Bruhn, Eric J.

Introduction: Heart failure patients with preserved ejection fraction (HFpEF) may exhibit inspiratory muscle dysfunction potentially contributing to exercise intolerance. Activation of neural afferents in response to inspiratory muscle contraction (metaboreflex) elicits increases in mean arterial pressure (MAP) and leg vascular resistance (LVR) through enhanced sympathetic outflow leading to decreases in leg blood flow (LBF) in healthy humans. It is unknown if HFpEF patients exhibit exaggerated cardiovascular responses to inspiratory muscle metaboreflex activation. Hypothesis: We hypothesize that patients with HFpEF will exhibit a greater increase in MAP and LVR with a decrease in LBF during inspiratory muscle metaboreflex activation than controls. Methods: HFpEF patients (n=15, 10M/5W, 69±10 yrs; 33±4 kg/m2) and controls (n=14; 10M/4W; 70±8 yrs; 28±4 kg/m2) performed inspiratory resistive breathing tasks (IRBT) at 2% and 60% of their maximal inspiratory pressure. During the IRBTs, the breathing frequency was 20 breaths/min with a 50% duty cycle. At rest and during the IRBTs, MAP was measured by photoplethysmography, venous norepinephrine was measured, LBF was measured by near-infrared spectroscopy and indocyanine green dye injections, and LVR was calculated. Results: During the 2% IRBT, there were no differences between groups in the changes from rest in MAP (HFpEF: 2±4 vs. CTL: 3±4 mmHg) or LBF (HFpEF: 1±14 vs. CTL: 1±12%) (both, p>0.05). During the 60% IRBT, venous norepinephrine increased from rest in HFpEF and controls (p<0.05), while no differences existed between groups (p>0.05). During the 60% IRBT, HFpEF patients, compared to controls, exhibited a greater increase from rest in MAP (HFpEF: 16±7 vs. CTL: 10±6 mmHg) and LVR (HFpEF: 76±45 vs. CTL: 32±19%) coupled with a greater decrease in LBF (HFpEF: -32±14 vs. CTL: -17±9%) (all, p<0.05). Conclusions: These data indicate that patients with HFpEF exhibit exaggerated cardiovascular responses with inspiratory muscle metaboreflex activation compared to healthy individuals. These findings have important implications for the integrative physiology of exercise in HFpEF patients.

Locomotor and respiratory muscle feedback via group III/IV afferents influences the blood pressure response during exercise. Specifically, stimulation of the inspiratory and locomotor muscle afferents (via inspiratory loading (IL) and subsystolic circulatory occlusion (CUFF), respectively) increases the blood pressure response during exercise with combined IL and CUFF (IL+CUFF) further augmenting the blood pressure response. Sex differences in blood pressure have been observed in both IL and CUFF when investigated individually, while the influence of sex hormones is unclear. It is unknown if sex and menstrual cycle phase influences the blood pressure response to IL+CUFF during exercise. Purpose To determine if sex and menstrual cycle phase influence the blood pressure response during IL+CUFF in men and premenopausal women. We hypothesized that women will exhibit attenuated increases in blood pressure compared to age‐matched men during IL, CUFF, and IL+CUFF, while no differences would be present across the menstrual cycle. Methods To date, 13 adults (7M/6W; M: 28±6 vs. W: 29±4 yrs, p=0.30; M: 27±5 vs. W: 25±2 kg/m 2 , p=0.85) have participated in this study. Participants performed four 10 min exercise bouts at 40% of their peak oxygen uptake. The participants performed spontaneously breathing (SB) during the first 5 minutes and voluntary hyperventilation (i.e. breathing frequency of 40 breaths/min with 50% duty cycle) during the last 5 minutes. During this last 5 min, IL (30% maximal inspiratory pressure), CUFF (80 mmHg), IL + CUFF, or no intervention (CTL) occurred in a randomized order. Women completed the study protocol twice, once during midluteal (ML) phase and once during early follicular (EF) phase. Blood pressure was measured using manual sphygmomanometry. Changes in systolic blood pressure (ΔSBP), diastolic blood pressure (ΔDBP), and mean arterial pressure (ΔMAP) were determined by subtracting values obtained during IL, CUFF, IL+CUFF, or CTL from SB. Results There were no significant differences in ΔMAP across groups during CTL (M: 5±5; ML 2±2; EF: 2±2 mmHg, all p>0.24), IL (M: 11±4; ML 10±2; EF 12±5 mmHg, all p>0.60), CUFF (M: 19±6; ML 16±4; EF 20±2 mmHg, all p>0.20), or IL + CUFF (M: 24±5; ML 23±6; EF 23±3 mmHg, all p>0.82). There were no significant differences in ΔSBP across groups during CTL (M: 5±4; ML 5±4; EF: 8±13 mmHg, all p>0.49), IL (M: 17±6; ML 17±5; EF 19±8 mmHg, all p>0.63), CUFF (M: 24±12; ML 23±7; EF 28±5 mmHg, all p>0.31), or IL + CUFF (M: 34±8; ML 33±11; EF 33±8 mmHg, all p>0.94). There were no significant differences in ΔDBP across group during CTL (M: 5±8; ML 0±1; EF: −1±4 mmHg, all p>0.05), IL (M: 8±3; ML 7±2; EF 9±4 mmHg, all p>0.71), CUFF (M: 16±4; ML 13±4; EF 16±2 mmHg, all p>0.20), or IL + CUFF (M: 19±6; ML 18±6; EF 18±3 mmHg, all p>0.75). Conclusion With this limited sample size, our data suggest that neither sex nor menstrual cycle phase influences the blood pressure response with IL, CUFF or IL+CUFF. Support or Funding Information NIH HL126638 AHA 18POST3990251 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Introduction Peripheral nervous system feedback arising from mechanically and metabolically sensitive afferents (Group III/IV, respectively) are central components of the exercise pressor reflex. Experimentally, locomotor venous distention can be simulated via subsytolic regional circulatory occlusion (SubRCO) thereby augmenting the exercise pressor reflex. Furthermore, high pedal frequency increases type II muscle fiber recruitment during exercise likely increasing non‐oxidative metabolism. To date, studies investigating the influence of aging on the exercise pressor reflex have presented conflicting data with most utilizing small muscle mass exercise (e.g. handgrip). Therefore, the purpose of this study was to determine the influence of SubRCO, pedal frequency, and the combination thereof on blood pressure (BP) during exercise in older and younger adults. We hypothesized that during exercise 1) independent of pedal frequencies and age, SubRCO will augment BP and 2) older adults will have greater increases in BP at high pedal frequencies with and without SubRCO compared younger adults. Methods 10 younger (22±2 yrs; 4M/6W; 24±4 kg/m 2 ) and 10 older (63±10yrs; 4M/6W; 24±4 kg/m 2 ) adults participated in two study visits each consisting of two cycling exercise sessions at 20 W, with bilateral upper thigh pressure cuffs. Participants engaged in 3 minutes of exercise at 35 (LOW) or 100 (HIGH) rpm with 5 additional minutes of exercise at that rpm with no cuffing (CTL) or SubRCO in randomized order. Systolic and diastolic blood pressure (SBP and DBP, respectively) were measured via manual sphygmomanometry. Mean arterial pressure (MAP) was calculated as (SBP‐DBP)/3+DBP and the changes in MAP from rest are reported. Results During LOW, SubRCO resulted in greater MAP than CTL in younger (CTL: 4±7; SubRCO: 13±7 mmHg) and older adults (CTL: 4±6; SubRCO: 13±4 mmHg) (both p<0.01). During HIGH, SubRCO resulted in greater MAP than CTL in younger (CTL: 7±4; SubRCO: 20±6 mmHg) and older adults (CTL: 20±9; SubRCO: 31±8 mmHg) (both p<0.01). Younger and older adults had greater increases in MAP during HIGH CTL and SubRCO compared to LOW CTL and SubRCO, respectively (all, p<0.01). Within LOW, there were no differences between younger and older adults during CTL or SubRCO (all, p>0.05). Within HIGH, older adults had greater increases in MAP than younger adults during CTL and SubRCO (both p<0.01). Conclusion These data support the hypothesis that older compared to younger adults have a greater BP response at higher pedal frequencies during exercise. Our results suggest that aging contributes to a greater exercise pressor response to exercise, possibly due to greater feedback from group III/IV afferents. Support or Funding Information NIH HL126638AHA 18POST3990251 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

