The rationale

Let us briefly review the rationale of this concept. In normal conditions,1 when dynamic exercise starts, signals generated by subthalamic neurons, the so-called central command, determine vagal withdrawal with an immediate increase in heart rate and cardiac output. Sympathetic nerve activity begins to increase later on, when the heart rate approaches 100 beats/min and vagal withdrawal is already almost complete. Central command has little direct influence on the sympathetic nervous system, which mostly responds to chemoreflex, mechanoreflex, and baroreflex signals through the release of several mediators, either endothelial generated mediators (mainly nitric oxide), or myocyte generated metabolites (such as adenosine), which regulate the tone of vessels in active muscles. The short life of these substances allows an instantaneous regulation of the muscle flow according to the rapidly changing metabolic needs of the muscles.2 Thus, in daily life activity central command and parasympathetic modulation prevail in regulating cardiovascular function; during physical exercise, sympathetic activity dominates the scene. The limitations of exercise capacity in normal subjects are determined by both the ability to increase cardiac output and the ability of (usually deconditioned) skeletal muscle to perform aerobic activity.

In the heart failure syndrome, two of the main symptoms are fatigue and limitation in exercise capacity. It was assumed that these were caused by the impairment of the mechanical performance of the heart. However, several lines of reasoning …