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 journalArticle

66 Citations (Scopus)

Abstract

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
Volume114
Issue number9
DOIs
StatePublished - Apr 25 2014

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Ryanodine Receptor Calcium Release Channel
Sarcoplasmic Reticulum
Ventricular Fibrillation
Action Potentials
Caffeine
Cardiac Arrhythmias
Voltage-Sensitive Dye Imaging
Excitation Contraction Coupling

Keywords

  • Arrhythmias, cardiac
  • ventricular fibrillation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Optical mapping of sarcoplasmic reticulum Ca2+ in the intact heart : Ryanodine receptor refractoriness during alternans and fibrillation. / Wang, Lianguo; Myles, Rachel C.; De Jesus, Nicole M.; Ohlendorf, Alex K P; Bers, Donald M; Ripplinger, Crystal M.

In: Circulation Research, Vol. 114, No. 9, 25.04.2014, p. 1410-1421.

Research output: Contribution to journalArticle

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abstract = "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.",
keywords = "Arrhythmias, cardiac, ventricular fibrillation",
author = "Lianguo Wang and Myles, {Rachel C.} and {De Jesus}, {Nicole M.} and Ohlendorf, {Alex K P} and Bers, {Donald M} and Ripplinger, {Crystal M}",
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T1 - Optical mapping of sarcoplasmic reticulum Ca2+ in the intact heart

T2 - Ryanodine receptor refractoriness during alternans and fibrillation

AU - Wang, Lianguo

AU - Myles, Rachel C.

AU - De Jesus, Nicole M.

AU - Ohlendorf, Alex K P

AU - Bers, Donald M

AU - Ripplinger, Crystal M

PY - 2014/4/25

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N2 - 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.

AB - 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.

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KW - ventricular fibrillation

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