The digitalis glycosides exert their effects in patients with HF by virtue of their ability to inhibit sodium-potassium (Na+-K+) adenosine triphosphatase (ATPase). Inhibition of this enzyme in cardiac cells results in increased intracellular sodium and calcium contents leading to an augmentation of cardiac contractility. For many decades, the benefits of digitalis in HF were ascribed exclusively to this positive inotropic action.
However, recent evidence suggests that the benefits of digitalis may be related in part to enzyme inhibition in non-cardiac tissues.
Inhibition of Na+-K+ ATPase in vagal afferent fibers acts to sensitize cardiac baroreceptors, which in turn reduces sympathetic outflow from the central nervous system. In addition, by inhibiting Na+-K+ ATPase in the kidney, digitalis reduces the renal tubular reabsorption of sodium; the resulting increase in the delivery of sodium to the distal tubules leads to the suppression of renin secretion from the kidneys. These observations have led to the hypothesis that digitalis acts in HF primarily by attenuating the activation of neurohormonal systems (sympathetic tone and renin-angiotensin system) and not as a positive inotropic drug80. Although a variety of digitalis glycosides have been used in the treatment of HF for the last 200 years, the most commonly used preparation in the United States is digoxin.
Effect of digitalis in the treatment of HF
Several placebo-controlled trials have shown that treatment with digoxin for 1 to 3 months can improve symptoms, quality of life, and exercise tolerance in patients with mild to moderate HF81. These benefits have been seen regardless of the underlying rhythm (normal sinus rhythm or atrial fibrillation), cause of HF (ischemic or non- ischemic cardiomyopathy), or concomitant therapy (with or without ACE inhibitors). In a long-term trial that enrolled patients who primarily had class II or III symptoms, treatment with digoxin for 2 to 5 years had little effect on mortality but modestly reduced the combined risk of death and hospitalization82.
Practical use of digitalis in HF
Selection of patients
80 Gheorghiade M, Ferguson D. Digoxin. A neurohormonal modulator in heart failure? Circulation 1991;84:2181-6.
81 Guyatt GH, Sullivan MJ, Fallen EL, et al. A controlled trial of digoxin in congestive heart failure. Am J Cardiol 1988;61:371-5.
82 The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. N Engl J Med 1997;336:525-33.