Effect of Ultra-Marathon Trail Running at Sea Level and Altitude on Alveolar-Capillary Function and Lung Diffusion.

INTRODUCTION: Endurance exercise at altitude can increase cardiac output and pulmonary vascular pressure to levels that may exceed the stress-tolerability of the alveolar-capillary unit. This study examined the effect of ultra-marathon trail racing at different altitudes (ranging from <1000 m to between 1500 - 2700 m) on alveolar-capillary recruitment and lung diffusion. METHODS: Cardiac and lung function were examined before and after an ultra-marathon in 67 runners (age:41 ± 9y, BMI:23 ± 2 kg/m2, 10 females), and following 12-24 h of recovery in a subset (n = 27). Cardiac biomarkers (cTnI & BNP) were assessed from whole blood, while lung fluid accumulation (comet tails), stroke volume (SV) and cardiac output (Q) were quantified via echocardiography. Lung diffusing capacity for carbon monoxide (DLco) and its components, alveolar membrane conductance (Dm) and capillary blood volume (Vc), were determined via a single-breath method at rest and during three stages of submaximal semi-recumbent cycling (20, 30, & 40 W). RESULTS: Average race time was 25 ± 12 h. From pre- to post-race, there was an increase in cardiac biomarkers (cTnI: 0.04 ± .02 vs 0.13 ± .03 ng/ml; BNP: 20 ± 2 vs 112 ± 21 pg/ml, p < 0.01) and lung comet tails (2 ± 1 vs 7 ± 6, p < 0.01), a decrease in resting and exercise SV (76 ± 2 vs 69 ± 2 ml; 40 W: 93 ± 2 vs 88 ± 2 ml, p < 0.01), and an elevation in Q at rest (4.1 ± 0.1 vs 4.6 ± 0.2 l/min, p < 0.01; 40 W: 7.3 ± 0.2 vs 7.4 ± 0.3 l/min, p = 0.899). Resting DLco and Vc decreased after the race (p < 0.01), while Dm was unchanged (p = 0.465); however, during the three stages of exercise DLco, Vc and Dm were all reduced from pre- to post-race (40 W: 36.3 ± 0.9 vs 33.0 ± 0.8 mL/min/mmHg; 83 ± 3 vs 73 ± 2 mL; 186 ± 6 vs 170 ± 7 mL/min/mmHg, respectively, p < 0.01). When corrected for alveolar volume and Q, DLco decreased from pre- to post-race (p < 0.01), and changes in DLco were similar for all ultra-marathon events (p > 0.05). CONCLUSIONS: Competing in an ultra-marathon leads to a transient increase in cardiac injury biomarkers, mild lung-fluid accumulation, and impairments in lung diffusion. Reductions in DLco are predominantly caused by a reduced Vc and possible pulmonary capillary de-recruitment at rest. However, impairments in alveolar-capillary recruitment and Dm both contribute to a fall in exertional DLco following an ultra-marathon. Perturbations in lung diffusion were evident across a range of event distances and varying environmental exposures.

Metabolic insights at the finish line: deciphering physiological changes in ultramarathon runners through breath VOC analysis.

Exhaustive exercise can induce unique physiological responses in the lungs and other parts of the human body. The volatile organic compounds (VOCs) in exhaled breath are ideal for studying the effects of exhaustive exercise on the lungs due to the proximity of the breath matrix to the respiratory tract. As breath VOCs can originate from the bloodstream, changes in abundance should also indicate broader physiological effects of exhaustive exercise on the body. Currently, there is limited published data on the effects of exhaustive exercise on breath VOCs. Breath has great potential for biomarker analysis as it can be collected non-invasively, and capture real-time metabolic changes to better understand the effects of exhaustive exercise. In this study, we collected breath samples from a small group of elite runners participating in the 2019 Ultra-Trail du Mont Blanc ultra-marathon. The final analysis included matched paired samples collected before and after the race from 24 subjects. All 48 samples were analyzed using the Breath Biopsy Platform with GC-Orbitrap™ via thermal desorption gas chromatography-mass spectrometry. The Wilcoxon signed-rank test was used to determine whether VOC abundances differed between pre- and post-race breath samples (adjustedP-value < .05). We identified a total of 793 VOCs in the breath samples of elite runners. Of these, 63 showed significant differences between pre- and post-race samples after correction for multiple testing (12 decreased, 51 increased). The specific VOCs identified suggest the involvement of fatty acid oxidation, inflammation, and possible altered gut microbiome activity in response to exhaustive exercise. This study demonstrates significant changes in VOC abundance resulting from exhaustive exercise. Further investigation of VOC changes along with other physiological measurements can help improve our understanding of the effect of exhaustive exercise on the body and subsequent differences in VOCs in exhaled breath.

Reproducibility and responsiveness of airway impedance measures derived from the forced oscillation technique across different operating lung volumes.

