title: Triggered activity in atrial myocytes is influenced by Na+/Ca2+exchanger activity in genetically altered mice.
abstract: OBJECTIVE
  In atrial fibrillation, increased function of the Na+/Ca2+-exchanger (NCX) is one among several electrical remodeling mechanisms.
  
  
  RESULTS
  Using the patch-clamp- and Ca2+imaging-methods, we investigated atrial myocytes from NCX-homozygous-overexpressor (OE)- and heterozygous-knockout (KO)-mice and their corresponding wildtypes (WTOE; WTKO). NCX mediated Ca2+extrusion capacity was reduced in KO and increased in OE. There was no evidence for structural or molecular remodeling. During a proarrhythmic pacing-protocol, the number of low amplitude delayed afterdepolarizations (DADs) was unaltered in OE vs. WTOEand KO vs. WTKO. However, DADs triggered full spontaneous action potentials (sAP) significantly more often in OE vs. WTOE(ratio sAP/DAD: OE:0.18±0.05; WTOE:0.02±0.02; p<0.001). Using the same protocol, a DAD triggered an sAP by tendency less often in KO vs. WTKO(p=0.06) and significantly less often under a more aggressive proarrhythmic protocol (ratio sAP/DAD: KO:0.01±0.003; WT KO: 0.12±0.05; p=0.007). The DAD amplitude was increased in OE vs. WTOEand decreased in KO vs. WTKO. There were no differences in SR-Ca2+-load, the number of spontaneous Ca2+-release-events or IKACh/IK1.
  
  
  CONCLUSIONS
  Atrial myocytes with increased NCX expression exhibited increased vulnerability towards sAPs while atriomyocytes with reduced NCX expression were protected. The underlying mechanism consists of a modification of the DAD-amplitude by the level of NCX-activity. Thus, although the number of spontaneous Ca2+-releases and therefore DADs is unaltered, the higher DAD-amplitude in OE made a transgression of the voltage-threshold of an sAP more likely. These findings indicate that the level of NCX activity could influence triggered activity in atrial myocytes independent of possible remodeling processes.
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University Hospital Münster, Münster, Germany. Electronic address: nils.boegeholz@ukmuenster.de.
authors.forename: N
authors.initials: N
authors.lastname: Bögeholz
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University Hospital Münster, Münster, Germany; Institute of Pharmacology and Toxicology, University Hospital Münster, Münster, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Pauls
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University Hospital Münster, Münster, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kaese
authors.affiliation: Institute of Pharmacology and Toxicology, University Hospital Münster, Münster, Germany.
authors.forename: J S
authors.initials: JS
authors.lastname: Schulte
authors.affiliation: Department of Cardiology-Electrophysiology, University Heart Center, University Hospital Eppendorf, Hamburg, Germany.
authors.forename: M D
authors.initials: MD
authors.lastname: Lemoine
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University Hospital Münster, Münster, Germany.
authors.forename: D G
authors.initials: DG
authors.lastname: Dechering
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University Hospital Münster, Münster, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Frommeyer
authors.affiliation: Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: J I
authors.initials: JI
authors.lastname: Goldhaber
authors.affiliation: Institute of Pharmacology and Toxicology, University Hospital Münster, Münster, Germany.
authors.forename: M D
authors.initials: MD
authors.lastname: Seidl
authors.affiliation: Institute of Pharmacology and Toxicology, University Hospital Münster, Münster, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Kirchhefer
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University Hospital Münster, Münster, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Eckardt
authors.affiliation: Institute of Pharmacology and Toxicology, University Hospital Münster, Münster, Germany.
authors.forename: F U
authors.initials: FU
authors.lastname: Müller
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University Hospital Münster, Münster, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Pott
mesh_terms: D000200:Action Potentials / Q000235:genetics; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D005260:Female; D015870:Gene Expression; D006325:Heart Atria / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000235:genetics; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism*
chemical_list: D019831:Sodium-Calcium Exchanger; D002118:Calcium
keywords: Afterdepolarizations; Atrial fibrillation; Atrial myocytes; Na(+)/Ca(2+) exchanger