Key Points
- To evaluate the structural, electrical, and hemodynamic effects of a primary reduction in the transient outward potassium current (Ito) in cardiac tissue.
- Generated transgenic mice expressing a dominant-negative N-terminal fragment of the Kv4.2 channel subunit regulated by the cardiac alpha-myosin heavy chain promoter.
- Assessed myocyte electrophysiology, action potential durations, and in vivo hemodynamics at 2 to 4 weeks of age.
- Monitored progression to heart failure, cellular remodeling, myocyte capacitance, and histological changes at 10 to 12 weeks of age.
- At 2 to 4 weeks, transgenic mice exhibited reduced Ito density, prolonged action potential durations, and elevated mean arterial pressure, peak systolic pressure, and +/-dP/dt.
- By 10 to 12 weeks, transgenic mice developed congestive heart failure with cardiac hypertrophy, chamber dilatation, interstitial fibrosis, and marked reductions in Ito and IK1 current densities.
Structured PICO
PPopulationTransgenic mice expressing a dominant-negative N-terminal fragment of the Kv4.2 pore-forming potassium channel subunit under the control of the mouse alpha-myosin heavy chain promoter
IInterventionTargeted expression of a dominant-negative Kv4.2 K+ channel subunit
OOutcomeElectrophysiological properties (Ito density, action potential duration) and hemodynamic performancesurrogate
Targeted reduction of Ito current via Kv4.2 mutation in mice prolongs action potentials and initially enhances contractility, but ultimately leads to congestive heart failure.