BACKGROUND: The forced oscillation technique (FOT) enables non-invasive measurement of respiratory system impedance. Limited data exists on how changes in operating lung volume (OLV) impact FOT-derived measures of airway resistance (Rrs) and reactance (Xrs). OBJECTIVES: This study examined the reproducibility and responsiveness of FOT-derived measures of Rrs and Xrs during simulated changes in OLV. METHODS: Participants simulated breathing at six OLVs: total lung capacity (TLC), ∼50% of inspiratory reserve volume (IRV50), ∼two-times tidal volume (VT2), tidal volume (VT), ∼50% of expiratory reserve volume (ERV50), and residual volume (RV), on a commercially available FOT device. Each simulated OLV manuever was performed in triplicate and in random order. Total Rrs and Xrs were recorded at 5, 11, and 19 Hz. RESULTS: Twelve healthy participants (2 female) completed the study (weight: 76.5 ± 13.6 kg, height: 178.6 ± 9.7 cm, body mass index: 23.9 ± 3.1 kg/m2). Reproducibility of Rrs and Xrs at VT, VT2 and IRV50 was good to excellent (Range: ICC: 0.89-0.98, 95% confidence interval (CI): 0.70-0.98), while reproducibility at TLC, RV, and ERV50 was poor to excellent (Range: ICC: 0.60-0.98, 95% CI: 0.36-0.97). Rrs and Xrs were not different between VT and VT2 at any frequency (P > .05). With lung hyperinflation from VT to TLC, Rrs and Xrs decreased at all three frequencies (e.g., At 5 Hz Rrs: mean difference (MD): - 0.89, 95%CI: - 0.03 to - 1.75, P = .04; Xrs: MD: - 0.56, 95%CI: - 0.25 to - 0.86, P < .01). With lung hypoinflated from VT to RV, Rrs increased, and Xrs decreased for all frequencies (e.g., MD at 5 Hz, Rrs: MD: 2.31, 95%CI: 0.94-3.67, P < .01; Xrs: MD: -2.53, 95%CI: -4.02 to -1.04, P < .01). CONCLUSION: FOT-derived measures of airway Rrs and Xrs are reproducible across a range of OLV's, and are responsive to hyper- and hypo-inflation of the lung. To further understand the impact of lung hyper- and hypo-inflation on FOT-derived airway impedance additional study is required in individuals with pathological variations in operating lung volume.

Lung "Comet Tails" in Healthy Individuals: Accumulation or Clearance of Extravascular Lung Water?

Parks, Jordan K, Courtney M. Wheatley-Guy, Glenn M. Stewart, Caitlin C. Fermoyle, Bryan J. Taylor, Jesse Schwartz, Briana Ziegler, Kay Johnson, Alice Gavet, Loïc Chabridon, Paul Robach, and Bruce D. Johnson. Lung "Comet Tails" in healthy individuals: accumulation or clearance of extravascular lung water? High Alt Med Biol. 24:230-233, 2023-Ultrasound lung comet tails (or B-lines) tend to be limited in number (<5) or absent under ultrasound examination, and the appearance of diffuse B-lines with lung sliding has been suggested to identify pulmonary edema. Clinical evaluation of B-lines has been utilized as a bedside test to assess pulmonary congestion in patients with heart failure. Exposure to altitude or prolonged exercise can alter fluid regulation and can lead to pulmonary congestion or edema. As such, B-lines have been utilized in the field to monitor for pathological lung fluid accumulation. However, ultrasound lung comet lines might not be as reliable for identifying extravascular lung water (EVLW) as previously thought in healthy individuals exercising at altitude where an increase in the number of ultrasound lung comets would reflect fluid buildup in the interstitial space of the alveoli and pulmonary capillaries. This report will focus on reviewing the literature and our data from a group of ultraendurance runners that completed the Ultra Trail Mont Blanc race that demonstrates that lung comet tails may not always be evidence of pathological fluid accumulation in healthy individuals and as such should be used to assess EVLW in concert with other diagnostic testing.

The severity of acute hypoxaemia determines distinct changes in intracortical and spinal neural circuits.

The purpose of this study was to examine how two common methods of continuous hypoxaemia impact the activity of intracortical circuits responsible for inhibition and facilitation of motor output, and spinal excitability. Ten participants were exposed to 2 h of hypoxaemia at 0.13 fraction of inspired oxygen ( F I O 2 ${F_{{\mathrm{I}}{{\mathrm{O}}_{\mathrm{2}}}}}$ clamping protocol) and 80% of peripheral capillary oxygen saturation ( S p O 2 ${S_{{\mathrm{p}}{{\mathrm{O}}_{\mathrm{2}}}}}$ clamping protocol) using a simulating altitude device on two visits separated by a week. Using transcranial magnetic and peripheral nerve stimulation, unconditioned motor evoked potential (MEP) area, short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF), and F-wave persistence and area were assessed in the first dorsal interosseous (FDI) muscle before titration, after 1 and 2 h of hypoxic exposure, and at reoxygenation. The clamping protocols resulted in differing reductions in S p O 2 ${S_{{\mathrm{p}}{{\mathrm{O}}_{\mathrm{2}}}}}$ by 2 h ( S p O 2 ${S_{{\mathrm{p}}{{\mathrm{O}}_{\mathrm{2}}}}}$ clamping protocol: 81.9 ± 1.3%, F I O 2 ${F_{{\mathrm{I}}{{\mathrm{O}}_{\mathrm{2}}}}}$ clamping protocol: 90.6 ± 2.5%). Although unconditioned MEP peak to peak amplitude and area did not differ between the protocols, SICI during F I O 2 ${F_{{\mathrm{I}}{{\mathrm{O}}_{\mathrm{2}}}}}$ clamping was significantly lower at 2 h compared to S p O 2 ${S_{{\mathrm{p}}{{\mathrm{O}}_{\mathrm{2}}}}}$ clamping (P = 0.011) and baseline (P < 0.001), whereas ICF was higher throughout the F I O 2 ${F_{{\mathrm{I}}{{\mathrm{O}}_{\mathrm{2}}}}}$ clamping compared to S p O 2 ${S_{{\mathrm{p}}{{\mathrm{O}}_{\mathrm{2}}}}}$ clamping (P = 0.005). Furthermore, a negative correlation between SICI and S p O 2 ${S_{{\mathrm{p}}{{\mathrm{O}}_{\mathrm{2}}}}}$ (rrm  = -0.56, P = 0.002) and a positive correlation between ICF and S p O 2 ${S_{{\mathrm{p}}{{\mathrm{O}}_{\mathrm{2}}}}}$ (rrm  = 0.69, P = 0.001) were determined, where greater reductions in S p O 2 ${S_{{\mathrm{p}}{{\mathrm{O}}_{\mathrm{2}}}}}$ correlated with less inhibition and less facilitation of MEP responses. Although F-wave area progressively increased similarly throughout the protocols (P = 0.037), persistence of responses was reduced at 2 h and reoxygenation (P < 0.01) during the S p O 2 ${S_{{\mathrm{p}}{{\mathrm{O}}_{\mathrm{2}}}}}$ clamping protocol compared to the F I O 2 ${F_{{\mathrm{I}}{{\mathrm{O}}_{\mathrm{2}}}}}$ clamping protocol. After 2 h of hypoxic exposure, there is a reduction in the activity of intracortical circuits responsible for inhibiting motor output, as well as excitability of spinal motoneurones. However, these effects can be influenced by other physiological responses to hypoxia (i.e., hyperventilation and hypocapnia). NEW FINDINGS: What is the central question of this study? How do two common methods of acute hypoxic exposure influence the excitability of intracortical networks and spinal circuits responsible for motor output? What is the main finding and its importance? The excitability of spinal circuits and intracortical networks responsible for inhibition of motor output was reduced during severe acute exposure to hypoxia at 2 h, but this was not seen during less severe exposure. This provides insight into the potential cause of variance seen in motor evoked potential responses to transcranial magnetic stimulation (corticospinal excitability measures) when exposed to hypoxia.

