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In patients with chronic obstructive pulmonary disease (COPD), pulmonary vascular dysfunction and destruction are observable before the onset of detectable emphysema, but it is unknown whether this is associated with central hypovolemia. We investigated if COPD patients have reduced pulmonary blood volume (PBV) evaluated by 82Rb-positron emission tomography(PET) at rest and during adenosine-induced hyperemia. This single-center retrospective cohort study assessed 6301 82Rb-PET myocardial perfusion imaging (MPI) examinations performed over a 6-year period. We compared 77 COPD patients with 44 healthy kidney donors (controls). Cardiac output (Q̇) and mean 82Rb bolus transit time (MBTT) were used to calculate PBV. Q̇ was similar at rest (COPD: 3649 ± 120 mL vs. control: 3891 ± 160 mL, p=0.368) but lower in COPD patients compared to controls during adenosine infusion (COPD: 5432 ± 124 mL vs. control: 6185 ± 161 mL, p < 0.050). MBTT was shorter in COPD patients compared to controls at rest (COPD: 8.7 ± 0.28 seconds vs. control: 11.4 ± 0.37 seconds, p < 0.001) and during adenosine infusion (COPD: 9.2 ± 0.28 seconds vs. control: 10.2 ± 0.37 seconds, p < 0.014). PBV was lower in COPD patients, even after adjustment for body surface area, sex, and age at rest (COPD: 530 (29) mL vs. 708 (38) mL, p < 0.001) and during adenosine infusion (COPD: 826 (29) mL vs. 1044 (38) mL, p<0.001). In conclusion, patients with COPD show evidence of central hypovolemia, but it remains to be determined whether this has any diagnostic or prognostic impact.

The combined single-breath measurement of the diffusing capacity of carbon monoxide (DL,CO) and nitric oxide (DL,NO) is a useful technique to measure pulmonary alveolar-capillary reserve in both healthy and patient populations. The measurement provides an estimate of the participant's ability to recruit and distend pulmonary capillaries. The method has recently been reported to exhibit a high test-retest reliability in healthy volunteers during exercise of light to moderate intensity. Of note, this technique permits up to 12 repeated maneuvers and only requires a single breath with a relatively short breath-hold time of 5 s. Representative data are provided showing the gradual changes in DL,NO and DL,CO from rest to exercise at increasing intensities of up to 60% of maximal workload. The measurement of diffusing capacity and evaluation of alveolar-capillary reserve is a useful tool to evaluate the lung's ability to respond to exercise both in the healthy population as well as in patient populations such as those with chronic lung disease.

Objectives High-intensity interval training (HIIT) during pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD) may alleviate the symptom burden, but the fidelity and tolerability of HIIT using long or short intervals in patients with COPD are unknown. Methods Twelve patients with moderate-to-severe COPD were included in a randomised cross-over pilot study. They completed two supervised HIIT protocols (4×4 and 10×1). To compare the two HIIT protocols, completed training amount, exercise intensity and perceived tolerability (assessed by a 10-point Likert scale) were integrated in a red-amber-green rating system. If a training session received a red ranking, it was considered unacceptable, if it received an amber ranking it was applicable with precautions, and if it received a green ranking it was considered feasible. Results All patients completed the total training amount in both protocols. The 4×4 protocol resulted in three amber training sessions due to low perceived tolerability. The 10×1 protocol resulted in two red training sessions due to intensity reductions, and two amber training sessions because of low perceived tolerability. There was no statistical difference in perceived tolerability or time spent with an HR ≥85% of HR max. Conclusions HIIT using longer intervals (4×4) at a relatively lower intensity resulted in higher fidelity expressed by fewer adjustments to the protocol, whereas there was no difference between protocols in perceived tolerance. The 4×4 protocol seems to have a higher fidelity compared with the 10×1 protocol in patients with moderate-to-severe COPD. Trial registration number NCT05273684.

