Arrhythmogenic Remodeling of β 2 Versus β 1 Adrenergic Signaling in the Human Failing Heart

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 β 1 - and β 2 -adrenergic responses in left ventricular wedge preparations of human donor and failing hearts. β 1 -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 β 1 -adrenergic receptor in heart failure. In contrast, β 2 -stimulation increased conduction velocity in both donor and failing hearts but shortened action potential duration only in failing hearts. β 2 -Stimulation also affected transmural heterogeneity in action potential duration but not in [Ca 2+ ] i transients duration. Both β 1 - and β 2 -stimulation augmented the vulnerability and frequency of ectopic activity and enhanced substrates for ventricular tachycardia in failing, but not in donor, hearts. Both β 1 - and β 2 -stimulation enhanced Purkinje fiber automaticity, whereas only β 2 -stimulation promoted Ca-mediated premature ventricular contractions in heart failure. Conclusions— During end-stage heart failure, β 2 -stimulation creates arrhythmogenic substrates via conduction velocity regulation and transmurally heterogeneous repolarization. β 2 -Stimulation is, therefore, more arrhythmogenic than β 1 -stimulation. In particular, β 2 -stimulation increases the transmural difference between [Ca 2+ ] i transients duration and action potential duration, which facilitates the formation of delayed afterdepolarizations.