BACKGROUND Increased activation of Group III/IV skeletal muscle afferents is suggested to play a role in exercise intolerance in heart failure (HF). PURPOSE The purpose of this study was to examine if skeletal muscle afferent feedback inhibition improves exercise tolerance in HF. METHODS 8 HF patients [59±8 yr, mean±SD] participated in two randomized incremental recumbent cycling exercise sessions to peak capacity (peak oxygen consumption, VO 2 ). Session 1: The synthetic opioid fentanyl (50 mcg), known to block afferent feedback, was injected intrathecally (INJ) in the lumbar spine (L3‐L4 intervertebral space) prior to exercise. Session 2: Participants were prepared similarly with a sham injection (placebo, PLA). Gas exchange, dyspnea and RPE were measured. RESULTS HF patients exercised for a longer duration (Δ3±3 min, p=0.02) and reached a higher power output (PLA:109±30 vs. INJ:128±34 W, p=0.02) with locomotor afferent inhibition. Additionally, peak VO 2 was non‐significantly greater (PLA:18.7±3.3 vs. INJ:21.8±4.4 ml/kg/min, p=0.10). With INJ workload matched to peak PLA workload, RPE was reduced (PLA:18±2 vs. INJ:15±2, respectively, p=0.005) and dyspnea was lower (PLA:7.5±2 vs. INJ:4.2±1, p=0.003) with no difference in VO 2 (p>0.05). CONCLUSION Inhibition of group III/IV locomotor muscle afferent feedback contributes to improved exercise tolerance and exertional symptoms in HF patients.

Introduction Age related declines in oxidative metabolic capacity have been attributed to slowing of O 2 delivery and utilization. While these declines are pronounced in postmenopausal women, it is unclear how these changes compare with age‐matched men. This study aimed to phenotype adjustments of muscle oxy‐ and‐ deoxygenation during transitions of low intensity fixed‐load exercise in postmenopausal women and age‐matched men. Methods Healthy postmenopausal women (PW) and men (M) (N = 7 and 6; age 57 ± 7 and 61 ± 10 years; BMI 26 ± 2 and 27 ± 4 kg/m 2 , respectively, all P >0.05) completed 3 identical 8 min transients of fixed pedal rate (=35) and load (=20W) ergometry wearing bilateral thigh cuffs. After 5 min of rest, exercise began with 3 min without thigh cuff inflation followed by 5 min of exercise+cuff inflation at 90 mm Hg (to provoke locomotor congestion). Deoxy (HHb)‐ and total (Hb tot )‐ hemoglobin were measured by near‐infrared spectroscopy (NIRS) at the right calf. Data were sampled at 1 s intervals and ensemble averaged across 3 transients and binned to 10 s epochs for each participant prior to mono‐exponential modeling: Y B + A [1 − e −(t‐TD)/τ ]; where Y B = baseline value of Y for the 30 s prior to the step transition; τ = time constant; A = asymptote; TD = time delay. Mean response time (MRT) = TD + τ. Kinetics were modelled for the transition from exercise without to exercise+cuff inflation. Results Following the exercise on‐transient, TD was 9±4 vs. 7±3 s (P=0.35) and 8±4 vs. 6±3 s (P=0.28) for PW vs. M prior to the rise in ΔHHb or ΔHb tot , respectively. For PW vs. M, the A representing the rise in ΔHHb was 8±7 vs. 15±7 μM (P=0.04) and for ΔHb tot it was 13±8 vs. 18±8 μM (P=0.17), respectively. The kinetics of HHb following the exercise+cuff onset were similar for PW and M (τ=53±38 vs. 34±9 s, respectively, P=0.36) as well as for Hb tot (τ=43±29 vs. 29±16 s, respectively, P=0.43). The overall time course for the change in HHb (MRT=62±35 vs. 41±8 s, P=0.27) or Hb tot (MRT=51±27 vs. 35±14 s, P=0.31) did not differ for PW and M, respectively. Conclusions Despite age‐matched men demonstrating greater ΔHHb compared with PW, these data do not support the hypothesis that following exercise onset, the rate of locomotor hemodynamic adjustment and O 2 extraction for a given metabolic demand differ between these groups. Thus, as opposed to gross factors of blood flow and O 2 delivery, effects such as slowing of the rate of activation and/or processes regulating oxidative phosphorylation and mitochondrial respiration may play a stronger role in explaining differences in oxidative metabolic capacity between PW and M. Support or Funding Information Funding for this work was supported by National Institutes of Health [RO1‐HL126638 to TPO]; and American Heart Association [16POST30260021 to EHV] and National Institutes of Health [HL138814 to EHV]. