—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, I_to). To examine the effects of a primary reduction in I_to current in the heart, transgenic mice were generated that express a dominant-negative N-terminal fragment of the K_v4.2 pore-forming potassium channel subunit under the control of the mouse α-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 I_to density was specifically reduced and action potential durations were prolonged in a subset of transgenic myocytes. The heterogeneous reduction in I_to 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 I_to and I_K1 densities, action potential duration prolongation, and increased cell capacitance. Our results confirm that K_v4.2 subunits contribute to I_to in the mouse and demonstrate that manipulation of cardiac excitability may secondarily influence contractile performance.