Keller‐Ross, Manda L.

Background Locomotor muscle group III/IV afferent feedback contributes to sympathoexcitation. Sub‐systolic lower limb occlusion may stimulate this reflex. Purpose To examine the cardiovascular response to lower limb venous occlusion in healthy humans during rest and exercise. Methods Nineteen adults (9 men, 25±5 yr; mean±SD) participated in two visits. V1: 3 min seated rest followed by randomized bilateral thigh tourniquet inflation to 20, 40, 60, 80, 100 mmHg for 2 min with 2 min deflation between occlusions. V2: Recumbent cycle ergometer exercise at 30% peak work with occlusion described in V1. We measured mean, systolic and diastolic pressure, cardiac output, heart rate, and stroke volume (MAP, SBP, DBP, CO, HR, and SV, respectively). Results At rest, MAP (85±18 mmHg) increased at 100 mmHg (Δ4±5, p<0.05) mediated by increased DBP (71±15 mmHg) at 100 mmHg (Δ5±4, p<0.05) with no change in SBP. During exercise, MAP (89±11 mmHg) increased at 60 (Δ7±7), 80 (Δ14±8), and 100 (Δ16±8) mmHg occlusions via increased SBP (133±22 mmHg) at 60 (Δ12±14), 80 (Δ20±13), and 100 (Δ26±13) mmHg and DBP (68±9 mmHg) at 60 (Δ5±5), 80 (Δ10±7), and 100 (Δ12±7) (p<0.05, all). Although, CO and SV did not change, HR (108±11 bpm) increased at 40 (Δ5±4), 60 (Δ8±5), 80 (Δ13±7), and 100 mmHg (Δ15±7) (p<0.05, all). Conclusion Stimulation of locomotor muscle group III/IV afferents via sub‐systolic occlusion contributes to cardiovascular control.

Feedback from active locomotor muscles contributes to the pressor response and may be more prominent in heart failure (HF) due to muscle myopathy, greater metabolite production and/or heightened sensitivity of receptors. We sought to examine the influence of metaboreflex stimulation on mean arterial pressure (MAP) in HF. Eleven HF patients (51±15yrs, NYHA Class I/II, LVEF 32±9%) and 11 controls (CTL) (42±9yrs) were recruited. Participants completed 3 study visits; 1) maximal cycle ergometry, 2) and 3) constant‐work cycling (60% peak power) for 4 min with 2 min recovery. Recovery was randomized to normal or regional circulatory occlusion (metaboreflex stimulation). Oxygen consumption (VO 2 ), carbon dioxide production (VCO 2 ), blood pressure and heart rate (HR) were measured at rest, end‐exercise and recovery. With metaboreflex stimulation, MAP and systolic blood pressure (SBP) increased in HF compared to CTL (6.8±5.8% vs −3.0±7.8%, p <0.01 and 3.4±6.4% vs −12.7±10.4%, p <0.01, respectively), with no difference in diastolic pressure ( p =0.61). HR and O 2 pulse demonstrated an attenuated return to baseline in HF (6.7±5.9% vs 1.0±6.6%, p <0.01 and −50.4±15.6 vs −72.4±6.9%, p <0.01, respectively). Metaboreflex stimulation resulted in a marked pressor response in HF relative to CTL due primarily to an influence of SBP and attenuated cardiac recovery as suggested by the persistent elevation in HR and O 2 pulse.

Increased locomotor muscle afferent feedback may be linked to the reduced exercise capacity (peak VO 2 ) and poor ventilatory efficiency (high V E /VCO 2 slope) observed in heart failure (HF). We examined the relationship between peak VO 2 and change in V E /VCO 2 with afferent inhibition during exercise in HF. 9 HF (60±6 yr) and 9 controls (CTL) (63±7 yr) completed 3 visits. Visit 1: cycle exercise to volitional exhaustion. Visits 2‐ 3: 5 min constant‐load cycling (65% of peak work) randomized to lumbar intrathecal fentanyl injection (afferent block) or placebo. VO 2 , ventilation (V E ), carbon dioxide production (VCO 2 ), and end‐tidal CO 2 (P ET CO 2 ) were measured. In HF, peak work (120±34 vs 176±54 W, p <0.05) and VO 2 (18.4±2.7 vs 27.2±4.7 ml/kg/min, p <0.05) were reduced, whereas V E /VCO 2 slope was elevated (39.7±1.8 vs 35.3±0.8, p<0.05) compared with CTL. With afferent inhibition, HF patients had a greater reduction in V E /VCO 2 (‐18.8±8.1 vs ‐5.4±13.3%, p <0.05) and increase in P ET CO 2 (20.3±10.5 vs 6.1±9.5%, p <0.01) during constant‐load cycling. Lower VO 2peak was related to a greater decline in V E /VCO 2 and rise in P ET CO 2 after afferent inhibition in HF (r=0.82, p <0.01 and r=‐0.69, p <0.05, respectively) but not CTL ( p >0.05). Our data demonstrate that patients with the lowest VO 2peak have the greatest improvement in V E /VCO 2 , suggesting a close link between afferent feedback, ventilatory efficiency and exercise capacity in HF. Grant Funding Source : Supported by AHA 12GRNT11630027 and National Center for Advancing Translational Science KL2TR000136.

Key points Heart failure patients with reduced ejection fraction (HFrEF) exhibit severe limitations in exercise capacity ( 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 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, 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 peak and thus exercise capacity. AbstractTo 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 ( 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 peak with lumbar intrathecal fentanyl or placebo. During exercise, cardiac output and leg blood flow () were measured via open‐circuit acetylene wash‐in technique and constant infusion thermodilution, respectively. Radial artery and femoral venous blood gases were measured. 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 , 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 peak and thus exercise capacity. These findings have important clinical implications as peak is highly predictive of morbidity and mortality in HF.

We propose that abnormalities of the pulmonary system contribute significantly to the exertional dyspnea and exercise intolerance observed in patients with chronic heart failure. Interventions designed to address the deleterious pulmonary manifestations of heart failure may, therefore, yield promising improvements in exercise tolerance in this population.