Olson, Thomas P.

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 .

Background Heart failure (HF) causes abnormal ventilatory responses to exercise which are inked to poor prognosis. We examined the impact of blocking fine afferents from locomotor muscles on exercise ventilatory efficiency in HF. Methods 9 HF patients (60±6yrs, LVEF 27±6%) and 9 healthy controls (63±7yrs) underwent two 5 min cycling sessions at 65% peak workload with and without intrathecal fentanyl. VO 2 , VCO 2 , V E , breathing frequency (fb), tidal volume (V T ), and chemoreceptor sensitivity (CO 2 rebreathe) were measured. Results Fentanyl did not influence exercise VO 2 in either group (HF=1.5±0.3 vs 1.5±0.3 L/min, control=1.7±0.4 vs 1.7±0.5 L/min). V E was lower with fentanyl in HF but not control (−12.3±7.1 vs 0.8±6.2%, p<0.001) due to lower fb (−10.5±4.6 vs 0.5±7.1%, p<0.01) with no change in V T (−1.2±9.4 vs 0.4±5.7%, p=0.67). V E /VCO 2 improved during exercise with fentanyl in HF but not in controls (−14.8±7.1 vs ‐ 0.5±7.0, p<0.01). Fentanyl did not influence chemoreceptor sensitivity in either group. Conclusion Blocking group III and IV afferent feedback from the locomotor muscles during exercise improves ventilatory efficiency in HF. NIH/NCRR grant KL2‐RR024151.

Background Increased pulmonary capillary pressure and a possible desensitization of lung β 2 adrenergic receptors (β 2 AR) involved in fluid removal mechanisms may increase extravascular lung water (E LW ) in stable heart failure (HF) patients. Whether these patients exhibit increased E LW remains controversial. Purpose To determine if HF patients have elevated E LW versus controls (CTL) and if acute β 2 AR agonist inhalation stimulates fluid removal. Methods/Results 14 stable HF patients and 19 healthy age/gender matched CTL were studied. Lung tissue volume (V tis ) (includes tissue, blood and water) and pulmonary capillary blood volume (Vc) were assessed pre and post nebulized albuterol via CT and rebreathe, respectively. E LW was derived as V tis – Vc. Pre albuterol, E LW was greater in HF vs. CTL (861±241 vs. 739±143 ml, P <0.01), with no difference in V tis (938±246 vs. 830±151 ml, P =0.08). Albuterol decreased V tis (–4±2%, P =0.02) but did not change E LW (739±143 vs. 724±132 ml) ( P >0.05) in CTL. In HF, albuterol decreased both V tis (–5±3%) and E LW (– 4±2%) ( P <0.05). There was a negative relationship between baseline values and the pre to post albuterol change for V tis ( r 2 =0.38) and E LW ( r 2 =0.42) ( P <0.01) in HF. Conclusion Lung fluid is elevated in stable HF patients relative to healthy subjects. Stimulation of β 2 ARs appears to enhance fluid removal in HF, especially in patients with elevated lung water at rest.

Our lab has demonstrated a lower cardiac output (Q) in patients with heart failure (HF) vs. controls (CTL) using acetylene rebreathing (ACET). This technique may be dependent on lung health, which is altered in HF. Therefore, we examined the relationship between Q from echocardiography (echo) and Q from ACET at rest and during exercise. Additionally, we examined the relationship between stroke volume (SV) estimated from O 2 pulse compared to SV by ACET (SV A ). 26 controls (CTL) and 18 HF patients with preserved ejection fraction (EF) completed an exercise test on a cycle ergometer. Lung conductance was measured by lung diffusion for carbon monoxide (DL CO ). Measures of Q (Q A , Acetylene rebreathe; Q E , transthoracic echo), heart rate (HR, 12‐lead ECG), and oxygen consumption (VO 2 , metabolic cart) were taken at rest and peak exercise. Stroke volume (SV) and O 2 pulse were calculated as Q/HR and VO 2 /HR, respectively. HF patients had lower DL CO compared to CTL (Rest: DL CO =11±0.5 vs 14±0.6 ml/min/mmHg, p<0.05). At rest and exercise, Q E was moderately correlated with Q A in CTL (Rest: r=0.47; Pk Ex: r=0.51, p<0.05) and HF (rest: r=0.47; Pk Ex: r=0.77, p<0.05). O 2 pulse was significantly related to SV A at rest and exercise in CTL (Rest: r=0.76; Pk Ex: r=0.81, p<0.05) and HF (Rest: r=0.81; Pk Ex: r=0.82, p<0.05). Cardiac function assessed via ACET is related to cardiac function by echo and O 2 pulse in patients with HF with preserved EF.

