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Exposing the mechanisms driving wasted ventilation is key to advancing the field towards new therapeutic approaches to improve dyspnoea and exercise tolerance in this growing patient sub-population.<\/jats:p><\/jats:sec><jats:sec><jats:title>Central hypothesis<\/jats:title><jats:p>Increased areas of high alveolar ventilation (<jats:italic>V\u0307<\/jats:italic><jats:sub>A<\/jats:sub>)\/capillary perfusion (<jats:italic>Q\u0307<\/jats:italic><jats:sub>c<\/jats:sub>) due to impaired<jats:italic>Q\u0307<\/jats:italic><jats:sub>c<\/jats:sub>in nonemphysematous, non-air trapping areas of the lungs add to any underlying emphysema to increase wasted ventilation and exertional dyspnoea in mild COPD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>40 patients (20 women) showing post-bronchodilator forced expiratory volume in 1\u2005s \u226570% predicted and 20 sex- and age-matched controls will perform constant load exercise tests in a flutter-kicking device in the physiology laboratory and, in another visit, a magnetic resonance imaging (MRI) facility. Volumetric capnography will be used to breath-by-breath quantify rest and exercise<jats:italic>V<\/jats:italic><jats:sub>D<\/jats:sub><jats:sub>phys<\/jats:sub>. Free-breathing, noncontrast proton MRI (phase-resolved functional lung (PREFUL))<jats:italic>V\u0307<\/jats:italic><jats:sub>A<\/jats:sub>,<jats:italic>Q\u0307<\/jats:italic><jats:sub>c<\/jats:sub>and<jats:italic>V\u0307<\/jats:italic><jats:sub>A<\/jats:sub>\/<jats:italic>Q\u0307<\/jats:italic><jats:sub>c,<\/jats:sub>maps will be co-registered to emphysema and air trapping severity and distribution as established by computed tomography (parametric response mapping).<\/jats:p><\/jats:sec><jats:sec><jats:title>Study implications<\/jats:title><jats:p>Confirmation of the study's main hypothesis will provide the first evidence that increased wasted ventilation in dyspnoeic patients with mild COPD is not a mere consequence of emphysematous destruction being also reflective of impaired perfusion across apparently preserved lung tissue. This will set the stage for subsequent interventional studies geared to address this potentially treatable disease trait.<\/jats:p><\/jats:sec>","DOI":"10.1183\/23120541.00686-2024","type":"journal-article","created":{"date-parts":[[2025,1,31]],"date-time":"2025-01-31T11:45:32Z","timestamp":1738323932000},"page":"00686-2024","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Wasted ventilation in mild COPD: protocol for a clinical physiology and functional imaging study"],"prefix":"10.1183","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1586-6897","authenticated-orcid":false,"given":"Matthew D.","family":"James","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Voskrebenzev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filip","family":"Klime\u0161","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon","family":"Zanette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karam","family":"Alosta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abed A.","family":"Hijleh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra G.","family":"Vincent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6883-4720","authenticated-orcid":false,"given":"Nicolle J.","family":"Domnik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devin B.","family":"Phillips","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Pourafkari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chu-Yi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8102-7384","authenticated-orcid":false,"given":"Michele","family":"Girardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carrie","family":"Ferguson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2951-784X","authenticated-orcid":false,"given":"Miranda","family":"Kirby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giles","family":"Santyr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Stringer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janos","family":"Porszasz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7593-2433","authenticated-orcid":false,"given":"Denis E.","family":"O'Donnell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Vogel-Claussen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8019-281X","authenticated-orcid":false,"given":"J. 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