TY - JOUR
T1 - In vivo effect of a dominant negative Kv4.2 loss-of-function mutation eliminating Ito,f on atrial refractoriness and atrial fibrillation in mice
AU - Odening, Katja E.
AU - Nerbonne, Jeanne M.
AU - Bode, Christoph
AU - Zehender, Manfred
AU - Brunner, Michael
PY - 2009/3
Y1 - 2009/3
N2 - Background: Gain-of-function K+ channel mutations cause familial atrial fbrillation (AF) by shortening of the atrial action potential duration (APD). APD-prolonging K+ channel blockers are an effective therapeutic option in AF. In vitro, the dominant negative Kv4.2W362F mutation (Kv4DN) eliminates Ito,f in murine atrial myocytes and markedly prolongs the APD, so whether this loss-of-function of Ito,f alters the atrial effective refractory period (AERP) in vivo and/or affects AF-inducibility was investigated in the present study. Methods and Results: Transvenous electrophysiological studies were performed in vivo in Kv4DN and wild-type littermate control (LMC) mice. Intriguingly, no difference was found between Kv4DN and LMC for the AERP in vivo either at baseline or after carbachol. Consequently, AF-inducibility at baseline (Kv4DN: 10/16 vs LMC: 7/13) and after carbachol (Kv4DN: 9/16 vs LMC: 6/13) did not differ between groups. However, AF-inducibility was associated with a signifcantly shorter AERP (inducible 51.1±1.4 vs non-inducible 58.4±1.6; P<0.01) irrespective of genotype. Conclusions: The loss-of-function of Ito,f prolongs the APD in mouse atrial myocytes in vitro, but this effect on single cells does not translate into measurable AERP prolongation in vivo and hence does not exert an anti-arrhythmic effect. However, the susceptibility of mice to AF in vivo is determined by the individual AERP, irrespective of genotype.
AB - Background: Gain-of-function K+ channel mutations cause familial atrial fbrillation (AF) by shortening of the atrial action potential duration (APD). APD-prolonging K+ channel blockers are an effective therapeutic option in AF. In vitro, the dominant negative Kv4.2W362F mutation (Kv4DN) eliminates Ito,f in murine atrial myocytes and markedly prolongs the APD, so whether this loss-of-function of Ito,f alters the atrial effective refractory period (AERP) in vivo and/or affects AF-inducibility was investigated in the present study. Methods and Results: Transvenous electrophysiological studies were performed in vivo in Kv4DN and wild-type littermate control (LMC) mice. Intriguingly, no difference was found between Kv4DN and LMC for the AERP in vivo either at baseline or after carbachol. Consequently, AF-inducibility at baseline (Kv4DN: 10/16 vs LMC: 7/13) and after carbachol (Kv4DN: 9/16 vs LMC: 6/13) did not differ between groups. However, AF-inducibility was associated with a signifcantly shorter AERP (inducible 51.1±1.4 vs non-inducible 58.4±1.6; P<0.01) irrespective of genotype. Conclusions: The loss-of-function of Ito,f prolongs the APD in mouse atrial myocytes in vitro, but this effect on single cells does not translate into measurable AERP prolongation in vivo and hence does not exert an anti-arrhythmic effect. However, the susceptibility of mice to AF in vivo is determined by the individual AERP, irrespective of genotype.
KW - Atrial fibrillation
KW - Atrial refractoriness
KW - In vivo electrophysiological study
KW - Ito,f loss-of-function mutation
KW - Kv4DN transgenic mice
UR - http://www.scopus.com/inward/record.url?scp=62649112042&partnerID=8YFLogxK
U2 - 10.1253/circj.CJ-08-0840
DO - 10.1253/circj.CJ-08-0840
M3 - Article
C2 - 19145035
AN - SCOPUS:62649112042
SN - 1346-9843
VL - 73
SP - 461
EP - 467
JO - Circulation Journal
JF - Circulation Journal
IS - 3
ER -