Published Online
on May 2, 2005

A more recent version of this article appeared on May 10, 2005

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Submitted on September 21, 2004
Revised on December 9, 2004
Accepted on December 29, 2004

Female Mice Lacking Estrogen Receptor Display Prolonged Ventricular Repolarization and Reduced Ventricular Automaticity After Myocardial Infarction

Thomas Korte MD^*, Martin Fuchs MD, Andreas Arkudas BS, Sebastian Geertz BS, Rainer Meyer PhD, Ajmal Gardiwal MD, Gunnar Klein MD, Michael Niehaus MD, Andrée Krust PhD, Pierre Chambon PhD, Helmut Drexler MD, Klaus Fink MD, and Christian Grohé MD

From the Department of Cardiology and Angiology, Medical School Hannover, Hannover, Germany (T.K., M.F., A.A., S.G., A.G., G.K., M.N., H.D.); Institute of Physiology (R.M.), Institute of Pharmacology and Toxicology (K.F.), and Medizinische University Poliklinik (C.G.), University of Bonn, Bonn, Germany; and Institute de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP/, Collège de France, Illkirch, CU de Strasbourg, France (A.K., P.C.).

^* To whom correspondence should be addressed. E-mail: korte.thomas{at}mh-hannover.de.

Background--Major gender-based differences in the incidence of ventricular tachyarrhythmia after myocardial infarction have been shown in humans. Although the underlying mechanisms are unclear, earlier studies suggest that estrogen receptor-mediated effects play a major role in this process.

Methods and Results--We examined the effect of estrogen receptor (ER) and estrogen receptor (ER) on the electrophysiological phenotype in female mice with and without chronic anterior myocardial infarction. There was no significant difference in overall mortality, infarct size, and parameters of left ventricular remodeling when we compared infarcted ER-deficient and ER-deficient mice with infarcted wild-type animals. In the 12-hour telemetric ECG recording 6 weeks after myocardial infarction, surface ECG parameters did not show significant differences in comparisons of ER-deficient mice versus wild-type controls, infarcted versus noninfarcted ER-deficient mice, and infarcted ER-deficient versus infarcted wild-type mice. However, infarcted ER-deficient versus noninfarcted ER-deficient mice showed a significant prolongation of the QT (61±6 versus 48±8 ms; P<0.05) and QTc intervals (61±7 versus 51±9 ms; P<0.05) and the JT (42±6 versus 31±4 ms; P<0.05) and JTc intervals (42±7 versus 33±4 ms; P<0.05). Furthermore, infarcted ER-deficient versus infarcted wild-type mice showed a significant prolongation of the QT (61±6 versus 53±8 ms; P<0.05) and QTc intervals (61±7 versus 53±7 ms; P<0.05) and the JT (42±6 versus 31±5 ms; P<0.05) and JTc intervals (42±7 versus 31±5 ms; P<0.05), accompanied by a significant decrease of ventricular premature beats (7±21/h versus 71±110/h; P<0.05). Finally, real-time polymerase chain reaction-based quantitative analysis of mRNA levels showed a significantly lower expression of Kv4.3 (coding for I_to) in ER-deficient mice (P<0.05).

Conclusions--Estrogen receptor deficiency results in prolonged ventricular repolarization and decreased ventricular automaticity in female mice with chronic myocardial infarction.

Key words: estrogens • receptors • mice • myocardial infarction • arrhythmia

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