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Angiotensin-converting enzyme 2 (ACE2) and serine protease TMPRSS2 have been implicated in cell entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). The expression of ACE2 and TMPRSS2 in the lung epithelium might have implications for the risk of SARS-CoV-2 infection and severity of COVID-19. We use human genetic variants that proxy angiotensin-converting enzyme (ACE) inhibitor drug effects and cardiovascular risk factors to investigate whether these exposures affect lung ACE2 and TMPRSS2 gene expression and circulating ACE2 levels. We observed no consistent evidence of an association of genetically predicted serum ACE levels with any of our outcomes. There was weak evidence for an association of genetically predicted serum ACE levels with ACE2 gene expression in the Lung eQTL Consortium ( p = 0.014), but this finding did not replicate. There was evidence of a positive association of genetic liability to type 2 diabetes mellitus with lung ACE2 gene expression in the Gene-Tissue Expression (GTEx) study ( p = 4 × 10 -4 ) and with circulating plasma ACE2 levels in the INTERVAL study ( p = 0.03), but not with lung ACE2 expression in the Lung eQTL Consortium study ( p = 0.68). There were no associations of genetically proxied liability to the other cardiometabolic traits with any outcome. This study does not provide consistent evidence to support an effect of serum ACE levels (as a proxy for ACE inhibitors) or cardiometabolic risk factors on lung ACE2 and TMPRSS2 expression or plasma ACE2 levels., Competing Interests: D.G. is a part-time employee of Novo Nordisk. A.S.B. reports grants outside of this work from AstraZeneca, Biogen, BioMarin, Bioverativ, Merck, Novartis, Pfizer and Sanofi and personal fees from Novartis. B.E.E. is on the scientific advisory boards of Freenome and Celsius Therapeutics and is a full-time employee at Genomics plc while on a leave of absence from Princeton University. J.E.P. has received travel and accommodation expenses and hospitality from Olink to speak at Olink-sponsored academic meetings. E.P. is a full-time employee of Pfizer. J.D. reports grants, personal fees and non-financial support from Merck Sharp & Dohme (MSD), grants, personal fees and non-financial support from Novartis, grants from Pfizer and grants from AstraZeneca outside the submitted work. J.D. sits on the International Cardiovascular and Metabolic Advisory Board for Novartis (since 2010); the Steering Committee of UK Biobank (since 2011); the MRC International Advisory Group (ING) member, London (since 2013); the MRC High Throughput Science 'Omics Panel Member, London (since 2013); the Scientific Advisory Committee for Sanofi (since 2013); the International Cardiovascular and Metabolism Research and Development Portfolio Committee for Novartis; and the AstraZeneca Genomics Advisory Board (since 2018). All other authors have no conflicts of interest to declare., (© 2020 The Authors.)

Overweight asthmatic children report greater symptoms than normal weight asthmatics, despite comparable airflow obstruction. This has been widely assumed to be due to heightened perception of respiratory effort. Three groups of children (healthy weight controls, healthy weight asthmatics, overweight asthmatics) rated perceived respiratory effort throughout an inspiratory resistive loading protocol. Parasternal intercostal electromyogram was used as an objective marker of respiratory load; this was expressed relative to tidal volume and reported as a ratio of the baseline value (neuroventilatory activity ratio (NVEAR)). Significant increases in perception scores (p<0.0001), and decreases in NVEAR (p<0.0001) were observed from lowest to highest resistive load. Higher BMI increased overall perception scores, with no influence of asthma or BMI-for-age percentile on the resistance-perception relationships. These data, indicating elevated overall respiratory effort in overweight asthmatic children but comparable responses to dynamic changes in load, suggest that the greater disease burden in overweight asthmatic children may be due to altered respiratory mechanics associated with increased body mass., (Copyright © 2017 Elsevier B.V. All rights reserved.)

New Findings: What is the central question of this study? The parasternal intercostal electromyogram (EMGpara) is known to provide an accurate, non-invasive index of respiratory load-capacity balance. Although relationships between EMGpara and both airflow obstruction and hyperinflation have been shown, the independent contribution of each factor has not been examined. What is the main finding and its importance? Reductions in airway calibre and inspiratory capacity along with increases in EMGpara were induced via methacholine challenge. A strong inverse relationship was observed between EMGpara and airway obstruction, with no influence of inspiratory capacity. These data suggest that EMGpara is more strongly influenced by airway calibre than by changes in end-expiratory lung volume during airway challenge testing. Neural respiratory drive, measured via the parasternal intercostal electromyogram (EMGpara), provides a non-invasive index of the load-capacity balance of the respiratory muscle pump. Previous studies in patients with obstructive lung disease have shown strong relationships between EMGpara and the extent of both airflow obstruction and hyperinflation. The relative influence of the two factors has not, however, been described. Airflow obstruction was induced via methacholine challenge testing in 25 adult humans. Forced expiratory volume in 1 s (FEV 1 ) and surface EMGpara during tidal breathing were measured after each dose, with 20 of the participants also undergoing measurements of inspiratory capacity (IC) at each stage. Linear mixed model analysis was used to assess dose-wise changes in FEV 1 and EMGpara, and thereafter to determine the influence of changes in FEV 1 and IC on change in EMGpara. Median (interquartile range) FEV 1 decreased significantly [from 96.00 (80.00-122.30) to 67.80 (37.98-92.27)% predicted, P < 0.0001] and EMGpara increased significantly [from 5.37 (2.25-8.92) to 6.27 (3.37-19.60) μV, P < 0.0001] from baseline to end of test. Linear mixed model analysis showed a significant interaction between methacholine dose and induced change in EMGpara, with an increase in EMGpara of 0.24 (95% confidence interval 0.11-0.37) μV per methacholine dose 2 . Change in FEV 1 further influenced this relationship [increase in slope of 0.002 (0.004-0.001) μV dose -2 per % predicted fall in FEV 1 , P = 0.011], but not with change in IC. These data suggest that bronchoconstriction exerts a more potent influence on levels of EMGpara than changes in end-expiratory lung volume during methacholine challenge., (© 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.)

Background: Neural respiratory drive (NRD) measured from the diaphragm electromyogram (EMGdi) reflects the load/capacity balance of the respiratory muscle pump and is a marker of lung disease severity. EMGdi measurement is invasive, but recording the EMG from the parasternal intercostal muscles using surface electrodes (sEMGpara) could provide a non-invasive method of assessing NRD and disease severity. Objectives To test the hypothesis that NRD measured by sEMGpara correlates with EMGdi, to provide an index of disease severity in cystic fibrosis (CF) and to relate to exercise-induced breathlessness., Methods: 15 patients with CF (mean forced expiratory volume in 1&emsp14;s (FEV(1)) 53.5% predicted) and 15 age-matched healthy controls were studied. sEMGpara and EMGdi were recorded at rest and during exercise. sEMGpara was recorded using surface electrodes and EMGdi using a multipair oesophageal electrode catheter. Signals were normalised using the peak EMG recorded during maximum respiratory manoeuvres and expressed as EMG%max. The respiratory pattern, metabolic data, oesophageal and gastric pressures and Borg scores were also recorded., Results: Mean (SD) resting sEMGpara%max and EMGdi%max were higher in patients with CF than in controls (13.1 (7)% and 18.5 (7.5)% vs 5.8 (3)% and 7.5 (2)%, respectively, p<0.001). In the patients with CF, resting sEMGpara%max and EMGdi%max were related to the degree of airways obstruction (FEV(1)) (r = -0.91 and r = -0.82, both p<0.001), hyperinflation (r = 0.63 and r = 0.56, both p<0.001) and dynamic lung compliance (r = -0.53 and r = -0.59, both p<0.001). During exercise, sEMGpara%max and EMGdi%max were strongly correlated with breathlessness in the patients with CF before (r = 0.906, p<0.001) and after (r = 0.975, p<0.001) the onset of neuromechanical dissociation., Conclusion: sEMGpara%max provides a non-invasive marker of neural drive, which reflects disease severity and exercise-induced breathlessness in CF.