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(Circulation Research. 2008;102:1389.)
© 2008 American Heart Association, Inc.

Cellular Biology

Arrhythmogenic Effects of β₂-Adrenergic Stimulation in the Failing Heart Are Attributable to Enhanced Sarcoplasmic Reticulum Ca Load

Jaime DeSantiago, Xun Ai, Mohammed Islam, Georgia Acuna, Mark T. Ziolo, Donald M. Bers, Steven M. Pogwizd

From the Department of Pharmacology, University of California-Davis (J.D., D.M.B.), Department of Medicine, University of Illinois at Chicago (G.A., M.I.), Department of Physiology, Ohio State University (M.T.Z.), and Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham (X.A., S.M.P.).

Correspondence to Steven M. Pogwizd, MD, Cardiac Rhythm Management Laboratory, University of Alabama at Birmingham, 1530 3rd Avenue South, Volker Hall-B140, Birmingham, AL 35294. E-mail spogwizd{at}uab.edu

Ventricular tachycardia in heart failure (HF) can initiate by nonreentrant mechanisms such as delayed afterdepolarizations. In an arrhythmogenic rabbit model of HF, we have shown that isoproterenol induces ventricular tachycardia in vivo and aftercontractions and transient inward currents in HF myocytes. To determine whether β₂-adrenergic receptor (β₂-AR) stimulation contributes, we performed in vivo drug infusion, in vitro myocyte and biochemical studies. Intravenous zinterol (2.5 µg/kg) led to ventricular arrhythmias, including ventricular tachycardia up to 13 beats long in 4 of 6 HF rabbits (versus 0 of 5 controls, P<0.01), an effect blocked by β₂-AR antagonist ICI-118,551 (0.2 mg/kg). In field-stimulated myocytes (0.5 to 4 Hz, 37°C), β₂-AR stimulation (1 µmol/L zinterol+300 nmol/L β₁-AR antagonist CGP-29712A) induced aftercontractions and Ca aftertransients in 88% of HF versus 0% of control myocytes (P<0.01). β₂-AR stimulation in HF (but not control) myocytes increased Ca transient amplitude (by 29%), sarcoplasmic reticulum (SR) Ca load (by 28%), the rate of [Ca]_i decline (by 28%; n=12, all P<0.05), and phospholamban phosphorylation at Ser16, but Ca current was unchanged. All of these effects in HF myocytes were blocked by ICI-118,551 (100 nmol/L). Although total β-AR expression was reduced by 47% in HF rabbit left ventricle, β₂-AR number was unchanged, indicating more potent β₂-AR–dependent SR Ca uptake and arrhythmogenesis in HF. Human HF myocytes showed similar β₂-AR–induced aftercontractions, aftertransients, and enhanced Ca transient amplitude, SR Ca load and twitch [Ca]_i decline rate. Thus, β₂-AR stimulation is arrhythmogenic in HF, mediated by SR Ca overload-induced spontaneous SR Ca release and aftercontractions.

Key Words: heart failure • β₂-adrenergic stimulation • arrhythmia • sarcoplasmic reticulum • zinterol

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