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Abstract Background Exercise intolerance is the cardinal manifestation of heart failure (HF), yet its underlying mechanism(s) remain poorly understood. Measures of ventricular function such as ejection fraction often have no relationship with exercise capacity in HF. 2D-STE has proved to be more reliable method to evaluate myocardial mechanical function. Our hypothesis is Resistance exercise training (Resist-HFpEF) will improve exercise tolerance and exertional symptoms in patients with HFpEF. Purpose The study aims to evaluate myocardial mechanical function by strain imaging during resistance exercise training in Heart Failure patients with Preserved Ejection Fraction (HFpEF) Methods This is a single centre prospective pilot study. 24 HFpEF patients were enrolled and their baseline comorbidities were recorded. Baseline 2D-STE imaging was performed at rest and during exercise (Visit 1). Patients were then randomized to either a novel resistance exercise training program for 36 sessions (3 sessions per week for 12 weeks) or a standard of care control group. 2D STE imaging was then repeated at follow-up (Visit 2). Peak Global Longitudinal strain (GLS), systolic strain rate (SSR), early diastolic strain rate (SRe) were measured offline. Results Mean age of the Rehab cohort was 68.57±10.52 years and the control cohort was 68.1±6.47 years. 23 study subjects were male (96%). 17% of the study subjects were hypertensive, 63% were diabetic, 42% had NYHA I, 46% had NYHA II and 13% had NYHA III of heart failure. The mean LV ejection fraction in the control and Rehab group after the training program at rest was 61.88±2.26% & 54.74±2.07% (p-value 0.04) and during exercise was 59.90±2.05% and 53.13±2.05% (p-value 0.04). The peak GLS was −18.80±4.29% and −17.7±2.21% in controls during rest and exercise at Visit 1 (p-value 0.27) while the rehab cohort had −18.71±4.7% and −20.82±2.4% respectively (p-value 0.0268). The peak GLS was −17.40±3.05% and −17.96±2.65% in controls during rest and exercise at Visit 2 (p-value 0.3430) while rehab cohort had −17.97±6.21% and −16.57±3.82% respectively (p-value 0.67). (Figure 1a and 1b shows GLS, SRS, SRe at Baseline and after exercise program respectively) Conclusion This pilot study suggest systolic and diastolic reserve can be measured reliably during low grade exercise. These results could reflect improvement in clinical status and exercise tolerance. Figure 1. Comparison of peak GLS, SSR, SRe amongst HFpEF patients at rest and during exercise before and after the rehab training program. Funding Acknowledgement Type of funding source: None

Introduction The exercise pressor reflex contributes to cardiovascular regulation during exercise. The primary components of the exercise pressor reflex response are the mechanically and metabolically sensitive skeletal muscle afferents (group III and IV, respectively). Experimentally, subsystolic regional circulatory occlusion (SubRCO) leads to venous distention, stimulating primarily group III afferents, thereby augmenting the exercise pressor reflex. Previous studies have reported sex differences in the metaboreflex induced exercise pressor reflex induced cardiovascular responses. Specifically, pre‐menopausal women, compared to age‐matched men, were found to have attenuated cardiovascular responses with mechanoreflex stimulation. However, it is unclear if sex differences are also present in the cardiovascular responses during exercise with locomotor limb venous distention. Therefore, the purpose of this study was to determine the influence of SubRCO during submaximal exercise in men and women. We hypothesized that women will have attenuated increases in mean arterial pressure (MAP) and systemic vascular resistance (SVR) than men during exercise with SubRCO. Methods Twelve men and thirteen women completed two study visits (Age: M: 30±6vs. W: 27±8yrs, p>0.05; BMI: M: 25.4±3.6 vs. W: 22±3 kg/m 2 , p<0.05). The first visit consisted of a peak exercise ergometry test. The second visit consisted of constant‐load cycle ergometry at 30% peak workload with different SubRCO pressures via bilateral upper thigh pressure cuffs. The cuffs remained uninflated (0 mmHg) (CTL) during the first three min of exercise, then were intermittently inflated to 20, 40, 60, 80, or 100 mmHg for two minutes (randomized order). Each