Cardiovascular Research 42 (1999) 571–575

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Editorial

Preconditioning and limitation of stunning : one step closer to the

protected protein(s)?

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Jos M.J. Lamers*
Department of Biochemistry, Cardiovascular Research Institute COEUR, Faculty of Medicine & Health Sciences, Erasmus University, Rotterdam,
The Netherlands

Received 2 March 1999; accepted 2 March 1999

Keywords: Ischaemia; Reperfusion; Stunning; Preconditioning; Contractile apparatus

Brief periods of ischaemia, are known to induce a
reversible deficit in myocardial function despite the
maintenance of histological and metabolic integrity, a
phenomenon initially described by Heyndrickx et al. in
1975, and called stunning several years after [1]. In that
first study it was reported that several hours were required
for complete recovery of regional contractility following a
5 min occlusion of the left anterior descending coronary
artery in conscious dogs and up to 24 h were needed for
complete recovery following a 15 min occlusion [1].
Therefore, myocardial stunning is considered to represent
reversible injury contrasting the irreversible injury of
myocardial infarction. The phenomenon has been de-
scribed in every species studied so far, does occur in
several clinical settings and likely plays an important role
in the morbidity of patients with coronary artery disease
[2]. Although the principal cause of the reversible contrac-
tile dysfunction is not fully understood, there is now
consensus that loss of Ca 21 responsiveness of the myofila-
ments represents a major underlying mechanism as first
proposed by Kusuoka et al. in 1987 on basis of experi-
ments with isolated perfused ferret hearts [3]. Initially
some studies suggested an additional role of failing
sarcoplasmic reticulum Ca 21 pump, but this could not be
substantiated [4]. There is evidence that abnormalities in
myofilaments also underly stunning induced in clinically
relevant large animal models. For instance, it was shown in
the in situ porcine model that the potent Ca 21 sensitizer
(EMD 60263), without phosphodiesterase inhibitory prop-
erties, increased segment length shortening to a greater
extent in stunned than in non-stunned myocardium [5].
These findings were consistent with the left-and upward
*Corresponding author. Tel.: 131-10-408-7335; fax: 131-10-4089472.
shifts of the p[Ca 21 ] / Mg 21 -ATPase curves induced by
Ca 21 sensitizer as observed with isolated myofibrils from
stunned pig myocardium [6]. Moreover, another group
found a decrease in the Ca 21 sensitivity of isometric
tension and the rate of cross-bridge cycling in skinned
myocytes isolated from stunned pig myocardium [7].
Regarding the mechanism(s) upstream of the contractile
apparatus, it has become clear that oxidant stress and
Ca 21 -overload are the two initial triggers that induce
myocardial stunning [8]. However, the chain of events
between free radical burst, increased [Ca 21 ] i and develop-
ment of the abnormalities in the myofilaments remains to
be established.
One or several brief episode(s) of ischaemia, of in-
sufficient duration to cause myocyte necrosis, do(es) not
only induce myocardial stunning but is (are) also known to
increase the heart’s tolerance to a subsequent sustained
period of ischaemia, such that there is a delay of myocar-
dial necrosis. This beneficial effect on the heart, first
described by Murry et al. in 1986, is termed ischaemic
preconditioning and has also been demonstrated in a wide
variety of species including man [9]. The protective state
afforded by the preconditioning stimulus lasts 1–2 h
depending on the species and model. This is called the first
window of protection in contrast to the second window of
protection present after 24 h. At first, a cause and effect
relationship between stunning and preconditioning was
suggested because both phenomena are observed in re-
versibly injured myocardium. However, results described
in a second report by Murry et al. [10] proved that
stunning is not involved in preconditioning which was
confirmed by others (see e.g. ref. [12]). For instance,
whereas a 15 min coronary occlusion followed by a 5 min
reperfusion period before a 40 min sustained occlusion