Exertional dyspnea responses to the Dyspnea Challenge in heart failure: Comparison to chronic obstructive pulmonary disease.

BACKGROUND: In heart failure (HF), exertional dyspnea is a common symptom, but validated field-based tests for its measurement are limited. The Dyspnea Challenge is a two-minute uphill treadmill walk designed to measure exertional dyspnea in cardiopulmonary disease. OBJECTIVES: The purpose of this study was to establish the test-retest reliability of the Dyspnea Challenge in HF and to compare the exercise responses to a group with chronic obstructive pulmonary disease (COPD). METHODS: The study was an experimental, single-blind, randomized, multi-site project that recruited individuals with HF (New York Heart Association I-III) and COPD (Global Initiative for Chronic Obstructive Lung Disease II-IV). Participants completed two visits. On the first visit, participants performed two six-minute walk tests (6MWT), followed by two to three Dyspnea Challenges to calculate treadmill speed and gradient. At Visit Two, participants performed two separate Dyspnea Challenges, with one including measures of pulmonary gas exchange and central hemodynamics. RESULTS: Twenty-one individuals with HF (10 female; 66±11years; ejection fraction:45.3 ± 6.1%; six-minute distance(6MWD) 520 ± 97 m), and 25 COPD (11 female; 68 ± 10 yr; forced expiratory volume in 1 s:47.6 ± 11.5%; 6MWD: 430 ± 101 m). Intraclass correlation coefficients demonstrated excellent test-retest reliability for HF (0.94, P<.01) and COPD (0.95, P<.01). While achieving similar end-exercise exertional dyspnea intensities (P=.60), the HF group walked at a higher average speed (4.2 ± 0.8 vs. 3.5 ± 0.8km·h-1) and gradient (10.3 ± 2.8 vs. 9.6 ± 2.8%) and a greater oxygen uptake (P<.01) and ventilation (P<.01) than those with COPD. While achieving similar cardiac outputs (P=.98), stroke volumes (P=.97), and heart rates (P=.83), those with HF displayed a larger arteriovenous oxygen difference (P<.01), while those with COPD exhibited greater decreases in inspiratory capacity (P=.03), arterial oxygen saturation (P=.02), and breathing reserve (P<.01). CONCLUSIONS: The Dyspnea Challenge is a reliable test-retest measure of exertional dyspnea in HF. Typical to their pathologies, HF seemed limited by an inadequate modulation of cardiac output, while ventilatory constraints hampered those with COPD.

Exertional Dyspnoea responses reported in the Dyspnoea Challenge and measures of disease severity in COPD.

BACKGROUND: The Dyspnoea Challenge has been developed to facilitate the field-based measure of exertional dyspnoea(ED). To further validate the test, we aimed to; investigate the relationship between end-exercise ED, generated by a fixed-intensity Dyspnoea Challenge(DCFIX), and measures of disease severity (Forced expiratory volume in 1 s(FEV1), six-minute walk distance(6MWD), breathing reserve(V̇E/MVV), modified medical research council dyspnoea scale (mMRC), Body-mass index, airflow Obstruction, Dyspnoea, and Exercise (BODE index) and compare the physiological response of the DCFIX to a six-minute walk test(6MWT). METHODS: Thirty-two individuals (15 female) with COPD (GOLD II-IV) (age: 69.7 ± 9.4 yrs; FEV1: 49.1 ± 18.2 %) performed 2×6MWT and 2xDCFIX at a treadmill speed of 3 km h-1 and gradient of 4 %. The intensity of ED was measured using the modified Borg dyspnoea scale at baseline and end-exercise with heart rate (HR) and oxygen saturation (SpO2) monitored continuously. During 1×6MWT and 1xDCFIX pulmonary gas exchange, cardiac output (Q̇) and dynamic hyperinflation were measured. RESULTS: End-exercise ED measured during the DCFIX was not correlated to FEV1, but moderately correlated to; 6MWD(rs = -0.54, P < .01), V̇E/MVV (rs = 0.46, P = .02), mMRC(rs = 0.45, P = .01), and the BODE index(rs = 0.53, P < .01). When comparing the DCFIX and 6MWT, participants walked to comparable levels of oxygen consumption(P = .38), ventilation(P = .37), Q̇(P = .20), V̇E/MVV(P = .83), maximum HR percentages(P = .67) and dynamically hyperinflated to a similar degree(P = .37). CONCLUSIONS: The Dyspnoea Challenge is correlated to different parameters of disease severity and produces a similar physiological and ED response to that of the 6MWT with the added benefit of being appropriate for longitudinal assessment of ED.

