title: Regional ion channel gene expression heterogeneity and ventricular fibrillation dynamics in human hearts.
abstract: BACKGROUND
  Structural differences between ventricular regions may not be the sole determinant of local ventricular fibrillation (VF) dynamics and molecular remodeling may play a role.
  
  
  OBJECTIVE
  To define regional ion channel expression in myopathic hearts compared to normal hearts, and correlate expression to regional VF dynamics.
  
  
  RESULTS
  High throughput real-time RT-PCR was used to quantify the expression patterns of 84 ion-channel, calcium cycling, connexin and related gene transcripts from sites in the LV, septum, and RV in 8 patients undergoing transplantation. An additional eight non-diseased donor human hearts served as controls. To relate local ion channel expression change to VF dynamics localized VF mapping was performed on the explanted myopathic hearts right adjacent to sampled regions. Compared to non-diseased ventricles, significant differences (p<0.05) were identified in the expression of 23 genes in the myopathic LV and 32 genes in the myopathic RV. Within the myopathic hearts significant regional (LV vs septum vs RV) expression differences were observed for 13 subunits: Nav1.1, Cx43, Ca3.1, Cavα2δ2, Cavβ2, HCN2, Na/K ATPase-1, CASQ1, CASQ2, RYR2, Kir2.3, Kir3.4, SUR2 (p<0.05). In a subset of genes we demonstrated differences in protein expression between control and myopathic hearts, which were concordant with the mRNA expression profiles for these genes. Variability in the expression of Cx43, hERG, Na(+)/K(+) ATPase ß1 and Kir2.1 correlated to variability in local VF dynamics (p<0.001). To better understand the contribution of multiple ion channel changes on VF frequency, simulations of a human myocyte model were conducted. These simulations demonstrated the complex nature by which VF dynamics are regulated when multi-channel changes are occurring simultaneously, compared to known linear relationships.
  
  
  CONCLUSIONS
  Ion channel expression profile in myopathic human hearts is significantly altered compared to normal hearts. Multi-channel ion changes influence VF dynamic in a complex manner not predicted by known single channel linear relationships.
authors.affiliation: Toronto General Hospital, Ontario, Canada.
authors.forename: Gopal
authors.initials: G
authors.lastname: Sivagangabalan
authors.affiliation: Toronto General Hospital, Ontario, Canada.
authors.forename: Hamed
authors.initials: H
authors.lastname: Nazzari
authors.affiliation: INSERM, UMR915, l'institut du thorax, Nantes, France ; CNRS, ERL3147, Nantes, France ; Université de Nantes, Nantes, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Bignolais
authors.affiliation: IHU LIRYC, Electrophysiology and Heart Modeling Institute, Pessac, France ; Lab IMB, University Bordeaux 1, Talence, France.
authors.forename: Ange
authors.initials: A
authors.lastname: Maguy
authors.affiliation: IHU LIRYC, Electrophysiology and Heart Modeling Institute, Pessac, France ; Lab IMB, University Bordeaux 1, Talence, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Naud
authors.affiliation: Toronto General Hospital, Ontario, Canada.
authors.forename: Talha
authors.initials: T
authors.lastname: Farid
authors.affiliation: Toronto General Hospital, Ontario, Canada.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Massé
authors.affiliation: INSERM, UMR915, l'institut du thorax, Nantes, France ; CNRS, ERL3147, Nantes, France ; Université de Nantes, Nantes, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gaborit
authors.affiliation: University of Szeged and Division of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Andras
authors.initials: A
authors.lastname: Varro
authors.affiliation: Toronto General Hospital, Ontario, Canada.
authors.forename: Krishnakumar
authors.initials: K
authors.lastname: Nair
authors.affiliation: Toronto General Hospital, Ontario, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Backx
authors.affiliation: IHU LIRYC, Electrophysiology and Heart Modeling Institute, Pessac, France ; Lab IMB, University Bordeaux 1, Talence, France.
authors.forename: Edward
authors.initials: E
authors.lastname: Vigmond
authors.affiliation: Montreal Heart Institute (MHI) and Université de Montréal Faculty of Medicine, Montreal, Canada.
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
authors.affiliation: INSERM, UMR915, l'institut du thorax, Nantes, France ; CNRS, ERL3147, Nantes, France ; Université de Nantes, Nantes, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Demolombe
authors.affiliation: Toronto General Hospital, Ontario, Canada.
authors.forename: Kumaraswamy
authors.initials: K
authors.lastname: Nanthakumar
mesh_terms: D000328:Adult; D003198:Computer Simulation; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006321:Heart / Q000503:physiopathology*; D006439:Hemodynamics; D006801:Humans; D007473:Ion Channels / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism*; D040901:Proteomics; D014158:Transcription, Genetic; D059467:Transcriptome; D014693:Ventricular Fibrillation / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D007473:Ion Channels