Digoxin did not reduce overall mortality, but it reduced the rate of hospitalization both overall and for worsening heart failure. These findings define more precisely the role of digoxin in the management of chronic heart failure.

NCT01176968.

Vascular endothelium has been shown to modify the contractile characteristics of vascular smooth muscle, and endocardial endothelium has been shown to modify the contractile characteristics of adjacent myocardium. In this study, whether vascular endothelium also modifies the contractile characteristics of adjacent myocardium and whether these effects are additive to those of endocardial endothelium were investigated. Rabbit hearts (n=54) were excised and mounted in a Langendorif preparation. Vascular reactivity was verified by acetylcholine infusion. One group of these hearts had Triton X-100 injected as a bolus into the coronaries to render the vascular endothelium dysfunctional. The other portion served as control hearts. Triton X-100 bolus injection resulted in little or no pathological changes on morphological examination; however, the vasodilatory response to acetylcholine in these hearts was abolished, suggesting vascular endothelial dysfunction. Vascular smooth muscle reactivity was verified in Triton X-100-injected hearts by nitroprusside infusion. In the control Langendorff-perfused hearts, there was little evidence of vascular endothelial dysfunction, with the coronary perfusion rate increasing from 8.9±0.4 to 11.0±0.3 ml/g per minute (p<0.01) in response to acetylcholine. All hearts were then removed, and right ventricular papillary muscles were excised for myocardial mechanical studies. Control Langendorffperfused hearts had myocardial mechanical characteristics similar to those of muscles from 18 other control hearts without Langendorff perfusion, indicating that the Langendorff perfusion itself had little effect on myocardial mechanics. The muscles from the Triton X-100-injected Langendorff hearts had marked changes: a shortening of twitch duration (363± 16 versus 449±9 msec, p<0.01) and decreases in total tension (2.2±0.2 versus 2.9±0.2 g/mm2, p<0.01), dT/dt (9±1 versus 12±1 g/mm2 per second, p<0.05), and maximum velocity of unloaded muscle shortening (Vmax) (0.89±0.06 versus 1.14±0.07 length at which maximum developed tension occurred [Lm.]/sec, p<0.05). Endocardial endothelial removal of the papillary muscles in the two control groups (with and without Langendorif perfusion) by Triton X-100 caused the same changes in twitch characteristics as occurred in muscles from the Langendorff-perfused hearts injected with Triton X-100 but with intact endocardial endothelium, suggesting that vascular endothelial dysfunction had similar effects on contractile characteristics as endocardial endothelial removal. Endocardial endothelial removal of the papillary muscles from Langendorif-perfused hearts that had a bolus injection of Triton X-100 caused further shortening of twitch duration and a further decrease in total tension (1.7±0.2 versus 2.1±0.1 g/mm2, p

The multiple indicator-dilution technique was employed in the exercising dog to evaluate the effect of increasing activity on the pulmonary extraction and kinetics of removal of tracer 3H-labeled serotonin (5-HT) and on the measured central blood volume and tracer-accessible extravascular lung water. 51Cr-labeled red blood cells, 125I-labeled albumin, and 14C-labeled 1,8-octanediol were injected with labeled 5-HT at rest and at two increasing levels of exercise (lower and higher in 9 dogs). Blood flow approximately tripled at the highest level of exercise, and the central blood volume increased linearly with increasing blood flow. The tracer-accessible extravascular lung water increased in the transition from rest to low-level exercise and stabilized at an average proportion of 0.85 of the gravimetric extravascular lung water at the higher values of blood flow. The average labeled 5-HT extraction at rest was 42 +/- 11%, and this slowly decreased with increase in flow. The calculated permeability-surface area product for 5-HT increased approximately directly with increasing blood flow. We conclude that exercise results in an increase in the central blood volume that is accompanied by an increase in the tracer-accessible extravascular lung water (lung tissue recruitment) over low exercise levels, with no change at higher levels of exercise, and that the pulmonary capillary surface area subserving 5-HT uptake increases almost linearly with flow over the range of flows attained.

We examined exercise-induced changes in indicator-dilution estimates of the angiotensin-converting enzyme first-order kinetic parameter, the ratio of a normalized maximal enzymatic conversion rate to the Michaelis constant (Amax/Km), which, under stable enzymatic conditions, will vary with the pulmonary vascular surface area accessible to vascular substrate, the extravascular lung water (an index of the proportion of lung tissue perfused), and the central blood volume (from pulmonary trunk to aorta). Experiments were performed in 10 mongrel dogs at rest and through two increasing levels of treadmill exercise, with the use of two vascular space tracers (labeled erythrocytes and albumin), a water space tracer ([1,8-14C]-octanediol), and a vascular endothelium surface area marker, benzoyl-Phe-Gly-Pro ([3H]BPGP), which is a pharmacologically inactive angiotensin-converting enzyme substrate. The exercise-induced increase in cardiac output was accompanied by a linear increase in central blood volume, and dilutional extravascular lung water rapidly increased to an asymptotic proportion close to 100% of postmortem vascular lung water. There was an average 55% [3H]BPGP hydrolysis, which did not vary with flow, and the computed Amax/Km increased linearly with exercise. We conclude that exercise results in complete lung tissue recruitment and increases the pulmonary vascular surface area available for BPGP hydrolysis linearly with flow, so that pulmonary vascular recruitment continues after full tissue recruitment.