Sex-Specific Physiological Responses to Ultramarathon.

PURPOSE: Despite a growing body of literature on the physiological responses to ultramarathon, there is a paucity of data in females. This study assessed the female physiological response to ultramarathon and compared the frequency of perturbations to a group of race- and time-matched males. METHODS: Data were collected from 53 contestants of an ultramarathon trail race at the Ultra-Trail du Mont-Blanc (UTMB®) in 2018/19. Before and within 2 h of the finish, participants underwent physiological assessments, including blood sampling for biomarkers (creatine kinase-MB isoenzyme [CK-MB], cardiac troponin I [cTnI], brain natriuretic peptide [BNP], and creatinine [Cr]), pulmonary function testing (spirometry, exhaled NO, diffusing capacities, and mouth pressures), and transthoracic ultrasound (lung comet tails, cardiac function). Data from eight female finishers (age = 36.6 ± 6.9 yr; finish time = 30:57 ± 11:36 h:min) were compared with a group of eight time-matched males (age = 40.3 ± 8.3 yr; finish time = 30:46 ± 10:32 h:min). RESULTS: Females exhibited significant pre- to postrace increases in BNP (25.8 ± 14.6 vs 140.9 ± 102.7 pg·mL -1 ; P = 0.007) and CK-MB (3.3 ± 2.4 vs 74.6 ± 49.6 IU·L -1 ; P = 0.005), whereas males exhibited significant pre- to postrace increases in BNP (26.6 ± 17.5 vs 96.4 ± 51.9 pg·mL -1 ; P = 0.002), CK-MB (7.2 ± 3.9 vs 108.8 ± 37.4 IU·L -1 ; P = 0.002), and Cr (1.06 ± 0.19 vs 1.23 ± 0.24 mg·dL -1 ; P = 0.028). Lung function declined in both groups, but males exhibited additional reductions in lung diffusing capacities (DL CO = 34.4 ± 5.7 vs 29.2 ± 6.9 mL⋅min -1 ⋅mm Hg -1 , P = 0.004; DL NO = 179.1 ± 26.2 vs 152.8 ± 33.4 mL⋅min -1 ⋅mm Hg -1 , P = 0.002) and pulmonary capillary blood volumes (77.4 ± 16.7 vs 57.3 ± 16.1 mL; P = 0.002). Males, but not females, exhibited evidence of mild postrace pulmonary edema. Pooled effect sizes for within-group pre- to postrace changes, for all variables, were generally larger in males versus females ( d = 0.86 vs 0.63). CONCLUSIONS: Ultramarathon negatively affects a range of physiological functions but generally evokes more frequent perturbations, with larger effect sizes, in males compared to females with similar race performances.

Optimising the Dyspnoea Challenge: exertional dyspnoea responses to changing treadmill gradients.

BACKGROUND: The Dyspnoea Challenge is a two-minute treadmill walk designed to measure exertional dyspnoea(ED). To efficiently individualise workload, we aimed to assess; 1) whether the Dyspnoea Challenge is responsive to 1% changes in treadmill gradient and 2) the minimum gradient variation necessary to generate a clinically meaningful change in ED (≥1 modified Borg scale). METHODS: Thirty individuals with COPD(GOLD II-IV) (age: 69.2 ± 9.2 years; FEV1: 49.3 ± 19.1%) completed six Dyspnoea Challenges at a fixed treadmill speed of 3 km·h-1 and at a gradient of between 3% and 8%, performed in random order. ED intensity and leg fatigue were measured using the 0-10 modified Borg scale. Heart rate(HR) and oxygen saturation(SpO2) were monitored continuously. A multidimensional dyspnoea profile(MDP) was used to quantify the discomfort, physical, e.g., work/effort and breathing frequency, and emotional components of ED. RESULTS: Higher treadmill gradients generated stronger intensities of ED (3%:2.6 ± 1.8; 4%:2.8 ± 2.2; 5%:3.2 ± 2.2; 6%:3.4 ± 2.2; 7%:3.7 ± 1.8; 8%:4.0 ± 2.1units). Statistical changes were observed in ED(e.g.,3 vs. 5%: P = .03) and the MDP discomfort data(e.g.,4 vs. 6%: P = .04) at ≥ a 2% variation in treadmill gradient. Linear regression found a 4% variation in treadmill gradient corresponded to a rise in ED ≥ 1unit. Increases in ED intensity corresponded to heightened sensations of work/effort(P < .01) and breathing frequency(P < .01). There were no changes in emotional constructs(P = .27). While there was an increase in HR with increasing gradient(P < .01), no differences were observed in end-exercise SpO2(P = .79) or leg fatigue(P = .06). CONCLUSION: To significantly change ED, the treadmill gradient must be manipulated by ≥ 2%, with a ≥ 4% change in gradient required to induce a clinically meaningful change in ED.

