title: Myocardial protection using fructose-1,6-diphosphate during coronary artery bypass graft surgery: a randomized, placebo-controlled clinical trial.
abstract: In vitro and in vivo studies suggest that fructose-1,6-diphosphate (FDP), an intermediary glycolytic pathway metabolite, ameliorates ischemic tissue injury through increased high-energy phosphate levels and may therefore have cardioprotective properties in patients undergoing coronary artery bypass graft (CABG) surgery. We designed a randomized, placebo-controlled, double-blinded, sequential-cohort, dose-ranging safety study to test 5 FDP dosage regimens in patients (n = 120; 60 FDP, 60 control) undergoing CABG surgery. Of these dosage regimens, 3 produced no benefit, 1 produced improved cardiac function, and 1 required adjustment as a result of metabolic acidosis. This suggests that we achieved the intended effect of a dose-ranging study. The expected response was observed in patients treated with 250 mg/kg FDP IV before surgery and 2.5 mM FDP as a cardioplegic additive (n = 15). These patients had lower serum creatine kinase-MB levels 2, 4, and 6 h after reperfusion (P < 0.05), fewer perioperative myocardial infarctions (P < 0.05), and improved postoperative cardiac function, as evidenced by higher left ventricular stroke work index (LVSWI) 6, 12, and 16 h (P < 0.01) and cardiac index (CI) at 12 and 16 h (P < 0.05) after reperfusion. Overall efficacy of FDP was tested across all regimens that included IV FDP (n = 88; 44 FDP, 44 control) using 2 (FDP versus placebo) x 3 (dose size) factorial analyses. Area-under-curve (AUC) analysis demonstrated a significant increase in CI (AUC-16h, P = 0.013) and LVSWI (AUC-16h, P = 0.003) and reduction in CK-MB levels (AUC-16h, P < 0.05) in FDP-treated patients. The internal consistency of this dataset suggests that FDP may provide myocardial protection in CABG surgery and supports previous laboratory and clinical studies of FDP in ischemic heart disease.
  
  
  CONCLUSIONS
  Fructose-1,6-diphosphate (FDP) may increase high-energy phosphate levels under anaerobic conditions and therefore ameliorate ischemic injury. A dose-ranging safety study for FDP was conducted in patients undergoing coronary artery surgery. Preischemic provision of FDP significantly improved cardiac function and reduced perioperative ischemic injury. These myocardial protective effects may improve patient outcome after cardiac surgery.
authors.affiliation: *Department of Anesthesiology, Royal Brompton & Harefield NHS Trust, London, UK and †Cypros Pharmaceutical Corporation, Carlsbad, California (now incorporated into Questcor Pharmaceuticals, Inc., Hayward, California).
authors.forename: Bernhard J
authors.initials: BJ
authors.lastname: Riedel
authors.forename: Janos
authors.initials: J
authors.lastname: Gal
authors.forename: Gillian
authors.initials: G
authors.lastname: Ellis
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Marangos
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Fox
authors.forename: David
authors.initials: D
authors.lastname: Royston
mesh_terms: D000368:Aged; D002302:Cardiac Output / Q000502:physiology; D002317:Cardiovascular Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001026:Coronary Artery Bypass; D003402:Creatine Kinase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D005635:Fructosediphosphates / Q000009:adverse effects / Q000627:therapeutic use*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007036:Hypothermia, Induced; D007262:Infusions, Intravenous; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D018401:Sample Size
chemical_list: D002317:Cardiovascular Agents; D005635:Fructosediphosphates; D007527:Isoenzymes; D003402:Creatine Kinase; C029063:fructose-1,6-diphosphate