In vivo effect of a dominant negative Kv4.2 loss-of-function mutation eliminating I(to,f) on atrial refractoriness and atrial fibrillation in mice

Circulation Journal : Official Journal of the Japanese Circulation Society
Katja E OdeningMichael Brunner

Abstract

Gain-of-function K(+) channel mutations cause familial atrial fibrillation (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 I(to,f) in murine atrial myocytes and markedly prolongs the APD, so whether this loss-of-function of I(to,f) alters the atrial effective refractory period (AERP) in vivo and/or affects AF-inducibility was investigated in the present study. 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 significantly shorter AERP (inducible 51.1 +/-1.4 vs non-inducible 58.4 +/-1.6; P<0.01) irrespective of genotype. The loss-of-function of I(to,f) prolongs the APD in mouse atrial myocytes in vitro, but this effect on single cells does not translate into measurable AERP prolongation...Continue Reading

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Citations

Nov 5, 2010·Circulation Journal : Official Journal of the Japanese Circulation Society·Makoto TakanoKoichiro Kuwahara
May 19, 2010·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Simon D W Frost, Erik M Volz
May 23, 2020·Journal of Inherited Metabolic Disease·Hannes TodtJohannes Berger

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