Purpose Oxygen pulse (O 2 pulse) is often used clinically as a surrogate for stroke volume during cardiopulmonary exercise testing; however, little data exists on the validity of this measure in patient populations (e.g. heart failure with preserved ejection fraction – HFpEF). Therefore, the purpose of this study was to examine the relationship between O 2 pulse and stroke volume (SV) measured using an accepted technique, echocardiography, at rest and during exercise. Methods Eighteen HFpEF (EF=62±1%) patients and 26 healthy controls (CTL) completed an exercise test on a cycle ergometer. Average measures of oxygen consumption (VO 2 , metabolic cart), heart rate (HR, 12‐lead ECG), and SV (transthoracic echocardiography) were taken at rest and peak exercise. O 2 pulse was calculated as VO 2 divided by HR. Results O 2 pulse was significantly correlated with SV at rest and at peak exercise in CTL (r=0.60 and r=0.55, p<0.05 for both respectfully). O 2 pulse was similarly significantly correlated with SV at rest in HFpEF (r=0.58, p<0.05) whereas this relationship demonstrated a trend at peak exercise (r=0.44, p=0.06). Conclusion Our results demonstrate a moderate relationship between O 2 pulse and SV measured using echocardiography in healthy control participants at rest and during exercise. There is a similar relationship at rest in patients with HFpEF; however, this relationship is less strong during exercise.

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.

Background Patients with heart failure (HF) often develop pulmonary system abnormalities. Specifically, an abnormal ventilation relative to metabolic demand (V E /VCO 2 , ventilatory efficiency) during exercise has been shown to be an important marker of disease severity and prognosis. The purpose of this investigation was to focus on the factors that underlie the abnormal breathing efficiency in this population. Methods 14 controls (10 male) and 40 (36 male) mod‐severe HF patients, age 52±12 and 56±8 yrs, respectively, performed graded exercise on a cycle ergometer. Gas exchange and blood gas measurements were made during submaximal exercise (~65% peak VO 2 ) and used to quantify the influence of hyperventilation (PaCO 2 ) and dead space ventilation (V D ) on V E /VCO 2 . Results The V E /VCO 2 ratio was lower in controls (30±4) than in HF (45±9, p<0.001) due to a lower PaCO 2 and higher V D /V T that contributed an estimated 29% and 71%, respectively, to the increased V E /VCO 2 (p<0.05). The elevated V D /V T in HF was in turn the result of a tachypneic breathing pattern (lower V T , 877±306 vs 2003±504ml, p<0.01) in the presence of a relatively normal V D (9.6±3.8 vs 11.9±5.7 L/min, p=0.094). Conclusion The abnormal ventilation in relation to metabolic demand in HF during exercise is predominantly due to alterations in breathing pattern, rather than hyperventilation or changes in ventilation/perfusion relationships. HL71478

Background Exposure to hypoxia causes pulmonary vasoconstriction (HPV) and may contribute to the pathogenesis of HAPE. The site of HPV, however, is controversial. While the majority of data suggests HPV occurs in the pulmonary arterioles (precapillary), there is evidence that HPV may also occur in postcapillary vessels. Expansion of pulmonary capillary blood volume (Vc) is primarily passive and thus closely linked to cardiac output (Q). Purpose To examine relationships between Q and Vc during exposure to hypoxia and fluid loading. Methods/Results Healthy adults (n=25, age=31±2 yr) reported to the lab for 2 exposures: 1) 17‐h 12.5% F I O 2 in a hypoxia tent, and 2) fluid loading using IV saline (30 ml/kg over ~15 min). Q, Vc and Dm (alveolar‐capillary conductance) were measured using a rebreathe method with small amounts of C 2 H 2 , CO and NO gas. Saline infusion caused an increase in Q (32±6%, P <0.01) and Vc (39±13%, P <0.05), and a decrease in Dm (−9±3%, P <0.05). Vc/Q was not different pre‐ vs post‐saline (17±2 vs 18±3, P =0.40). Hypoxic exposure caused an increase in pulmonary arterial pressure (67±11%, P <0.01), Vc (57±20%, P =0.04) and Dm (35±6%, P <0.01) despite no change in Q (0.2±2.8%, P =0.98). Vc/Q was greater post‐ vs. pre‐hypoxia (24±4 vs. 17±2, P =0.06). Conclusion The rise in Vc with a constant Q during hypoxic exposure suggests a post capillary site for HPV causing the expansion of the pulmonary capillary bed. HL71478.