Abstract
Hypothermia induced at the onset of ischemia is a potent experimental cardioprotective strategy for myocardial infarction. The aim of our study was to determine whether the beneficial effects of hypothermia may be due to decreasing mitochondria-mediated mechanisms of damage that contribute to the pathophysiology of ischemia/reperfusion injury. New Zealand male rabbits were submitted to 30 min of myocardial ischemia with hypothermia (32 °C) induced by total liquid ventilation (TLV). Hypothermia was applied during ischemia alone (TLV group), during ischemia and reperfusion (TLV-IR group) and normothermia (Control group). In all the cases, ischemia was performed by surgical ligation of the left anterior descending coronary artery and was followed by 3 h of reperfusion before assessment of infarct size. In a parallel study, male C57BL6/J mice underwent 30 min myocardial ischemia followed by reperfusion under either normothermia (37 °C) or conventionally induced hypothermia (32 °C). In both the models, the levels of the citric acid cycle intermediate succinate, mitochondrial complex I activity were assessed at various times. The benefit of hypothermia during ischemia on infarct size was compared to inhibition of succinate accumulation and oxidation by the complex II inhibitor malonate, applied as the pro-drug dimethyl malonate under either normothermic or hypothermic conditions. Hypothermia during ischemia was cardioprotective, even when followed by normothermic reperfusion. Hypothermia during ischemia only, or during both, ischemia and reperfusion, significantly reduced infarct size (2.8 ± 0.6%, 24.2 ± 3.0% and 49.6 ± 2.6% of the area at risk, for TLV-IR, TLV and Control groups, respectively). The significant reduction of infarct size by hypothermia was neither associated with a decrease in ischemic myocardial succinate accumulation, nor with a change in its rate of oxidation at reperfusion. Similarly, dimethyl malonate infusion and hypothermia during ischemia additively reduced infarct size (4.8 ± 2.2% of risk zone) as compared to either strategy alone. Hypothermic cardioprotection is neither dependent on the inhibition of succinate accumulation during ischemia, nor of its rapid oxidation at reperfusion. The additive effect of hypothermia and dimethyl malonate on infarct size shows that they are protective by distinct mechanisms and also suggests that combining these different therapeutic approaches could further protect against ischemia/reperfusion injury during acute myocardial infarction.
Highlights
MethodsAcute myocardial infarction (AMI) is a leading cause of cardiovascular death, and the primary cause of chronic heart failure worldwide [4]
Rabbits cooled by the same method and maintained cool during reperfusion showed a significant decrease of infarct size compared to discrete hypothermia only during ischemia (2.8 ± 0.6%, 24.9 ± 3.0% and 49.6 ± 2.6% of the area at risk, in total liquid ventilation (TLV)-IR, TLV and Control groups, respectively; Fig. 1c)
This was consistent with the effect of cooling on mice maintained at 32 °C during ischemia and reperfusion, which showed a significant decrease of infarct size in hypothermic mice as compared to normothermic controls (16.0 ± 1.9% vs. 39.8 ± 3.7%, respectively; Fig. 2b)
Summary
MethodsAcute myocardial infarction (AMI) is a leading cause of cardiovascular death, and the primary cause of chronic heart failure worldwide [4]. PCI-mediated tissue reperfusion of ischemic tissue in itself causes irreversible myocardial damage due to reperfusion injury [12]. The induction of mild hypothermia of 32–34 °C at the onset of ischemia that is maintained throughout reperfusion provides effective cardioprotection in experimental models of AMI [5, 10, 28]. Induction of cooling at reperfusion alone does not reduce infarct size, both in experimental [11, 21, 28] and clinical settings [9]. This suggests that hypothermic cardioprotection is related to pathways associated with ischemia, rather than during reperfusion. An appealing potential cardioprotective mechanism of hypothermia during ischemia is to decrease the extent of succinate accumulation during ischemia and thereby lessen tissue injury upon reperfusion
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