Robert H. Goldman

The relation between myocardial 3H-digoxin concentration and its hemodynamic effects☆

Abstract The relation between myocardial digoxin concentration and its nemodynamic effects in the same animal was studied in 23 open chest anesthetized dogs with intact circulations given digoxin, 0.08 mg/kg body weight (0.04 mg/kg 3 H-digoxin) intravenously. During the succeeding 5 to 240 minutes, hemodynamic measurements were made, and plasma and myocardial 3 H-digoxin concentrations were determined. At 5 minutes there was no change in left ventricular dp/dt or right ventricular contractile force, but at 15 minutes 33 to 66 percent of peak positive inotropic effect was observed. Peak effect occurred at 60 minutes for the left ventricle, and at 180 minutes for the right ventricle. In contrast, myocardial 3 H-digoxin concentration increased more rapidly with 50 percent of maximal ventricular concentration present at 5 minutes and near maximal concentration reached at 15 minutes. Thus, the hemodynamic effects of digoxin lagged behind the myocardial 3 H-digoxin concentration. This finding suggested that the total myocardial 3 H-digoxin concentration was not the only determinant of the rate of onset and development of the inotropic effects of digoxin. Other possible determinants are discussed. An additional observation was the difference in distribution of 3 H-digoxin in the various parts of the heart and skeletal muscle. Right ventricular 3 H-digoxin concentrations were 78.2 percent, atrial concentrations 44.9 percent, and skeletal muscle concentrations 12.9 percent of left ventricular concentrations, which were about the same as those of the interventricular septum. One possible explanation offered for this observation is differences in blood flow to the various parts of the myocardium.

Left ventricular dynamics during long-term digoxin treatment in patients with stable coronary artery disease

Abstract Ten patients with stable coronary artery disease who did not have clinical congestive heart failure and had recovered (3 or more months) from coronary bypass graft surgery were given both intravenous and oral digoxin. Left ventricular performance was assessed weekly for 3 control weeks, during 4 weeks of long-term oral digoxin treatment and during 2 to 3 weeks of recovery. Serial noninvasive measurements of velocity of circumferential fiber shortening, ejection fraction, end-diastolic volume and cardiac output were obtained with computer-assisted fluoroscopic analysis of the motion of surgically implanted mid wall myocardial markers that outline the left ventricular cavity. During 4 weeks of oral digoxin therapy, mean serum digoxin levels were maintained between 1.2 ± 0.1 and 1.4 ± 0.1 ng/ml (mean ± standard error of the mean). Mean velocity of circumferential fiber shortening increased 15.6 percent from 0.65 ± 0.05 to 0.75 ± 0.05 circumferences/sec (P

The inotropic effects of digoxin in hyperkalemia. Relation to (Na+,K+)-ATPase inhibition in the intact animal.

The effects of hyperkalemia on the inotropic properties of digoxin were studied in anesthetized mongrel dogs. With preload, afterload and heart rate maintained constant in dogs who received atropine and practolol to block cardiac reflexes, 0.08 mg/kg digoxin increased the first derivative of the left ventricular pressure curve (LV dp/dt) 53.1 ± 8.3% (SEM) in normokalemic animals but only 9.5 ± 2.5% in hyperkalemic animals at 60 min. This decrease in the inotropic effects of digoxin by hyperkalemia was accompanied by significant decreases in both total left ventricular digoxin concentration and microsomal-bound digoxin. (Na+, K+)-ATPase was inhibited 43.3 ± 2.4% in normokalemic animals but only 27.4 ± 2.5% in hyperkalemic animals (P < 0.01), while (Mg++)-ATPase levels were similar in normokalemia and hyperkalemia. In animals not given digoxin, hyperkalemia had no effect on either LV dp/dt or (Na+, K+)-ATPase. There was a good correlation between the positive inotropic effects of digoxin and percent inhibition of (Na+, K+)-ATPase.These studies provide further support for the importance of (Na+, K+)-ATPase inhibition and microsomal-bound digoxin in determining the inotropic effects of digoxin. Hyperkalemia alters the inotropic effects of digoxin by decreasing binding of digoxin to a microsomal cell fraction containing (Na+, K+)-ATPase activity.These studies also provide support for the importance of reflex withdrawal of sympathetic tone in modifying the inotropic properties of digoxin in normokalemic and hyperkalemic animals.

