(Circulation. 1998;97:1211-1212.)
© 1998 American Heart Association, Inc.
Effects of Ischemic Preconditioning
Dirk J. Duncker, MD, PhD;
; Pieter D. Verdouw, PhD
Experimental Cardiology, Thoraxcenter,
Erasmus University Rotterdam,
Rotterdam, The Netherlands
To the Editor:
The clinical existence and relevance of ischemic
preconditioning will remain difficult to prove because patients cannot
be subjected to the rigorous protocols performed in laboratory animals
and because of our inability to accurately determine infarct size and
its determinants in humans. Furthermore, the presence of
atherosclerotic lesions in coronary arteries can result in
intermittent/chronic ischemia that could result in tolerance to
the ischemic stimulus.1 Consequently,
investigating the phenomenon of ischemic preconditioning in
animal models that mimic the clinical situation is important. It was
therefore with great interest that we read the article by Kapadia et
al2 in which they describe that the protective
effect of ischemic preconditioning is not abolished in the
presence of a critical stenosis. Although this study in a
closed chest swine model is another major step forward in bridging the
gap between the laboratory and the clinical setting, there are a number
of issues that deserve comment.
The authors did not find a protective effect of the
stenosis alone, which reduced blood flow by approximately 35%
(P=NS), and indicated that this finding is at variance with
the results of a study from our laboratory in which we showed that
30-minute 70% flow reduction resulted in a reduction of infarct size
produced by 60 minutes of coronary artery
occlusion.3 However, in a subsequent
study4 we demonstrated that when flow was reduced
by only 30% for up to 90 minutes immediately preceding the 60 minutes
of total coronary occlusion, cardioprotection was absent.
Furthermore, Ovize et al5 reported that 25
minutes of 50% flow reduction immediately preceding the total
coronary occlusion failed to limit infarct size, suggesting
that the flow reduction in the study by Kapadia et
al2 was not severe enough to produce
cardioprotection.
Although the stenosis did not abolish ischemic
preconditioning, the authors concluded that the presence of a critical
stenosis might limit preconditioning despite a nonsignificant
trend (versus P=.60) toward a difference in infarct size in
the preconditioning+stenosis group (PC/S) and the
preconditioning group (PC). Such a conclusion appears premature in view
of a number of methodologic considerations. First, collateral
myocardial blood flow tended to be higher in the PC than in the PC/S
group. Second, the relation between area of necrosis (AN) and the area
at risk (AAR) is linear but not proportional because of a positive
intercept on the AR-axis, so that at an AAR that comprises 5% of the
left ventricle, no infarction occurs.4
Consequently the ratio of AN/AAR depends on the AAR, so that AN/AAR
decreases at smaller AAR. In the present study there was a trend
toward a smaller AAR in PC versus PC/S, which could have contributed to
the trend toward a larger infarct size in PC/S than in PC. Finally,
body temperature may have varied considerably despite the closed chest,
particularly during recovery from anesthesia, when the
animals exhibited tremulousness. Because temperature is an important
determinant of infarct size in swine,6 this could
have further added to differences between experimental groups.
In contrast to the obvious advantages of this closed chest swine
model, the very high dropout rates caused by refractory fibrillation
and technical problems pose a serious disadvantage, making such studies
laborious and expensive. Nonetheless we may have to rely on such models
for assessment of clinical relevance of the ischemic
preconditioning phenomenon. Development of a chronically instrumented
animal model in which myocardial function, perfusion, and
metabolism can be monitored and the effects of the presence
of a chronic (days to weeks) stenosis possibly resulting in
repetitive stunning and/or hibernation will be a next step in the
assessment of the clinical relevance of ischemic
preconditioning.
References
1.
Cohen MV, Yang XM, Downey JM. Conscious rabbits become
tolerant to multiple episodes of ischemic preconditioning.
Circ Res.. 1994;74:998–1004.[Abstract/Free Full Text]
2.
Kapadia SJ, Terlato JS, Most AS. Presence of a critical
coronary artery stenosis does not abolish the
protective effect of ischemic preconditioning.
Circulation.. 1997;95:1286–1292.[Abstract/Free Full Text]
3.
