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PURPOSE To determine the influence of locomotor muscle group III/IV afferent inhibition on central and peripheral hemodynamics at multiple levels of submaximal cycling exercise in heart failure patients with reduced ejection fraction (HFrEF). METHODS Eleven HFrEF patients and 9 healthy matched controls were recruited. The participants performed a multiple stage (i.e. 30 W, 50%peak workload (WL), and a workload eliciting a respiratory exchange ratio (RER) of ~1.0) exercise test with lumbar intrathecal fentanyl (FENT) or placebo (PLA). Cardiac output (Q̇TOT) was measured via open-circuit acetylene wash-in technique and stroke volume was calculated. Leg blood flow (Q̇L) was measured via constant infusion thermodilution and leg vascular conductance (LVC) was calculated. Radial artery and femoral venous blood gases were measured. RESULTS For HFrEF, stroke volume was higher at the 30 W (FENT: 110±21 vs. PLA: 100±18 mL), 50%peak WL (FENT: 113±22 vs. PLA: 103±23 mL), and RER=1.0 (FENT: 119±28 vs. PLA: 110±26 mL) stages, while heart rate and systemic vascular resistance were lower with fentanyl compared to placebo (all, p<0.05). Q̇TOT in HFrEF and Q̇TOT, stroke volume, and heart rate in controls were not different between fentanyl and placebo (all, p>0.19). During submaximal exercise, controls and HFrEF patients exhibited increased LVC with fentanyl compared to placebo (all, p<0.04), while no differences were present in Q̇L or O2 delivery with fentanyl (all, p>0.20). CONCLUSION Taken together, these findings provide support for locomotor muscle group III/IV afferents playing a role in integrative control mechanisms during submaximal cycling exercise in HFrEF patients and older controls.