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Background: Acute, high-dose folic acid (FA) administration has recently been shown to possess unprecedented effective cardioprotection against ischaemia/reperfusion (I/R) injury. Here we explore the translation potential of FA as treatment modality for cardiac I/R. Methods: Dependency of FA protection on dose, ischaemia duration, and eNOS was examined in an isolated mouse heart I/R model, whereas dependency on animal health status and anaesthesia was examined in an in vivo rat model of regional cardiac I/R. Results: 50 μM FA provided maximal reduction (by 95%) of I/R-induced cell death following 25 min ischaemia in isolated wild-type hearts, with protection associated with increased coupled eNOS protein. No protection was observed with 35 min I or in eNOS-/- hearts. Acute intravenous administration of FA during a 25 min ischaemic period reduced infarct size by 45% in in vivo pentobarbital-anaesthetised young, healthy rats. FA did not reduce infarct size in aged or pre-diabetic rats, although it did preserve hemodynamics in the pre-diabetic rats. Finally, using a clinically-relevant anaesthetic regimen of fentanyl-propofol anaesthesia, FA treatment was ineffective in young, aged and pre-diabetic animals. Conclusions: The protective potential of an initially promising cardioprotective treatment of high dose FA against cardiac I/R infarction, is critically dependent on experimental conditions with relevance to the clinical condition. Our data indicates the necessity of expanded pre-clinical testing of cardioprotective interventions before embarking on clinical testing, in order to prevent too many "lost-in-translation" drugs and unnecessary clinical studies.
Zuurbier, C. J., Heinen, A., Koeman, A., Stuifbergen, R., Hakvoort, T. B. M., Weber, N. C., & Hollmann, M. W. (2014). Cardioprotective efficacy depends critically on pharmacological dose, duration of ischaemia, health status of animals and choice of anaesthetic regimen: A case study with folic acid. Journal of Translational Medicine, 12(1). https://doi.org/10.1186/s12967-014-0325-8