Effects of digitalis on normal and abnormal left ventricular segmental dynamics

To study the effects of digoxin on regional left ventricular performance, continuous ventricular dynamics were assessed in nine patients with stable coronary disease. Computer-assisted analysis of the fluoroscopic motion of surgically implanted mid wall myocardial markers was used. The markers define six minor ventricular radii and outline the left ventricle. One and one-half hours after administration of 1 mg of intravenous digoxin, mean velocity of circumferential fiber shortening for all segments increased 19 percent, from 0.67 +/- 0.06 to 0.78 +/- 0.06 circumference/sec (P less than 0.01) and ejection fraction increased 4.5 percent, from 0.50 +/- 0.03 to 0.53 +/- 0.03 (P less than 0.05). Segmental velocity of circumferential fiber shortening, total segmental shortening and early segmental systolic shrtening increased in 83 percent to 91 percent of normal segments, depending on which index was used. Only 45 to 55 percent of initially abnormal segments benefited from digoxin. In general, segmental dyssynergy increased even when net ventricular function was enhanced. These results suggest that in pateints with chronic left ventricular contraction abnormalities due to coronary disease, deterioration of performance in abnormal regions after administration of digoxin may result from increased stress imposed by increased afterload and by improved segmental dynamics in more normal areas.

Correlation between microsomal (Na+ + K+)-ATPase activity and [3H] ouabain binding to heart tissue homogenates

ATP plus Mg2+ plus Na+ supported [3H]ouabain binding to canine left ventricular tissue homogenates and microsomal (Na+ + K+)-ATPase (ATP phosphohydrolase, EC 3.6.1.3) activity from the same tissue were measured. A linear relationship was found between the initial velocity of [3H]ouabain binding to tissue homogenates and microsomal (Na+ + K+)-ATPase activity from the same tissue in the presence and absence of in vivo bound digoxin. In vivo bound digoxin reduced both measurements. With tissue from digoxin-free hearts, a linear relationship was also obtained between the initial velocity and the maximum level of [3H]ouabain binding to tissue homogenate. Binding of [3H]ouabain to whole tissue homogenate is a convenient method for estimating (Na+ + K+)-ATPase activity in small left ventricular biopsy samples.

The effect on myocardial 3H-digoxin of magnesium deficiency.

Summary The hearts of magnesium-deficient mice accumulate less 3H-digoxin 1 hr after intraperitoneal injection than do controls. At 3, 6, 18, and 24 hr, magnesium-deficient mice retained more 3H-digoxin than controls. The difference in the initial uptake of 3H-digoxin between control and magnesium-deficient animals is not due to different blood 3H-digoxin levels. The role of magnesium deficiency-induced potassium deficiency in altering myocardial 3H-digoxin metabolism is discussed.

Circulatory responses to beta adrenergic blockade with alprenolol: Studies in patients with chronic heart disease

Abstract Fourteen patients with acquired heart disease received 0.2 mg/kg body weight of alprenolol, a beta adrenergic blocking agent with intrinsic sympathomimetic properties, during cardiac catheterization. A high degree of beta blockade was demonstrated by injection of 3 μg of isoproterenol before and after alprenolol, the chronotropic effect of isoproterenol being almost completely abolished by alprenolol. After administration of alprenolol, significant decreases at rest and during bicycle exercise were noted in heart rate, cardiac index, maximal rate of rise of left ventricular pressure (dp/dt), left ventricular work and aortic systolic pressure, and (on exercise alone) in tensiontime index and mean systolic ejection rate. Mean right atrial and pulmonary arterial pressures were significantly increased at rest after alprenolol. In patients with heart disease, alprenolol has substantial negative chronotropic and inotropic effects, similar to those of propranolol, which are not overcome by its intrinsic beta stimulating properties.