Ischemic Conditioning-Mediated Myocardial Protection in Relation to Duration of Coronary Occlusion

Abstract

Background: Myocardial ischemia is a dynamic process whereby a cascade of events is initiated to stimulate transition from reversible to irreversible cellular injury. Non-pharmacologic approaches to cellular protection, such as ischemic conditioning, delay onset of cellular injury in most organs in a host of animal species; however the degree of protection is limited to rather short durations of ischemia. In the present study, we examined whether protection afforded by ischemic conditioning could be extended beyond currently established limits of coronary occlusion in an in situ animal model. Methods: Rabbits (n = 106) were exposed to 30-, 60-, 120-, 180-, 240-, or 360-min coronary occlusion followed by 180-min coronary reperfusion (i.e. non-conditioned control groups). Ischemic conditioned rabbits were pre-treated by ischemic conditioning (i.e. 2-cycles of 5-min coronary occlusion and 5-min reperfusion) prior to a prolonged period of ischemia as described above. Area at risk (AR; by fluorescent microparticles) and area of necrosis (AN; by tetrazolium staining) were quantified by planimetry. Serum troponin I levels were assessed at baseline (i.e. before experimental protocol) and at the end of the experiment. Results: Changes in heart rate and hemodyamic indices were similar for all groups regardless of duration of ischemia and regardless of treatment (i.e. non-conditioned vs. ischemic conditioned). Infarcts (as percent AR) were markedly smaller (~35%) in ischemic conditioned rabbits (vs. controls) for the 30-min coronary occlusion group. With longer durations of coronary occlusion (60-, 120-, 180-, 240-min) infarcts were smaller (~20%) in ischemic conditioned groups but protection afforded was not statistically significant. With 360-min coronary occlusion, infarct size was the same for both treatment groups. Serum troponin I levels were greater in relation to infarct size as expected but no differences were detected between treatments regardless of ischemic duration. Conclusions: Ischemic conditioning limits infarct development; however, protection is limited when the duration of ischemia is extended beyond 4 hours. These findings provide further support for the concept that ischemic conditioning can delay, but does not limit myocyte necrosis. Underlying mechanisms for cellular protection remain to be established.