Dissecting the exercise pressor reflex in heart failure: A multi-step failure

The contribution of neural feedback originating from exercising limb muscles to the cardiovascular response to exercise was first recognized nearly 100 years ago. Today, it is well established that this influence is initiated by the activation of group III and IV sensory neurons with terminal endings located within contracting skeletal muscle. During exercise, these sensory neurons project feedback related to intramuscular mechanical and metabolic perturbations to medullary neural circuits which reflexively evoke decreases in parasympathetic and increases in sympathetic nervous system activity with the purpose of optimizing central and peripheral hemodynamics. Considerable evidence from animal and human studies suggests that the function of this regulatory control system, known as the exercise pressor reflex (EPR), is abnormal in heart failure and exaggerates sympatho-excitation which impairs the hemodynamic response to exercise and contributes to the functional limitations characterizing these patients. This review briefly introduces the key determinants of EPR control in health and covers the impact of heart failure on the integrity of each of its components and overall function. These include the sensitivity of group III/IV muscle afferents, afferent signal transmission in the spinal cord, and the central integration and processing of sensory feedback within the brainstem. Importantly, although most data relevant for this review come from studies in HFrEF, the limited HFpEF-specific insights are included when available. While arguably not part of the EPR, we also discuss the impact of heart failure on the exercise-induced increase of intramuscular stimuli of group III/IV muscle afferents and end-organ responsiveness to sympathetic/neurochemical stimulation.