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March 19, 1999Circulation ResearchOpen Access

Mechanisms of Altered Excitation-Contraction Coupling in Canine Tachycardia-Induced Heart Failure, I

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Population

Left ventricular midmyocardial myocytes isolated from dogs subjected to 3 to 4 weeks of rapid pacing

Comparison

Rapid pacing for 3 to 4 weeks vs Unpaced control dogs/myocytes

Design

Preclinical

Follow-up

3 to 4 weeks

Key result

In a canine model of pacing-induced heart failure, the time constant for cytosolic Ca2+ removal was prolonged to 292±23 ms compared to 216±25 ms in controls (P<0.05), driven by impaired SR Ca2+ uptake.

Authors

BOBrian O’RourkeDKDavid A. KassGTGordon F. Tomaselli

Discussion

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Overview

Ca2+ handling defects in experimental HF mirror human disease; leaves open whether targeting SR uptake improves outcomes.

Key Points

  • Investigate mechanisms of altered calcium handling in pacing-induced heart failure in dogs.
  • Isolated left ventricular myocytes from dogs subjected to pacing for 3-4 weeks were studied.
  • Voltage-clamp steps were performed to assess cytosolic Ca2+ removal time constant (τ Ca).
  • Protein levels of SERCA2a, phospholamban, and Na+/Ca2+ exchanger were measured.
  • Cytosolic Ca2+ removal time constant (τ Ca) was 292±23 ms in failing myocytes vs. 216±25 ms in controls, P<0.05.
  • Na+/Ca2+ exchange significantly increased τ Ca in failing myocytes to 576±83 ms when Na+/Ca2+ exchange was inhibited, P<0.005.
  • SERCA2a and phospholamban were reduced by 28% in failing hearts, while Na+/Ca2+ exchange increased by 104% relative to controls.

Structured PICO

P
Population
Left ventricular midmyocardial myocytes isolated from dogs subjected to 3 to 4 weeks of rapid pacing (pacing-induced heart failure model)
I
Intervention
Rapid pacing for 3 to 4 weeks
C
Comparator
Unpaced control dogs/myocytes
O
Outcome
Time constant for cytosolic Ca2+ removal (τCa) and protein levels of SERCA2a, phospholamban, and Na+/Ca2+ exchangersurrogate

Main Result

Absolute Event Rate: 292% vs 216%

p-value: p=<0.05

In a canine model of pacing-induced heart failure, SR Ca2+ uptake is markedly downregulated but partially compensated by enhanced Na+/Ca2+ exchange, mirroring human heart failure.

Cite This Study

O’Rourke et al. (1999) studied Tachycardia-Induced Heart Failure. Rapid pacing vs. Controls (unpaced) was evaluated on Time constant for cytosolic Ca2+ removal (τ Ca) in physiological solutions (p=<0.05). In a canine model of pacing-induced heart failure, the time constant for cytosolic Ca2+ removal was prolonged to 292±23 ms compared to 216±25 ms in controls (P<0.05), driven by impaired SR Ca2+ uptake.

synapsesocial.com/papers/6a0984874db79685905153a4https://doi.org/10.1161/01.res.84.5.562
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