Effects of Ischemic Preconditioning
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.
- Copyright © 1998 by American Heart Association
Cohen MV, Yang XM, Downey JM. Conscious rabbits become tolerant to multiple episodes of ischemic preconditioning. Circ Res.. 1994;74:998–1004.
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.
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.
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.
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.
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.
We appreciate the comments of Drs Duncker and Verdouw.
Their 1995 publicationR1 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 findingR2 and antedates our publication. Koning et alR1 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 alR3 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.
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.
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.
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.