0008-6363 / 99 / $ – see front matter  1999 Elsevier Science B.V. All rights reserved.
PII: S0008-6363( 99 )00086-3
572 J.M. J. Lamers / Cardiovascular Research 42 (1999) 571 – 575
significantly limited infarct size, much less salvage was
realized if the reperfusion period between the brief and
sustained occlusion was 120 min [10,11]. Stunning during
the reperfusion interval (5–120 min) was, however, similar
in magnitude.
Otherwise, a cause and effect relationship between
preconditioning and limitation of stunning at first seemed
more likely. Cohen et al. first showed that in addition to a
delay in development of irreversible necrosis caused by
sustained ischaemia, preconditioning improved the re-
covery of contractile function but improvement of wall
motion could be entirely explained by reduction in infarct
size [11]. Nevertheless, many subsequent reports kept the
question alive whether improved contractile recovery
following ischaemic preconditioning during the first win-
dow is solely based upon the limitation of the infarct size
or also on the attenuation of stunning of salvaged myocar-
dium [11,13–16]. As previously commented by Ovize et
al. [13], the analysis of the preconditioning effect on
contractile function after prolonged coronary artery occlu-
sion in open-chest or conscious models is confounded by
many factors, e.g. 1) the presence of subendocardial
necrosis which influences wall motion in surrounding
viable myocardium; 2) preconditioning results in stunning
before the sustained ischaemia and may therefore limit or
mask a beneficial effect of preconditioning on wall motion.
Except for one study in favor [15], the in situ studies failed
to demonstrate that early preconditioning alleviates the
severity of stunning independent of reduction of infarct
size [11,13,14,16]. On the other hand, Bolli et al. demon-
strated that when the heart was subjected to a sequence of
brief (5 min) ischaemic episodes, the first episode pre-
conditions against the stunning induced by the next two
episodes and this protection disappears at some point
between the fourth and tenth episodes [17,18]. They
suggested that the protective effect on stunning in the early
phase is rather weak in contrast to the powerful and
long-lasting (at least 3 days) protection against stunning by
brief ischaemia induced in the late phase. A major reason
that the dispute on whether preconditioning limits stunning
remains timely, is that many subsequent reports have
extended the use of the term ischaemic preconditioning to
include several endpoints in addition to the originally
described limiting effect on infarct size (reviewed in [13]).
For instance, it was reported that ischaemic precondition-
ing protects against post-ischaemic contractile dysfunction,
enzyme release, increased [H 1 ] i and arrhythmias in the
isolated perfused rat and rabbit hearts [13,19–21]. Like-
wise, these in vitro investigations taken on the whole are
not conclusive. But in this issue of Cardiovascular Re-
´
search Perez et al. presents results which strongly indicate
that at least in the perfused rat heart model, ischaemic
preconditioning limits reversible contractile dysfunction
[22]. Other studies in isolated perfused hearts, in which
both myocardial necrosis (infarct size) and post-ischaemic
functional recovery were measured, indicated that post-
ischaemic improvement in global left ventricular function
produced by preconditioning was secondary to reduced
infarction size, and that preconditioning did not reduce
stunning (see e.g. [23]). Thus, where we now stand is: in
order to obtain definite proof of protection against stunning
in vivo and reversible post-ischaemic contractile dysfunc-
tion in vitro, selective molecular markers measuring the
degree of stunning of salvaged myocardium must become
available.
´
The study of Perez et al. [22] of this issue elegantly
characterizes the principal cellular abnormality that was
previously proven to cause reversible post-ischaemic con-
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tractile dysfunction in the isolated perfused rat heart by
measuring Ca 21 transients and [Ca 21 ] i / force relationships
in dissected thin right ventricular trabeculae. Recovery of
these isolated muscle parameters, as indicators of the
degree of reversible injury, in parallel with recovery of left
ventricular developed pressure was measured after 20 min
reperfusion of retrogradely-perfused rat heart that had been
subjected to global ischaemia for 20 min [22]. Perhaps one
limitation of the chosen experimental set-up is that the
possibly existing slight differences between muscle re-
sponses of right- versus left ventricle to ischaemia and
reperfusion, may have become unnoticed. Nonetheless, the
fact that the effect of a previous 5 min lasting precondi-
tioning stimulus is measured too on isolated muscle
parameters makes this study so noteworthy. Direct evi-
dence is obtained for ischaemic preconditioning to prevent
the development of abnormalities localized in the myofila-
