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Background: Individuals with α 1 -antitrypsin deficiency have increased elastase activity resulting in continuous degradation of elastin and early onset of COPD. Increased elastase activity may also affect elastic properties of the heart, which may impact risk of heart failure. We tested the hypothesis that α 1 -antitrypsin deficiency is associated with increased risk of heart failure in two large populations., Methods: In a nationwide nested study of 2209 patients with α 1 -antitrypsin deficiency and 21 869 controls without α 1 -antitrypsin deficiency matched on age, sex and municipality, we recorded admissions and deaths due to heart failure during a median follow-up of 62 years. We also studied a population-based cohort of another 102 481 individuals from the Copenhagen General Population Study including 187 patients from the Danish α 1 -Antitrypsin Deficiency Registry, all with genetically confirmed α 1 -antitrypsin deficiency., Results: Individuals with versus without α 1 -antitrypsin deficiency had increased risk of heart failure hospitalisation in the nationwide cohort (adjusted hazard ratio 2.64, 95% CI 2.25-3.10) and in the population-based cohort (1.77, 95% CI 1.14-2.74). Nationwide, these hazard ratios were highest in those without myocardial infarction (3.24, 95% CI 2.70-3.90), without aortic valve stenosis (2.80, 95% CI 2.38-3.29), without hypertension (3.44, 95% CI 2.81-4.22), without atrial fibrillation (3.33, 95% CI 2.75-4.04) and without any of these four diseases (6.00, 95% CI 4.60-7.82). Hazard ratios for heart failure-specific mortality in individuals with versus without α 1 -antitrypsin deficiency were 2.28 (95% CI 1.57-3.32) in the nationwide cohort and 3.35 (95% CI 1.04-10.74) in the population-based cohort., Conclusion: Individuals with α 1 -antitrypsin deficiency have increased risk of heart failure hospitalisation and heart failure-specific mortality in the Danish population., Competing Interests: Conflict of interest: B.G. Nordestgaard has consultancies with Amarin, Akcea, Amgen, AstraZeneca, Denka Seiken, Kowa, Novartis, Novo Nordisk and Silence Therap. Conflict of interest: No conflicts of interest exist for S.V. Winther, E.M. Landt, N. Seersholm and M. Dahl., (Copyright ©The authors 2023.)

Background: Randomised controlled trials found that low-density lipoprotein (LDL) cholesterol-lowering statins increase lung function and possibly decrease rate of exacerbations in individuals with COPD. However, it is unknown whether high levels of LDL cholesterol are associated with increased susceptibility to COPD., Methods: We tested the hypothesis that high LDL cholesterol is associated with increased risk of COPD, severe COPD exacerbation and COPD-specific mortality. We examined 107 301 adults from the Copenhagen General Population Study. COPD outcomes were ascertained at baseline and prospectively through nationwide registries., Results: In cross-sectional analysis, low LDL cholesterol was associated with increased risk of COPD (odds ratio for 1st versus 4th quartile: 1.07 (95% CI 1.01-1.14)). Prospectively, low LDL cholesterol was associated with increased risk of COPD exacerbations with hazard ratios of 1.43 (1.21-1.70) for 1st versus 4th quartile, 1.21 (1.03-1.43) for 2nd versus 4th quartile, and 1.01 (0.85-1.20) for 3rd versus 4th quartile of LDL cholesterol (p-value for trend=6×10 -6 ). Finally, low LDL cholesterol was likewise associated with increased risk of COPD-specific mortality (log-rank test: p=0.0009). Sensitivity analyses with death as competing risk provided similar results., Conclusion: Low LDL cholesterol was associated with increased risks of severe COPD exacerbation and COPD-specific mortality in the Danish general population. As this is opposite of that observed in randomised controlled trials with statins, our findings might be a result of reverse causation indicating that individuals with severe phenotypes of COPD have lower plasma levels of LDL cholesterol due to wasting., Competing Interests: Conflict of interest: J. Freyberg, E.M. Landt, S. Afzal, B.G. Nordestgaard and M. Dahl have nothing to disclose., (Copyright ©The authors 2023.)