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Circ Arrhythm Electrophysiol. 2015 Apr;8(2):409-19. doi: 10.1161/CIRCEP.114.002065. Epub 2015 Feb 11.

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

Author information

1
From the Department of Biomedical Engineering (D.L., K.H., C.K., M.X., H.J.H., I.R.E.) and Department of Medicine (G.A.E., K.A.Y., I.R.E.), Washington University School of Medicine, St. Louis, MO; L'Institut de Rythmologie et Modélisation Cardiaque LIRYC, Université de Bordeaux, Bordeaux, France (I.R.E.); and Moscow Institute of Physics and Technology, Moscow, Russia (I.R.E.).
2
From the Department of Biomedical Engineering (D.L., K.H., C.K., M.X., H.J.H., I.R.E.) and Department of Medicine (G.A.E., K.A.Y., I.R.E.), Washington University School of Medicine, St. Louis, MO; L'Institut de Rythmologie et Modélisation Cardiaque LIRYC, Université de Bordeaux, Bordeaux, France (I.R.E.); and Moscow Institute of Physics and Technology, Moscow, Russia (I.R.E.). igor@wustl.edu.

Abstract

BACKGROUND:

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 [Ca(2+)]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 [Ca(2+)]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 [Ca(2+)]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 [Ca(2+)]i transients duration and action potential duration, which facilitates the formation of delayed afterdepolarizations.

KEYWORDS:

arrhythmia (mechanisms); calcium; heart failure; receptors, adrenergic

PMID:
25673629
PMCID:
PMC4608687
DOI:
10.1161/CIRCEP.114.002065
[Indexed for MEDLINE]
Free PMC Article

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