Circulation. 1999;100:II-340-II-344
(Circulation. 1999;100:II-340.)
© 1999 American Heart Association, Inc.
Myocardial Protection and Vascular Biology |
Evidence for Preconditioning by Isoflurane in Coronary Artery Bypass Graft Surgery
Denis Belhomme, MD;
Jacqueline Peynet, MD;
Moez Louzy, MD;
Jean-Marie Launay, MD;
Masafumi Kitakaze, MD, PhD;
Philippe Menasché, MD, PhD
From the Departments of Cardiovascular Surgery (D.B., M.L., P.M.), and
Biochemistry (J.P., J.M.L.), and INSERM U-127 (P.M.), Hôpital
Lariboisière, Paris, France; and the First Department of Medicine,
Osaka University School of Medicine (M.K.), Suita, Japan.
 |
Abstract
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Background—Experimentally,
isoflurane, a commonly used
volatile anesthetic agent, mimics the
cardioprotective effects
of ischemic preconditioning via a
mechanism that could involve
the activation of protein kinase C. The
present study was designed
to assess the clinical relevance of this
observation in patients
undergoing elective CABG.
Methods and Results—Twenty patients were included in the study.
In 10 of them, preconditioning was elicited after the onset of
cardiopulmonary bypass via a 5-minute exposure to isoflurane
(2.5 minimum alveolar concentration), followed by a 10-minute washout
before aortic cross-clamping and cardioplegic arrest. Ten case-matched
control patients underwent an equivalent period (15 minutes) of
prearrest isoflurane-free bypass. Outcome measurements included
troponin I and creatine kinase–MB isoenzyme (until the third
postoperative day) levels and the activity of ecto-5'-nucleotidase,
which contributes to adenosine production and is
considered to be a reporter of protein kinase C activation, as
assessed in right atrial biopsy samples taken before bypass and at the
end of the preconditioning protocol (or after 15 minutes of bypass in
control patients). Aortic cross-clamping times did not differ between
the 2 groups: 52±14 and 48±14 minutes (mean±SD) in control and
isoflurane-preconditioned patients, respectively. Likewise, prebypass
values of ecto-5'-nucleotidase were similar in control (3.54±0.86
nmol · mg protein-1 · min-1)
and isoflurane-treated (2.98±1.08 nmol · mg
protein-1 · min-1) patients. The
values subsequently remained unchanged in control patients (3.62±0.94
nmol · mg protein-1 · min-1),
whereas they significantly increased after isoflurane preconditioning
(4.74±0.50 nmol · mg protein-1 ·
min-1; P<0.002 versus baseline values,
P<0.004 versus time-matched values in control
patients). This was paralleled by a consistently smaller
release of troponin I, which yielded an area under the curve and a peak
value of 204±147 ng · mL-1 ·
min-1 and 3.98±2.83 ng/mL, respectively, versus 284±136
ng · mL-1 · min-1 and
5.88±3.64 ng/mL, respectively, in control patients. The release of
creatine kinase–MB featured a similar pattern. There were no adverse
effects related to isoflurane.
Conclusions—These data support a cardioprotective effect of
isoflurane and, more generally, demonstrate the feasibility of
pharmacologically preconditioning the human heart during cardiac
surgery.
Key Words: ischemia • bypass • anesthesia
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Introduction
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Ischemic preconditioning is recognized as one of the most
effective
means of reducing cellular necrosis. As such, its
implementation
during cardiac surgery might be clinically relevant,
particularly
in high-risk patients in whom any additional myocardial
ischemic
injury induced with cardiopulmonary bypass and
superimposed
cardioplegic arrest can adversely affect postoperative
outcome.
Because in this setting it is particularly desirable to avoid
an
ischemic-type preconditioning stimulus,
1 2 3
extensive research
is targeted toward identifying the pharmacological
mediators
of the preconditioning phenomenon in an attempt to exploit
them
therapeutically.
There is compelling evidence that the preconditioning signal
activates various membrane receptors, which triggers a
signaling pathway leading to the activation of several
kinases,4 in particular, protein kinase C
(PKC),5 and the subsequent opening of ATP-dependent
potassium channels, possibly at the mitochondrial
level.6 7 How opening of these channels elicits
cardioprotection is not yet established but might involve the
limitation of calcium influx, better control of cellular volume, or
both. This scheme provides a framework for rationalizing interventions
targeted at mimicking preconditioning and, in this perspective, makes
logical the use, among other drugs, of potassium channel
openers.
