Locomotor muscle group III/IV afferents constrain stroke volume and contribute to exercise intolerance in human heart failure.

To better understand the underlying mechanisms contributing to exercise limitation in heart failure with reduced ejection fraction (HFrEF), we investigated the influence of locomotor muscle group III/IV afferent inhibition via lumbar intrathecal fentanyl on peak exercise capacity ( V ̇ O 2 peak) and the contributory mechanisms. Eleven HFrEF patients and eight healthy matched controls were recruited. The participants performed an incremental exercise test to volitional exhaustion to determine V ̇ O 2 peak with lumbar intrathecal fentanyl or placebo. During exercise, cardiac output and leg blood flow ( Q ̇ L ) were measured via open-circuit acetylene wash-in technique and constant infusion thermodilution, respectively. Radial artery and femoral venous blood gases were measured. V ̇ O 2 peak was 15% greater with fentanyl compared with placebo for HFrEF (P < 0.01), while no different in the controls. During peak exercise with fentanyl, cardiac output was 12% greater in HFrEF secondary to significant decreases in systemic vascular resistance and increases in stroke volume compared with placebo (all, P < 0.01). From placebo to fentanyl, leg V ̇ O 2 , Q ̇ L and O2 delivery were greater for HFrEF during peak exercise (all, P < 0.01), but not control. These findings indicate that locomotor muscle group III/IV afferent feedback in patients with HFrEF leads to increased systemic vascular resistance, which constrains stroke volume, cardiac output and O2 delivery, thereby impairing V ̇ O 2 peak and thus exercise capacity. These findings have important clinical implications as V ̇ O 2 peak is highly predictive of morbidity and mortality in HF.