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Title: Association between active smoking, secondhand smoke and peripheral arterial disease
Author: Lu, Liya
ISNI:       0000 0004 6347 1686
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2017
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Worldwide, cardiovascular disease (CVD) is the leading cause of death. It is widely accepted that both active smoking and exposure to secondhand smoke (SHS) are associated with CVD. About 20% of the global population smoke tobacco or tobacco-related products. The global prevalence of smoking is increasing, although it is decreasing in some high-income and upper middle-income countries. Globally, about a third of adults and 40% children are regularly exposed to SHS. According to the World Health Organisation (WHO), only 16% of the global population is protected by a comprehensive smoke-free legislation. Coronary heart disease (CHD), stroke and peripheral arterial disease (PAD) are all types of atherosclerosis and often co-exist in the same patients. Therefore, they share many common risk factors including cigarette smoking. However, previous epidemiological studies on CVD including those on cigarette smoking mainly focused on CHD and stroke and pay little attention to PAD. Evidence is increasing in support of the association between exposure to SHS and both CHD and stroke. In contrast, there is a paucity of studies on SHS and the risk of PAD. The overarching aim of this thesis was to collate the published evidence on the association between active cigarette smoking and PAD, and examine the association between exposure to SHS and PAD in the general population. This thesis starts with a systematic review on the association between active cigarette smoking, SHS and PAD undertaken using four databases: Medline, Embase, PubMed and Web of Science to identify existing published evidence up to 30 April 2012 (Chapter 2). Prior to the published studies contained in this thesis, there had been no meta-analyses on the association between active cigarette smoking and PAD and only two studies published on the association between SHS and PAD. Therefore, this systematic review was followed by a meta-analysis on the association between active cigarette smoking and PAD. This meta-analysis identified 55 studies: 43 cross-sectional, 10 cohort and 2 case-control. Of the 68 results for current smokers, 59 (86.8%) were statistically significant and the pooled odds ratio (OR) was 2.72 (95% confidence interval [CI] 2.28-3.21). Of the 40 results for ex-smokers, 29 (72.5%) were statistically significant and the pooled OR was 1.67 (95% CI 1.54-1.81). Active cigarette smoking significantly increases the risk of PAD, compared with never smokers. The magnitude of association between active cigarette smoking and PAD was greater in current smokers than ex-smokers. In contrast, prior to my studies in this thesis, only two studies on SHS were identified. Only one showed an overall association between self-report SHS and PAD in Chinese never smokers, with a clear dose-response relationship. The other study used serum cotinine as measure for SHS exposure and found neither an overall association nor a dose-response relationship but suggested a very high cotinine concentration as threshold. Chapter 3 examines the association between SHS exposure and PAD in adult non-smokers in Scotland. This chapter includes two cross-sectional studies using the Generation Scotland: Scottish Family Health Study (GS: SFHS) and the Scottish Health Survey (SHeS), and one retrospective cohort study using the record linkage of the SHeS. In the cross-sectional study using SFHS, PAD was measured using ankle brachial pressure index (ABPI) but SHS exposure was self-report. Of the 5,686 never smokers, 134 (2.4%) had PAD (defined as an ABPI < 0.9). Participants who reported overall high level of SHS exposure (exposed to ≥40 hours per week) were more likely to have PAD, compared with those who reported no exposure to SHS. After adjustment for potential confounders, the association between SHS and PAD persisted (adjusted OR 4.53, 95% CI 1.51-13.56, p=0.007), with suggestion of a dose-response relationship. In the other cross-sectional study using SHeS, SHS exposure was measured objectively using cotinine concentration but PAD was based on self-report symptoms of intermittent claudication (IC) using the Edinburgh Claudication Questionnaire. Of the 4,231 non-smokers (defined as self-reported non-smokers with a salivary cotinine concentration <15 ng/mL), 134 (3.2%) had IC. Participants with high exposure to SHS (cotinine ≥2.7 ng/mL) were at significantly higher risk of IC, after