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

Abstract：

RATIONALE:Sarcoplasmic reticulum (SR) Ca(2+) 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+)] ([Ca(2+)]SR) changes in intact hearts during alternans and ventricular fibrillation (VF). METHODS AND RESULTS:Simultaneous optical mapping of Vm (with RH237) and [Ca(2+)]SR (with Fluo-5N AM) was performed in Langendorff-perfused rabbit hearts. Alternans and VF were induced by rapid pacing. SR Ca(2+) and action potential duration (APD) alternans occurred in-phase, but SR Ca(2+) 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 Ca(2+) alternans, with SR Ca(2+) 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 Ca(2+) and APD alternans (188±15 and 173±12 ms; P<0.05 versus baseline). Caffeine also reduced the magnitude of spatially discordant SR Ca(2+) alternans, but not APD alternans, the pacing threshold for discordance, or threshold for VF. During VF, [Ca(2+)]SR was high, but RyR remained nearly continuously refractory, resulting in minimal SR Ca(2+) release throughout VF. CONCLUSIONS:In intact hearts, RyR refractoriness initiates SR Ca(2+) release alternans that can be amplified by diastolic [Ca(2+)]SR alternans and lead to APD alternans. Sensitizing RyR suppresses spatially concordant but not discordant SR Ca(2+) and APD alternans. Despite increased [Ca(2+)]SR during VF, SR Ca(2+) release was nearly continuously refractory. This novel method provides insight into SR Ca(2+) handling during cardiac alternans and arrhythmia.

journal_name

Circ Res

journal_title

Circulation research

authors

Wang L,Myles RC,De Jesus NM,Ohlendorf AK,Bers DM,Ripplinger CM

doi

10.1161/CIRCRESAHA.114.302505

subject

Has Abstract

pub_date

2014-04-25 00:00:00

pages

1410-21

issue

eissn

0009-7330

issn

1524-4571

pii

CIRCRESAHA.114.302505

journal_volume

114

pub_type

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