Within this class of drugs, only nicorandil is currently available for
human use. However, aside from the fact that nicorandil cannot be
administered intravenously, this compound has marked
nitrovasodilatory properties, which can be of concern. Alternatively,
isoflurane is a volatile anesthetic agent that has been reported in
animal models of regional ischemia8 9 10 to have
infarct-limiting properties similar to those of ischemic
preconditioning and presumably involving the activation of potassium
channels.8 Although isoflurane is commonly used during
cardiac surgery to relieve bursts of hypertension, the effects of its
administration as a preconditioning agent have not yet been tested. The
present clinical study was designed to address this issue.
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Methods
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Protocol
Twenty patients undergoing elective CABG were prospectively
studied
after approval by our institutional review committee. The
conduct
of anesthesia and surgery was similar in all
patients. For anesthesia,
fentanyl, flunitrazepam, and
pancuronium were used in a standard
combination, but care was taken to
avoid the administration
of isoflurane until the onset of
cardiopulmonary bypass. The
heart was approached through a
median sternotomy. After heparinization,
cardiopulmonary bypass
was established with a single 2-stage
right atrial cannula and an
ascending aortic cannula, and the
left ventricle was vented through the
right superior pulmonary
vein. The extracorporeal circuit
consisted of a nonpulsatile
roller pump, a membrane oxygenator, and a
20-µm arterial
line filter. Once bypass was run at full
flow (2.2 L ·
min
-1 ·
m
2 body area
-1) with the
heart totally decompressed,
patients were randomly assigned to the
control or preconditioning
group. Preconditioning was achieved with a
5-minute exposure
to isoflurane (2.5 minimum alveolar concentration),
followed
by 10 minutes of isoflurane-free bypass before aortic
cross-clamping.
Isoflurane was added to the gas mixture admitted in the
oxygenator.
Control patients underwent a time-matched (15-minute)
period
of isoflurane-free cardiopulmonary bypass. After aortic
cross-clamping,
myocardial protection was provided with minimally
diluted blood
cardioplegia delivered retrogradely through the
coronary sinus
in a continuous fashion, as previously
described. The core temperature
was allowed to drift
spontaneously to 33°C to 34°C,
and blood cardioplegia was
administered at this same tepid temperature.
End Points
The assessment of results was made on blood markers of
myocardial necrosis and tissue markers of PKC activation. To detect
perioperative myocardial necrosis, blood levels of
creatine kinase–MB isoenzyme (CK-MB) and troponin I were serially
measured with the mass technique and the Stratus II automated 2-site
fluorometric enzyme immunoassay (Dade Diagnostika), respectively, after
the induction of anesthesia, on arrival in the intensive
care unit, and at 6 hours and 1, 2, and 3 days after surgery. To detect
PKC activation, right atrial biopsy samples were taken before bypass
and then either at the end of the 15-minute preconditioning cycle in
isoflurane-treated patients or after an equivalent pump time in control
patients. Tissue specimens were frozen and stored under liquid
nitrogen, and the ectosolic and cytosolic 5'-nucleotidase activities
were measured as previously described.11 In brief, the
myocardium was separated into its membrane (ectosolic and
cytosolic) fractions as follows. The tissue was homogenized
for 5 minutes in 10 vol of ice-cold 10 mmol/L HEPES-KOH buffer (pH
7.4) containing 0.25 mol/L sucrose, 1 mmol/L
MgCl2, and 1 mmol/L mercaptoethanol at
0°C. The crude homogenate was strained through a
double-layer nylon sieve and homogenized again for 1
minute. To prepare a crude membrane fraction, part of the
homogenate was centrifuged at 1000g for
10 minutes. The resulting pellet was washed 3 times and resuspended in
the HEPES-KOH buffer. To prepare the cytosolic fraction, the remaining
portion of the homogenate was first centrifuged at
3000g for 10 minutes, and the supernatant was
centrifuged at 200 000g for 1 hour. The membrane
and cytosolic fractions were dialyzed at 4°C for 4 hours against
10 mmol/L HEPES-KOH (pH 7.4) containing 1 mmol/L
MgCl2, 1 mmol/L mercaptoethanol, and 0.01%
activated charcoal and were divided into aliquots that were
frozen immediately and stored at -80°C. We have previously shown
that with this procedure, the recovery of 5'-nucleotidase activity in
the membrane fraction is 97%. 5'-Nucleotidase activity was assessed
with the enzymatic assay technique and is reported in units of
nanomoles per milligrams of protein per minute. Protein
concentration was measured according to the method of Lowry et
al,12 with BSA used as standard.
