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

Key points: Heart failure patients with reduced ejection fraction (HFrEF) exhibit severe limitations in exercise capacity ((Formula presented.) peak). One of the primary peripheral mechanisms suggested to underlie exercise intolerance in HFrEF is excessive locomotor muscle group III/IV afferent feedback; however, this has never been investigated in human heart failure. HFrEF patients and controls performed an incremental exercise test to volitional exhaustion to determine (Formula presented.) peak with lumbar intrathecal fentanyl or placebo. During exercise, cardiac output, leg blood flow and radial artery and femoral venous blood gases were measured. With fentanyl, compared with placebo, patients with HFrEF achieved a higher peak workload, (Formula presented.) peak, cardiac output, stroke volume and leg blood flow. These findings suggest that locomotor muscle group III/IV afferent feedback in HFrEF leads to increased systemic vascular resistance, which constrains stroke volume, cardiac output and O₂ delivery thereby impairing (Formula presented.) peak and thus exercise capacity. Abstract: 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 ((Formula presented.) 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 (Formula presented.) peak with lumbar intrathecal fentanyl or placebo. During exercise, cardiac output and leg blood flow ((Formula presented.)) were measured via open-circuit acetylene wash-in technique and constant infusion thermodilution, respectively. Radial artery and femoral venous blood gases were measured. (Formula presented.) 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 (Formula presented.), (Formula presented.) 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 (Formula presented.) peak and thus exercise capacity. These findings have important clinical implications as (Formula presented.) peak is highly predictive of morbidity and mortality in HF.