title: Perturbed atrial calcium handling in an ovine model of heart failure: potential roles for reductions in the L-type calcium current.
abstract: Heart failure (HF) is commonly associated with reduced cardiac output and an increased risk of atrial arrhythmias particularly during β-adrenergic stimulation. The aim of the present study was to determine how HF alters systolic Ca(2+) and the response to β-adrenergic (β-AR) stimulation in atrial myocytes. HF was induced in sheep by ventricular tachypacing and changes in intracellular Ca(2+) concentration studied in single left atrial myocytes under voltage and current clamp conditions. The following were all reduced in HF atrial myocytes; Ca(2+) transient amplitude (by 46% in current clamped and 28% in voltage clamped cells), SR dependent rate of Ca(2+) removal (kSR, by 32%), L-type Ca(2+) current density (by 36%) and action potential duration (APD90 by 22%). However, in HF SR Ca(2+) content was increased (by 19%) when measured under voltage-clamp stimulation. Inhibiting the L-type Ca(2+) current (ICa-L) in control cells reproduced both the decrease in Ca(2+) transient amplitude and increase of SR Ca(2+) content observed in voltage-clamped HF cells. During β-AR stimulation Ca(2+) transient amplitude was the same in control and HF cells. However, ICa-L remained less in HF than control cells whilst SR Ca(2+) content was highest in HF cells during β-AR stimulation. The decrease in ICa-L that occurs in HF atrial myocytes appears to underpin the decreased Ca(2+) transient amplitude and increased SR Ca(2+) content observed in voltage-clamped cells.
authors.affiliation: Institute of Cardiovascular Science, Manchester Academic Health Science Centre, 3.24 Core Technology Facility, 46 Grafton St, Manchester M13 9PT, UK.
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Clarke
authors.affiliation: Institute of Cardiovascular Science, Manchester Academic Health Science Centre, 3.24 Core Technology Facility, 46 Grafton St, Manchester M13 9PT, UK.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Caldwell
authors.affiliation: Institute of Cardiovascular Science, Manchester Academic Health Science Centre, 3.24 Core Technology Facility, 46 Grafton St, Manchester M13 9PT, UK.
authors.forename: Margaux A
authors.initials: MA
authors.lastname: Horn
authors.affiliation: Institute of Cardiovascular Science, Manchester Academic Health Science Centre, 3.24 Core Technology Facility, 46 Grafton St, Manchester M13 9PT, UK.
authors.forename: Elizabeth F
authors.initials: EF
authors.lastname: Bode
authors.affiliation: Institute of Cardiovascular Science, Manchester Academic Health Science Centre, 3.24 Core Technology Facility, 46 Grafton St, Manchester M13 9PT, UK.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Richards
authors.affiliation: Liverpool Heart and Chest Hospital, Thomas Drive, Liverpool L14 3PE, UK.
authors.forename: Mark C S
authors.initials: MC
authors.lastname: Hall
authors.affiliation: Institute of Cardiovascular Science, Manchester Academic Health Science Centre, 3.24 Core Technology Facility, 46 Grafton St, Manchester M13 9PT, UK.
authors.forename: Helen K
authors.initials: HK
authors.lastname: Graham
authors.affiliation: Institute of Cardiovascular Science, Manchester Academic Health Science Centre, 3.24 Core Technology Facility, 46 Grafton St, Manchester M13 9PT, UK.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Briston
authors.affiliation: Institute of Cardiovascular Science, Manchester Academic Health Science Centre, 3.24 Core Technology Facility, 46 Grafton St, Manchester M13 9PT, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Greensmith
authors.affiliation: Institute of Cardiovascular Science, Manchester Academic Health Science Centre, 3.24 Core Technology Facility, 46 Grafton St, Manchester M13 9PT, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Eisner
authors.affiliation: Institute of Cardiovascular Science, Manchester Academic Health Science Centre, 3.24 Core Technology Facility, 46 Grafton St, Manchester M13 9PT, UK.
authors.forename: Katharine M
authors.initials: KM
authors.lastname: Dibb
authors.affiliation: Institute of Cardiovascular Science, Manchester Academic Health Science Centre, 3.24 Core Technology Facility, 46 Grafton St, Manchester M13 9PT, UK. Electronic address: Andrew.W.Trafford@manchester.ac.uk.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Trafford
mesh_terms: D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006325:Heart Atria / Q000378:metabolism* / Q000473:pathology; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology; D006706:Homeostasis; D042541:Intracellular Space / Q000378:metabolism; D015640:Ion Channel Gating; D008954:Models, Biological; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D012756:Sheep; D013599:Systole
chemical_list: D020746:Calcium Channels, L-Type; D011943:Receptors, Adrenergic, beta; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium
keywords: Atria; Calcium; Heart failure; Sarcoplasmic reticulum