Tobacco smoking and the risk of aortic aneurysm in the UK biobank

A total of 495,993 participants were included in the analytical dataset. When compared to never smokers, a higher proportion of current smokers were women than men. In addition, current smokers were younger, more deprived, and had lower education levels. We found few differences in smoking prevalence by ethnicity, physical activity, body mass index, height and connective tissue disease (Table 1). During an average of 12.3 years (6.1 million person-years) follow-up, a total of 3,353 incident aortic aneurysm cases were identified, including 778 thoracic, 1,985 abdominal, 26 thoracoabdominal and 519 unspecified aortic aneurysms. Of the total, 121 ruptured and 3,232 were non-ruptured aortic aneurysm cases, and 184 aortic aneurysm deaths occurred.

Smoking and aortic aneurysm

The hazard ratios (95% CIs) of aortic aneurysm overall for current, former and ever vs. never smokers were 4.32 (3.93–4.76), 1.70 (1.56–1.84), and 2.15 (1.99–2.32), respectively. There was a strong dose-response relationship between increasing number of cigarettes per day and aortic aneurysm with HRs (95% CIs) of 3.62 (2.84–4.62), 5.66 (4.93–6.50), and 5.67 (4.93–6.52) for < 10, 10-<20 and ≥ 20 cigarettes per day vs. never smokers and a significant linear trend (p_trend = < 0.001). Pack-years of smoking was positively associated with aortic aneurysm risk with HRs (95% CIs) of 1.37 (1.18–1.60), 1.64 (1.44–1.88), 2.47 (2.19–2.80), and 3.77 (3.43–4.14; p_trend = < 0.001) for < 10, 10-<20, 20-<30, and ≥ 30 pack-years vs. never smokers. Similarly, greater duration of smoking was associated with dose-dependent increases in risk among current smokers and former smokers, with HRs (95% CIs) 2.52 (1.66–3.84), 3.48 (2.78–4.35), 5.86 (5.24–6.56; p_trend = < 0.001) for < 10, 10-<20, and ≥ 20 years in current smokers and 1.09 (0.95–1.24), 1.61 (1.40–1.84), and 3.18 (2.87–3.53; p_trend = < 0.001) for the same comparison in former smokers. Younger age (< 16 vs. ≥16 years) at starting smoking was slightly more strongly associated with aortic aneurysm both in former smokers (2.11, 1.87–2.37 vs. 1.79, 1.62–1.96) and current smokers (5.62, 4.87–6.47 vs. 4.82, 4.29–5.42). Years since quitting smoking was associated with a dose-dependent reduction in risk of aortic aneurysm with HRs (95% CIs) of 0.77 (0.69–0.87), 0.50 (0.44–0.57), 0.32 (0.28–0.37), and 0.23 (0.20–0.27; p_trend = < 0.001) for < 10, 10-<20, 20-<30, ≥ 30 years vs. current smoking, and which at ≥ 30 years duration approached that of never smokers (0.22, 0.20–0.25) (Table 2).

Smoking and aortic aneurysm subsites (thoracic, abdominal, thoracoabdominal and unspecified site)

When analyses were conducted separately for thoracic, abdominal, thoracoabdominal and unspecified site aortic aneurysms, strong positive associations were observed for current vs. never smokers and abdominal (8.90, 7.79–10.16), thoracoabdominal (11.64, 4.20-32.25), and unspecified site (2.06, 1.61–2.65) aortic aneurysms, but no clear association was observed for thoracic aortic aneurysm (1.13, 0.88–1.44), and there was significant heterogeneity by subsite (p_{heterogeneity}<0.0001) (Table 3). Similar trends were observed for ≥ 20 cigarettes/day vs. never smoking for abdominal (12.32, 10.34–14.68), thoracoabdominal (21.59, 6.14–75.96), and unspecified site (2.48, 1.65–3.72), and thoracic (0.99, 0.60–1.62) aortic aneurysms (p_{heterogeneity}<0.0001), and for ≥ 30 pack-years vs. never smoking for abdominal (7.24, 6.35–8.26), thoracoabdominal (8.02, 2.73–23.55), unspecified site (1.63, 1.26–2.10), and thoracic (1.17, 0.93–1.48) aortic aneurysms (p_{heterogeneity}<0.0001). Consistent with these findings, ≥ 20 years duration of smoking among current smokers vs. never smoking was positively associated with abdominal aortic aneurysm (11.47, 9.89–13.30), thoracoabdominal (11.88, 3.53–39.92), unspecified site (2.51, 1.84–3.44), but not thoracic (1.25, 0.88–1.77) aortic aneurysm (p_{heterogeneity}<0.0001), and for the same comparison in former smokers positive associations were observed for abdominal (5.76, 5.00-6.63), thoracoabdominal (4.70, 1.40-15.79), unspecified site (1.48, 1.12–1.97), but not thoracic (1.06, 0.82–1.37) aortic aneurysm (p_{heterogeneity}<0.0001). Younger age at starting smoking (< 16 vs. ≥16 years) was more strongly positively associated with abdominal aortic aneurysm both in former (3.72, 3.18–4.35 vs. 2.97, 2.59–3.40) and current (12.28, 10.31–14.64 vs. 10.04, 8.61–11.71) smokers when compared to never smokers, while for thoracoabdominal (8.64, 1.59–46.86 vs. 9.80, 2.88–33.28), and unspecified site (2.28, 1.50–3.46 vs. 2.19, 1.58–3.03), the associations were limited to current smokers and no association was observed for thoracic aortic aneurysms (p_{heterogeneity}<0.0001 for both former and current smokers). Longer duration of quitting smoking was inversely associated with risk of abdominal aortic aneurysm (0.14, 0.11–0.17 for ≥ 30 years), thoracoabdominal (0.12, 0.02–0.97 for 10-<20 years), and unspecified site (0.46, 0.32–0.68), but not thoracic (0.89, 0.64–1.24) aortic aneurysms (p_{heterogeneity}<0.0001) (Table 3).

