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Remodeling of Outward K+ Currents in Pressure-Overload Heart Failure


  • This work was supported by grants from the Donald W. Reynolds Cardiovascular Clinical Research Center (JAH), NIH (HL-075173, HL-006296, HL-080144 to JAH; HL-088168 to YW), AHA (0640084N, JAH; 0665178Y, YW), and AHAF (H2007-019, Y.W.).

Address for correspondence: Joseph A. Hill, M.D., Ph.D., Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573. Fax: 214-648-1450; E-mail: or


Objectives: Outward K+ currents are critical determinants of action potential repolarization and the site of action of a number of electrophysiologically active drugs. Further, expression and processing of the channels underlying these currents is altered in heart disease. Here, we investigated the native transmural gradient of outward K+ currents in murine left ventricle (LV) and delineated disease-related remodeling of these currents in heart failure (HF).

Methods: Pressure-overload heart failure was induced in mice by thoracic aortic constriction. Outward K+ currents were recorded using the whole-cell patch clamp technique in acutely dissociated ventricular myocytes.

Results: Unambiguous gradients of outward K+ current density and Kv4.2 protein abundance were observed across the wall of the LV, with significantly larger current density and protein levels in subepicardial (SEP) myocytes, compared with subendocardial (SEN) myocytes. Voltage dependences of current activation and inactivation were similar in SEP and SEN myocytes. In failing LV, however, outward K+ current density was significantly decreased in SEP but not in SEN cells leading to elimination of the native transmural gradient. In failing LV, the voltage dependences of K+ current activation and inactivation were not altered. However, current inactivation (decay) was significantly accelerated and recovery from inactivation was significantly slowed. Consistent with this, Western blot analysis revealed a decrease in KChIP2 protein abundance in failing LV.

Conclusions: This is the first report of HF-related remodeling of outward K+ currents in murine LV. Similar to humans, disease-related remodeling occurs differentially across the murine ventricular wall, leading to loss of the native gradient of repolarization. Together with slowed recovery from inactivation, these alterations likely promote abnormal impulse conduction, a major proarrhythmic mechanism.