adjustment for potential confounders (adjusted OR 1.76, 95% CI 1.04-3.00, p=0.036). A dose-response relationship was suggested, whereby the risk of IC increased with increasing cotinine concentration. However, the association varied by age category. Participants aged <60 were more strongly associated with PAD. This may be explained by survival bias. For the third, retrospective cohort study in Chapter 3, I used record linkage of SHeS to Scottish Morbidity Record 01 (SMR01) records and death certificates to identify the first hospital admission/death following the SHeS in which PAD was recorded as the primary or secondary cause. Of the 4,045 confirmed non-smokers who were free of baseline IC were included. Over the follow-up period (mean follow-up 9 years), there were 568 deaths, none of which were coded as due to PAD, and 64 participants were hospitalised for PAD. High exposure to SHS was associated with increased risk of all-cause mortality (adjusted hazard ratio [HR] 1.42, 95% CI 1.09- 1.86, p=0.011) among all non-smokers and increased risk of incident PAD (adjusted HR 2.82, 95% CI 1.14-6.96, p=0.024) among male non-smokers. Increased cotinine concentrations at baseline were associated with increased risk of all-cause mortality, with a dose-response relationship. SHS contains both sidestream smoke, from burning cigarette tips, and exhaled mainstream smoke. Shortened telomere length is broadly viewed as a biomarker for biological ageing including atherosclerosis phenotypes such as PAD. Evidence is strong that active smoking increases telomere length attrition but whether such association occurs between SHS and telomere length is unknown. Therefore, Chapter 4 aimed to add to growing evidence that exposure to SHS is associated with disproportionately higher biomarkers of cardiovascular risk compared with active smoking and may accelerate normal biological ageing. This chapter includes two cross-sectional studies. The first study investigated the relationship between salivary cotinine and several preclinical cardiovascular biomarkers: C-reactive protein (CRP), high-density lipoprotein (HDL) cholesterol, TC/HDL cholesterol ratio and fibrinogen in 10,081 adults from the SHeS. CRP concentration and the TC/HDL cholesterol ratio increased, and HDL cholesterol concentration decreased with increasing cotinine concentration among both non-smokers and active smokers. There were step changes in the relationship between tobacco exposure and cardiovascular biomarkers at the interface of non-smokers exposed to SHS and active smokers. Non-smokers with high exposure to SHS had lower cotinine concentrations than light active smokers but comparable concentrations of CRP (p=0.709), HDL cholesterol (p=0.931) and the TC/HDL cholesterol ratio (p=0.405). Fibrinogen concentration was less clear-cut and only increased in moderate and heavy active smokers. The second study in this chapter explored the association between self-reported levels of SHS exposure and telomere shortening per annum using a subgroup of participants from the SFHS. Of the 1,303 non-smokers, telomere length decreased more rapidly with increasing age among participants with high level of SHS exposure, compared with both those with no exposure (adjusted coefficient -0.006, 95% CI -0.008- -0.004) (high vs no SHS: p=0.010) or low exposure (adjusted coefficient -0.005, 95% CI -0.007- -0.003) (high vs low SHS: p=0.005). In summary, there is now substantial evidence of an association between active cigarette smoking and PAD. This thesis adds to the limited existing evidence on SHS as an independent risk factor for PAD. There was an overall association between exposure to SHS and PAD, with suggestion of a dose-response relationship. However, the association varied by age category. Individuals aged <60 were more strongly associated with the prevalence of IC. SHS was significantly associated with incident PAD only in men. This thesis further demonstrates that exposure to SHS carries a disproportionately higher cardiovascular risk than active smoking for a given level of smoke exposure. Telomere shortening per year of age may be an intermediate step between SHS and CVD including PAD. This also supports the association between SHS exposure and the atherosclerosis-related biomarkers, which play an important role in the pathophysiology of PAD. Further research is needed in the future to better understand the association between SHS and PAD, and the underlying mechanisms. The research in this thesis supports the need to protect the general public from exposure to SHS.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RA0421 Public health. Hygiene. Preventive Medicine