Smoking and ruptured and non-ruptured aortic aneurysm

The HR (95% CIs) for current vs. never smokers was 10.47 (6.12–17.90) for ruptured aortic aneurysm and 4.19 (3.80–4.62) for non-ruptured aortic aneurysm (p_{heterogeneity}=0.01) (Table 4). The HRs of ruptured and non-ruptured aortic aneurysm relative to never smokers were 13.29 (6.40-27.61) and 5.51 (4.77–6.36) for ≥ 20 cigarettes/day (p_{heterogeneity}=0.02), 7.51 (4.40-12.84) and 3.68 (3.35–4.05) for ≥ 30 pack-years (p_{heterogeneity}=0.01), 10.12 (5.47–18.71) and 5.77 (5.14–6.47) for ≥ 20 years duration in current smokers (p_{heterogeneity}=0.08), 6.36 (3.63–11.14) and 3.10 (2.79–3.44) for ≥ 20 years duration in former smokers (p_{heterogeneity}=0.01), and 4.96 (2.68–9.16) and 2.04 (1.81–2.30) for < 16 years age at starting smoking in former smokers and 15.65 (7.73–31.71) vs. 5.41 (4.68–6.25) for < 16 years age at starting smoking in current smokers (p_{heterogeneity}=0.008), respectively. The HRs for ≥ 30 years of smoking cessation vs. current smoking was 0.10 (0.04–0.23) for ruptured and 0.24 (0.21–0.26) for non-ruptured aortic aneurysm (p_{heterogeneity}=0.002) (Table 4).

Smoking and aortic aneurysm mortality

The HR (95% CIs) for current vs. never smokers was 8.78 (5.75–13.38) for aortic aneurysm mortality (Table 4). The HRs of aortic aneurysm mortality relative to never smokers were 11.94 (6.86–20.79) for ≥ 20 cigarettes/day, 7.09 (4.67–10.76) for ≥ 30 pack-years, 10.95 (6.90-17.36) for ≥ 20 years duration in current smokers, 4.75 (3.01–7.51) for ≥ 20 years duration in former smokers, and 3.58 (2.17–5.92) and 12.73 (7.38–21.98) for < 16 years age at starting smoking in former and current smokers, respectively. The HR for ≥ 30 years of smoking cessation vs. current smoking was 0.16 (0.09–0.30) for aortic aneurysm mortality (Table 4).

Stratified analyses and sensitivity analyses

In stratified analyses, interactions were observed when the analyses of smoking status were stratified by age (p < 0.001), sex (p < 0.001), BMI (p = 0.002), but not for hypertension (p = 0.89) (Supplementary Table 1). Stronger associations for current vs. never smokers were observed among older vs. younger participants (≥ 60 vs. <60 years) (5.13, 4.58–5.75 vs. 2.84, 2.37–3.41), for men vs. women (5.43, 4.47–6.60 vs. 4.09, 3.67–4.57), for those with normal BMI vs. those with overweight or obesity (5.39, 4.48–6.48 vs. 4.13, 3.58–4.75 vs. 3.81, 3.17–4.59), but associations were similar in those with vs. without hypertension (4.32, 3.86–4.84 vs. 4.45, 3.71–5.34) (Supplementary Table 1).

Further adjustment for prevalent bicuspid aortic valve at baseline did not alter the results of the main analysis (results not shown).