Influence of flosequinan on autonomic tone in congestive heart failure: implications for the mechanism of the positive chronotropic effect and survival influence of long-term vasodilator administration.

The vasodilator flosequinan has been shown to be effective in the management of symptoms of congestive heart failure but has been found to influence survival adversely when administered in selected doses. A moderate positive chronotropic response accompanies long-term administration of this agent, which may be associated with an activation of the neurohormonal axis that itself may contribute to the reported increase in mortality. This investigation used the technique of spectral analysis of heart rate variability to examine the autonomic response to long-term flosequinan administration in 39 patients enrolled in a double-blind placebo-controlled trial of this vasodilator to determine whether autonomic mechanisms account for the observed changes in heart rate. Although heart rate significantly increased in the flosequinan-treated patients, parasympathetic tone increased and sympathetic drive decreased compared with placebo, as reflected by high- and low-frequency heart rate variabilities, respectively. It is concluded that (1) autonomic inputs to the myocardium that would be expected to produce increases in heart rate do not result from long-term flosequinan administration; (2) accordingly, a direct positive chronotropic effect must account for the heart rate changes observed with this vasodilator; and (3) the increased mortality associated with the administration of this agent in the doses examined does not appear to result from reflex changes in autonomic tone and must result from other properties of this vasodilator.