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Background: Short-term studies suggest that dietary nitrate (NO 3 - ) supplementation may improve the cardiovascular risk profile, lowering blood pressure (BP) and enhancing endothelial function. It is not clear if these beneficial effects are sustained and whether they apply in people with COPD, who have a worse cardiovascular profile than those without COPD. Nitrate-rich beetroot juice (NR-BRJ) is a convenient dietary source of nitrate., Methods: The ON-BC trial was a randomised, double-blind, placebo-controlled parallel group study in stable COPD patients with home systolic BP (SBP) measurement ≥130 mmHg. Participants were randomly allocated (1:1) using computer-generated, block randomisation to either 70 mL NR-BRJ (400 mg NO 3 - ) (n=40) or an otherwise identical nitrate-depleted placebo juice (0 mg NO 3 - ) (n=41), once daily for 12 weeks. The primary end-point was between-group change in home SBP measurement. Secondary outcomes included change in 6-min walk distance (6MWD) and measures of endothelial function (reactive hyperaemia index (RHI) and augmentation index normalised to a heart rate of 75 beats·min -1 (AIx75)) using an EndoPAT device. Plasma nitrate and platelet function were also measured., Results: Compared with placebo, active treatment lowered SBP (Hodges-Lehmann treatment effect -4.5 (95% CI -5.9- -3.0) mmHg), and improved 6MWD (30.0 (95% CI 15.7-44.2) m; p<0.001), RHI (0.34 (95% CI 0.03-0.63); p=0.03) and AIx75 (-7.61% (95% CI -14.3- -0.95%); p=0.026)., Conclusions: In people with COPD, prolonged dietary nitrate supplementation in the form of beetroot juice produces a sustained reduction in BP, associated with an improvement in endothelial function and exercise capacity., Competing Interests: Conflict of interest: T.D. Warner reports grants from British Heart Foundation, outside the submitted work. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

The aim of this study was to test the hypothesis that neural respiratory drive, measured using diaphragm electromyogram (EMGdi) activity expressed as a percentage of maximum (EMGdi%max), is closely related to breathlessness in chronic obstructive pulmonary disease. We also investigated whether neuroventilatory uncoupling contributes significantly to breathlessness intensity over an awareness of levels of neural respiratory drive alone. EMGdi and ventilation were measured continuously during incremental cycle and treadmill exercise in 12 chronic obstructive pulmonary disease patients (forced expiratory volume in 1 s±sd was 38.7±14.5 % pred). EMGdi was expressed both as EMGdi%max and relative to tidal volume expressed as a percentage of predicted vital capacity to quantify neuroventilatory uncoupling. EMGdi%max was closely related to Borg breathlessness in both cycle (r=0.98, p=0.0001) and treadmill exercise (r=0.94, p=0.005), this relationship being similar to that between neuroventilatory uncoupling and breathlessness (cycling r=0.94, p=0.005; treadmill r=0.91, p=0.01). The relationship between breathlessness and ventilation was poor when expansion of tidal volume became limited. In chronic obstructive pulmonary disease the intensity of exertional breathlessness is closely related to EMGdi%max. These data suggest that breathlessness in chronic obstructive pulmonary disease can be largely explained by an awareness of levels of neural respiratory drive, rather than the degree of neuroventilatory uncoupling. EMGdi%max could provide a useful physiological biomarker for breathlessness in chronic obstructive pulmonary disease., (Copyright ©ERS 2015.)

Usual gait speed is a consistent predictor of adverse outcomes in community-dwelling elderly people. The reliability and validity of the 4-m gait speed (4MGS) has recently been demonstrated in patients with chronic obstructive pulmonary disease (COPD). The aims of this study were to assess the responsiveness of the 4MGS and to estimate the minimal clinically important difference (MCID). In 301 COPD patients, 4MGS and incremental shuttle walk (ISW) were measured before and after pulmonary rehabilitation. 4MGS and ISW were also measured at baseline and 1 year later in a separate cohort of 162 COPD patients. The MCID of 4MGS was estimated using distribution and anchor-based methods. 4MGS improved significantly with pulmonary rehabilitation (mean change 0.08 m·s(-1), p<0.001). The minimal detectable change at 95% confidence was 0.11 m·s(-1). The MCID was estimated at 0.11 m·s(-1) (anchored against ISW) and 0.08 m·s(-1) (anchored against self-reported improvement). The effect size for 4MGS was greatest in frail individuals. After 12 months, mean 4MGS declined by 0.04 m·s(-1). When anchored against a decline of more than the MCID for ISW, change in 4MGS was -0.11 m·s(-1). The 4MGS is responsive to pulmonary rehabilitation and longitudinal change in COPD, and has potential as a simple functional assessment tool in COPD. The 4MGS may be particularly useful in frail individuals with COPD.

