(Circulation. 2001;103:1577.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Decreased Sarcoplasmic Reticulum Calcium Content Is Responsible for Defective Excitation-Contraction Coupling in Canine Heart Failure
From the Institute of Molecular Cardiobiology, Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Md.
Correspondence to Brian O’Rourke, PhD, Johns Hopkins University, Department of Medicine, Division of Cardiology, 844 Ross Building, 720 Rutland Ave, Baltimore, MD 21205. E-mail bor{at}jhmi.edu
Background—Altered excitation-contraction (E-C) coupling in canine pacing-induced heart failure involves decreased sarcoplasmic reticulum (SR) Ca uptake and enhanced Na/Ca exchange, which could be expected to decrease SR Ca content (CaSR) and may explain the reduced intracellular Ca (Cai) transient. Studies in other failure models have suggested that the intrinsic coupling between L-type Ca current (ICa,L) and SR Ca release is reduced without a change in SR Ca load. The present study investigates whether CaSR and/or coupling is altered in midmyocardial myocytes from failing canine hearts (F).
Methods and Results—Myocytes were indo-1–loaded via patch pipette (37°C), and Cai transients were elicited with voltage-clamp steps applied at various frequencies. ICa,L density was not significantly decreased in F, but steady-state Cai transients were reduced to 20% to 40% of normal myocytes (N). CaSR, measured by integrating Na/Ca exchange currents during caffeine-induced release, was profoundly decreased in F, to 15% to 25% of N. When CaSR was normalized in F by preloading in 5 mmol/L external Ca before a test pulse at 2 mmol/L Ca, a normal-amplitude Cai transient was elicited. E-C coupling gain was dependent on CaSR but was affected similarly in both groups, indicating that intrinsic coupling is unaltered in F.
Conclusions—A decrease in CaSR is sufficient to explain the diminished Cai transients in F, without a change in the effectiveness of coupling. Therefore, therapeutic approaches that increase CaSR may be able to fully correct the Ca handling deficit in heart failure.
Key Words: sarcoplasmic reticulum • calcium • heart failure
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