Local β-adrenergic stimulation overcomes source-sink mismatch to generate focal arrhythmia

Myles, R.C. , Wang, L., Kang, C., Bers, D.M. and Ripplinger, C.M. (2012) Local β-adrenergic stimulation overcomes source-sink mismatch to generate focal arrhythmia. Circulation Research, 110(11), pp. 1454-1464. (doi: 10.1161/CIRCRESAHA.111.262345)

Abstract

<b>Rationale:</b> β-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. <b>Objective:</b> To determine whether local β-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. <b>Methods and Results:</b> Simultaneous optical mapping of transmembrane potential and Ca²⁺ transients was performed in normal rabbit hearts during subepicardial injections (50 μ) 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 μmol/L], 0.45±0.62 PVCs per injection; high-dose [125-250 μmol/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 μmol/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. <b>Conclusions:</b> These data provide the first experimental demonstration that localized β-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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Myles, Dr Rachel
• Authors: Myles, R.C., Wang, L., Kang, C., Bers, D.M., and Ripplinger, C.M.
• Subjects: Q Science > QP Physiology; R Medicine > RZ Other systems of medicine
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Circulation Research
• ISSN: 0009-7330
• Published Online: 26 April 2012

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
55023	1	Electrophysiological remodelling and mechanisms of ventricular arrhythmia in dilated cardiomyopathy.	Rachel Myles	British Heart Foundation (BHF)	FS/10/64/28532	Institute of Cardiovascular and Medical Sciences