ments that in their previous work were shown to be
associated with reversible post-ischaemic contractile
dysfunction [22,25]. It is also important to notice that the
protection was obtained when there was no initial depres-
sion of contractile function. Therefore, the preconditioning
effects on myofilament function and left ventricular de-
veloped pressure can not be ascribed to contractile
dysfunction prior to the ischaemia. Another essential point
is the author’s claim that 20 min of global ischaemia of the
isolated perfused rat heart is a true model of stunning
because it shows no signs of irreversible injury based upon
intact cell–cell coupling, unaffected Ca 21 transients, ab-
sence of contracture, maintained response to inotropic
stimulation, the triphenyltetrazolium and actin staining
were not different from control perfused hearts (compare
also ref. [24]). In view of the foregoing introduction, the
´
findings of Perez et al. [22] are of utmost importance
because for the first time, one is directly referred to the
myofilaments as the potential site to find molecular
markers for stunning. The results take us one step closer to
the intracellular protein(s) protected by ischaemic pre-
conditioning. The following questions have become topi-
cal: how far are we with the identification of molecular
abnormalities in the myofilaments during post-ischaemic
contractile dysfunction in vitro and / or stunning in vivo?
Secondly: if in general, preconditioning and limitation of
stunning have a cause and effect relationship, what could
 J.M. J. Lamers / Cardiovascular Research 42 (1999) 571 – 575
we learn from setting side by side the central steps of the
currently known mechanism(s) involved in both phenom-
ena?
Marban and coworkers [3,25] were the first to provide
strong evidence for the hypothesis that post-reversible
post-ischaemic contractile dysfunction is associated with
reversible breakdown and replacement of damaged
myofilament proteins, in particular cardiac troponin I
(cTnI). Western blots revealed an additional band of 26
kDa compared with 32 kDa for the full length cTnI. This
degradation could be prevented by a low Ca 21 / low pH
reperfusion which also prevented the post-ischaemic con-
tractile dysfunction [25]. Also calpastatin, a naturally
occurring inhibitor of calpain (a Ca 21 dependent protease),
prevented post-ischaemic contractile dysfunction in the
perfused rat heart. These results fit well with cellular Ca 21
overload as initial trigger in the mechanism of stunning
´
[8]. In this respect, it is interesting to note that Perez et al.
previously showed that xanthine oxydase inhibitors, which
are known to blunt the dysfunction of stunning, sensitize
myofilaments to Ca 21 [26]. These data are in line with the
concept that free oxygen radicals play a role in stunning as
well [8]. Recently, other groups could substantiate the
findings on cTnI by correlating altered thin-filament regu-
lation with contractile dysfunction resulting from 15 min
global ischaemia and more severe periods of global
ischaemia (60 min) with and without 45 min of reperfusion
[27,28]. The authors hypothetize on basis of the identified
cTnI breakdown products and additional modifications
within the Tn complex (binary covalent complexes formed
by ischaemia–reperfusion-induced activation of trans-
glutaminase (TGase)), that the balance between the forma-
tion of the stabilized covalent Tn complexes and the
amount of TnI degradation (initially to cTnI 1 – 193 ) may
determine whether finally necrotic or apoptotic pathways
are activated in stunned myocardium [28]. The in-
volvement of TGase in ischaemia–reperfusion induced
injury was first suggested by Gorza et al. [29] because
unidentified covalent complexes containing cTnT in is-
chaemic–reperfused cardiomyocytes accompanied changes
in cTnT immunoreactivity in cryosections (60 min is-
chaemia followed by 30 min of reperfusion) [28]. Van Eyk
and coworkers propose on basis of the obtained data the
following sequence of reactions for mildly ischaemic (15
min)–reperfusion induced TnI modification: Ca 21 over-
load, free radical burst and / or receptor-mediated activation
of phospholipase C result in both proteolytic and TGase
activation, possibly through interaction between calpain
and TGase [27,28]. The selective degradation of the Tn
complex (cTnI to cTnI 1 – 193 , cTnC to cTnC 1 – 94 and cTnT
to cTnT 191 – 298 ) may occur either before or after the
formation of covalent links between these components.
More severe ischaemia generates two other N-terminal
breakdown products of TnI (cTnI 63 – 193 and cTnI 73 – 193 )
[28]. From the thorough investigations of Solaro’s group in
particular, it has become clear that normally cTnI plays a
573
central role in the transferring the signal of Ca 21 binding
on the TnC regulatory site to crossbridge formation
between myosin and actin [30]. The N-terminal domain of
cTnI anchors cTnC to the thin filament by interaction with
its C-terminus. When no Ca 21 is bound to the cTnC