Koning MMG, Simonis LAJ, De Zeeuw S, Nieukoop S, Post S,
Verdouw PD. Ischaemic preconditioning by partial occlusion without
intermittent reperfusion. Cardiovasc Res.. 1994;28:1146–1151.[Abstract/Free Full Text]
4.
Koning MMG, Gho BCG, Van Klaarwater E, Duncker DJ, Verdouw PD.
Endocardial and epicardial infarct size after preconditioning by a
partial coronary occlusion without intervening reperfusion:
importance of the degree and duration of flow reduction.
Cardiovasc Res.. 1995;30:1017–1027.[Medline]
[Order article via Infotrieve]
5.
Ovize M, Przyklenk K, Kloner RA. Partial coronary
stenosis is sufficient and complete reperfusion is mandatory
for preconditioning the canine heart. Circ Res.. 1992;71:1165–1173.[Abstract/Free Full Text]
6.
Duncker DJ, Klassen CL, Herrlinger SH, Pavek TJ, Ishibashi Y,
Bache RJ. Effect of temperature on myocardial infarction in swine.
Am J Physiol.. 1996;39:H1189–H1199.
Response
Albert S. Most, MD;
; Joseph S. Terlato, MD
Department of Medicine,
Rhode Island Hospital,
Providence, RI
Shaival J. Kapadia, MD
Richmond, Va
We appreciate the comments of Drs Duncker and Verdouw.
Their 1995 publication1 was
inadvertently overlooked in our search of the
literature. They found no cardioprotection as a result of a 30%
reduction in coronary blood flow before coronary
occlusion. This is consistent with our
finding2 and antedates our publication. Koning et
al1 allowed full reperfusion in the period after
release of the total coronary occlusion, a difference between
our studies that is not clear in its implication for myocardial
preservation. The study by Ovize et al3 was cited
but the difference between our protocols was quite significant. In that
report, 15 minutes (not 25 minutes) of an approximately 50% flow
reduction failed to produce a preconditioning effect when there was no
intervening period of full reperfusion after the partial flow
restriction. The difference in severity of ischemia, the added
effect of full reperfusion after the period of total occlusion, and the
use of dogs rather than swine render that study considerably different
from the one we reported. Nevertheless, it is another negative study
with respect to a partial coronary artery occlusion as a
preconditioning agent.
Our results with the stenosis group that received the
preconditioning occlusion (PC/S) left us with a seemingly intermediate
result in terms of infarct as a percentage of area at risk, although
statistically, the preconditioned (PC) and PC/S groups did not differ
significantly. We wanted to recognize this difference and used
tentative language to describe it. In the last paragraph of our
article, the wording was less tentative than intended. We agree that
there is no clear evidence that the stenosis attenuated the
preconditioning effect of brief occlusions.
We agree with Drs Duncker and Verdouw that in our study there was "a
trend toward a smaller AAR in PC versus PC/S, which could have
contributed to the trend toward a larger infarct size in PC/S than in
PC." As noted, the differences in AAR/LV were not significant, albeit
working with small sample sizes (30.3±3.0% in PC/S and 25.9±3.0% in
PC).
Regarding the temperature of the animals during the study, there was no
significant difference between mean temperature of PC and PC/S animals
after the first preconditioning occlusion (PC=36.8±1.26°C;
PC/S=36.5±1.08°C; x±SD).
Studies such as these are handicapped by the very high mortality
of animals and numerous technical problems. Nevertheless, efforts to
closely approximate the human condition are needed. We agree that a
reliable chronic animal model is needed and would be a significant step
forward in studies of preconditioning.
References
1.
Koning MMG, Gho BCG, Van Klaarwater E, Duncker DJ, Verdouw
PD. Endocardial and epicardial infarct size after preconditioning by a
partial coronary occlusion without intervening reperfusion:
importance of the degree and duration of flow reduction.
Cardiovasc Res. 1995;30:1017–1027.
2.
Kapadia SJ, Terlato JS, Most AS. Presence of a critical
coronary artery stenosis does not abolish the
protective effect of ischemic preconditioning.
Circulation. 1997;95:1286–1292.
3.
Ovize M, Przyklenk K, Kloner RA. Partial coronary
stenosis is sufficient and complete reperfusion is mandatory
for preconditioning the canine heart. Circ Res. 1992;71:1165–1173.
