© 1999 American Heart Association, Inc.
Integrative Physiology |
Targeted Expression of a Dominant-Negative Kv4.2 K+ Channel Subunit in the Mouse Heart
From the Department of Medicine, Division of Cardiology (P.H.B., A.D.W.), The Toronto Hospital, and the Departments of Medicine and Physiology (P.H.B., A.D.W., R.S.), University of Toronto, Ontario, Canada, and the Section of Myocardial Biology, Cardiovascular Institute, Departments of Medicine (P.L., G.I.F.), Physiology & Biophysics and Biochemistry and Molecular Biology (G.I.F.), Mount Sinai School of Medicine, New York, NY. A.D.W.’s current address is ICAgen Inc, Durham, NC. Q.H.’s current address is Merck & Co, Inc, West Point, Pa.
Correspondence to Glenn I. Fishman, MD, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1269, New York, NY 10029. E-mail fishmg01{at}doc.mssm.edu
Abstract—Action potential
duration is prolonged in many forms of heart disease, often as a result
of reductions in Ca2+-independent transient outward
K+ currents (ie, Ito). To
examine the effects of a primary reduction in
Ito current in the heart, transgenic mice
were generated that express a dominant-negative N-terminal fragment of
the Kv4.2 pore-forming potassium channel subunit under the
control of the mouse 
-myosin heavy chain promoter. Two of 6 founders
died suddenly, and only 1 mouse successfully transmitted the transgene
in mendelian fashion. Electrophysiological
analysis at 2 to 4 weeks of age demonstrated that
Ito density was specifically reduced and
action potential durations were prolonged in a subset of transgenic
myocytes. The heterogeneous reduction in
Ito was accompanied by significant
prolongation of monophasic action potentials. In vivo
hemodynamic studies at this age revealed significant
elevations in the mean arterial pressure, peak
systolic ventricular pressures, and ±dP/dt,
indicative of enhanced contractility. Surprisingly, by
10 to 12 weeks of age, transgenic mice developed clinical and
hemodynamic evidence of congestive heart failure.
Failing transgenic hearts displayed molecular and cellular remodeling,
with evidence of hypertrophy, chamber dilatation, and
interstitial fibrosis, and individual myocytes showed sharp
reductions in Ito and
IK1 densities, action potential duration
prolongation, and increased cell capacitance. Our results confirm that
Kv4.2 subunits contribute to Ito
in the mouse and demonstrate that manipulation of cardiac excitability
may secondarily influence contractile performance.
Key Words: K+ channel • transgenic • cardiac electrophysiology • mouse • heart failure
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