Studies into the cardiovascular and respiratory effects of electronic cigarettes

Tobacco smoking remains the single largest preventable cause of social health inequalities, morbidity and deaths in the United Kingdom (UK), accounting for approximately 122,000 deaths in the UK each year (Royal Collage of Physicians, 2016). Tobacco smokers lose an average of 3 months of life expectancy for every year smoked after the age of 35, dying around 10 years younger than a non-smoker (Doll et al., 2004). Annually, smoking related illness is estimated to cost the National Health Service (NHS) £2.6 billon (Public Health England, 2017). Despite tobacco smoking being entirely preventable and a widely known modifiable risk factor, with significant risk reduction benefits in morbidity and mortality (Doll et al., 2004, Freund et al., 1993), one billion adults worldwide continue to smoke (World Lung Foundation, 2018), primarily because their desire to smoke is driven by nicotine addiction. Although nicotine is the principle addictive chemical within tobacco smoke and produces withdrawal symptoms on discontinuation, it is the exposure from the toxins and carcinogens found in the tobacco smoke which are predominately deleterious to health, rather than nicotine itself. The importance of "harm reduction" cannot be overemphasised. Tobacco harm reduction strategies in relation to smoking cessation, have focused on delivering nicotine without the products of combustion to support quit attempts. It is widely accepted that nicotine replacement therapy (NRT) reduces the motivation to smoke and NRT is recommend to individuals seeking pharmacological help to stop smoking (National Institute for Health and Care Excellance, 2018). Data from a Cochrane review published in 2012, concluded that all commercially available forms of NRT (gum, transdermal patch, nasal spray, inhaler and sublingual tablets and lozenges) increase the likelihood of smoking cessation by 50-70% amongst smokers. There is no evidence that NRT increases the risk of major cardiovascular events in patients with cardiovascular disease (Stead et al., 2012a). Since 2011, the use of electronic cigarettes (e-cigarettes) as a smoking cessation aid has gained unprecedented popularity. Within the UK it is estimated that there are 2.9 million e-cigarettes users (Action on Smoking and Health, 2019b). Subsequently e-cigarettes have replaced medicinal NRT as the preferred nicotine replacement product to support quit attempts (Smoking in England, 2015). Unlike conventional NRT, nicotine containing e-cigarettes are hand-held devices capable of emulating both the physicality and modality of nicotine delivery associated with tobacco smoking without the products of combustion. Despite the potential harm reduction associated with e-cigarettes, their use remains controversial and has raised global debate and public health concerns regarding their effectiveness and safety. UK health policy considers e-cigarettes as a safer alternative to tobacco smoking, which offers a viable harm-reduction option (Public Health England, 2017). Other nations such as the United States (US) and Australia have adopted a more precautionary stance; as there are concerns regarding their safety and concern that e-cigarettes may act as a gateway to tobacco smoking (Leventhal et al., 2015). This predicament has arisen mainly because the use of e-cigarettes has evolved far faster than the scientific understanding of their potential biological health effects. In the "real life setting" patients are 1.6 times more likely to attempt quitting if they are advised to quit smoking by their physician (Pignone M and Salazar R, 2017). The National Institute for Health and Care Excellence (NICE) is concerned that the uncertainties surrounding the safe use of e- cigarettes makes it challenging for healthcare professionals to have informed discussions with their patients on the use of e-cigarettes, and as such this may discourage some tobacco smokers from switching to e-cigarettes (NICE, 2018). This thesis seeks to evaluate the cardiovascular and respiratory health effects of e-cigarettes which can be translated into "real-world" practice. A multifaceted approach was taken to address several key themes. 1. Conducting research within a framework governed by tobacco control policy. 2. Understanding healthcare professionals' perceptions of nicotine, NRT and e-cigarettes. 3. Investigating the acute cardiorespiratory effects of e-cigarettes compared to tobacco cigarettes. 