Pacing-induced heart failure in the dog recapitulates many of the electrophysiological and hemodynamic abnormalities of the human disease; however, the mechanisms underlying altered Ca2+ handling have not been investigated in this model. We now show that left ventricular midmyocardial myocytes isolated from dogs subjected to 3 to 4 weeks of rapid pacing have prolonged action potentials and Ca2+ transients with reduced peaks, but durations ≃3-fold longer than controls. To discriminate between action potential effects on Ca2+ kinetics and direct changes in Ca2+ regulatory processes, voltage-clamp steps were used to examine the time constant for cytosolic Ca2+ removal (τ(Ca)). τ(Ca) was prolonged by just 35% in myocytes from failing hearts after fixed voltage steps in physiological solutions (τ(Ca) control, 216 ± 25 ms, n = 17; τ(Ca) failing, 292 ± 23 ms, n = 22; P < 0.05), but this difference was markedly accentuated when Na+/Ca2+ exchange was eliminated (τ(Ca) control, 282 ± 30 ms, n = 13; τ(Ca) failing, 576 ± 83 ms, n = 11; P < 0.005). Impaired sarcoplasmic reticular (SR) Ca2+ uptake and a greater dependence on Na+/Ca2+ exchange for cytosolic Ca2+ removal was confirmed by inhibiting SR Ca2+ ATPase with cyclopiazonic acid, which slowed Ca2+ removal more in control than in failing myocytes. β-Adrenergic stimulation of SR Ca2+ uptake in cells from failing hearts sufficed only to accelerate τ(Ca) to the range of unstimulated controls. Protein levels of SERCA2a, phospholamban, and Na+/Ca2+ exchanger revealed a pattern of changes qualitatively similar to the functional measurements; SERCA2a and phospholamban were both reduced in failing hearts by 28%, and Na+/Ca2+ exchange protein was increased 104% relative to controls. Thus, SR Ca2+ uptake is markedly downregulated in failing hearts, but this defect is partially compensated by enhanced Na+/Ca2+ exchange. The alterations are similar to those reported in human heart failure, which reinforces the utility of the pacing-induced dog model as a surrogate for the human disease.
- Action potential
- Ca uptake
- Excitation-contraction coupling
- Heart failure
- Sarcoplasmic reticulum
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine