full Text] [PDF] |
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R. A. Kloner Preinfarct angina and exercise: yet another reason to stay physically active J. Am. Coll. Cardiol., November 1, 2001; 38(5): 1366 - 1368. [Full Text] [PDF] |
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P. J. Gheeraert, J. P. S. Henriques, M. L. De Buyzere, M. De Pauw, Y. Taeymans, and F. Zijlstra Preinfarction angina protects against out-of-hospital ventricular fibrillation in patients with acute occlusion of the left coronary artery J. Am. Coll. Cardiol., November 1, 2001; 38(5): 1369 - 1374. [Abstract] [Full Text] [PDF] |
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D. S. Schwartz, R. M. Bremner, C. J. Baker, K. M. Uppal, M. L. Barr, R. G. Cohen, and V. A. Starnes Regional topical hypothermia of the beating heart: preservation of function and tissue Ann. Thorac. Surg., September 1, 2001; 72(3): 804 - 809. [Abstract] [Full Text] [PDF] |
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B. Stadler, J. Phillips, Y. Toyoda, M. Federman, S. Levitsky, and J. D. McCully Adenosine-enhanced ischemic preconditioning modulates necrosis and apoptosis: effects of stunning and ischemia-reperfusion Ann. Thorac. Surg., August 1, 2001; 72(2): 555 - 563. [Abstract] [Full Text] [PDF] |
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M. Marzilli and M. Mariani About EMIP-FR and reperfusion damage in AMI: a comment to the comment Eur. Heart J., June 1, 2001; 22(11): 973 - 975. [PDF] |
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E. Braunwald Congestive heart failure: a half century perspective Eur. Heart J., May 2, 2001; 22(10): 825 - 836. [PDF] |
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F. J. Giordano, H.-P. Gerber, S.-P. Williams, N. VanBruggen, S. Bunting, P. Ruiz-Lozano, Y. Gu, A. K. Nath, Y. Huang, R. Hickey, et al. A cardiac myocyte vascular endothelial growth factor paracrine pathway is required to maintain cardiac function PNAS, April 25, 2001; (2001) 91415198. [Abstract] [Full Text] |
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T. Hara, S. Tomiyasu, C. Sungsam, M. Fukusaki, and K. Sumikawa Sevoflurane Protects Stunned Myocardium Through Activation of Mitochondrial ATP-Sensitive Potassium Channels Anesth. Analg., April 1, 2001; 92(5): 1139 - 1145. [Abstract] [Full Text] [PDF] |
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F. Farhat, D. Loisance, J.-P. Garnier, and M. Kirsch Norepinephrine release after acute brain death abolishes the cardioprotective effects of ischemic preconditioning in rabbit Eur. J. Cardiothorac. Surg., March 1, 2001; 19(3): 313 - 320. [Abstract] [Full Text] [PDF] |
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A. C. Nicolosi, C. S. Kwok, S. J. Contney, G. N. Olinger, and Z. J. Bosnjak Gadolinium prevents stretch-mediated contractile dysfunction in isolated papillary muscles Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1122 - H1128. [Abstract] [Full Text] [PDF] |
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G. D. Dispersyn and M. Borgers Apoptosis in the Heart: About Programmed Cell Death and Survival Physiology, February 1, 2001; 16(1): 41 - 47. [Abstract] [Full Text] [PDF] |
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C.H. Davies Revascularization for cardiogenic shock QJM, February 1, 2001; 94(2): 57 - 67. [Full Text] [PDF] |
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E. R. Gross, M. Gare, W. G. Toller, J. R. Kersten, D. C. Warltier, and P. S. Pagel Ethanol Enhances the Functional Recovery of Stunned Myocardium Independent of KATP Channels in Dogs Anesth. Analg., February 1, 2001; 92(2): 299 - 305. [Abstract] [Full Text] [PDF] |
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A. T. SAURIN, J. L. MARTIN, R. J. HEADS, C. FOLEY, J. W. MOCKRIDGE, M. J. WRIGHT, Y. WANG, and M. S. MARBER The role of differential activation of p38-mitogen-activated protein kinase in preconditioned ventricular myocytes FASEB J, November 1, 2000; 14(14): 2237 - 2246. [Abstract] [Full Text] |
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S. Jovanovic, A. Jovanovic, W. K. Shen, and A. Terzic Low concentrations of 17{beta}-estradiol protect single cardiac cells against metabolic stress-induced Ca2+ loading J. Am. Coll. Cardiol., September 1, 2000; 36(3): 948 - 952. [Abstract] [Full Text] [PDF] |
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P. Theroux Myocardial Cell Protection : A Challenging Time for Action and a Challenging Time for Clinical Research Circulation, June 27, 2000; 101(25): 2874 - 2876. [Full Text] [PDF] |
