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

Research output: Contribution to journalArticle

70 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1389-1397
Number of pages9
JournalCirculation Research
Volume102
Issue number11
DOIs
StatePublished - Jun 6 2008

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Keywords

  • Β2-adrenergic stimulation
  • Arrhythmia
  • Heart failure
  • Sarcoplasmic reticulum
  • Zinterol

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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