Atrial Fibrillation in KCNE1-Null Mice

Abstract

Abstract-Although atrial fibrillation is the most common serious cardiac arrhythmia, the fundamental molecular pathways remain undefined. Mutations in KCNQ1, one component of a sympathetically activated cardiac potassium channel complex, cause familial atrial fibrillation, although the mechanisms in vivo are unknown. We show here that mice with deletion of the KCNQ1 protein partner KCNE1 have spontaneous episodes of atrial fibrillation despite normal atrial size and structure. Isoproterenol abolishes these abnormalities, but vagomimetic interventions have no effect. Whereas loss of KCNE1 function prolongs ventricular action potentials in humans, KCNE1 Ϫ/Ϫ mice displayed unexpectedly shortened atrial action potentials, and multiple potential mechanisms were identified: (1) K ϩ currents (total and those sensitive to the KCNQ1 blocker chromanol 293B) were significantly increased in atrial cells from KCNE1 Ϫ/Ϫ mice compared with controls, and (2) when CHO cells expressing KCNQ1 and KCNE1 were pulsed very rapidly (at rates comparable to the normal mouse heart and to human atrial fibrillation), the sigmoidicity of I Ks activation prevented current accumulation, whereas cells expressing KCNQ1 alone displayed marked current accumulation at these very rapid rates. Thus, KCNE1 deletion in mice unexpectedly leads to increased outward current in atrial myocytes, shortens atrial action potentials, and enhances susceptibility to atrial fibrillation. Key Words: arrhythmia Ⅲ atrial fibrillation Ⅲ cardiac electrophysiology Ⅲ mouse Ⅲ potassium channels A trial fibrillation (AF) is a major public health problem, affecting 2% of people over the age of 60 and 9% of people over 80. 1 AF is the proximate cause of 20% to 25% of strokes and is implicated in disability attributable to heart failure. 2 Despite the magnitude of this problem, the development of increasingly sophisticated animal models, and advances in pharmacological and nonpharmacological therapy, our understanding of the molecular effector mechanisms underlying AF remains incomplete. 3 Whereas the critical mass hypothesis suggested that the mouse atrium was too small to support AF, 4,5 spontaneous atrial arrhythmias are now well-documented in mice with atrial dilation. 6 -9 However, atrial dilation results in multiple changes in gene expression that complicate identification and validation of AF effector molecules. A strong familial component in AF 10 -12 suggests that identification of predisposing DNA variants may provide new insights into underlying biology. Indeed, rare kindreds with a high incidence of AF have been described, and 3 disease genes, each linked to arrhythmias in a single kindred, 13-15 as well as 3 other loci, 16 -18 have been reported. Mutations in one of these disease genes, KCNQ1, also cause the most common form of the congenital long QT syndrome. 19 KCNQ1 associates with the ancillary subunit KCNE1 to generate the adrenergically regulated 20 potassium current I Ks . Mutations in either gene reduce I Ks prolong action potentials in human ventricle ...

Simulations of propagated mouse ventricular action potentials: effects of molecular heterogeneity

“…Our own simulations also suggest that reentry would be difficult to sustain without some slowing of propagation (10). On the other hand, the small heart size may not be the limiting factor in mouse, as fibrillation in the mouse atrium, which is much smaller than the ventricle, has been observed experimentally (17,56,66,71).…”

Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses

“…ECG recordings of awake, free-moving mice were obtained using a telemetric method (PhysioTel; Data Science International). AF was induced by transesophageal rapid atrial pacing in mice as described previously (52).…”

Reduced Phosphoinositide 3-Kinase (p110α) Activation Increases the Susceptibility to Atrial Fibrillation

“…Despite these limitations, there are some genetically modified mouse models that are susceptible to AF. These include gene disruption/mutation of connexin40, KCNE1, or nuclear core component NUP155, [5][6][7] overexpression of RhoA, 8 basic leucine zipper inhibitor protein: JDP2, 9 angiotensin converting enzyme, 10 tumor necrosis factor ␣, 11 Rac1, 12 and MURC. 13 AF often occurs in combination with heart failure, although the factors that precipitate the onset of AF in patients with (or without) pre-existing heart disease remain unclear.…”