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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.
Highlights
Abundant scientific reports have documented that exposure to brief and repetitive episodes of acute vascular occlusion with intermittent reperfusion prior to a prolonged period of sustained vessel occlusion—“ischemic conditioning”—can significantly reduce the extent of organ injury [1] [2] in animals [3] and humans [4] [5] as long as there is adequate reperfusion of the ischemic zone.In the heart, “ischemic conditioning” reduces the incidence of ventricular dysrhythmias and post-ischemic contractile dysfunction
Nonconvertible ventricular fibrillation (VF) occurred in two rabbits that were excluded from the statistical analysis
Values for this index decreased relative to baseline in all groups but a significant group effect was not observed; these data are consistent with previous observations for ischemia-reperfusion in this animal model
Summary
“ischemic conditioning” reduces the incidence of ventricular dysrhythmias and post-ischemic contractile dysfunction (i.e. myocardial stunning) Protection afforded by this non-pharmacologic intervention is immediate and can be triggered by release of endogenous mediators (nitric oxide, adenosine, bradykinin) [6] [7] and activation of complex second messenger systems [8] and antioxidant pathways [9]. Non-pharmacologic approaches to cellular protection, such as ischemic conditioning, delay onset of cellular injury in most organs in a host of animal species; the degree of protection is limited to rather short durations of ischemia. 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.
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