Optical mapping of sarcoplasmic reticulum Ca2+ in the intact heart: ryanodine receptor refractoriness during alternans and fibrillation

Wang, L., Myles, R. C. , De Jesus, N. M., Ohlendorf, A. K.P., Bers, D. M. and Ripplinger, C. M. (2014) Optical mapping of sarcoplasmic reticulum Ca2+ in the intact heart: ryanodine receptor refractoriness during alternans and fibrillation. Circulation Research, 114(9), pp. 1410-1421. (doi: 10.1161/CIRCRESAHA.114.302505)

Abstract

Rationale: Sarcoplasmic reticulum (SR) Ca2+ cycling is key to normal excitation–contraction coupling but may also contribute to pathological cardiac alternans and arrhythmia.<p></p> Objective: To measure intra-SR free [Ca2+] ([Ca2+]SR) changes in intact hearts during alternans and ventricular fibrillation (VF).<p></p> Methods and Results: Simultaneous optical mapping of Vm (with RH237) and [Ca2+]SR (with Fluo-5N AM) was performed in Langendorff-perfused rabbit hearts. Alternans and VF were induced by rapid pacing. SR Ca2+ and action potential duration (APD) alternans occurred in-phase, but SR Ca2+ alternans emerged first as cycle length was progressively reduced (217±10 versus 190±13 ms; P<0.05). Ryanodine receptor (RyR) refractoriness played a key role in the onset of SR Ca2+ alternans, with SR Ca2+ release alternans routinely occurring without changes in diastolic [Ca2+]SR. Sensitizing RyR with caffeine (200 μmol/L) significantly reduced the pacing threshold for both SR Ca2+ and APD alternans (188±15 and 173±12 ms; P<0.05 versus baseline). Caffeine also reduced the magnitude of spatially discordant SR Ca2+ alternans, but not APD alternans, the pacing threshold for discordance, or threshold for VF. During VF, [Ca2+]SR was high, but RyR remained nearly continuously refractory, resulting in minimal SR Ca2+ release throughout VF.<p></p> Conclusions: In intact hearts, RyR refractoriness initiates SR Ca2+ release alternans that can be amplified by diastolic [Ca2+]SR alternans and lead to APD alternans. Sensitizing RyR suppresses spatially concordant but not discordant SR Ca2+ and APD alternans. Despite increased [Ca2+]SR during VF, SR Ca2+ release was nearly continuously refractory. This novel method provides insight into SR Ca2+ handling during cardiac alternans and arrhythmia.<p></p>

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Myles, Dr Rachel
• Authors: Wang, L., Myles, R. C., De Jesus, N. M., Ohlendorf, A. K.P., Bers, D. M., and Ripplinger, C. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Circulation Research
• Publisher: Lippincott Williams & Wilkins
• ISSN: 1524-4571
• ISSN (Online): 1524-4571