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B. Z. Atkins, S. C. Silvestry, R. N. Samy, A. S. Shah, D. C. Sabiston Jr, and D. D. Glower CALCITONIN GENE-RELATED PEPTIDE ENHANCES THE RECOVERY OF CONTRACTILE FUNCTION IN STUNNED MYOCARDIUM J. Thorac. Cardiovasc. Surg., June 1, 2000; 119(6): 1246 - 1254. [Abstract] [Full Text] [PDF] |
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T. N. James Homage to James B. Herrick: A Contemporary Look at Myocardial Infarction and at Sickle-Cell Heart Disease : The 32nd Annual Herrick Lecture of the Council on Clinical Cardiology of the American Heart Association Circulation, April 18, 2000; 101(15): 1874 - 1887. [Full Text] [PDF] |
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G. Longobardi, P. Abete, N. Ferrara, A. Papa, R. Rosiello, G. Furgi, C. Calabrese, F. Cacciatore, and F. Rengo "Warm-Up" Phenomenon in Adult and Elderly Patients With Coronary Artery Disease: Further Evidence of the Loss of "Ischemic Preconditioning" in the Aging Heart J. Gerontol. A Biol. Sci. Med. Sci., March 1, 2000; 55(3): 124M - 129. [Abstract] [Full Text] |
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E Barnes, C S R Baker, D P Dutka, O Rimoldi, C A Rinaldi, P Nihoyannopoulos, P G Camici, and R J C Hall Prolonged left ventricular dysfunction occurs in patients with coronary artery disease after both dobutamine and exercise induced myocardial ischaemia Heart, March 1, 2000; 83(3): 283 - 289. [Abstract] [Full Text] |
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C. Depre and H. Taegtmeyer Metabolic aspects of programmed cell survival and cell death in the heart Cardiovasc Res, February 1, 2000; 45(3): 538 - 548. [Abstract] [Full Text] [PDF] |
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G. D. Dispersyn, M. Borgers, and W. Flameng Apoptosis in chronic hibernating myocardium: sleeping to death? Cardiovasc Res, February 1, 2000; 45(3): 696 - 703. [Abstract] [Full Text] [PDF] |
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P Kay, J Kittelson, and R A H Stewart Relation between duration and intensity of first exercise and "warm up" in ischaemic heart disease Heart, January 1, 2000; 83(1): 17 - 21. [Abstract] [Full Text] [PDF] |
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M. Avkiran Protection of the Myocardium During Ischemia and Reperfusion : Na+/H+ Exchange Inhibition Versus Ischemic Preconditioning Circulation, December 21, 1999; 100(25): 2469 - 2472. [Full Text] [PDF] |
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S. Banerjee, X.-L. Tang, Y. Qiu, H. Takano, S. Manchikalapudi, B. Dawn, G. Shirk, and R. Bolli Nitroglycerin induces late preconditioning against myocardial stunning via a PKC-dependent pathway Am J Physiol Heart Circ Physiol, December 1, 1999; 277(6): H2488 - H2494. [Abstract] [Full Text] [PDF] |
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M. V. Brahmajothi and D. L. Campbell Heterogeneous Basal Expression of Nitric Oxide Synthase and Superoxide Dismutase Isoforms in Mammalian Heart : Implications for Mechanisms Governing Indirect and Direct Nitric Oxide-Related Effects Circ. Res., October 1, 1999; 85(7): 575 - 587. [Abstract] [Full Text] [PDF] |
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M. A. Leesar, M. F. Stoddard, S. Manchikalapudi, and R. Bolli Bradykinin-induced preconditioning in patients undergoing coronary angioplasty J. Am. Coll. Cardiol., September 1, 1999; 34(3): 639 - 650. [Abstract] [Full Text] [PDF] |
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E. L Holmuhamedov, L. Wang, and A. Terzic ATP-sensitive K+ channel openers prevent Ca2+ overload in rat cardiac mitochondria J. Physiol., September 1, 1999; 519(2): 347 - 360. [Abstract] [Full Text] [PDF] |
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R. D Rakhit, R. J Edwards, and M. S Marber Nitric oxide, nitrates and ischaemic preconditioning Cardiovasc Res, August 15, 1999; 43(3): 621 - 627. [Full Text] [PDF] |
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E. N. Morgan, E. M. Boyle Jr, W. Yun, J. M. Griscavage-Ennis, A. L. Farr, T. G. Canty Jr, T. H. Pohlman, and E. D. Verrier An essential role for NF-{kappa}B in the cardioadaptive response to ischemia Ann. Thorac. Surg., August 1, 1999; 68(2): 377 - 382. [Abstract] [Full Text] [PDF] |
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D. F. Stowe Understanding the temporal relationship of ATP loss, calcium loading, and rigor contracture during anoxia, and hypercontracture after anoxia in cardiac myocytes Cardiovasc Res, August 1, 1999; 43(2): 285 - 287. [Full Text] [PDF] |
