Iterson, Erik H. Van

Patients with HFrEF exhibit severe exercise intolerance. One of the primary peripheral mechanisms contributing to exercise intolerance in patients with HFrEF is locomotor muscle group III/IV afferent feedback. However, it is unknown whether these afferents impact the central and peripheral responses during submaximal cycling exercise. Herein, we demonstrate that inhibition of locomotor muscle group III/IV afferent feedback elicited increases in stroke volume during submaximal exercise in HFrEF, but not in healthy controls.

Introduction: Neural feedback from skeletal muscle during exercise contributes to changes in pulmonary pressures in healthy individuals. Heart failure patients (HF) often develop pulmonary hypertension; however, the relationship between muscle afferent feedback and the pulmonary vasculature in HF remains unclear. Hypothesis: We examined the influence of metaboreceptor stimulation on pulmonary vascular capacitance using a validated non-invasive gas exchange equivalent (GX CAP ) in HF. Methods: Eleven HF patients (age 51±5 yrs; EF, 32±3%; NYHA class, 1.6±0.2) and 11 controls (CTL; age 43±3 yrs) completed 3 cycling session (4-min at 60% of peak oxygen consumption, VO 2 ). Session one: baseline control trial. Sessions 2 and 3: bilateral upper-thigh tourniquets inflated suprasystolic for 2 min at end-exercise (regional circulatory occlusion, RCO) with or without addition of inspired CO 2 to maintain end-exercise end-tidal CO 2 (P ET CO 2 ) (RCO+CO 2 ) (randomized). Rest, exercise, and recovery heart rate (HR), P ET CO 2 , and VO 2 were measured. O 2 pulse (VO 2 /HR) and GX CAP (O 2 pulseхP ET CO 2 ) were calculated. Results: During all conditions at end-exercise, HF demonstrated significantly lower GX CAP compared to CTL (p<0.01). Percent change in GX CAP from end-exercise to 2 min post-exercise was attenuated in HF compared to CTL (41±5% vs 64±1%, respectively, p<0.01) during the baseline trial. During RCO, HF had a 55±6% reduction in GX CAP from end-exercise compared to 77±2% in CTL (p<0.01). During RCO+CO 2 , HF had a 49±4% reduction in GX CAP from end-exercise compared to 69±2% in CTL (p<0.01). GX CAP was similar between sessions within HF. The CTL group demonstrated an attenuated return of GX CAP during RCO compared to both baseline and RCO+CO 2 (p<0.01) with no difference between baseline and RCO+CO 2 . Conclusion: These data suggest the exercise mediated rise and post-exercise recovery of pulmonary vascular capacitance are attenuated in HF during constant-load submaximal exercise compared to CTL. Additionally, our data confirm previous reports that locomotor muscle afferent feedback influences pulmonary vascular capacitance in CTL; however, this model of locomotor muscle metaboreflex stimulation appears to a differential response in HF compared to CTL.

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 Although lower vs. healthy individuals, diffusion capacity of lungs for carbon monoxide (DL CO ) and nitric oxide (DL NO ) (may influence oxygen uptake, VO 2 ) are higher during exercise vs. rest in cystic fibrosis patients (CF). Thus, because the Fick equation suggests cardiac output (Q) increases linearly with VO 2 , we sought to study relationships between VO 2 with cardiac function from rest to peak exercise as increases in Q, DL CO and DL NO occur during exercise in CF. Methods 50 individuals participated (ages 22 ± 2 vs. 27 ± 2, BSA = 1.7 ± 0.1 vs. 1.8 ± 0.0 m 2 , VO 2peak = 24 ± 2 vs. 35 ± 2 ml/kg/min, CF (n = 19) vs. controls (CTL, n = 31), mean ± SEM, p<0.05 for all). Acetylene rebreathe was used to assess Q and calculate stroke volume (SV), and standard gas‐exchange was used to assess VO 2 (mL/kg/min). Cardiac power (CP, Q i × MAP) and stroke work (SW, SV i × MAP) were calculated. Q and SV were indexed to BSA (Q i and SV i ). Results Linear regression (R 2 ) between VO 2 with SV i , Q i , CP, and SW at rest were similarly negligible for CF vs. CTL (p=ns). At 50 % VO 2peak , R 2 between VO 2 with SV i (0.25 and 0.43, p<0.05), Q i (0.37 and 0.41, p<0.05), CP (0.18, p=ns and 0.25, p<0.05), and SW (0.12 and 0.30, p=ns) improved for CF and CTL, respectively. At VO 2peak , stronger R 2 between VO 2 with SV i (0.41, p<0.05), Q i (0.47, p<0.05), CP (0.24, p<0.05), and SW (0.19, p=ns) occurred in CF; but, R 2 weakened in CTL (0.28, p<0.05; 0.33, p<0.05; 0.07, p=ns; 0.02, p=ns, respectively). Conclusions From rest to VO 2peak the relationship between VO 2 with cardiac function improves in CF patients. Participation in exercise may benefit relationships between gas‐transfer with cardiac hemodynamics in CF 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 .

Introduction Exercise intolerance is a hallmark of heart failure with reduced ejection fraction (HFrEF) resulting from a variety of factors including comprised oxygen delivery. A common comorbidity of HFrEF is chronic obstructive pulmonary disease (COPD), which is independently associated with reduced exercise tolerance and cardiac output (Q) as well as peripheral dysfunction similar to HFrEF. It is currently unknown if HFrEF and coexisting COPD (HFrEF+COPD) exhibit worsened exercise tolerance and whether the mechanisms thereof are similar to HFrEF alone. We hypothesized that patients with HFrEF+COPD demonstrate further reductions in peak VO 2 and workload subsequent to a lower peak Q and arterio‐mixed venous O 2 content difference (C(a‐v)O 2 ) compared to HFrEF alone. Methods HFrEF+COPD (n=16) and HFrEF (n=17) (age: 57±7 vs 54±6 yrs; EF%: 20±5 vs 21±5; height: 173±7 vs 174±7 cm; weight: 88±14 vs 86±17 kg; all p>0.18) underwent peak exercise testing during right heart catheterization. At rest and peak exercise, invasive hemodynamic, cardiac pressures, and arterial pressures were performed. Heart rate and oxygen uptake (VO 2 ) were measured at rest and peak exercise via 12‐lead ECG and metabolic measurement system, respectively. Convective oxygen delivery was calculated as Q multiplied by CaO 2 . Results Peak exercise VO 2 and workload were lower in HFrEF+COPD compared to HFrEF (7.0±1.9 vs. 9.9±2.7 mL/min/kg; 34±7 vs. 45±12 watts; both p<0.01). At peak exercise, Q and stroke volume were lower in HFrEF+COPD than HFrEF (4.8±1.3 vs. 7.0±3.0 L/min; 52±16 vs. 75±28 mL; both p<0.01). Significant relationships existed between delta VO 2 and Q (peak exercise minus resting) in HFrEF+COPD and HFrEF (r=0.84 and r=0.89; both p<0.01); however, HFrEF+COPD had a significantly lower slope (p=0.02). Peak exercise C(a‐v)O 2 was not different between HFrEF+COPD and HFrEF (12.9±2.3 vs. 12.8±2.6 mL/dL; p=0.89). No differences were present in heart rate or hemoglobin at peak exercise (p>0.73). Delta VO 2 and C(a‐v)O 2 was significantly related for HFrEF+COPD (r=0.68; p<0.01), but not HFrEF (r=0.14, p=0.57). At peak exercise, HFrEF+COPD had lower convective oxygen delivery (845±239 vs. 1230±517 mL/min; p<0.01). Conclusions Patients with HFrEF and concurrent COPD demonstrate worsened exercise tolerance compared to HFrEF resulting from reduced oxygen delivery. These data suggest HFrEF with COPD exhibit more severe central and peripheral abnormalities than HFrEF alone. Support or Funding Information NHLBI RO1 HL126638 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

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.

Background: Cystic fibrosis (CF) is a genetic disease affecting multiple organ systems of the body and is characterized by mutation in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR). Previous work has shown that a single dose of aβ-agonist increases cardiac output (Q) and stroke volume (SV) and decreases systemic vascular resistance (SVR) in healthy subjects. This effect is attenuated in patients with CF; however, the mechanism is unknown. Potential explanations for this decreased cardiovascular response to a β-agonist in CF include inherent cardiovascular deficits secondary to the CFTR mutation, receptor desensitization from prolonged β-agonist use as part of clinical care, or inhibited drug delivery to the bloodstream due to mucus buildup in the lungs. This study sought to determine the effects of endogenous epinephrine (EPI) and norepinephrine (NE) on cardiovascular function in CF and to evaluate the relationship between cardiovascular function and CFTR F508del mutation. Methods: A total of 19 patients with CF and 31 healthy control subjects completed an assessment of Q (C 2 H 2 rebreathing), SV (calculated from Q and heart rate [HR]), Q and SV indexed to body surface area (BSA, QI, and SVI, respectively), SVR (through assessment of Q and mean arterial blood pressure [MAP]), and HR (from 12-lead electrocardiogram [ECG]) at rest along with plasma measures of EPI and NE. We compared subjects by variables of cardiovascular function relative to EPI and NE, and also based on genetic variants of the F508del mutation (homozygous deletion for F508del, heterozygous deletion for F508del, or no deletion of F508del). Results: Cystic fibrosis patients demonstrated significantly lower BSA (CF = 1.71 ± 0.05 m 2 vs healthy = 1.84 ± 0.04 m 2 , P = .03) and SVI (CF = 30.6 ± 2.5 mL/beat/m 2 vs healthy = 39.9 ± 2.5 mL/beat/m 2 , P = .02) when compared with healthy subjects. Cystic fibrosis patients also demonstrated lower Q (CF = 4.58 ± 0.36 L/min vs healthy = 5.71 ± 0.32 L/min, P = .03) and SV (CF = 54 ± 5.5 mL/beat vs healthy = 73.3 ± 4.5 mL/beat, P = .01), and a higher HR (CF = 93.2 ± 3.9 bpm vs healthy = 80.5 ± 2.7 bpm, P < .01) and SVR (CF = 2082 ± 156 dynes*s/cm −5 vs healthy = 1616 ± 74 dynes*s/cm −5 , P = .01) compared with healthy subjects. Furthermore, CF patients demonstrated a lower SV ( P < .01) corrected for NE when compared with healthy subjects. No significant differences were seen in HR or Q relative to NE, or SVR relative to EPI. Differences were seen in SV (F (2,14) = 7.982, P < .01) and SV index (F (2,14) = 2.913, P = .08) when patients with CF were stratified according to F508del mutation (number of deletions). Conclusions: Individuals with CF have lower cardiac and peripheral hemodynamic function parameters at rest. Furthermore, these results suggest that impairment in cardiovascular function is likely the result of F508del CFTR genotype, rather than receptor desensitization or inhibited drug delivery.