Statistical Analysis
The release of CK-MB mass (ng ·
mL-1 · h-1) and
troponin I (ng · mL-1 ·
h-1) over the first postoperative 72 hours was
calculated as the area under the curve (AUC) by use of a curve-fitting
application that generated a series of rectangles between consecutive
points on the curve. The area of these rectangles was then summed.
Postoperative enzymatic values were also compared with the use of a
2-factor ANOVA with repeated measures. Data on 5'-nucleotidase activity
were compared with the use of paired and unpaired t tests.
Significance was set at the 0.05 level. Results are reported as
mean±SD values.
|
Results
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The clinical profile and intraoperative data for the patients
are
summarized in the Table
. The 2
cohorts were similar with
respect to all parameters. As
shown in Figure 1
, prebypass values
for
ecto-5'-nucleotidase activity did not differ between the
2 groups. The
values subsequently remained unchanged in control
patients, whereas
they significantly increased after isoflurane
preconditioning
(
P<0.002 versus baseline values,
P<0.004
versus
time-matched values in control patients). Likewise, baseline
activities
for cyto-5'-nucleotidase were similar in control
(9.1±0.9 nmol
· mg protein
-1 ·
min
-1) and
isoflurane-preconditioned (9.3±2.3
nmol · mg protein
-1 ·
min
-1) patients. However, in contrast to the
ectosolic
fraction, the cytosolic fraction did not change significantly
thereafter
and, after 15 minutes of bypass, averaged 8.1±2.5 and
9.2±1.7
nmol · mg protein
-1 ·
min
-1 in control and isoflurane-preconditioned
patients,
respectively.
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Figure 1. Effects of isoflurane preconditioning on ectosolic
activities of 5'-nucleotidase. For each patient (n=10 per group), right
atrial biopsy samples were taken before bypass (baseline) and either at
the end of the preconditioning (PC) protocol or at a time-matched study
point in control patients. Data are expressed as mean±SD values. CPB
indicates cardiopulmonary bypass.
|
|
The postoperative release of CK-MB was consistently smaller in
the isoflurane-preconditioned group than in the control group, with
AUCs being 1043±338 and 1393±570 ng ·
mL-1 · h-1,
respectively (Figure 2). The release of
troponin I displayed a similar pattern; it yielded an AUC of
204.5±146.7 and 284.5±136.4 ng ·
mL-1 · h-1 in
isoflurane-preconditioned and control patients, respectively (Figure 3). In keeping with these data, peak
values of CK-MB (recorded on arrival in the intensive care unit)
and troponin I (recorded 6 hours after surgery) were also lower in
patients receiving isoflurane preconditioning than in
nonpreconditioned patients (41.60±13.11 versus
70.67±33.67 µg/L and 3.98±2.83 versus 5.88±3.64 µg/L,
respectively). However, none of the differences in enzyme levels
between the 2 groups reached the threshold of statistical
significance.
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|
Figure 2. Effects of isoflurane preconditioning on
postoperative CK-MB release. Data are expressed as mean±SD.
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Figure 3. Effects of isoflurane preconditioning on
postoperative troponin I release. Data are expressed as mean±SD.
|
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There were no isoflurane-related side effects. Postoperatively, there
were no deaths, and no patient had a transmural myocardial infarction.
Inotropic support was required in 1 control patient and in none of the
isoflurane-preconditioned group. The time to extubation was 10±3 and
9±3 hours in the control and isoflurane groups, respectively.
|
Discussion
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The major finding of this study is that ecto-5'-nucleotidase
activity
significantly increased in patients receiving isoflurane
according
to a preconditioning protocol. There is a large body of
evidence
implicating PKC as a critical mediator of the cardioprotective
response
to this preconditioning phenomenon.
