title: 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.
abstract: 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.
authors.affiliation: Laboratory of Experimental Anaesthesiology, Department of Anaesthesiology, Academic Medical Centre, Amsterdam, The Netherlands. c.j.zuurbier@amc.uva.nl.|Department of Anaesthesiology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands. c.j.zuurbier@amc.uva.nl.
authors.forename: Coert J
authors.initials: CJ
authors.lastname: Zuurbier
authors.affiliation: Institute of Cardiovascular Physiology, Heinrich-Heine University, Düsseldorf, Germany. AHeinen@med.uni-duesseldorf.de.
authors.forename: Andre
authors.initials: A
authors.lastname: Heinen
authors.affiliation: Laboratory of Experimental Anaesthesiology, Department of Anaesthesiology, Academic Medical Centre, Amsterdam, The Netherlands. a.vangalen@amc.uva.nl.
authors.forename: Anneke
authors.initials: A
authors.lastname: Koeman
authors.affiliation: Laboratory of Experimental Anaesthesiology, Department of Anaesthesiology, Academic Medical Centre, Amsterdam, The Netherlands. roystuifbergen@hotmail.com.
authors.forename: Roy
authors.initials: R
authors.lastname: Stuifbergen
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre, Amsterdam, The Netherlands. t.hakvoort@amc.uva.nl.
authors.forename: Theodorus B M
authors.initials: TB
authors.lastname: Hakvoort
authors.affiliation: Laboratory of Experimental Anaesthesiology, Department of Anaesthesiology, Academic Medical Centre, Amsterdam, The Netherlands. n.c.hauck@amc.uva.nl.
authors.forename: Nina C
authors.initials: NC
authors.lastname: Weber
authors.affiliation: Laboratory of Experimental Anaesthesiology, Department of Anaesthesiology, Academic Medical Centre, Amsterdam, The Netherlands. m.w.hollmann@amc.uva.nl.
authors.forename: Markus W
authors.initials: MW
authors.lastname: Hollmann
mesh_terms: D000777:Anesthetics / Q000008:administration & dosage*; D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005492:Folic Acid / Q000008:administration & dosage*; D006304:Health Status; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats
chemical_list: D000777:Anesthetics; D002316:Cardiotonic Agents; D005492:Folic Acid