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H.-S. V. Chen, S. C. Body, and S. K. Shernan Myocardial Preconditioning: Characteristics, Mechanisms, and Clinical Applications Seminars in Cardiothoracic and Vascular Anesthesia, July 1, 1999; 3(2): 85 - 97. [Abstract] [PDF] |
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A. C. Nicolosi, J. G. Markley, and G. N. Olinger EFFECTS OF POSTISCHEMIC LEFT VENTRICULAR PRESSURE-VOLUME UNLOADINGON CONTRACTILE RECOVERY AND MYOCARDIAL BLOOD FLOW IN THE REGIONALLY STUNNEDCANINE HEART J. Thorac. Cardiovasc. Surg., July 1, 1999; 118(1): 181 - 188. [Abstract] [Full Text] [PDF] |
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J. M. Canty Jr. and J. A. Fallavollita Resting myocardial flow in hibernating myocardium: validating animal models of human pathophysiology Am J Physiol Heart Circ Physiol, July 1, 1999; 277(1): H417 - H422. [Full Text] [PDF] |
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C. Perez-Terzic, A. M. Gacy, R. Bortolon, P. P. Dzeja, M. Puceat, M. Jaconi, F. G. Prendergast, and A. Terzic Structural Plasticity of the Cardiac Nuclear Pore Complex in Response to Regulators of Nuclear Import Circ. Res., June 11, 1999; 84(11): 1292 - 1301. [Abstract] [Full Text] [PDF] |
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H. Hu, T. Sato, J. Seharaseyon, Y. Liu, D. C. Johns, B. O'Rourke, and E. Marbán Pharmacological and Histochemical Distinctions Between Molecularly Defined Sarcolemmal KATP Channels and Native Cardiac Mitochondrial KATP Channels Mol. Pharmacol., June 1, 1999; 55(6): 1000 - 1005. [Abstract] [Full Text] |
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J. A. Fallavollita and J. M. Canty Jr Differential 18F-2-Deoxyglucose Uptake in Viable Dysfunctional Myocardium With Normal Resting Perfusion : Evidence for Chronic Stunning in Pigs Circulation, June 1, 1999; 99(21): 2798 - 2805. [Abstract] [Full Text] [PDF] |
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K. W. Saupe, F. R. Eberli, J. S. Ingwall, and C. S. Apstein Hypoperfusion-induced contractile failure does not require changes in cardiac energetics Am J Physiol Heart Circ Physiol, May 1, 1999; 276(5): H1715 - H1723. [Abstract] [Full Text] [PDF] |
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W. K. Laskey Beneficial Impact of Preconditioning During PTCA on Creatine Kinase Release Circulation, April 27, 1999; 99(16): 2085 - 2089. [Abstract] [Full Text] [PDF] |
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D. Pucar, E. Janssen, P. P. Dzeja, N. Juranic, S. Macura, B. Wieringa, and A. Terzic Compromised Energetics in the Adenylate Kinase AK1 Gene Knockout Heart under Metabolic Stress J. Biol. Chem., December 22, 2000; 275(52): 41424 - 41429. [Abstract] [Full Text] [PDF] |
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F. J. Giordano, H.-P. Gerber, S.-P. Williams, N. VanBruggen, S. Bunting, P. Ruiz-Lozano, Y. Gu, A. K. Nath, Y. Huang, R. Hickey, et al. A cardiac myocyte vascular endothelial growth factor paracrine pathway is required to maintain cardiac function PNAS, May 8, 2001; 98(10): 5780 - 5785. [Abstract] [Full Text] [PDF] |
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E. Barnes, D. P. Dutka, M. Khan, P. G. Camici, and R. J. Hall Effect of repeated episodes of reversible myocardial ischemia on myocardial blood flow and function in humans Am J Physiol Heart Circ Physiol, May 1, 2002; 282(5): H1603 - H1608. [Abstract] [Full Text] [PDF] |
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P. Abete, G. Testa, N. Ferrara, D. De Santis, P. Capaccio, L. Viati, C. Calabrese, F. Cacciatore, G. Longobardi, M. Condorelli, et al. Cardioprotective effect of ischemic preconditioning is preserved in food-restricted senescent rats Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H1978 - H1987. [Abstract] [Full Text] [PDF] |
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K. Imahashi, T. Nishimura, J. Yoshioka, and H. Kusuoka Role of Intracellular Na+ Kinetics in Preconditioned Rat Heart Circ. Res., June 8, 2001; 88(11): 1176 - 1182. [Abstract] [Full Text] [PDF] |
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J. Muller-Ehmsen, K. L. Peterson, L. Kedes, P. Whittaker, J. S. Dow, T. I. Long, P. W. Laird, and R. A. Kloner Rebuilding a Damaged Heart: Long-Term Survival of Transplanted Neonatal Rat Cardiomyocytes After Myocardial Infarction and Effect on Cardiac Function Circulation, April 9, 2002; 105(14): 1720 - 1726. [Abstract] [Full Text] [PDF] |
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