Arrhythmogenic remodeling of β2 versus β1 adrenergic signaling in the human failing heart

Di Lang, Katherine Holzem, Chaoyi Kang, Mengqian Xiao, Hye Jin Hwang, Gregory A. Ewald, Kathryn A. Yamada, Igor R. Efimov*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Arrhythmia is the major cause of death in patients with heart failure, for which β-adrenergic receptor blockers are a mainstay therapy. But the role of β-adrenergic signaling in electrophysiology and arrhythmias has never been studied in human ventricles. Methods and Results-We used optical imaging of action potentials and [Ca2+]i transients to compare the β1-and β2-adrenergic responses in left ventricular wedge preparations of human donor and failing hearts. β1-Stimulation significantly increased conduction velocity, shortened action potential duration, and [Ca2+]i transients duration (CaD) in donor but not in failing hearts, because of desensitization of β1-adrenergic receptor in heart failure. In contrast, β2-stimulation increased conduction velocity in both donor and failing hearts but shortened action potential duration only in failing hearts. β2-Stimulation also affected transmural heterogeneity in action potential duration but not in [Ca2+]i transients duration. Both β1-and β2-stimulation augmented the vulnerability and frequency of ectopic activity and enhanced substrates for ventricular tachycardia in failing, but not in donor, hearts. Both β1-and β2-stimulation enhanced Purkinje fiber automaticity, whereas only β2-stimulation promoted Ca-mediated premature ventricular contractions in heart failure. Conclusions-During end-stage heart failure, β2-stimulation creates arrhythmogenic substrates via conduction velocity regulation and transmurally heterogeneous repolarization. β2-Stimulation is, therefore, more arrhythmogenic than β1-stimulation. In particular, β2-stimulation increases the transmural difference between [Ca2+]i transients duration and action potential duration, which facilitates the formation of delayed afterdepolarizations.

Original languageEnglish (US)
Pages (from-to)409-419
Number of pages11
JournalCirculation: Arrhythmia and Electrophysiology
Volume8
Issue number2
DOIs
StatePublished - Apr 20 2015
Externally publishedYes

Keywords

  • Arrhythmia (mechanisms)
  • calcium
  • heart failure
  • receptors, adrenergic

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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