inflation period was followed by a 2minute deflation period where the participant continued to exercise. Cardiacoutput (Q) and MAP were measured via continuous hemodynamic photoplethysmography and systemic vascular resistance (SVR) was calculated. Data were reported as delta changes from CTL. Results Compared to 0 mmHg, MAP increased with SubRCO inflation pressures of 60, 80, and 100mmHg in men and women during submaximal exercise (all, p<0.05); however, no differences were present between groups (60 mmHg: M: 6.2±4.2 vs. W: 8.0±5.2; 80mmHg: M: 11.6±5.5 vs. W: 15.1±4.8; 100 mmHg: M: 18.2±6.6 vs. W: 20.5±7.2 mmHg(all, p>0.05)). Similarly, SVR increased with cuff inflation pressures of60, 80, and 100 mmHg compared to 0 mmHg in men and women (p<0.05), while no differences existed between groups (60 mmHg: M: 0.3±0.4 vs W: 0.4±0.5;80 mmHg: M: 0.9±0.5 vs W: 1.1± 0.9; 100 mmHg M: 1.3±0.8vs W: 1.5±0.8mmHg/L/min (all, p>0.05)). In contrast, Q did not change with cuff inflation pressures of 20, 40, 60, 80, or100 mmHg compared to 0 mmHg in men or women during submaximal exercise(p>0.05). Conclusion In contrast to our hypothesis, the MAP and SVR responses were not different between men and women with SubRCO during submaximal exercise. Our findings suggest that sex differences are not present in the cardiovascular response to low‐intensity constant‐load exercise with stimulation of the exercise pressor reflex via lower limb venous distention.

Introduction It is well established that the exercise pressor reflex contributes to cardiovascular control (e.g. mean arterial pressure (MAP)) during exercise. One arm of the exercise pressor reflex includes the metabolically sensitive group IV afferents (i.e. metaboreflex). The metaboreflex‐induced cardiovascular responses to exercise are incompletely understood, especially in women across the aging spectrum. For example, post‐menopausal women have greater increases in MAP and systemic vascular resistance (SVR) during locomotor muscle exercise compared to pre‐menopausal women. However, it is unclear if an exaggerated metaboreflex arising from the locomotor muscles is contributing to these cardiovascular adjustments with exercise in post‐menopausal women. We hypothesized that 1) post‐menopausal women will have an augmented MAP response with isolated metaboreflex activation compared to pre‐menopausal women and 2) the exaggerated increase in MAP in the post‐menopausal women will be primarily due to greater increases in SVR. Methods Pre‐ (n= 10, 25±3yrs, 24±3 kg/m 2 ) and post‐menopausal women (n=12, 58±4yrs, 24±3 kg/m 2 ) performed 2 sessions of cycling exercise at 20 W for 5 min with bilateral upper thigh pressure tourniquets inflated to 90 mmHg. At end exercise, the recovery was randomized to post‐exercise circulatory occlusion (PECO) to isolate the metaboreflex (via bilateral upper thigh pressure tourniquets rapidly inflated to suprasystolic pressure for 2 min) or normal recovery (NR) without intervention. Systolic and diastolic blood pressure were measured via manual sphygmomanometry and MAP was calculated. Cardiac output was measured via open circuit acetylene wash‐in and systemic vascular resistance (SVR) was calculated. Data is reported as the absolute change from rest to recovery. Results MAP was elevated during PECO compared to NR in both groups (p<0.05), while MAP during PECO was greater in post‐ compared to pre‐menopausal women (20±9 vs. 13±5 mmHg, respectively) (p<0.05). Similarly, SVR was elevated during PECO compared to NR in both groups (p<0.05), while SVR was greater during PECO in post‐ compared to pre‐menopausal women (5±3 vs. 3±1 mmHg/L/min, respectively) (p<0.05). In contrast, cardiac output was not different between NR and PECO in either pre‐ (NR: 0.3±1 vs. PECO: −0.2±1 L/min) and post‐menopausal (NR: −0.1±1 vs. PECO: −0.7±0.9 L/min) (all, p>0.05). Conclusion These data demonstrate that isolated metaboreflex stimulation following whole‐body exercise results in exaggerated increases in MAP and SVR in post‐ compared to pre‐menopausal women. These data suggest that exercise pressor reflex‐mediated control of MAP during exercise is accentuated in post‐menopausal women with menopause status.

