Key result
The dominant negative Kv4.2W362F mutation eliminating Ito,f did not prolong the atrial effective refractory period or reduce atrial fibrillation inducibility in vivo compared to wild-type mice.
Why the study?
Does the Kv4DN mutation alter AERP and AF-inducibility in vivo in mice?
Does the Kv4DN mutation alter AERP and AF-inducibility in vivo in mice?
Absolute Event Rate: 62.5% vs 53.8%
p-value: p=NS
The loss-of-function of Ito,f prolongs APD in vitro but does not translate to AERP prolongation or anti-arrhythmic effects in vivo in mice.
Does not confirm anti-arrhythmic effects of Ito,f loss in vivo; leaves open translation of in vitro APD changes to AF protection in mice.
BACKGROUND: 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. 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 significantly 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 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 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.
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Odening et al. (2009) studied Atrial fibrillation and atrial refractoriness (n=29). Kv4.2W362F mutation (Kv4DN) eliminating Ito,f vs. Wild-type littermate control (LMC) mice was evaluated on Atrial fibrillation inducibility at baseline (p=NS). The dominant negative Kv4.2W362F mutation eliminating Ito,f did not prolong the atrial effective refractory period or reduce atrial fibrillation inducibility in vivo compared to wild-type mice.
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