5 In the human
heart, however,
such an involvement has, until now, been exclusively
based on
in vitro studies that used cultured
cardiomyocytes
13 or right
atrial
trabeculae
14 subjected to "simulated"
ischemia/reperfusion
(in fact,
anoxia/reoxygenation) and showed that PKC agonists
and
antagonists trigger or blunt the preconditioning response,
respectively.
More direct evidence for a role of PKC has been the
demonstration
of the cytosol-to-membrane translocation of its
-isoform induced
through the exposure of human
cardiomyocytes to adenosine.
13
However, until the assay of the PKC isoforms most relevant
to
cardioprotection can be accurately performed in human biopsy
samples
taken during cardiac surgery, one has to rely on surrogate
markers like
ecto-5'-nucleotidase. This enzyme, which releases
adenosine
from 5'-cAMP, is 1 of the substrates that is
phosphorylated
by PKC,
15 16 and elevation
of its levels therefore stands as
a reporter of PKC activation.
The more direct involvement of ecto-5'-nucleotidase in mediating the
cardioprotective preconditioning response is a different and more
controversial issue. The activity of ecto-5'-nucleotidase has been
reported to increase after ischemic
preconditioning,17 and this increase has been linked to an
improvement in cardioprotection, because (1) the loss of the
infarct-limiting effect of preconditioning correlates with the decay of
activation of ecto-5'-nucleotidase18 and (2) this
infarct-limiting effect is equally blunted after the administration of
an inhibitor of ecto-5'-nucleotidase.11 Other
studies,19 however, have failed to show that
ecto-5'-nucleotidase is required for ischemic preconditioning
to elicit an infarct-limiting effect. Several factors can account for
these discrepant data, including differences in species, experimental
protocols, and end points. This controversy also arises in large part
from the fact that if ecto-5'-nucleotidase played a major role in
mediating preconditioning, one would expect it to cause an elevation of
adenosine levels in myocardial tissue, whereas an opposite
pattern (ie, a decrease in tissue adenosine) has been reported
during classic ischemic preconditioning,20 as well
as after pharmacological preconditioning with isoflurane21
or potassium channel openers.22 In turn, one could argue
that because of the predominantly endothelial location
of ecto-5'-nucleotidase,18 20
endothelium-derived adenosine may be
preferentially released into the vascular compartment and thus escape
interstitial fluid sampling with microdialysis techniques
(indeed, a reduction in ischemic changes occurring with
repeated balloon occlusions during angioplasty procedures correlates
with an increased release of adenosine in the coronary
venous effluent).23 Together, these considerations suggest
that it is important to make a clear distinction between
ecto-5'-nucleotidase, taken as a surrogate marker of PKC activation,
which sounds acceptable, and ecto-5'-nucleotidase, taken as an
intrinsically cardioprotective compound mediating the preconditioning
response, which remains more uncertain. The results of the present
study cannot help clarify this issue, primarily because the small size
of the patient groups made it predictable that statistical
analysis would lack the power to demonstrate significant
differences in postoperative enzymatic or clinical outcomes. One can
only speculate that if elevated levels of ecto-5'-nucleotidase reflect
PKC activation, then the intervention causing such an elevation should
be cardioprotective because of the link between PKC activation and
enhancement of cardioprotection.24 25 The mechanism of
this relationship is thought to involve a modulatory activity of PKC on
mitochondrial potassium channels,7 which are currently
considered the likely cardioprotective end effectors of the
preconditioning signal. The involvement of these channels in humans is
strongly suggested by the finding that right atrial
trabeculae harvested intraoperatively can be preconditioned
by the potassium channel opener cromakalim,14 except for
those retrieved from diabetic patients receiving preoperative
sulfonylurea drugs known to block potassium
channels.26
Previous studies using rabbit9 10 and dog8
models of regional ischemia have shown that isoflurane could
duplicate the infarct-limiting effects of ischemic
preconditioning. The cardioprotection conferred by the anesthetic agent
does not seem to be related to changes in myocardial oxygen consumption
or coronary flow.9 A possible mechanism is that
isoflurane causes an activation of potassium channels, as suggested by
the abolishment of its infarct-limiting effects with potassium channel
blockers.8 This hypothesis is more directly supported by
the results of patch-clamp techniques showing that isoflurane increases
the probability of potassium channel opening for any given
concentration of ATP.27 This opening could then account
for the increase in ecto-5'-ectosolic activity that has been reported
after pharmacological activation of the potassium
channels.28 Alternatively, the primary target of
isoflurane could be PKC itself. The subsequent increased activity of
ecto-5'-nucleotidase would then cause a release of adenosine
and, downstream, the adenosine-induced opening of potassium
channels.28 Regardless of the precise sequence of events,
the fact that simultaneous administration of
ischemic preconditioning and isoflurane does not confer
additional protection over that yet provided by each intervention
alone8 suggests that the drug exerts its cardioprotective
effects via the same pathway as classic ischemic
preconditioning. Additional support for this hypothesis comes from the
observation that in the present study, isoflurane increased
ecto-5'-nucleotidase levels despite a 10-minute washout period, which
suggests a "memory" phase consistent with a preconditioning
pattern.
