CELLULAR BASIS FOR IMPROVED LEFT-VENTRICULAR PUMP FUNCTION AFTER DIGOXIN THERAPY IN EXPERIMENTAL LEFT-VENTRICULAR FAILURE

Objectives. The present study examined left ventricular (LV) and myocy te contractile performance and electrophysiologic variables after long term digoxin treatment in a model of LV failure. Background. A fundam ental therapeutic agent for patients with chronic LV dysfunction is th e cardiac glycoside digoxin. However, whether digoxin has direct effec ts on myocyte contractile function and electrophysiologic properties i n the setting of chronic LV dysfunction remains unexplored. Methods. L eft ventricular and isolated myocyte function and electrophysiologic v ariables were examined in five control dogs, five dogs after the devel opment of long-term rapid pacing (rapid pacing, 220 beats/min, 4 weeks ) and five dogs with rapid pacing given digoxin (0.25 mg/day) during t he pacing period (rapid pacing and digoxin). Results. Left ventricular ejection fraction decreased in the dogs with rapid pacing compared,vi th that in control dogs (30 +/- 2% vs. 68 +/- 3%, p < 0.05) and was hi gher with digoxin than that in the rapid pacing group (38 +/- 3%, p = 0.038), Left ventricular end diastolic volume increased in the rapid p acing group compared with the control group (84 +/- 6 ml vs, 59 +/- 7 ml, p < 0.05) and remained increased with digoxin (79 +/- 6 ml). Isola ted myocyte shortening velocity decreased in the rapid pacing group co mpared with the control group (37 +/- 1 mu m/s vs. 59 +/- 1 mu m/s, p < 0.05) and increased with digoxin compared,vith rapid pacing (46 +/- 1 mu m/s, p < 0.05). Action potential maximal upstroke velocity was di minished in the rapid pacing group compared with the control group (13 5 +/- 6 V/s vs, 163 +/- 9 V/s, p < 0.05) and increased with digoxin co mpared with rapid pacing (155 +/- 12 V/s, p < 0.05). Action potential duration increased in the rapid pacing group compared with the control group (247 +/- 10 vs. 216 +/- 6 ms, p < 0.05) and decreased with digo xin compared with rapid pacing (219 +/- 12 ms, p < 0.05). Conclusions. In this model of rapid pacing induced LV failure, digoxin treatment i mproved LV pump function, enhanced isolated myocyte contractile perfor mance and normalized myocyte action potential characteristics. This st udy provides unique evidence to suggest that the cellular basis for im proved LV pump function with digoxin treatment in the setting of LV fa ilure has a direct and beneficial effect on myocyte contractile functi on and electrophysiologic measures.