Examining the repeatability of a novel test to measure exertional dyspnoea in chronic obstructive pulmonary disease.

BACKGROUND: Exertional dyspnoea(ED) is a hallmark of chronic obstructive pulmonary disease(COPD). We examined the repeatability and face validity of the end-exercise ED(EDend) response during the Dyspnoea Challenge and compared those to the six-minute walk test (6MWT) in COPD. METHODS: Twenty-six individuals with COPD(13 Females, age:69 ± 5.5yrs, FEV1:63.4 ± 11.9 %) completed 2 × 6MWTs and 4 x Dyspnoea Challenges on three occasions. The challenge consisted of a two-minute treadmill walk at 80 % of 6MWT speed(3.9 ± 0.5 km·hr-1) at either a low(LIDC:5.3 ± 2%) or high angle of incline(HIDC:9.5 ± 3%). Dyspnoea(0-10 scale), heart rate(HR) and oxygen saturation(SpO2) were monitored continuously. RESULTS: Mean 6MWT distance was 488 ± 58 m. End-exercise ED and HR were higher in the HIDC(EDend 6.2 ± 2.0; HR: 123 ± 17beats·min-1) compared to the LIDC(EDend 4.2 ± 2.0; HR: 119 ± 15beats·min-1) and the 6MWT(EDend 4.3 ± 2.0; HR: 115 ± 16beats·min-1)(P < 0.01). SpO2 was not different between 6MWT, LIDC or HIDC(P = 0.34). The intraclass correlation coefficient(ICC) for each intensity was excellent (HIDC, ICC = 0.88, LIDC, ICC = 0.93, P < 0.001) with neither reporting bias(HIDC, P = 0.63; LIDC, P = 0.94). CONCLUSIONS: The Dyspnoea Challenge is a simple measure of ED that appears to have both repeatability and face validity. With further optimisation, this test may enhance the field-based clinical assessment of ED.

Simultaneous Measurement of Lung Diffusing Capacity and Pulmonary Hemodynamics Reveals Exertional Alveolar-Capillary Dysfunction in Heart Failure With Preserved Ejection Fraction.

Background Hemodynamic perturbations in heart failure with preserved ejection fraction (HFpEF) may alter the distribution of blood in the lungs, impair gas transfer from the alveoli into the pulmonary capillaries, and reduce lung diffusing capacity. We hypothesized that impairments in lung diffusing capacity for carbon monoxide (DLCO) in HFpEF would be associated with high mean pulmonary capillary wedge pressures during exercise. Methods and Results Rebreathe DLCO and invasive hemodynamics were measured simultaneously during exercise in patients with exertional dyspnea. Pulmonary pressure waveforms and breath-by-breath pulmonary gas exchange were recorded at rest, 20 W, and symptom-limited maximal exercise. Patients with HFpEF (n=20; 15 women, aged 65±11 years, body mass index 36±8 kg/m2) achieved a lower symptom-limited maximal workload (52±27 W versus 106±42 W) compared with controls with noncardiac dyspnea (n=10; 7 women, aged 55±10 years, body mass index 30±5 kg/m2). DLCO was lower in patients with HFpEF compared with controls at rest (DLCO 10.4±2.9 mL/min per mm Hg versus 16.4±6.9 mL/min per mm Hg, P<0.01) and symptom-limited maximal exercise (DLCO 14.6±4.7 mL/min per mm Hg versus 23.8±10.8 mL/min per mm Hg, P<0.01) because of a lower alveolar-capillary membrane conductance in HFpEF (rest 16.8±6.6 mL/min per mm Hg versus 28.4±11.8 mL/min per mm Hg, P<0.01; symptom-limited maximal exercise 25.0±6.7 mL/min per mm Hg versus 45.5±22.2 mL/min per mm Hg, P<0.01). DLCO was lower in HFpEF for a given mean pulmonary artery pressure, mean pulmonary capillary wedge pressure, pulmonary arterial compliance, and transpulmonary gradient. Conclusions Lung diffusing capacity is lower at rest and during exercise in HFpEF due to impaired gas conductance across the alveolar-capillary membrane. DLCO is impaired for a given pulmonary capillary wedge pressure and pulmonary arterial compliance. These data provide new insight into the complex relationships between hemodynamic perturbations and gas exchange abnormalities in HFpEF.

Impact of Pharmacologically Left Shifting the Oxygen-Hemoglobin Dissociation Curve on Arterial Blood Gases and Pulmonary Gas Exchange During Maximal Exercise in Hypoxia.

