Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure, I: experimental studies.

, , , , , and . Circ. Res. 84 (5): 562--570 (March 1999)


Pacing-induced heart failure in the dog recapitulates many of the electrophysiological and hemodynamic abnormalities of the human disease; however, the mechanisms underlying altered Ca$^2+$ 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 Ca$^2+$ transients with reduced peaks, but durations approximately 3-fold longer than controls. To discriminate between action potential effects on Ca$^2+$ kinetics and direct changes in Ca$^2+$ regulatory processes, voltage-clamp steps were used to examine the time constant for cytosolic Ca$^2+$ removal (tauCa). tauCa was prolonged by just 35\% in myocytes from failing hearts after fixed voltage steps in physiological solutions (tauCa control, 216+/-25 ms, n=17; tauCa failing, 292+/-23 ms, n=22; P<0.05), but this difference was markedly accentuated when Na$^+$/Ca$^2+$ exchange was eliminated (tauCa control, 282+/-30 ms, n=13; tauCa failing, 576+/-83 ms, n=11; P<0. 005). Impaired sarcoplasmic reticular (SR) Ca$^2+$ uptake and a greater dependence on Na$^+$/Ca$^2+$ exchange for cytosolic Ca$^2+$ removal was confirmed by inhibiting SR Ca$^2+$ ATPase with cyclopiazonic acid, which slowed Ca$^2+$ removal more in control than in failing myocytes. beta-Adrenergic stimulation of SR Ca$^2+$ uptake in cells from failing hearts sufficed only to accelerate tauCa to the range of unstimulated controls. Protein levels of SERCA2a, phospholamban, and Na$^+$/Ca$^2+$ 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$^+$/Ca$^2+$ exchange protein was increased 104\% relative to controls. Thus, SR Ca$^2+$ uptake is markedly downregulated in failing hearts, but this defect is partially compensated by enhanced Na$^+$/Ca$^2+$ 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.


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