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Effect of Digoxin on Ventricular Remodeling and Responsiveness of beta-Adrenoceptors in Chronic Volume Overload
1Division of Cardiology, University of South Florida and Cardiology and Research Services, Tampa, Florida, USA
Insights
Digoxin prevented beta-adrenoceptor desensitization in rats with heart failure but did not improve cardiac function in vivo. This suggests beta-adrenoceptor desensitization is less critical in heart failure progression than previously thought.
Area of Science:
- Cardiology
- Pharmacology
- Physiology
Background:
- Digoxin's effects on ventricular remodeling and left ventricular dysfunction in severe heart failure remain unclear.
- Its impact on beta-adrenoceptor function and contractile reserve in vitro and in vivo requires further investigation.
Purpose of the Study:
- To investigate the effects of digoxin on ventricular remodeling, beta-adrenoceptor function, and contractile reserve in a rat model of chronic volume overload heart failure.
Main Methods:
- Rats with aortocaval fistula (volume overload) or sham surgery received digoxin or placebo.
- Echocardiography assessed left ventricular dimensions and function.
- Hemodynamic evaluation and in vitro beta-adrenoceptor assays were performed.
Main Results:
- Volume overload led to increased left ventricular size and mass, with reduced fractional shortening and blunted response to dobutamine.
- While digoxin prevented loss of adenylate cyclase responsiveness in vitro, it did not improve in vivo cardiac function or prevent remodeling.
Conclusions:
- Digoxin prevents beta-adrenoceptor desensitization and improves in vitro adenylate cyclase response but does not enhance in vivo adrenergic response in this heart failure model.
- Beta-adrenoceptor desensitization may play a lesser role in heart failure progression than anticipated, and digoxin did not prevent remodeling.
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 beta-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 creation, simultaneous echocardiographic and invasive hemodynamic evaluation at rest and in response to incremental dobutamine (1-10 µg/kg/min intravenously) were measured. Myocardial plasma membrane beta-adrenoceptor density and maximal adenylate cyclase responses (V(max)) 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 beta-adrenoceptor density (B(max)) and binding affinity (K(d)) 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 beta-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 beta-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 beta-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.