The measurement of peak oxygen uptake (VO2peak) is an important metric for evaluating cardiac transplantation (HTx) eligibility. However, it is unclear which factors (e.g., recipient demographics, clinical parameters, cardiac rehabilitation (CR) participation) influence VO2peak following HTx. Consecutive HTx patients with cardiopulmonary exercise testing (CPET) between 2007–2016 were included. VO2peak was measured from CPET standard protocol. Regression analyses determined predictors of the highest post-HTx VO2peak (i.e., quartile 4: VO2peak > 20.1 mL/kg/min). One hundred-forty HTx patients (women: n = 41 (29%), age: 52 ± 12 years, body mass index (BMI): 27 ± 5 kg/m2) were included. History of diabetes (Odds Ratio (OR): 0.17, 95% Confidence Interval (CI): 0.04–0.77, p = 0.021), history of dyslipidemia (OR: 0.42, 95% CI: 0.19–0.93, p = 0.032), BMI (OR: 0.90, 95% CI: 0.82–0.99, p = 0.022), hemoglobin (OR: 1.29, 95% CI: 1.04–1.61, p = 0.020), white blood cell count (OR: 0.81, 95% CI: 0.66–0.98, p = 0.033), CR exercise sessions (OR: 1.10, 95% CI: 1.04–1.15, p < 0.001), and pre-HTx VO2peak (OR: 1.17, 95% CI: 1.07–1.29, p = 0.001) were significant predictors. Multivariate analysis showed CR exercise sessions (OR: 1.10, 95% CI: 1.03–1.16, p = 0.002), and pre-HTx VO2peak (OR: 1.16, 95% CI: 1.04–1.30, p = 0.007) were independently predictive of higher post-HTx VO2peak. Pre-HTx VO2peak and CR exercise sessions are predictive of a greater VO2peak following HTx. These data highlight the importance of CR exercise session attendance and pre-HTx fitness in predicting VO2peak post-HTx.

Background Exercise intolerance, obesity, and low hemoglobin (hemoglobin<13 and <12 g/dl, men/women, respectively) are common features of heart failure. Despite serving as potent contributors to metabolic dysfunction, the impact of obesity and low hemoglobin on exercise intolerance is unknown. This study tested the hypotheses, compared with non-obese (NO) heart failure with normal hemoglobin, (a) counterparts with low hemoglobin and obesity or non-obesity will demonstrate reduced peak exercise oxygen uptake; (b) obese with normal hemoglobin will demonstrate decreased peak exercise oxygen uptake; (c) compared across stratifications, obese with low hemoglobin will demonstrate the sharpest decrement in peak exercise oxygen uptake. Methods Adults with heart failure ( n = 315; left ventricular ejection fraction≤40%; 77% men) (Group 1: normal hemoglobin and non-obese, n = 137; Group 2: low hemoglobin and non-obese, n = 51; Group 3: normal hemoglobin+obesity, n = 89; Group 4, n = 38: low hemoglobin+obesity; body mass index = 26 ± 3, 26 ± 2, 34 ± 4, 34 ± 4 kg/m 2 , respectively) completed treadmill cardiopulmonary exercise testing as part of routine clinical management. Peak exercise oxygen uptake was measured via standard metabolic system. Results There were no group-wise differences for heart failure class, gender, left ventricular ejection fraction, and resting cardiopulmonary function. Group 1 demonstrated increased peak exercise oxygen uptake versus Groups 2–4 (20 ± 6 versus 17 ± 6, 17 ± 5, 13 ± 4 ml/kg/min, respectively; all p < 0.001); whereas Group 4 peak exercise oxygen uptake was reduced versus all groups ( p < 0.001). Additionally, both body mass index (R 2 = 0.10) and hemoglobin (R 2 = 0.12) were significant predictors of peak exercise oxygen uptake in Group 1; which were relationships not mirrored for Groups 2–4. Conclusion These data suggest obesity together with low hemoglobin are potent contributors to impaired peak exercise oxygen uptake and, hence, oxidative metabolic capacity. In diverse populations of heart failure where obesity and/or low hemoglobin are present, it is important to consider these features together when interpreting peak exercise oxygen uptake and underlying exercise limitations.