Stewart, Glenn M., Troy J. Cross, Michael J. Joyner, Steven C. Chase, Timothy Curry, Josh Lehrer-Graiwer, Kobina Dufu, Nicholas E. Vlahakis, and Bruce D. Johnson. Impact of pharmacologically left shifting the oxygen-hemoglobin dissociation curve on arterial blood gases and pulmonary gas exchange during maximal exercise in hypoxia. High Alt Med Biol. 22:249-262, 2021. Introduction: Physiological and pathological conditions, which reduce the loading of oxygen onto hemoglobin (Hb), can impair exercise capacity and cause debilitating symptoms. Accordingly, this study examined the impact of pharmacologically left shifting the oxygen-hemoglobin dissociation curve (ODC) on arterial oxygen saturation (SaO2) and exercise capacity. Methods: Eight healthy subjects completed a maximal incremental exercise test in hypoxia (FIO2: 0.125) and normoxia (FIO2: 0.21) before (Day 1) and after (Day 15) daily ingestion of 900 mg of voxelotor (an oxygen/Hb affinity modulator). Pulmonary gas exchange and arterial blood gases were assessed throughout exercise and at peak. Data for a 1,500 mg daily drug dose are reported in a limited cohort (n = 3). Results: Fourteen days of drug administration left shifted the ODC (p50 measured under standard conditions, Day 1: 28.0 ± 2.1 mmHg vs. Day 15: 26.1 ± 1.8 mmHg, p < 0.05). Throughout incremental exercise in hypoxia, SaO2 was systematically higher after drug (peak exercise SaO2 on Day 1: 71 ± 2 vs. Day 15: 81% ± 2%, p < 0.001), whereas oxygen extraction (Ca-vO2 diff) and consumption (VO2) were similar (peak exercise Ca-vO2 diff on Day 1: 11.5 ± 1.7 vs. Day 15: 11.0 ± 1.8 ml/100 ml blood, p = 0.417; peak VO2 on Day 1: 2.59 ± 0.39 vs. Day 15: 2.47 ± 0.43 l/min, p = 0.127). Throughout incremental exercise in normoxia, SaO2 was systematically higher after drug, whereas peak VO2 was reduced (peak exercise SaO2 on Day 1: 93.9 ± 1.8 vs. Day 15: 95.8% ± 1.0%, p = 0.008; peak VO2 on Day 1: 3.62 ± 0.55 vs. Day 15: 3.26 ± 52 l/min, p = 0.001). Conclusion: Pharmacologically increasing the affinity of Hb for oxygen improved SaO2 during hypoxia without impacting exercise capacity; however, left shifting the ODC in healthy individuals appears detrimental to exercise capacity in normoxia. Left shifting the ODC to different magnitudes and under more chronic forms of hypoxia warrants further study.

Salutary Acute Effects of Exercise on Central Hemodynamics in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: A warmup period of priming exercise has been shown to improve peripheral oxygen transport in older adults. We sought to determine the acute effects of priming exercise on central hemodynamics at rest and during a repeat exercise in heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: This is a post hoc analysis from 3 studies. Patients with HFpEF (n = 42) underwent cardiac catheterization with simultaneous expired gas analysis at rest and during exercise (20 W for 5 minutes, priming exercise). Measurements were then repeated at rest and during a second bout of exercise at a 20-W workload (second exercise). During the priming exercise, patients with HFpEF displayed dramatic increases in biventricular filling pressures and exercise-induced pulmonary hypertension. After the priming exercise at rest, biventricular filling pressures and pulmonary artery (PA) pressures were lower and lung tidal volume was increased. During the second bout of exercise, biventricular filling (PA wedge pressure, 29 ± 8 mm Hg at second exercise vs 32 ± 7 mm Hg at first exercise, P = .0003) and PA pressures were lower, and PA compliance increased. CONCLUSIONS: This study shows that short duration, submaximal priming exercise attenuates the pathologic increases in filling pressures, improving pulmonary vascular hemodynamics at rest and during repeat exercise in patients with HFpEF.

Peripheral and pulmonary effects of inorganic nitrite during exercise in heart failure with preserved ejection fraction.

AIMS: To determine whether inorganic nitrite improves peripheral and pulmonary oxygen (O2 ) transport during exercise in heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: Data from two invasive, randomized, double-blind, placebo-controlled trials with matched workload exercise of inhaled and intravenous sodium nitrite were pooled for this analysis (n = 51). Directly measured O2 consumption (VO2 ) and blood gas data were used to evaluate the effect of nitrite on skeletal muscle O2 conductance (Dm), VO2 kinetics, alveolar capillary membrane O2 conductance (DL ), and O2 utilization during submaximal exercise. As compared to placebo, treatment with nitrite resulted in an improvement in Dm (+4.9 ± 6.5 vs. -0.9 ± 4.3 mL/mmHg*min, P = 0.0008) as well as VO2 kinetics measured by mean response time (-5.0 ± 6.9 vs. -0.6 ± 6.0 s, P = 0.03), with preserved O2 utilization despite increased convective O2 delivery through cardiac output (+0.4 ± 0.7 vs. -0.3 ± 0.9 L/min, P = 0.02). Nitrite improved DL (+2.5 ± 6.3 vs. -2.0 ± 9.0 mL/mmHg*min, P = 0.05) with exercise, which was associated with lower pulmonary capillary pressures (r = -0.34, P = 0.02), and reduced pulmonary dead space ventilation fraction (-0.01 ± 0.05 vs. +0.02 ± 0.05, P = 0.02). CONCLUSION: Sodium nitrite enhances skeletal muscle Dm during exercise as well as pulmonary O2 diffusion, optimizing O2 kinetics in tandem with increased convective O2 delivery through cardiac output augmentation. The favourable combined pulmonary, cardiac and peripheral effects of nitrite may improve exercise tolerance in people with HFpEF and requires further investigation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID NCT01932606 and NCT02262078.

Cardiac perturbations after high-intensity exercise are attenuated in middle-aged compared with young endurance athletes: diminished stress or depleted stimuli?