NEW FINDINGS: What is the central question in this study? How reliable is the combined measurement of the pulmonary diffusing capacity to carbon monoxide and nitric oxide (D LCO/NO ) during exercise and in the resting supine position, respectively? What is the main finding and its importance? The D LCO/NO technique is reliable with a very low day-to-day variability both during exercise and in the resting supine position, and may thus provide a useful physiological outcome that reflects the alveolar-capillary reserve in humans. ABSTRACT: D LCO/NO , the combined single-breath measurement of the diffusing capacity to carbon monoxide (D LCO ) and nitric oxide (D LNO ) measured either during exercise or in the resting supine position may be a useful physiological measure of alveolar-capillary reserve. In the present study, we investigated the between-day test-retest reliability of D LCO/NO -based metrics. Twenty healthy volunteers (10 males, 10 females; mean age 25 (SD 2) years) were randomized to repeated D LCO/NO measurements during upright rest followed by either exercise (n = 11) or resting in the supine position (n = 9). The measurements were repeated within 7 days. The smallest real difference (SRD), defined as the 95% confidence limit of the standard error of measurement (SEM), the coefficient of variance (CV), and intraclass correlation coefficients were used to assess test-retest reliability. SRD for D LNO was higher during upright rest (5.4 (95% CI: 4.1, 7.5) mmol/(min kPa)) than during exercise (2.7 (95% CI: 2.0, 3.9) mmol/(min kPa)) and in the supine position (3.0 (95% CI: 2.1, 4.8) mmol/(min kPa)). SRD for D LCOc was similar between conditions. CV values for D LNO were slightly lower than for D LCOc both during exercise (1.5 (95% CI: 1.2, 1.7) vs. 3.8 (95% CI: 3.2, 4.3)%) and in the supine position (2.2 (95% CI: 1.8, 2.5) vs. 4.8 (95% CI: 3.8, 5.4)%). D LNO increased by 12.3 (95% CI: 11.1, 13.4) and D LCOc by 3.3 (95% CI: 2.9, 3.7) mmol/(min kPa) f

Doppler ultrasound has revolutionized the assessment of organ blood flow and is widely used in research and clinical settings. While Doppler ultrasound-based assessment of contracting leg muscle blood flow is common in human studies, the reliability of this method requires further investigation. Therefore, this study aimed to investigate the within-day test-retest, between-day test-retest, and inter-rater reliability of Doppler ultrasound for assessing leg blood flow during rest and graded single-leg knee-extensions (0 W, 6 W, 12 W, and 18 W), with the ultrasound probe being removed between measurements. The study included thirty healthy subjects (age: 33 ± 9.3, male/female: 14/16) who visited the laboratory on two different experimental days separated by 10 days. The study did not control for major confounders such as nutritional state, time of day, or hormonal status. Across different exercise intensities, the results demonstrated high within-day reliability with a coefficient of variation (CV) ranging from 4.0% to 4.3%, acceptable between-day reliability with a CV ranging from 10.1% to 20.2%, and inter-rater reliability with a CV ranging from 17.9% to 26.8%. Therefore, in a real-life clinical scenario where controlling various environmental factors is challenging, Doppler ultrasound can be used to determine leg blood flow during submaximal single-leg knee-extensor exercise with high within-day reliability and acceptable between-day reliability when performed by the same sonographer.

Alcoholic liver cirrhosis (ALC) is accompanied by sarcopenia. The aim of this study was to investigate the acute effects of balanced parenteral nutrition (PN) on skeletal muscle protein turnover in ALC. Eight male patients with ALC and seven age- and sex-matched healthy controls were studied for three hours of fasting followed by three hours of intravenous PN (SmofKabiven 1206 mL: Amino acid 38 g, carbohydrates 85 g, fat 34 g) 4 ml/kg/hour. We measured leg blood flow, sampled paired femoral arterio-venous concentrations and quadriceps muscle biopsies while providing a primed continuous infusion of [ring-2D5]-phenylalanine to quantify muscle protein synthesis and breakdown. Patients with ALC exhibited shorter 6-min walking distance (ALC: 487 ± 38 vs. controls: 722 ± 14 m, p<0.05), lower hand-grip strength (ALC: 34 ± 2 vs. controls: 52 ± 2 kg, p<0.05), and CT-verified leg muscle loss (ALC: 5922 ± 246 vs. controls: 8110 ± 345 mm2, p<0.05). Net leg muscle phenylalanine uptake changed from negative (muscle loss) during fasting to positive (muscle gain) in response to PN (ALC: -0.18 ± +0.01 vs. 0.24 ± 0.03 µmol/kg muscle*min-1; p <0.001 and controls: -0.15 ± 0.01 vs. 0.09 ± 0.01 µmol/kg muscle*min-1; p <0.001), but with higher net muscle phenylalanine uptake in ALC than controls (p <0.001). Insulin concentrations were substantially higher in ALC patients during PN. Our results suggest a higher net muscle phenylalanine uptake during a single infusion of PN in stable ALC patients with sarcopenia compared with healthy controls., Alcoholic liver cirrhosis (ALC) is accompanied by sarcopenia. The aim of this study was to investigate the acute effects of balanced parenteral nutrition (PN) on skeletal muscle protein turnover in ALC. Eight male patients with ALC and seven age- and sex-matched healthy controls were studied for three hours of fasting followed by three hours of intravenous PN (SmofKabiven 1206 mL: Amino acid 38 g, carbohydrates 85 g, fat 34 g) 4 ml/kg/hour. We measured leg blood flow, sampled paired femoral arterio-venous concentrations and quadriceps muscle biopsies while providing a primed continuous infusion of [ring-2D5]-phenylalanine to quantify muscle protein synthesis and breakdown. Patients with ALC exhibited shorter 6-min walking distance (ALC: 487 ± 38 vs. controls: 722 ± 14 m, p<0.05), lower hand-grip strength (ALC: 34 ± 2 vs. controls: 52 ± 2 kg, p<0.05), and CT-verified leg muscle loss (ALC: 5922 ± 246 vs. controls: 8110 ± 345 mm2, p<0.05). Net leg muscle phenylalanine uptake changed from negative (muscle loss) during fasting to positive (muscle gain) in response to PN (ALC: -0.18 ± +0.01 vs. 0.24 ± 0.03 µmol/kg muscle*min-1; p <0.001 and controls: -0.15 ± 0.01 vs. 0.09 ± 0.01 µmol/kg muscle*min-1; p <0.001), but with higher net muscle phenylalanine uptake in ALC than controls (p <0.001). Insulin concentrations were substantially higher in ALC patients during PN. Our results suggest a higher net muscle phenylalanine uptake during a single infusion of PN in stable ALC patients with sarcopenia compared with healthy controls.

