Abstract 181: Cardiac Hypertrophy And Heart Failure In K-channel Ancillary Subunit Depleted Mice
Down regulation of cardiac K+ currents has been described in hypertrophic heart disease and heart failure. However, so far no mutations in potassium channel genes have been found in patients with cardiac hypertrophy/heart failure. It therefore remains controversial whether K+ current down regulation represents a primary cause of cardiac hypertrophy/heart failure or epiphenomena. KCNE2 is a voltage gated potassium channel ancillary subunit that is associated with inherited and acquired long QT syndrome. We recently developed KCNE2-/- mice. KCNE2-/- mice have normal cardiac morphology and function at 3-6 months of age despite a repolarization defect caused by disruption of IKslow, 1 and Ito, f. However, aged KCNE2-/- mice (12 months and older) develop significant cardiac hypertrophy and severe heart failure assessed by echocardiography, isolated heart (Langendorff) and reduced cellular shortening (IonOptix). Furthermore, after Angiotensin II stimulation 3-6 months old KCNE2-/- mice also develop significant cardiac hypertrophy and fibrosis compared to age-matched KCNE2+/+ siblings. Taqman PCR revealed molecular remodelling in hypertrophied failing KCNE2-/- hearts with induction of the fetal gene program (ANF re-expression), significant up regulation of Sodium-Calcium Exchanger (NCX) and significant down regulation of phospholamban. Alterations in Calcium handling proteins were also recapitulated on protein level by Western Blotting. Furthermore, electrophysiological studies by patch clamp analysis of isolated cardiomyocytes revealed a decrease in current densities of the L-type Ca2+-current and a strongly diminished response to isoprenaline stimulation in hypertrophied failing KCNE2-/- cardiomyocytes. We therefore conclude that primary disruption of repolarizing Kv currents by KCNE2 deletion leads to altered Calcium handling and consecutive induction of cardiac hypertrophy/heart failure.
- © 2013 by American Heart Association, Inc.