title: The effect of perhexiline on myocardial protection during coronary artery surgery: a two-centre, randomized, double-blind, placebo-controlled trial.
abstract: OBJECTIVE
  Perhexiline is thought to modulate metabolism by inhibiting mitochondrial carnitine palmitoyltransferase-1, reducing fatty acid uptake and increasing carbohydrate utilization. This study assessed whether preoperative perhexiline improves markers of myocardial protection in patients undergoing coronary artery bypass graft surgery and analysed its effect on the myocardial metabolome.
  
  
  METHODS
  In a prospective, randomized, double-blind, placebo-controlled trial, patients at two centres were randomized to receive either oral perhexiline or placebo for at least 5 days prior to surgery. The primary outcome was a low cardiac output episode in the first 6 h. All pre-specified analyses were conducted according to the intention-to-treat principle with a statistical power of 90% to detect a relative risk of 0.5 and a conventional one-sided α-value of 0.025. A subset of pre-ischaemic left ventricular biopsies was analysed using mass spectrometry-based metabolomics.
  
  
  RESULTS
  Over a 3-year period, 286 patients were randomized, received the intervention and were included in the analysis. The incidence rate of a low cardiac output episode in the perhexiline arm was 36.7% (51/139) vs 34.7% (51/147) in the control arm [odds ratio (OR) 0.92, 95% confidence interval (CI) 0.56-1.50, P = 0.74]. Perhexiline was associated with a reduction in the cardiac index at 6 h [difference in means 0.19, 95% CI 0.07-0.31, P = 0.001] and an increase in inotropic support in the first 12 h (OR 0.55, 95% CI 0.34-0.89, P = 0.015). There were no significant differences in myocardial injury with troponin-T or electrocardiogram, reoperation, renal dysfunction or length of stay. No difference in the preischaemic left ventricular metabolism was identified between groups on metabolomics analysis.
  
  
  CONCLUSIONS
  Preoperative perhexiline does not improve myocardial protection in patients undergoing coronary surgery and in fact reduced perioperative cardiac output, increasing the need for inotropic support. Perhexiline has no significant effect on the mass spectrometry-visible polar myocardial metabolome in vivo in humans, supporting the suggestion that it acts via a pathway that is independent of myocardial carnitine palmitoyltransferase inhibition and may explain the lack of clinical benefit observed following surgery.
  
  
  BACKGROUND
  NCT00845364.
authors.affiliation: Department of Cardiothoracic Surgery, Queen Elizabeth Hospital Birmingham, Birmingham, UK School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Nigel E
authors.initials: NE
authors.lastname: Drury
authors.affiliation: Department of Cardiothoracic Surgery, Queen Elizabeth Hospital Birmingham, Birmingham, UK School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Howell
authors.affiliation: School of Health and Population Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Calvert
authors.affiliation: Centre for Systems Biology, School of Biosciences, University of Birmingham, Birmingham, UK.
authors.forename: Ralf J M
authors.initials: RJ
authors.lastname: Weber
authors.affiliation: Department of Cardiothoracic Surgery, Queen Elizabeth Hospital Birmingham, Birmingham, UK School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Eshan L
authors.initials: EL
authors.lastname: Senanayake
authors.affiliation: Department of Cardiothoracic Surgery, Royal Sussex County Hospital, Brighton.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Lewis
authors.affiliation: Department of Cardiothoracic Surgery, Royal Sussex County Hospital, Brighton.
authors.forename: Jonathan A J
authors.initials: JA
authors.lastname: Hyde
authors.affiliation: Department of Cardiac Anesthesia, Queen Elizabeth Hospital Birmingham, Birmingham, UK.
authors.forename: David H
authors.initials: DH
authors.lastname: Green
authors.affiliation: Department of Cardiothoracic Surgery, Queen Elizabeth Hospital Birmingham, Birmingham, UK.
authors.forename: Jorge G
authors.initials: JG
authors.lastname: Mascaro
authors.affiliation: Department of Cardiothoracic Surgery, Queen Elizabeth Hospital Birmingham, Birmingham, UK.
authors.forename: Ian C
authors.initials: IC
authors.lastname: Wilson
authors.affiliation: Department of Cardiothoracic Surgery, Queen Elizabeth Hospital Birmingham, Birmingham, UK.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Graham
authors.affiliation: Department of Cardiothoracic Surgery, Queen Elizabeth Hospital Birmingham, Birmingham, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Rooney
authors.affiliation: Centre for Systems Biology, School of Biosciences, University of Birmingham, Birmingham, UK.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Viant
authors.affiliation: Department of Primary Care and Population Health, University College London, London, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Freemantle
authors.affiliation: School of Medicine, University of Aberdeen, Aberdeen, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Frenneaux
authors.affiliation: Department of Cardiothoracic Surgery, Queen Elizabeth Hospital Birmingham, Birmingham, UK School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK domenico.pagano@uhb.nhs.uk.
authors.forename: Domenico
authors.initials: D
authors.lastname: Pagano
mesh_terms: D000368:Aged; D002302:Cardiac Output / Q000187:drug effects; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D001026:Coronary Artery Bypass / Q000009:adverse effects / Q000379:methods*; D003331:Coronary Vessels / Q000601:surgery*; D004311:Double-Blind Method; D005260:Female; D006352:Heart Ventricles / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008297:Male; D055442:Metabolome / Q000187:drug effects; D008875:Middle Aged; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D010480:Perhexiline / Q000627:therapeutic use*; D010919:Placebos; D011183:Postoperative Complications; D011446:Prospective Studies
chemical_list: D002316:Cardiotonic Agents; D010919:Placebos; D010480:Perhexiline
keywords: Cardiac output; Metabolism; Metabolomics; Myocardial reperfusion injury; Myocardial stunning