Strenuous exercise elicits transient functional and biochemical cardiac imbalances. Yet, the extent to which these responses are altered owing to aging is unclear. Accordingly, echocardiograph-derived left ventricular (LV) and right ventricular (RV) global longitudinal strain (GLS) and high-sensitivity cardiac troponin I (hs-cTnI) were assessed before (pre) and after (post) a 60-min high-intensity cycling race intervention (CRIT60) in 11 young (18-30 yr) and 11 middle-aged (40-65 yr) highly trained male cyclists, matched for cardiorespiratory fitness. LV and RV GLS were measured at rest and during a semirecumbent exercise challenge performed at the same intensity (young: 93 ± 10; middle-aged: 85 ± 11 W, P = 0.60) pre- and post-CRIT60. Augmentation (change from rest-to-exercise challenge) of LV GLS (pre: -2.97 ± 0.65; post: -0.82 ± 0.48%, P = 0.02) and RV GLS (pre: -2.08 ± 1.28; post: 3.08 ± 2.02%, P = 0.01) was attenuated and completely abolished, in the young following CRIT60, while augmentation of LV GLS (pre: -3.21 ± 0.41; post: -3.99 ± 0.55%, P = 0.22) and RV GLS (pre: -3.47 ± 1.44; post: -1.26 ± 1.00%, P = 0.27) was preserved in middle-aged following CRIT60. While serum hs-cTnI concentration increased followingCRIT60 in the young (pre: 7.3 ± 1.6; post: 17.7 ± 1.6 ng/L, P < 0.01) and middle-aged (pre: 4.5 ± 0.6; post: 10.7 ± 2.0 ng/L, P < 0.01), serum hs-cTnI concentration increased to a greater extent in the young than in the middle-aged following CRIT60 (P < 0.01). These findings suggest that functional and biochemical cardiac perturbations induced by high-intensity exercise are attenuated in middle-aged relative to young individuals. Further study is warranted to determine whether acute exercise-induced cardiac perturbations alter the adaptive myocardial remodeling response.NEW & NOTEWORTHY High-intensity endurance exercise elicits acute cardiac imbalances that may be an important stimulus for adaptive cardiac remodeling. This study highlights that following a bout of high-intensity exercise that is typical of routine day-to-day cycling training, exercise-induced autonomic, biochemical, and functional cardiac imbalances are attenuated in middle-aged relative to young well-trained cyclists. These findings suggest that aging may alter exercise-induced stress stimulus response that initiates cardiac remodeling in athlete's heart.

Effects of exercise on thoracic blood volumes, lung fluid accumulation, and pulmonary diffusing capacity in heart failure with preserved ejection fraction.

Patients with heart failure with preserved ejection fraction (HFpEF) experience symptoms of exertional dyspnea that may be related to lung fluid accumulation during exercise. A computed tomography (CT)-based method was used to measure exercise-induced changes in extravascular lung fluid content and thoracic blood volumes and to determine the effect of lung fluid on lung diffusing capacity for carbon monoxide (DLCO) in stable subjects with HFpEF and healthy controls. Nine subjects with HFpEF (age = 68 ± 8 yr; body mass index = 32.1 ± 2.6 kg/m2) and eight healthy controls (62 ± 9 yr, 23.8 ± 2.4 kg/m2) performed triplicate rebreathe DLCO/DLNO (lung diffusing capacity for nitric oxide) tests in a supine position at rest and duplicate measurements during two 5-min submaximal exercise stages (15W and 35W) and recovery. Subjects subsequently performed a 5-min exercise bout (35W) inside a CT scanner, and extravascular lung fluid content and thoracic blood volumes were quantified at rest and immediately following exercise from thoracic and contrast perfusion scans, respectively. Subjects with HFpEF had a higher lung fluid content at rest compared with controls (means ± SD, HFpEF: 14.4 ± 1.7%, control: 12.8 ± 1.7%, P = 0.043) and a higher lung fluid content following exercise (15.2 ± 2.0% vs. 12.6 ± 1.5%, P = 0.009). Higher lung fluid content was associated with a lower DLCO and alveolar-capillary membrane conductance (Dm) in subjects with HFpEF (DLCO: R = -0.57, P = 0.022, Dm: R = -0.61, P = 0.012) but not in controls. Pulmonary blood volume was not altered by exercise and was similar between groups. Submaximal exercise elicited a greater accumulation of lung fluid in subjects with HFpEF compared with in controls, and lung fluid content was negatively correlated with lung diffusing capacity and alveolar-capillary membrane conductance in subjects with HFpEF.

Exercise Is Medicine? The Cardiorespiratory Implications of Ultra-marathon.

Regular physical activity decreases the risk of cardiovascular disease, type II diabetes, obesity, certain cancers, and all-cause mortality. Nevertheless, there is mounting evidence that extreme exercise behaviors may be detrimental to human health. This review collates several decades of literature on the physiology and pathophysiology of ultra-marathon running, with emphasis on the cardiorespiratory implications. Herein, we discuss the prevalence and clinical significance of postrace decreases in lung function and diffusing capacity, respiratory muscle fatigue, pulmonary edema, biomarkers of cardiac injury, left/right ventricular dysfunction, and chronic myocardial remodeling. The aim of this article is to inform risk stratification for ultra-marathon and to edify best practice for personnel overseeing the events (i.e., race directors and medics).

Pulmonary Vascular Pressures and Gas Exchange Response to Exercise in Heart Failure With Preserved Ejection Fraction.

