Local &bgr;-Adrenergic Stimulation Overcomes Source-Sink Mismatch to Generate Focal Arrhythmia

Rationale: &bgr;-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 &bgr;-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 &mgr;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 &mgr;mol/L], 0.45±0.62 PVCs per injection; high-dose [125–250 &mgr;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 &mgr;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 &bgr;-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.

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