Objective Cardiovascular adjustments to exercise, including increases in blood pressure (MAP) and heart rate, occur in response to several neural mechanisms. Specifically, stimulation of respiratory (via inspiratory loading (IL)) and locomotor muscle (via subsystolic cuff inflation (CUFF)) neurologic feedback via group III/IV afferents augments the MAP response during exercise. Further, we have recently shown that simultaneous stimulation of the respiratory and locomotor muscle afferents during exercise potentiates the MAP increase compared to when these reflexes are stimulated individually. To date, interventional strategies to attenuate the augmented MAP during IL+CUFF have not been investigated. Previous studies have shown that inspiratory muscle training (IMT) attenuates the IL‐induced increase in MAP at rest in healthy adults. We hypothesized that 8 weeks of IMT will attenuate the IL+CUFF‐induced increase in MAP during exercise in healthy adults. Methods Twenty adults were recruited and randomized to the IMT (n=10) or sham group (n=10). Participants performed 8 weeks of IMT twice a day, 7 days a week at 50% (IMT) or 10% (sham) maximum inspiratory pressure (MIP). On separate visits, participants performed an incremental cycling test to volitional fatigue and a 10 min cycling exercise bout at 40% maximal oxygen uptake Pre‐ and Post‐IMT. The exercise bout consisted of 5 min of spontaneous breathing followed by 5 min of voluntary hyperventilation (i.e. breathing frequency of 40 breaths per min) with IL (30% MIP) and bilateral locomotor subsystolic cuff inflation (80 mmHg). Systolic and diastolic blood pressure (SBP and DBP, respectively) were measured using manual sphygmomanometry and MAP was calculated. SBP and MAP were reported as the change from rest. Dyspnea was measured via Borg scale (1–10). Results After 8 weeks, MIP increased in the IMT (Pre: 99±26 vs. Post: 127±26 cmH 2 O, p<0.05), but not the sham group (Pre: 126±29 vs. Post: 129±28 cmH 2 O, p>0.05). Pre‐IMT, the increase in MAP with IL+CUFF was not different between groups (IMT: 28±6 vs. sham: 31±7 mmHg) (p>0.05). Post‐IMT, the increase in MAP with IL+CUFF was attenuated in IMT, but not sham (IMT: 23±7 vs. sham: 32±5 mmHg) (p<0.05). Pre‐IMT, the increase in SBP with IL+CUFF was not different between groups (IMT: 49±12 vs. sham: 53±16 mmHg) (p>0.05). Post‐IMT, the increase in SBP with IL+CUFF was attenuated in IMT, but not sham (IMT: 42±12 vs. sham: 57±14 mmHg) (both, p<0.05). The increase in DBP with IL+CUFF was not different between groups Pre or Post‐IMT (both, p>0.05). Lastly, dyspnea was not different Pre‐IMT between groups (IMT: 4±3 vs. sham: 4±2 Borg (1–10)) (p>0.05), but was lower in the IMT, but not sham Post‐IMT (IMT: 2±2 vs. sham: 4±1 Borg (1–10)) (p<0.05). Conclusions These data demonstrate that IMT attenuates the MAP response when the respiratory and locomotor afferents are stimulated simultaneously. These findings have important clinical implications for populations that exhibit exaggerated respiratory and locomotor muscle reflexes during exercise. Support or Funding Information This work was supported by the National Institutes of Health [HL126638 to TPO] and American Heart Association [18POST3990251 to JRS].

Reflexes arising from the respiratory and locomotor muscles influence cardiovascular regulation during exercise. However, it is unclear how the respiratory and locomotor muscle reflexes interact when simultaneously stimulated. Herein, we demonstrate that stimulation of the respiratory and locomotor muscle reflexes yielded additive cardiovascular responses during submaximal exercise.