Local β-Adrenergic Stimulation Overcomes Source-Sink Mismatch to Generate Focal Arrhythmia

Rationale: beta-Adrenergic receptor stimulation produces sarcoplasmic reticulum Ca2+ overload and delayed afterdepolarizations in isolated ventricular myocytes. How delayed afterdepolarizations are synchronized to overcome the source-sink mismatch and produce focal arrhythmia in the intact heart remains unknown. Objective: To determine whether local beta-adrenergic receptor stimulation produces spatiotemporal synchronization of delayed afterdepolarizations and to examine the effects of tissue geometry and cell-cell coupling on the induction of focal arrhythmia. Methods and Results: Simultaneous optical mapping of transmembrane potential and Ca2+ transients was performed in normal rabbit hearts during subepicardial injections (50 mu L) of norepinephrine (NE) or control (normal Tyrode's solution). Local NE produced premature ventricular complexes (PVCs) from the injection site that were dose-dependent (low-dose [30-60 mu mol/L], 0.45+/-0.62 PVCs per injection; high-dose [125-250 mu mol/L], 1.33+/-1.46 PVCs per injection; P<0.0001) and were inhibited by propranolol. NE-induced PVCs exhibited abnormal voltage-Ca2+ delay at the initiation site and were inhibited by either sarcoplasmic/endoplasmic reticulum Ca2+-ATPase inhibition or reduced perfusate [Ca2+], which indicates a Ca2+-mediated mechanism. NE-induced PVCs were more common at right ventricular than at left ventricular sites (1.48+/-1.50 versus 0.55+/-0.89, P<0.01), and this was unchanged after chemical ablation of endocardial Purkinje fibers, which suggests that source-sink interactions may contribute to the greater propensity to right ventricular PVCs. Partial gap junction uncoupling with carbenoxolone (25 mu mol/L) increased focal activity (2.18+/-1.43 versus 1.33+/-1.46 PVCs per injection, P<0.05), which further supports source-sink balance as a critical mediator of Ca2+-induced PVCs. Conclusions: These data provide the first experimental demonstration that localized beta-adrenergic receptor stimulation produces spatiotemporal synchronization of sarcoplasmic reticulum Ca2+ overload and release in the intact heart and highlight the critical nature of source-sink balance in initiating focal arrhythmias. (Circ Res. 2012;110:1454-1464.)