Impact of castration on changes in left ventricular diastolic pressure-volume relations induced by chronic adrenergic stimulation in rats

Abstract

A reduced testosterone concentration characterizes heart failure and independently predicts outcomes. Although testosterone replacement therapy may have non-cardiac-related therapeutic benefits in heart failure, whether reduced testosterone concentrations protect against adverse left ventricular remodelling (LV dilatation) is uncertain. I therefore evaluated whether surgical castration modifies LV dilatation following 6 months of daily injections of the β-adrenergic receptor (AR) agonist, isoproterenol (ISO) (0.015 mg/kg/day) to rats. The extent of LV dilatation and LV systolic chamber dysfunction were determined using both echocardiography and isolated perfused heart procedures. A load-independent measure of LV dilatation was determined from the volume intercept of the LV diastolic pressure-volume (P-V) relationships. As compared to the saline vehicle-treated group, after 6 months of β-AR activation in sham-castrated rats, a marked right shift in the LV diastolic P-V relationship was noted with an increased LV volume intercept at 0 mmHg diastolic pressure (LV V0 in ml)(ISO=0.38 ± 0.02, Saline vehicle=0.30 ± 0.02, p<0.05). However, chronic β-AR activation did not alter LV systolic chamber function either in vivo (LV endocardial fractional shortening, echocardiography) or ex vivo (LV end systolic elastance). Although castration decreased body weight, castration failed to modify the impact of ISO on the LV diastolic P-V relationships or the LV volume intercept at 0 mmHg diastolic pressure (LV V0 in ml)(Castration ISO=0.35 ± 0.02, Castration saline vehicle=0.27 ± 0.03, p<0.05). In conclusion, castration does not influence the extent of LV dilatation induced by chronic adrenergic activation in an animal model where adverse LV remodelling precedes LV systolic chamber dysfunction. These data lend support for the notion that testosterone replacement therapy in heart failure may not produce adverse effects on the degree of cardiac dilatation.