Mechanisms of sympathetic excitation during cycling exercise in heart failure with reduced ejection fraction

Leg muscle sympathetic nerve activity (MSNA) diminishes in healthy (HC) individuals during mild dynamic exercise but not in age-matched patients with heart failure due to reduced ejection fraction (HFrEF). To elucidate the neural mechanisms responsible for such sympathetic excitation, we studied 20 stable HFrEF patients (6F; mean age 62 ± 8 SD years) and 15 age-matched HC (6F; mean age 59 ± 7). We quantified peak oxygen uptake ( ${\dot{V}}_{O_{2\mathrm{peak}}}$ ) and separately, fibular MSNA (microneurography) at rest and during one-leg cycling (2 min each, mild (unloaded) and moderate intensity (loaded = 30-40% ${\dot{V}}_{O_{2\mathrm{peak}}}$ )) throughout three interventions: (1) post-exercise circulatory occlusion (PECO), which isolates the leg muscle metaboreflex (MMR); (2) supine posture, which stimulates cardiopulmonary baroreceptors (CPB); and (3) 32% inspired oxygen, to supress the peripheral chemoreflex (PC). One-leg cycling increased MSNA and activated the leg MMR in patients with HFrEF but not HC. MSNA at rest and during mild exercise was lower when supine than seated in both cohorts. Breathing 32% oxygen lowered the MSNA of HC but not HFrEF. In both groups, hyperoxia decreased burst frequency during low-intensity cycling. Hyperoxia abolished the 'paradoxical' sympatho-excitation of HFrEF. Thirteen participants with HFrEF were reassessed after 4 months of conventional cardiopulmonary rehabilitation. Exercise training improved ${\dot{V}}_{O_{2\mathrm{peak}}}$ by 17% and attenuated the leg MMR response without altering CPB activation or PC suppression. We conclude that in HFrEF, all three autonomic reflexes are engaged to a varying degree by one-leg cycling. Patient training attenuates the leg MMR without affecting CPB or PC modulation of MSNA during exercise. KEY POINTS: In HFrEF patients, an exaggerated leg MMR is the dominant sympatho-excitatory reflex during one-leg cycling at moderate work rates; with their MSNA response relating inversely to ${\dot{V}}_{O_{2\mathrm{peak}}}$ . Activation of the cardiopulmonary baroreflex and peripheral chemoreflex by exercise also contribute, suggesting that exercising supine or while breathing 32% O₂ may complement conventional training protocols. An exercise-based cardiac rehabilitation programme lowers sympathetic discharge at rest and during mild intensity cycling by abolishing specifically the leg MMR response.