Left ventricular assist devices (LVADs) are an increasingly utilized strategy for management of patients with advanced heart failure with reduced ejection fraction (HFrEF). While these devices improve survival, there are a number of complications associated with LVADs in the human body, such as hypertension and stroke, as well as persistent HF-related symptoms and impaired functional capacity despite normalization of a resting cardiac output. These devices provide “continuous-flow” circulatory support, meaning that pulsatility is markedly diminished and/or entirely absent. Further, current-generation devices are denervated machines, and in contrast to the normal heart, they do not participate in normal cardiovascular reflexes and there is no biofeedback loop to regulate flow. Emerging evidence suggests that these abnormalities are a major factor that predispose these patients to adverse outcomes and/or impairments in quality-of-life and functional capacity. The purpose of this discussion will be to provide an overview of the impact of chronic exposure to a nonphysiologic/diminished pulse on normal cardiovascular and cerebrovascular reflexes, and discuss the effect(s) of a denervated machine on the cardiovascular response to exercise. More specifically, emphasis will be placed on cerebral autoregulatory processes and the baroreceptor reflex pathway, as well as autonomic tone and sympathetic nerve activation. Novel insights into left and right ventricular function during exercise will be reviewed, based on emerging data derived from invasive cardiopulmonary exercise testing using traditional Swan-Ganz catheters, as well as high-fidelity conductance catheters to generate real-time pressure-volume loops.