In community-dwelling older adults, usual gait speed over 4 m (4MGS) consistently predicts greater risk of adverse health outcomes. The aims of the present study were to assess the reliability of the 4MGS and the relationship with established health outcome measures in chronic obstructive pulmonary disease (COPD). Test-retest and interobserver reliability of the 4MGS were measured in 80 and 58 COPD patients, respectively. In 586 COPD patients, the 4MGS, as well as forced expiratory volume in 1 s (FEV1), the incremental shuttle walk (ISW), Medical Research Council (MRC) dyspnoea scale and St George's Respiratory Questionnaire (SGRQ) were measured. Participants were stratified according to "slow" (<0.8 m·s(-1)) or "normal" 4MGS (≥0.8 m·s(-1)). Intra-class correlation coefficients for test-retest and interobserver reliability were 0.97 and 0.99, respectively. There was a significant positive correlation between 4MGS with ISW (ρ = 0.78; p<0.001) and a negative correlation with MRC dyspnoea scale and SGRQ (ρ = -0.55 and -0.44; p<0.001 for both). COPD patients with slow 4MGS had significantly reduced ISW and higher MRC dyspnoea scale and SGRQ than those with preserved walking speed, despite similar FEV1 % predicted. The 4MGS is reliable in COPD, correlates with exercise capacity, dyspnoea and health-related quality of life, and has potential as a simple assessment tool in COPD.

Reduced quadriceps endurance in chronic obstructive pulmonary disease (COPD) is associated with a predominance of type II glycolytic fibres over type I oxidative fibres (fibre shift) and reduced muscle energy stores. The molecular mechanisms responsible for this remain unknown. We hypothesised that expression of known regulators of type I fibres and energy production in quadriceps muscle would differ in COPD patients with and without fibre shift. We measured lung function, physical activity, exercise performance, quadriceps strength and endurance (nonvolitionally) in 38 Global Initiative for Chronic Obstructive Lung Disease stage I-IV COPD patients and 23 healthy age-matched controls. Participants underwent a quadriceps biopsy: type I and II fibre proportions were determined using immunohistochemistry and fibre shift defined using published reference ranges. Calcineurin A, phosphorylated AMP kinase (phospho-AMPK)-α, protein kinase A-α catalytic subunits, modulators of calcineurin activity and calmodulin, 14-3-3 proteins were measured by Western blotting, and myocyte-enriched calcineurin-interacting protein-1 mRNA measured by quantitative PCR. Downstream, nuclear myocyte enhancer factor-2 capable of DNA binding was quantified by transcription factor ELISA. Unexpectedly, calcineurin expression was higher, while phospho-AMPK was lower, in COPD patients with fibre shift compared to COPD patients without fibre shift. Phospho-AMPK levels correlated with quadriceps endurance in patients. Reduced phospho-AMPK may contribute to reduced quadriceps oxidative capacity and endurance in COPD.

It is not known whether vitamin D levels make a significant contribution to muscle dysfunction in chronic obstructive pulmonary disease (COPD). In 104 COPD patients (mean±sd forced expiratory volume in 1 s 44±22 % predicted) and 100 age- and sex-matched controls, serum 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)(2)D) and parathyroid hormone (PTH) levels were measured and related to quadriceps strength and endurance. In a subset of 26 patients and 13 controls, quadriceps biopsy was performed and mRNA expression of myogenic regulatory factors (mrf) and fibre-specific myosin heavy chains (MHC) was determined. COPD patients were weaker and less physically active than controls. 25(OH)D levels were similar in both groups (48.5±25.5 nmol·L(-1) COPD versus 55.4±28.3 nmol·L(-1) control, p=0.07) but PTH levels were significantly higher in patients (5.2±2.3 pmol·mL(-1) versus 4.4±2.0 pmol·L(-1), p=0.01). 1,25(OH)D was significantly correlated with strength in controls, but not in COPD patients and not with quadriceps endurance assessed using repetitive magnetic stimulation in COPD (n=35) or control (n=35) subjects. In controls, but not COPD patients, muscle biopsy analysis showed a negative relationship between 25(OH)D and MHCIIa expression (r(2)=0.5, p=0.01) and a positive relationship between mrf4 and MHCIIa expression (r(2)=0.5, p=0.009), and myogenic regulatory factor myf5 and MHCI expression (r(2)=0.72, p=0.004). In contrast with healthy controls, muscle strength is not associated with vitamin D levels in COPD, which may represent vitamin D resistance.

Quantification of daily physical activity is of clinical interest in chronic obstructive pulmonary disease (COPD). Objective measures using activity monitors may take several days to obtain reliable results. The aim of our study was to evaluate the Stanford Seven-Day Physical Activity Recall questionnaire (PAR) against the SenseWear armband (SWA) and compare its validity with three other physical activity questionnaires. 43 COPD patients wore the SWA for 7 days. Patients completed the PAR, Baecke, Physical Activity Scale for the Elderly (PASE) and Zutphen questionnaires. Spearman rank correlation, intraclass correlation coefficients (ICC) and receiver-operating characteristics (ROC) curves were used to assess the relationship between the questionnaires and SWA. Assessed by PAR, time spent at ≥3.0 metabolic equivalents (METs) correlated significantly (r=0.54, p<0.001) with equivalent measures from SWA, with an ICC of 0.40. No relationship was seen between the other questionnaires and the SWA. The PAR predicted active patients (≥30 min at ≥3.0 METs or a physical activity level (PAL) ≥1.55) and very inactive patients (PAL <1.40) with an area under ROC curve of 0.83, 0.77 and 0.70, respectively. While the PAR did not measure physical activity sufficiently accurately to make individual recommendations, it was able to identify COPD patients at extremes of the physical activity spectrum, potentially reducing the number of patients requiring direct measurement.