Because the primary effect of preconditioning is to reduce infarct
size, outcome analysis focused on 2 sensitive markers of
cellular necrosis: CK-MB and troponin I.29 Postoperative
values of these 2 enzymes were consistently lower in
preconditioned patients than in their control counterparts, which is
consistent with the cardioprotective effects of isoflurane.
That the between-group difference failed to achieve statistical
significance can be explained by (1) the small sample size and (2) the
already low levels of troponin I yielded by our control patients, which
makes more difficult the demonstration of a further significant
improvement. Thus, in this group, the 24-hour postoperative value
averaged 4.4 µg/L, which compares favorably with the value of 5.2
µg/L reported at the same time point by Sadony and
coworkers30 in patients classified as having minor
myocardial damage. Likewise, the peak value observed (at 6 hours
postoperatively) in our series (5.8 µg/L) is much lower than the
cutoff value (13.4 µg/L) shown by Jacquet and
associates31 to significantly separate those patients with
an uneventful recovery from those with ischemia/infarction.
We acknowledge several limitations of this study. First,
ecto-5'-nucleotidase activity was measured in right atrial biopsy
samples, which does not necessarily reflect changes occurring in
ventricular myocardium. Nevertheless, a study
of the activity of 5'-nucleotidase in the human heart failed to detect
differences between these 2 sites.32 Second,
ecto-5'-nucleotidase activity was determined only at baseline and at
the completion of the preconditioning protocol. A subsequent
measurement during the period of aortic cross-clamping was not possible
because of the limited amount of right atrial tissue available for
sampling; consequently, the time course of ecto-5'-nucleotidase
activity throughout the operation cannot be conclusively established.
However, previous experimental studies17 have shown that
the increase in ecto-5'-nucleotidase activity elicited by the
preconditioning signal tended to be further enhanced during the
subsequent period of prolonged ischemia, from which sustained
protection can be expected. Third, because the primary objective of
this study was to assess whether the use of isoflurane could elicit a
biochemical event characteristic of preconditioning, no functional
studies were performed. It is, however, noteworthy that experimentally,
this anesthetic agent has demonstrated marked antistunning
effects.33 This finding is consistent with the
previously mentioned observation that interventions that cause PKC
activation (as expected to have occurred in this study after isoflurane
treatment in view of the elevated levels of ecto-5'-nucleotidase)
improve the recovery of function after cardioplegic
arrest.24 25 Despite these caveats, the present data
demonstrate that even if cardiopulmonary bypass, by
itself,34 and opioid-based
anesthesia35 have a preconditioning effect,
there is still some room left for additional compounds like isoflurane
to act as preconditioning mimetics in the human heart. As such, these
results support additional studies to determine how this drug or others
can be optimally used to "turn on" the signaling pathway
responsible for the cardioprotective effects of preconditioning.
|
Acknowledgments
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This work was supported in part by European Commission,
Biomed-2
Concerted Action Grant 95-0838, "The New Ischemic
Syndromes."
|
Footnotes
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Reprint requests to Philippe Menasché, MD, PhD, Department
of Cardiovascular Surgery, Hoptial Laribosière, 2, rue
Ambroise Paré, 75475 Paris Cedex 10, France.
|
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Abstract
Introduction