Background β-Adrenergic receptor (β-AR) stimulation produces sarcoplasmic reticulum (SR) Ca2+ overload and delayed after-depolarisations (DADs) in isolated ventricular myocytes. However, in the intact heart, strong electrotonic coupling means that depolarisation from many thousands of cells is required for an action potential to propagate. The mechanisms by which cellular DADs are synchronised to overcome the source-sink mismatch and produce focal arrhythmia remain unknown. We aimed to determine if localised β-AR stimulation can produce spatio-temporal synchronisation of DADs in the intact heart, 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 (Vm) and Ca2+ transients was performed in normal rabbit hearts during subepicardial injections (50 μl) of norepinephrine (NE, 30–250 μM) or control (normal Tyrodes). The protocol was performed at baseline and during partial gap junction uncoupling with carbenoxolone (CBX). Local NE produced premature ventricular complexes (PVCs) arising from the application site in all 15 hearts, and a dose-response was evident (low-dose: 0.45±0.62 vs high-dose: 1.33±1.46 PVCs/application, p<0.0001). NE-induced PVCs demonstrated areas of abnormal Vm-Ca2+ delay at the initiation site, indicating a Ca2+-mediated mechanism. PVCs were more inducible with NE at RV vs LV injection sites (1.48±1.50 vs 0.55±0.89, p<0.01) and following CBX (2.18±1.43 vs 1.33±1.46, p<0.05). Analysis of NE tissue exposure and Vm-Ca2+ dynamics revealed that differences in focal arrhythmia propensity between RV and LV, and following gap junction uncoupling were due to modulation of source-sink interactions.
Conclusions These data provide the first experimental demonstration that localised β-AR stimulation can produce spatio-temporal synchronisation of SR Ca2+ overload and release in the intact heart and highlight the critical nature of the source-sink balance in the initiation of focal arrhythmias.
- optical mapping
- β-adrenergic stimulation
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