Experimental Investigations Effect of Digoxin on Ventricular Remodeling and Responsiveness of β-Adrenoceptors in Chronic Volume Overload

Background: Digoxin improves baroreflex function and reduces neurohumoral activation in severe heart failure, but it is uncertain how digoxin affects ventricular remodeling and progression to left ventricular dysfunction. In addition, the effect of digoxin in vitro β-adrenoceptor density and function, and contractile reserve in vivo is not well understood. Methods and Results: To study this, we compared digoxin with placebo treatment in rats with chronic volume overload induced by aortocaval fistula and in sham-operated control animals. Left ventricular end-diastolic cavity dimensions (LVDd) and wall thickness were measured weekly by in vivo transthoracic echocardiography, and left ventricular mass (LVM) and percent fractional shortening (%FS) were calculated. Six weeks after fistula cre-ation, simultaneous echocardiographic and invasive hemodynamic evaluation at rest and in response to incremental dobutamine (1-10 μg/kg/min intravenously) were measured. Myo-cardial plasma membrane β-adrenoceptor density and maximal adenylate cyclase responses (Vmax) to isoproterenol, 5’-guanylylimi dodiphosphate, and forskolin were measured in vitro. Volume overload induced progressive increases in LVDd and LVM over the 6-week study period. Percent fractional shortening at rest. and the change in %FS in response t