Affiliation:
1. From the Department of Pharmacology, School of Medicine, University of California, Davis (L.W., N.M.D.J., A.K.P.O., D.M.B., C.M.R.); and Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.C.M.).
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 V
m
(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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine,Physiology
Cited by
117 articles.
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