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

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.