SUMMARY We examined the effect of chronically administered digoxin on atrioventricular (A-V) conduction in nine cardiac transplant recipients. We assessed A-V conduction by measuring the duration from the pacing stimulus to the onset of the QRS complex (S'R interval) and by determining the occurrence of Wenckebach periodicity during rapid atrial pacing. We made measurements during a control period and during a period of digoxin administration of up to 37 days. During the digoxin period, the cycle length at which BECAUSE DIGITALIS has both clinical utility and, serious toxicity which are dependent upon alterations of A-V conduction, knowledge of its various effects on A-V conduction in man is important. Most studies examining the mechanism whereby digitalis increases A-V nodal refractoriness and slows A-V conduction have emphasized its vagomimetic and antiadrenergic effects.1-6 The existence and magnitude of a direct (or non-neural) depressant effect upon A-V conduction remains controversial. In isolated heart preparations and anesthetized animals, a minor direct effect exists at high concentrations of digitalis.2 7 9 In man and in intact conscious animals, most studies of A-V conduction in the presence of vagal blockade101-2 or cardiac denervation13-l have failed to demonstrate that acute intravenous administration of digitalis prolongs A-V conduction, although one report limited to three patients showed that a small effect persisted after atropine administration.'6 Therefore, to further explore the mechanism of action of digitalis upon A-V conduction, we examined the effects of digoxin administered chronically to cardiac allograft recipients whose hearts are anatomically denervated. The results indicate that at therapeutic steady-state serum concentrations, digoxin acts directly to slow A-V conduction, but that this effect becomes manifest only when A-V conduction is stressed by tachycardia. MethodsWe performed studies in 12 recipients 2-10 weeks after cardiac transplantation. The investigations were initiated following the acute phase of convalescence after operation and at least one week after the disappearance of measurable serum digoxin concentrations known to persist for several days after cardiac transplantation in patients receiving digoxin prior to cardiac replacement (unpublished data, E.B. Stinson). Serial studies in three patients were interrupted by episodes of cardiac rejection or infection and 45 seconds of pacing at each of these predetermined rates. We then discontinued pacing and allowed sinus rhythm to become re-established for about 30 seconds before reinstituting pacing at the next higher rate. When Wenckebach block occurred at one of the predetermined heart rates, or at a higher rate, we identified the cycle length at which Wenckebach periodicity occurred (hereafter termed Wenckebach CL) by repeating the pacing procedure at increments in cycle length of 10 msec until block was no longer apparent. We confirmed the Wenckebach CL by repeating the pacing procedure at 10 msec decrements in cy...