DEFECTIVE INTRACELLULAR Ca²⁺ HOMEOSTASIS CONTRIBUTES TO MYOCYTE DYSFUNCTION DURING VENTRICULAR REMODELLING INDUCED BY CHRONIC VOLUME OVERLOAD IN RATS

Abstract

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.

Xanthine oxidase inhibition preserves left ventricular systolic but not diastolic function in cardiac volume overload

“…Allopurinol has also been shown to improve Ca 2ϩ homeostasis and oxidation/nitration of Ca 2ϩ -handling proteins in the tachypacing model in the dog (34) and in the spontaneously hypertensive rat (19). In the present study, there was no change in SERCA protein levels and that of its regulator, PLN, at 8 wk, whereas 12-wk ACF has been reported to have a decrease in SERCA2 expression associated with decreased LV contractility and the response to Ca 2ϩ infusion in the isolated ACF heart (13,36). It is of interest that we found an increase in SLN in ACF LVs that was decreased by allopurinol.…”

ETAselective receptor antagonism prevents ventricular remodeling in volume-overloaded rats

“…The modest elevation in maximum dP/dt observed in compensated and decompensated animals could be related to elevated neurohormonal input from chronic sympathetic stimulation and increased levels of circulating epinephrine/norepinephrine. A recent study by Ding et al (18) demonstrated that isolated myocytes from hearts 5 wk postfistula were still responsive to adrenergic stimulation. However, isolated myocytes from hearts 10 wk postfistula were unresponsive (lacking a response) to the same adrenergic challenge (18).…”

“…A recent study by Ding et al (18) demonstrated that isolated myocytes from hearts 5 wk postfistula were still responsive to adrenergic stimulation. However, isolated myocytes from hearts 10 wk postfistula were unresponsive (lacking a response) to the same adrenergic challenge (18). Regardless, the extent of chamber dilatation present in the decompensated group in conjunction with the depressed stroke volume, cardiac output, and ejection fraction are indicative of a heart that is beginning to fail.…”

Adiponectin downregulation is associated with volume overload-induced myocyte dysfunction in rats

“…Heart failure occurred subsequently between 8 to 16 weeks with depressed in vivo and in vitro LV systolic pressure. Previous study from our laboratory indicates that depressed ventricular contractility is intrinsic to the individual myocytes [7] . In that study the in vivo cardiac size and performance following fistula surgery was evaluated by M-mode echocardiography.…”