title: Chronic angiotensin II stimulation in the heart produces an acquired long QT syndrome associated with IK1 potassium current downregulation.
abstract: Cardiac hypertrophy is an independent predictor of cardiovascular morbidity and mortality. It predisposes patients to heart failure, QT interval prolongation and ventricular arrhythmias. Angiotensin II (Ang II) exerts direct actions on cardiac tissue inducing cardiomyocyte hypertrophy and electro-mechanical dysfunction. However, a direct association between Ang II and cardiomyocyte electrical remodeling has yet to be demonstrated. Transgenic TG1306/1R (TG) mice with cardiac-specific Ang II overproduction demonstrate blood pressure-independent cardiac hypertrophy and exhibit significant increase in sudden death associated with mechanical dysfunction. The present study makes use of TG mice to evaluate the direct effects of high levels of intracardiac Ang II on cardiac electrophysiology. Surface-limb ECG measurements were recorded on 50- to 60-week-old TG and wild-type (WT) mice. QT interval was significantly prolonged (+20%) in TG mice relative to WT. TG mice also showed an increased incidence of ventricular arrhythmias. QT prolongation was associated with prolongation of cardiomyocyte action potential at 90% repolarization (APD90). The change in APD90 correlated with a reduction in IK1 potassium current density in TG vs. WT cardiomyocytes (at -70 mV: 0.3+/-0.1 pA/pF vs. 0.8+/-0.2 pA/pF, P<0.05). In TG mice, reduction in IK1 was associated with a significant reduction (-50%) of the mRNA encoding Kir2.1 and Kir2.2 subunits of IK1-related KCNJ2 and KCNJ12 potassium channels. These data suggest that cardiac Ang II overproduction leads to the emergence of a long QT syndrome resulting from an IK1-dependent prolongation of the action potential duration through modulation of channel subunit expression.
authors.affiliation: Department of Medicine, University of Lausanne Medical School, CHUV MP14-220, CH-1011 Lausanne, Switzerland.
authors.forename: Andrea A
authors.initials: AA
authors.lastname: Domenighetti
authors.forename: Christophe
authors.initials: C
authors.lastname: Boixel
authors.forename: Daniel
authors.initials: D
authors.lastname: Cefai
authors.forename: Hugues
authors.initials: H
authors.lastname: Abriel
authors.forename: Thierry
authors.initials: T
authors.lastname: Pedrazzini
mesh_terms: D000200:Action Potentials; D000804:Angiotensin II / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001483:Base Sequence; D006332:Cardiomegaly / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation; D004562:Electrocardiography; D006801:Humans; D066298:In Vitro Techniques; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*; D008133:Long QT Syndrome / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000502:physiology; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D017931:DNA Primers; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496925:Kcnn4 protein, mouse; C489461:Kir2.1 channel; C489463:Kir2.2 channel; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger; D000804:Angiotensin II