title: Transmural expression of ion channels and transporters in human nondiseased and end-stage failing hearts.
abstract: The cardiac action potential is primarily shaped by the orchestrated function of several different types of ion channels and transporters. One of the regional differences believed to play a major role in the progression and stability of the action potential is the transmural gradient of electrical activity across the ventricular wall. An altered balance in the ionic currents across the free wall is assumed to be a substrate for arrhythmia. A large fraction of patients with heart failure experience ventricular arrhythmia. However, the underlying substrate of these functional changes is not well-established as expression analyses of human heart failure (HF) are sparse. We have investigated steady-state RNA levels by quantitative polymerase chain reaction of ion channels, transporters, connexin 43, and miR-1 in 11 end-stage HF and seven nonfailing (NF) hearts. The quantifications were performed on endo-, mid-, and epicardium of left ventricle, enabling us to establish changes in the transmural expression gradient. Transcripts encoding Cav1.2, HCN2, Kir2.1, KCNE1, SUR1, and NCX1 were upregulated in HF compared to NF while a downregulation was observed for KChIP2, SERCA2, and miR-1. Additionally, the transmural gradient of KCNE1, KChIP2, Kir6.2, SUR1, Nav1.5, NCX1, and RyR2 found in NF was only preserved for KChiP2 and Nav1.5 in HF. The transmural gradients of NCX1, Nav1.5, and KChIP2 and the downregulation of KChIP2 were confirmed by Western blotting. In conclusion, our results reveal altered expression of several cardiac ion channels and transporters which may in part explain the increased susceptibility to arrhythmia in end-state failing hearts.
authors.affiliation: The Danish National Research Foundation Centre for Cardiac Arrhythmia (DARC), Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark.
authors.forename: Ewa
authors.initials: E
authors.lastname: Soltysinska
authors.forename: Søren-Peter
authors.initials: SP
authors.lastname: Olesen
authors.forename: Torsten
authors.initials: T
authors.lastname: Christ
authors.forename: Erich
authors.initials: E
authors.lastname: Wettwer
authors.forename: Andras
authors.initials: A
authors.lastname: Varró
authors.forename: Morten
authors.initials: M
authors.lastname: Grunnet
authors.forename: Thomas
authors.initials: T
authors.lastname: Jespersen
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D005260:Female; D015870:Gene Expression; D006321:Heart / Q000502:physiology*; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D007473:Ion Channels / Q000096:biosynthesis*; D017136:Ion Transport; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D007473:Ion Channels; D012333:RNA, Messenger