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

Abstract

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 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 to dobutamine stress were dramatically reduced 6 weeks after fistula creation. Although 6- week fistula animals had unchanged β-adrenoceptor density (Bmax) and binding affinity (Kd) as compared with controls, maximal adenylate cyclase responses to stimulation in vitro (V max) were markedly reduced. Digoxin treatment prevented this loss of responsiveness of adenylate cyclase but did not affect β-adrenoceptor density or affinity in vitro. Digoxin had no effect on LVDd, LVM, %FS, or the response to dobutamine infusion in vivo. Conclusions: Although digoxin prevented β-adrenoceptor desensitization and improved in vitro myocardial adenylate cyclase response, the cardiac response to adrenergic stimulation in vivo was not significantly improved. These results suggest that the role of β-adrenoceptor desensitization in the progression from volume overload hypertrophy to left ventricular dysfunction and heart failure may be less important than previously thought. Furthermore, although digoxin treatment did produce modest hemodynamic benefits, it did not prevent progressive remodeling in this model.