In chronic obstructive pulmonary disease (COPD), the progressive loss of lung tissue is widely considered irreversible. Thus, various treatment and rehabilitation schemes, including exercise-based pulmonary rehabilitation (PR) are thought to slow down but not reverse or halt the disease. Nonetheless, the adult lung conceals the intrinsic capacity for de novo lung tissue formation in the form of abundant progenitor/stem cell populations. In COPD, these maintain their differentiation potential but appear to be halted by a state of cellular senescence in the mesenchyme, which normally functions to support and coordinate their function. We propose that notably high-intensity interval training may improve pulmonary gas exchange during exercise in patients with COPD by interrupting mesenchymal senescence, thus reestablishing adaptive angiogenesis. By means of this, the downward spiral of dyspnea, poor quality of life, physical inactivity, and early death often observed in COPD may be interrupted. If this is the case, the perception of the regenerative capacity of the lungs will be fundamentally changed, which will warrant future clinical trials on various exercise schemes and other treatments targeting the formation of new lung tissue in COPD.

Aim: Skeletal muscle convective and diffusive oxygen (O2) transport are peripheral determinants of exercise capacity in both patients with chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF). We hypothesised that differences in these peripheral determinants of performance between COPD and CHF patients are revealed during small muscle mass exercise, where the cardiorespiratory limitations to exercise are diminished. Methods: Eight patients with moderate to severe COPD, eight patients with CHF (NYHA II), and eight age- and sex-matched controls were studied. We measured leg blood flow (Q̇leg) by Doppler ultrasound during submaximal one-legged knee-extensor exercise (KEE), while sampling arterio-venous variables across the leg. The capillary oxyhaemoglobin dissociation curve was reconstructed from paired femoral arterial-venous oxygen tensions and saturations, which enabled the estimation of O2 parameters at the microvascular level within skeletal muscle, so that skeletal muscle oxygen conductance (DSMO2) could be calculated and adjusted for flow (DSMO2/Q̇leg) to distinguish convective from diffusive oxygen transport. Results: During KEE, Q̇leg increased to a similar extent in CHF (2.0 (0.4) L/min) and controls (2.3 (0.3) L/min), but less in COPD patients (1.8 (0.3) L/min) (p <0.03). There was no difference in resting DSMO2 between COPD and CHF and when adjusting for flow, the DSMO2 was higher in both groups compared to controls (COPD: 0.97 (0.23) vs. controls 0.63 (0.24) mM/kPa, p= 0.02; CHF 0.98 (0.11) mM/kPa vs. controls, p= 0.001). The Q̇-adjusted DSMO2 was not different in COPD and CHF during KEE (COPD: 1.19 (0.11) vs. CHF: 1.00 (0.18) mM/kPa; p= 0.24) but higher in COPD vs. controls: 0.87 (0.28) mM/kPa (p= 0.02), and only CHF did not increase Q̇-adjusted DSMO