eprintid: 10189951 rev_number: 6 eprint_status: archive userid: 699 dir: disk0/10/18/99/51 datestamp: 2024-04-05 12:36:10 lastmod: 2024-04-05 12:36:10 status_changed: 2024-04-05 12:36:10 type: article metadata_visibility: show sword_depositor: 699 creators_name: Sapey, E creators_name: Crowley, LE creators_name: Edgar, RG creators_name: Griffiths, D creators_name: Samanta, S creators_name: Crisford, H creators_name: Bolton, CE creators_name: Hurst, JR creators_name: Stockley, RA title: Cardiovascular disease in Alpha 1 antitrypsin deficiency: an observational study assessing the role of neutrophil proteinase activity and the suitability of validated screening tools ispublished: pub divisions: UCL divisions: B02 divisions: C10 divisions: D17 divisions: K71 keywords: Cardiovascular disease, Chronic obstructive pulmonary disease, Emphysema, Alpha 1 anti-trypsin deficiency, Arterial stiffness, Risk assessment, Neutrophils note: © 2024 BioMed Central Ltd. This article is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/). abstract: BACKGROUND: Alpha 1 Antitrypsin Deficiency (AATD) is a rare, inherited lung disease which shares features with Chronic Obstructive Pulmonary Disease (COPD) but has a greater burden of proteinase related tissue damage. These proteinases are associated with cardiovascular disease (CVD) in the general population. It is unclear whether patients with AATD have a greater risk of CVD compared to usual COPD, how best to screen for this, and whether neutrophil proteinases are implicated in AATD-associated CVD. This study had three aims. To compare CVD risk in never-augmented AATD patients to non-AATD COPD and healthy controls (HC). To assess relationships between CVD risk and lung physiology. To determine if neutrophil proteinase activity was associated with CVD risk in AATD. Cardiovascular risk was assessed by QRISK2® score and aortic stiffness measurements using carotid-femoral (aortic) pulse wave velocity (aPWV). Medical history, computed tomography scans and post-bronchodilator lung function parameters were reviewed. Systemic proteinase 3 activity was measured. Patients were followed for 4 years, to assess CVD development. RESULTS: 228 patients with AATD, 50 with non-AATD COPD and 51 healthy controls were recruited. In all COPD and HC participants, QRISK2® and aPWV gave concordant results (with both measures either high or in the normal range). This was not the case in AATD. Once aPWV was adjusted for age and smoking history, aPWV was highest and QRISK2® lowest in AATD patients compared to the COPD or HC participants. Higher aPWV was associated with impairments in lung physiology, the presence of emphysema on CT scan and proteinase 3 activity following adjustment for age, smoking status and traditional CVD risk factors (using QRISK2® scores) in AATD. There were no such relationships with QRISK2® in AATD. AATD patients with confirmed CVD at four-year follow up had a higher aPWV but not QRISK2® at baseline assessment. CONCLUSION: aPWV measured CVD risk is elevated in AATD. This risk is not captured by QRISK2®. There is a relationship between aPWV, lung disease and proteinase-3 activity. Proteinase-driven breakdown of elastin fibres in large arteries and lungs is a putative mechanism and forms a potential therapeutic target for CVD in AATD. date: 2024 date_type: published publisher: Springer Science and Business Media LLC official_url: http://dx.doi.org/10.1186/s13023-024-03124-x oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 2262444 doi: 10.1186/s13023-024-03124-x medium: Electronic pii: 10.1186/s13023-024-03124-x lyricists_name: Hurst, John lyricists_id: JHURS15 actors_name: Flynn, Bernadette actors_id: BFFLY94 actors_role: owner funding_acknowledgements: [Alpha-1 Foundation] full_text_status: public publication: Orphanet Journal of Rare Diseases volume: 19 number: 1 article_number: 130 event_location: England citation: Sapey, E; Crowley, LE; Edgar, RG; Griffiths, D; Samanta, S; Crisford, H; Bolton, CE; ... Stockley, RA; + view all <#> Sapey, E; Crowley, LE; Edgar, RG; Griffiths, D; Samanta, S; Crisford, H; Bolton, CE; Hurst, JR; Stockley, RA; - view fewer <#> (2024) Cardiovascular disease in Alpha 1 antitrypsin deficiency: an observational study assessing the role of neutrophil proteinase activity and the suitability of validated screening tools. Orphanet Journal of Rare Diseases , 19 (1) , Article 130. 10.1186/s13023-024-03124-x <https://doi.org/10.1186/s13023-024-03124-x>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10189951/1/s13023-024-03124-x.pdf