title: Adverse remodeling of the electrophysiological response to ischemia-reperfusion in human heart failure is associated with remodeling of metabolic gene expression.
abstract: BACKGROUND
  Ventricular arrhythmias occur more frequently in heart failure during episodes of ischemia-reperfusion although the mechanisms underlying this in humans are unclear. We assessed, in explanted human hearts, the remodeled electrophysiological response to acute ischemia-reperfusion in heart failure and its potential causes, including the remodeling of metabolic gene expression.
  
  
  RESULTS
  We optically mapped coronary-perfused left ventricular wedge preparations from 6 human end-stage failing hearts (F) and 6 donor hearts rejected for transplantation (D). Preparations were subjected to 30 minutes of global ischemia, followed by 30 minutes of reperfusion. Failing hearts had exaggerated electrophysiological responses to ischemia-reperfusion, with greater action potential duration shortening (P<0.001 at 8-minute ischemia; P=0.001 at 12-minute ischemia) and greater conduction slowing during ischemia, delayed recovery of electric excitability after reperfusion (F, 4.8±1.8 versus D, 1.0±0 minutes; P<0.05), and incomplete restoration of action potential duration and conduction velocity early after reperfusion. Expression of 46 metabolic genes was probed using custom-designed TaqMan arrays, using extracted RNA from 15 failing and 9 donor hearts. Ten genes important in cardiac metabolism were downregulated in heart failure, with SLC27A4 and KCNJ11 significantly downregulated at a false discovery rate of 0%.
  
  
  CONCLUSIONS
  We demonstrate, for the first time in human hearts, that the electrophysiological response to ischemia-reperfusion in heart failure is accelerated during ischemia with slower recovery after reperfusion. This can enhance spatial conduction and repolarization gradients across the ischemic border and increase arrhythmia susceptibility. This adverse response was associated with downregulation of expression of cardiac metabolic genes.
authors.affiliation: From the Department of Biomedical Engineering, Washington University in Saint Louis, MO (F.S.N., K.M.H., A.C.K., D.J., I.R.E.); National Heart & Lung Institute (F.S.N., N.S.P.) and Statistical Advisory Service (F.G.), Imperial College London, London, United Kingdom; and Department of Pharmacology, Columbia University, New York, NY (A.L.W.).
authors.forename: Fu Siong
authors.initials: FS
authors.lastname: Ng
authors.affiliation: From the Department of Biomedical Engineering, Washington University in Saint Louis, MO (F.S.N., K.M.H., A.C.K., D.J., I.R.E.); National Heart & Lung Institute (F.S.N., N.S.P.) and Statistical Advisory Service (F.G.), Imperial College London, London, United Kingdom; and Department of Pharmacology, Columbia University, New York, NY (A.L.W.).
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Holzem
authors.affiliation: From the Department of Biomedical Engineering, Washington University in Saint Louis, MO (F.S.N., K.M.H., A.C.K., D.J., I.R.E.); National Heart & Lung Institute (F.S.N., N.S.P.) and Statistical Advisory Service (F.G.), Imperial College London, London, United Kingdom; and Department of Pharmacology, Columbia University, New York, NY (A.L.W.).
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Koppel
authors.affiliation: From the Department of Biomedical Engineering, Washington University in Saint Louis, MO (F.S.N., K.M.H., A.C.K., D.J., I.R.E.); National Heart & Lung Institute (F.S.N., N.S.P.) and Statistical Advisory Service (F.G.), Imperial College London, London, United Kingdom; and Department of Pharmacology, Columbia University, New York, NY (A.L.W.).
authors.forename: Deborah
authors.initials: D
authors.lastname: Janks
authors.affiliation: From the Department of Biomedical Engineering, Washington University in Saint Louis, MO (F.S.N., K.M.H., A.C.K., D.J., I.R.E.); National Heart & Lung Institute (F.S.N., N.S.P.) and Statistical Advisory Service (F.G.), Imperial College London, London, United Kingdom; and Department of Pharmacology, Columbia University, New York, NY (A.L.W.).
authors.forename: Fabiana
authors.initials: F
authors.lastname: Gordon
authors.affiliation: From the Department of Biomedical Engineering, Washington University in Saint Louis, MO (F.S.N., K.M.H., A.C.K., D.J., I.R.E.); National Heart & Lung Institute (F.S.N., N.S.P.) and Statistical Advisory Service (F.G.), Imperial College London, London, United Kingdom; and Department of Pharmacology, Columbia University, New York, NY (A.L.W.).
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Wit
authors.affiliation: From the Department of Biomedical Engineering, Washington University in Saint Louis, MO (F.S.N., K.M.H., A.C.K., D.J., I.R.E.); National Heart & Lung Institute (F.S.N., N.S.P.) and Statistical Advisory Service (F.G.), Imperial College London, London, United Kingdom; and Department of Pharmacology, Columbia University, New York, NY (A.L.W.).
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Peters
authors.affiliation: From the Department of Biomedical Engineering, Washington University in Saint Louis, MO (F.S.N., K.M.H., A.C.K., D.J., I.R.E.); National Heart & Lung Institute (F.S.N., N.S.P.) and Statistical Advisory Service (F.G.), Imperial College London, London, United Kingdom; and Department of Pharmacology, Columbia University, New York, NY (A.L.W.). igor@wustl.edu.
authors.forename: Igor R
authors.initials: IR
authors.lastname: Efimov
mesh_terms: D000200:Action Potentials; D000328:Adult; D000368:Aged; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D006329:Heart Conduction System / Q000378:metabolism / Q000503:physiopathology*; D006333:Heart Failure / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D015428:Myocardial Reperfusion Injury / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D020411:Oligonucleotide Array Sequence Analysis; D020127:Recovery of Function
keywords: electrophysiology; heart failure; ischemia; metabolism; reperfusion
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