| Summary: | Hibernating mammals offer an intriguing example of natural adaptation to physiologic extremes, illustrating mechanisms of metabolic rate depression and cell preservation strategies. Using a model of surgical deep hypothermic circulatory arrest (DHCA), we hypothesized that hibernating arctic ground squirrels (AGS) display reduced myocardial injury following I/R compared to a non-hibernator (rat) by preservation of PPARα nuclear receptor induced myocardial fatty acid utilization. Methods: Euthermic AGS aroused from hibernation and BN rats underwent either DHCA (45min, followed by 3, 6, or 24h of reperfusion) or sham. The following parameters were compared between species/time points by two-way ANOVA: 1) biochemical severity of myocardial injury (plasma HFABP, TnI, ELISA); 2) myocardial PPARα activity (ELISA) and levels of 167 metabolites (MS); 3) myocardial inflammation and leukocyte extravasation (ELISA). Results: Compared to rats, AGS displayed robust myocardial ischemic tolerance following DHCA. This was accompanied by preservation of myocardial PPARα activity in AGS, which was significantly downregulated in the rat. Organic and amino acid acid profiles suggested compromised citric acid cycle flux, enhanced urea cycle, and myocardial accumulation of dicarboxylacylcarnitines in rats vs AGS. Furthermore, myocardial inflammation was robustly attenuated in AGS vs rat (Table). Conclusion: In the first study assessing myocardial ischemic tolerance in AGS following in vivo global I/R injury, we found an association between the hibernator cardioprotective phenotype and specific differences in myocardial fuel utilization. These findings challenge the current paradigm for metabolic optimization in human myocardial I/R and heart failure, which involves promotion of glucose oxidation at the expense of fatty acid oxidation during early reperfusion by inducing an “adaptive” substrate switch opposite to that demonstrated by natural hibernators.
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