Defective intracellular Ca2+ homeostasis contributes to myocyte dysfunction during ventricular remodelling induced by chronic volume overload in rats.

1. Previous studies have demonstrated progressive ventricular hypertrophy, dilatation and contractile depression in response to chronic volume overload. Whether this decompensation was related to intrinsic myocyte dysfunction was not clear. The present study evaluated ventricular myocyte function at critical times during the progression of ventricular remodelling induced by volume overload. 2. Chronic volume overload was induced with an infrarenal aortocaval fistula in rats. Myocyte contraction and intracellular Ca(2+) concentrations ([Ca(2+)](i)) were evaluated using a fura-2 fluorescence and edge detection system. Protein levels of sarcoplasmic reticulum (SR) Ca(2+) transporters were determined by western blots. Progressive ventricular dilatation developed following creation of the fistula. Although myocyte function in 5 week fistula rats was comparable to that of the control group, myocytes from rats 10 weeks post-fistula demonstrated significant depression of cell shortening and peak [Ca(2+)](i). Application of isoproterenol (0.1 micromol/L) was not able to compensate for the functional deficiency in myocytes from 10 week fistula rats. Caffeine (10 mmol/L) induced SR Ca(2+) release, as well as protein expression of SR Ca(2+)-ATPase, and ryanodine receptors were reduced in myocytes obtained from the same group of 10 week fistula rats. 3. These data indicate that the transition to heart failure secondary to chronic volume overload is related to depressed myocyte contractility secondary to altered intracellular Ca(2+) homeostasis.