Arrhythmogenic Remodeling of β2 Versus β1 Adrenergic Signaling in the Human Failing Heart. (April 2015)

• Record Type: Journal Article
• Authors: Lang, Di; Holzem, Katherine; Kang, Chaoyi; Xiao, Mengqian; Hwang, Hye Jin; Ewald, Gregory A.; Yamada, Kathryn A.; Efimov, Igor R.
• Is Part Of: Circulation. Volume 8:Number 2(2015)
• Publication Date: 2015-04
• Subjects: Arrhythmia -- Periodicals; Heart -- Electric properties -- Periodicals; 616.128
• DOI: 10.1161/CIRCEP.114.002065
• Languages: English
• ISSNs: 1941-3149

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background—</title> <p>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.</p> </sec> <sec> <title>Methods and Results—</title> <p>We used optical imaging of action potentials and [Ca<sup>2+</sup>]<sub>i</sub> transients to compare the β<sub>1</sub>- and β<sub>2</sub>-adrenergic responses in left ventricular wedge preparations of human donor and failing hearts. β<sub>1</sub>-Stimulation significantly increased conduction velocity, shortened action potential duration, and [Ca<sup>2+</sup>]<sub>i</sub> transients duration (CaD) in donor but not in failing hearts, because of desensitization of β<sub>1</sub>-adrenergic receptor in heart failure. In contrast, β<sub>2</sub>-stimulation increased conduction velocity in both donor and failing hearts but shortened action potential duration only in failing hearts. β<sub>2</sub>-Stimulation also affected transmural heterogeneity in action potential duration but not in [Ca<sup>2+</sup>]<sub>i</sub> transients duration. Both β<sub>1</sub>- and β<sub>2</sub>-stimulation augmented the vulnerability and frequency of ectopic activity and enhanced substrates for ventricular tachycardia in failing, but not in donor, hearts. Both β<sub>1</sub>- and β<sub>2</sub>-stimulation enhanced Purkinje fiber automaticity, whereas only β<sub>2</sub>-stimulation promoted Ca-mediated premature ventricular contractions in heart failure.</p> </sec> <sec> <title>Conclusions—</title> <p>During end-stage heart failure, β<sub>2</sub>-stimulation creates arrhythmogenic substrates via conduction velocity regulation and transmurally heterogeneous repolarization. β<sub>2</sub>-Stimulation is, therefore, more arrhythmogenic than β<sub>1</sub>-stimulation. In particular, β<sub>2</sub>-stimulation increases the transmural difference between [Ca<sup>2+</sup>]<sub>i</sub> transients duration and action potential duration, which facilitates the formation of delayed afterdepolarizations.</p> </sec> </abstract>