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

Lianguo Wang, Rachel C. Myles, Nicole M. De Jesus, Alex K P Ohlendorf, Donald M Bers, Crystal M Ripplinger

Research output: Contribution to journalArticlepeer-review

84 Scopus citations


Rationale: Sarcoplasmic reticulum (SR) Ca2+ cycling is key to normal excitation-contraction coupling but may also contribute to pathological cardiac alternans and arrhythmia. OBJECTIVE:: To measure intra-SR free [Ca 2+] ([Ca2+]SR) changes in intact hearts during alternans and ventricular fibrillation (VF). 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 Ca release alternans routinely occurring without changes in diastolic [Ca 2+]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. 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 Ca 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.

Original languageEnglish (US)
Pages (from-to)1410-1421
Number of pages12
JournalCirculation Research
Issue number9
StatePublished - Apr 25 2014


  • Arrhythmias, cardiac
  • ventricular fibrillation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


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