regulatory site, a C-terminal region of TnI is kept close to
actin. When Ca 21 is bound to the regulatory site of cTnC,
cTnI moves away from actin and binds to the N-terminus
of cTnC. This reveals a tropomyosin (Tm) binding site
which results in movement of Tm away, allowing
crossbridges to be formed between actin and myosin [30].
Therefore, loss and / or truncation of cTnI would be
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expected to alter the mechanism by which the myofila-
ments achieve diastolic state and their response to Ca 21
[30]. Recently, a first mutant mouse was generated in
which cTnI gene has been ablated by gene targeting. The
mice remain healthy up to the first two weeks of life but, at
the time their hearts stop to express the skeletal muscle TnI
(ssTnI), they develop diastolic dysfunction and reduced
cardiac myofibrillar Ca 21 responsiveness and die at about
day 18 of heart failure [31] This situation does surely not
resemble that present during post-ischaemic contractile
dysfunction when only a small percentage of cTnI is
degraded [25,27,28], but proves the essential role of this
protein for the contractile function of the heart. At present,
there are no data available on specific TnI degradation
during stunning in in vivo models. A recent study on
stunned pig myocardium did not identify cTnI breakdown
products, but substitution of the cTn complex purified from
stunned pig myocardium into normal rabbit psoas skeletal
muscle fibers demonstrated a decrease in Ca 21 sensitivity
of force generation with respect to cTn complex purified
from nonstunned myocardium [32]. We measured Ca 21
responsiveness of the Mg 21 -ATPase of myofibrils isolated
from stunned and non-stunned pig myocardium and in 3
out of 4 pigs a rightward shift of the p[Ca 21 ] / Mg 21
ATPase curves was observed, which result points in the
same direction as the results of the afore-mentioned study
[6,32]. Alltogether, these recent data are giving more
concrete forms to the thought that the appropriate anti-
bodies will soon become available for detection of specific
breakdown products of cTnI to be used as markers for
estimation of degree of stunning of salvaged myocardium
in vitro as well as in vivo.
As to the above mentioned second question, it is not the
purpose here to provide an overview of what is currently
known about the mechanism(s) involved in both stunning
and ischaemic preconditioning. Most reports on precondi-
tioning have taken infarct size and not stunning as end-
point, which would complicate such an effort. Anyhow,
the most favored current hypothesis for early precondition-
ing, first proposed by Downey coworkers [33], is that
endogenous ligands such as adenosine, noradrenaline,
endothelin and bradykinin initiate intracellular pathways
by activation of phospholipases C and D which lead to the
activation of protein kinase C isotypes (PKCs) via intracel-
574 J.M. J. Lamers / Cardiovascular Research 42 (1999) 571 – 575
lular inositol-1,4,5-trisphosphate-induced Ca 21 release
from the sarcoplasmic reticulum and diacylglycerol forma-
tion [33,34]. Activated PKCs then phosphorylate, up to
now, unknown proteins that induce protection. At present,
only target proteins, e.g. the cardiac mitochondrial ATP
dependent K 1 channel and Na 1 / H 1 -exchanger, have been
postulated, for which it is not at all clear whether they
become phosphorylated by PKC in intact cardiomyocytes.
However, cTnI is a well known substrate for cyclic AMP-
dependent protein kinase (PKA) as well as PKC [30]. Its
phosphorylation represents a major mechanism by which
myofilaments are normally able to sense sympathetic and
parasympathetic control of the heart. At present, the
physiological role of PKA induced phosphorylation in
b-adrenergic stimulation of the heart is well understood
but, unfortunately, not that of PKC. In intact car-
diomyocytes PKC-mediated cTnI phosphorylation takes
actually place when the cells are stimulated with e.g.
a 1 -adrenergic agonists [35]. However, the effects of
phosphorylation of myofibrils by PKC in vitro are not
consistent, either stimulation or inhibition of the Ca 21
stimulated Mg 21 -ATPase of isolated cardiac myofibrils or
reconstituted actomyosin preparations has been observed
[35,36]. Returning then to the possible interactions of
preconditioning and stunning mechanism(s), of crucial
importance may turn out to be the in vitro studies that have
shown that prior phosphorylation of cTnI by PKA reduces
the rate of its degradation by calpain [37]. Furthermore,
recently it was reported as an unpublished observation that
treatment of experimental animals with b-adrenergic agon-
ist provides protection against TnI degradation [28]. On
basis of these recent results it might be speculated that
PKC and / or PKA-mediated phosphorylation of cTnI by
(partially) preventing its proteolytic breakdown, contri-
butes to the mechanism by which ischaemic precondition-
ing limits stunning.
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