Elevated left ventricular filling pressure (measured as mean pulmonary capillary wedge pressure) at rest or with exercise is diagnostic of heart failure with preserved ejection fraction. However, the capacity of the right ventricle to compensate for a high mean pulmonary capillary wedge pressure and thus maintain an appropriate transpulmonary gradient (TPG) and perfusion of the pulmonary capillaries is likely an important contributor to gas exchange efficiency and exercise capacity. Therefore, this study aimed to determine whether a higher TPG at peak exercise is associated with superior exercise capacity and gas exchange. Gas exchange data from dyspneic patients referred for exercise right heart catheterization were retrospectively analyzed and patients were split into two groups based on TPG. Patients with a higher TPG at peak exercise had a higher peak VO2 (1025 ± 227 vs 823 ± 276, P = .038), end-tidal partial pressure of carbon dioxide (42.2 ± 7.9 vs 38.0 ± 4.7, P = .044), and gas exchange estimates of pulmonary vascular capacitance (408 ± 90 vs 268 ± 108, P = .001). A higher TPG at peak exercise correlated with a higher peak oxygen uptake, O2 pulse, and stroke volume (R = 0.42, 0.44 and 0.42, respectively, all P < 0.05). These findings indicate that a greater TPG with exercise might be important for improving exercise capacity in heart failure with preserved ejection fraction.

Impact of pulsed electromagnetic field therapy on vascular function and blood pressure in hypertensive individuals.

The present study investigated the impact of 12 weeks of pulsed electromagnetic field (PEMF) therapy on peripheral vascular function, blood pressure (BP), and nitric oxide in hypertensive individuals. Thirty hypertensive individuals (SBP > 130 mm Hg and/or MAP > 100 mm Hg) were assigned to either PEMF group (n = 15) or control group (n = 15). During pre-assessment, participants underwent measures of flow-mediated dilation (FMD), BP, and blood draw for nitric oxide (NO). Subsequently, they received PEMF therapy 3x/day for 12 weeks and, at conclusion, returned to the laboratory for post-assessment. Fifteen participants from the PEMF group and 11 participants from the control group successfully completed the study protocol. After therapy, the PEMF group demonstrated significant improvements in FMD and FMDNOR (normalized to hyperemia), but the control group did not (P = .05 and P = .04, respectively). Moreover, SBP, DBP, and MAP were reduced, but the control group did not (P = .04, .04, and .03, respectively). There were no significant alterations in NO in both groups (P > .05). Twelve weeks of PEMF therapy may improve BP and vascular function in hypertensive individuals. Additional studies are needed to identify the mechanisms by which PEMF affects endothelial function.

Effects of an allosteric hemoglobin affinity modulator on arterial blood gases and cardiopulmonary responses during normoxic and hypoxic low-intensity exercise.

Numerous pathophysiological conditions induce hypoxemia-related cardiopulmonary perturbations, decrements in exercise capacity, and debilitating symptoms. Accordingly, this study investigated the efficacy of an allosteric hemoglobin modulator (voxelotor) to enhance arterial oxygen saturation during low-intensity exercise in hypoxia. Eight normal healthy subjects (36 ± 7 yr; 73.8 ± 9.5 kg; 3 women) completed a submaximal cycling test (60 W) under normoxic ([Formula: see text]: 0.21; O2 partial pressure: 144 mmHg) and hypoxic ([Formula: see text]: 0.125; O2 partial pressure: 82 mmHg) conditions before (day 1) and after (day 15) 14 days of oral drug administration. While stationary on a cycle ergometer and during exercise, ratings of perceived exertion (RPE) and dyspnea, oxygen consumption (V̇o2), and cardiac output (Q) were measured noninvasively, while arterial blood pressure (MAP) and blood gases ([Formula: see text], [Formula: see text], and [Formula: see text]) were measured invasively. The 14-day drug administration left shifted the oxygen-hemoglobin dissociation curve (ODC; p50 measured at standard pH and Pco2; day 1: 28.0 ± 2.1 mmHg vs. day 15: 26.1 ± 1.8 mmHg, P < 0.05). RPE, dyspnea, V̇o2, Q, and MAP were not different between day 1 and day 15. [Formula: see text] was similar during normoxia on day 1 and day 15 while stationary but higher during exercise (day 1: 95.2 ± 0.4% vs. day 15: 96.6 ± 0.3%, P < 0.05). [Formula: see text] was higher during hypoxia on day 15 while stationary (day 1: 82.9 ± 3.4% vs. day 15: 90.9 ± 1.8%, P < 0.05) and during exercise (day 1: 73.6 ± 2.5% vs. day 15: 84.8 ± 2.7%, P < 0.01). [Formula: see text] and [Formula: see text]were systematically higher and lower, respectively, after drug (P < 0.01), while the alveolar-arterial oxygen difference was unchanged suggesting hyperventilation contributed to the rise in [Formula: see text]. Oral administration of voxelotor left shifted the ODC and stimulated a mild hyperventilation, leading to improved arterial oxygen saturation without altering V̇o2 and central hemodynamics during rest and low-intensity exercise. This effect was more pronounced during submaximal hypoxic exercise, when arterial desaturation was more evident. Additional studies are needed to determine the effects of voxelotor during maximal exercise and under chronic forms of hypoxia.NEW & NOTEWORTHY In humans, a novel allosteric hemoglobin-oxygen affinity modulator was administered to comprehensively examine the cardiopulmonary consequences of stabilizing a portion of the available hemoglobin in a high-oxygen affinity state during submaximal exercise in normoxia and hypoxia. Oral administration of voxelotor enhanced arterial oxygen saturation during submaximal exercise without altering oxygen consumption and central hemodynamics; however, the partial pressure of arterial carbon dioxide was reduced and the partial pressure of arterial oxygen was increased implying that hyperventilation also contributed to the increase in oxygen saturation. The preservation of arterial oxygen saturation and content was particularly evident during hypoxic submaximal exercise, when arterial desaturation typically occurs, but this did not influence arterial-venous oxygen difference.