ABSTRACT Patients with heart failure with preserved ejection fraction (HFpEF) are characterized by exercise intolerance and premature fatigue during physical activity. An abnormal exercise pressor reflex mediated by neural feedback from mechano- and/or metabosensitive group III and IV muscle afferents may contribute to these debilitating symptoms. However, little is known about the role and relative contribution of group III/IV afferents in circulatory control and fatigue development in patients with HFpEF. By studying both patients with HFpEF and well-matched controls, we will evaluate the contribution of these muscle afferents to circulatory control and fatigue development, factors recognized to be major contributors to exercise intolerance. We will use lumbar intrathecal fentanyl to block the central projection of group III/IV muscle afferents during voluntary and passive exercise (no concomitant effect on feedforward drive). This proven approach will enable us to evaluate, and distinguish between, the effects of group III and IV muscle afferents on central and peripheral hemodynamics during exercise, the exercise-induced development of central and peripheral fatigue (femoral nerve stimulation techniques), and on exercise tolerance. We will also study muscle morphometry, baroreflex and chemoreflex sensitivity, and investigate intramuscular metabolic changes of the quadriceps during exercise using 31phosphorus magnetic resonance spectroscopy to evaluate disease-related alterations in cardiovascular reflex sensitivity and intrinsic muscle characteristics as a potential factor determining alterations in circulatory control and fatigue resistance in patients with HFpEF. Finally, we will repeat these studies after a supervised 12-week knee-extension exercise training program, allowing us to investigate the effect of chronic exercise on the role of group III/IV muscle afferents in the hemodynamic response to exercise, the development of fatigue, and, ultimately, exerc