Abstract 13454: Globalization of β2-Adrenergic Response Following T-tubular Degradation is Arrhythmogenic
Transverse tubular (T-tubular, TT) degradation (TTD) contributes to heart failure (HF) pathology. Recent studies showed that TTD causes TT membrane contents, including β2 adrenergic receptors (β2R), to redistribute to the sarcolemmal membrane (SL). Thus, TTD allows ordinarily localized β2R dependent cAMP to increase throughout the cell. Potential effects on the action potential (AP) have not yet been established. Here, we probe these relationships using coupled Heijman et al β-adrenergic and O'Hara-Rudy AP computer models. TTD was parameterized as percent redistribution (0-100%, no kinetics changes) of membrane signaling proteins (β2R and associated G-proteins) and ion channels (including L-type, ICaL) to the SL (see figure). As in experiments, TTD caused the β2-response to globalize: cAMP in SL increased up to 2-fold with increased TTD (isoproterenol, ISO = 1 μM, a saturating dose). Relatedly, at the EC50 ISO dose (20 nM) PKA targets in the SL showed increased fractional phosphorylation with increased TTD. However, ICaL redistributed to the SL (ICaL,SL) was an exception: phosphorylation was 100% regardless of TTD. This is because ICaL is not native to the SL, where PKA is relatively high and phosphatase activity is relatively low. The stress response (1 μM ISO bolus and accelerated pacing from 1-2 Hz) elicited early afterdepolarizations (EADs) with mild TTD (25%, as seen in HF myocytes; no EADs for 0% TTD) during transition beats #11-40. Forcing ICaL,SL to sense TT Ca, or TT PKA eliminated EADs, suggesting that weak Ca dependent inactivation (CDI) and hyperphosphorylation in the SL drove the EADs. However, EADs required ISO, and did not occur with TTD alone (weak CDI alone). Some commonly prescribed β-blockers (e.g. metoprolol) are β1 selective. β1R block did not eliminate EADs. Interestingly, β2R block did. Global β2R response with TTD causes arrhythmogenic EADs via ICaL,SL hyperphosphorylation, and blocking β2R in particular may be a novel therapeutic strategy in HF.
- © 2012 by American Heart Association, Inc.