4. Investigating the short-term cardiorespiratory effects of e-cigarettes compared to NRT. The emphasis of this work was directed to finding a pragmatic and patient-centred approach to help direct future e-cigarette research and the healthcare professionals' everyday practice. Chapter 2, highlights how in the context of the ongoing e-cigarette debate, and major investments by the tobacco industry, it is crucial that independent researchers provide regulators and the public with evidence-based guidance. The key ethical, legislative and regulatory issues are discussed and the extent to which they influenced the research design and methodology of the studies presented in the subsequent chapters. Chapter 3 focuses on exploring the attitudes and risk perceptions concerning nicotine, tobacco cigarettes, NRT and e-cigarettes amongst healthcare professionals. Our study demonstrates that whilst the majority of healthcare professionals view e-cigarettes as a harm reduction product, there is a discrepancy amongst their perceptions and their clinical practice. There is an urgent need for evidence-based guidelines and education to establish congruence between healthcare professionals’ beliefs and tobacco harm reduction policy, so that smokers wishing to stop smoking are provided with both effective and consistent practitioner advice. Chapter 4 reports a cross-over study which evaluates the acute effects of e-cigarettes versus tobacco smoking on vascular and respiratory function and circulating microparticles (MPs), particularly platelet MPs (PMPs, biomarkers of thrombosis) and endothelial MPs (EMPs, biomarkers of endothelial function). Twenty healthy male tobacco smokers were recruited and randomised into one of two study arms after which they crossed over into the other study arm on a separate day. The interventions comprised of smoking one tobacco cigarette or taking 15 vapes of an e-cigarette with e-liquid containing 18mg/ml of nicotine. Vascular and respiratory function studies and venous blood sampling were performed before and following each intervention. The number of MPs was determined by flow cytometry. The vascular and respiratory function tests demonstrated that following e-cigarette exposure there was a significant increase in reactive hyperaemia index, (a measure of endothelial function) (p =.006), augmentation index (a measure of vascular stiffness) (p =.010), and a decrease in peak expiratory flow (p = .03), which was not demonstrated after tobacco cigarette use. Following tobacco cigarette exposure, the number of EMPs and PMPs significantly increased (all p < .001). Following e-cigarette exposure, no significant change in EMPs was observed, whereas the number of PMPs were significantly increased (p < .001). Our results demonstrate that e-cigarette and tobacco cigarette exposure elicit differential effects on the cardiovascular and respiratory system. Where tobacco smoking significantly increased microparticle formation, indicative of possible endothelial injury, e-cigarette use induced vasoreactivity and decreased peak expiratory flow. These findings suggest that both e- cigarettes and tobacco smoking negatively impact vascular function. Chapter 5 reports a randomised controlled trial investigating the short-term cardiovascular effects of e-cigarettes in comparison to nicotine replacement patches (NRPs) (The VAPOUR study). The primary aim of the study was to assess the 12-week effects of e-cigarettes versus nicotine replacement patches upon endothelial function as assessed by flow mediated dilation (FMD). Secondary outcomes included changes in blood pressure, heart rate, pulmonary function and weight. Fifty-five smokers with no established history of cardiovascular disease were recruited. Among the participants who were "smokefree" at 12 weeks there was a significant improvement in FMD (e-cigarettes 1.09 ± 0.61%; NRPs 1.10 ± 0.52%) and an associated decrease in blood pressure, systolic (e-cigarettes -7 ± 8mmHg; NRPs -6 ± 3 mmHg) and diastolic blood pressure (e- cigarettes -3 ± 5mmHg; NRPs -4 ± 4mmHg) in both the e-cigarette and NRP study arms (all p .05). These data demonstrate that within the context of a 12 week smoking cessation programme the use of both e-cigarettes and nicotine replacement patches have comparable and beneficial effects upon cardiovascular health. Although the long-term health effects of e-cigarettes await further clarification, the VAPOUR study provides evidence to support the use of e-cigarettes as a short-term smoking cessation intervention, which in turn may help inform evidence-based discussion between healthcare professionals and patients wishing to stop smoking. To conclude, the work presented in this thesis has highlighted that biomarker studies, such as ours, have an important role in predicting potential cardiovascular and respiratory risks of e-cigarettes, and developing an understanding of any potential cardiovascular and respiratory risks associated with long-term e-cigarette use. However, the judgement as to whether the observed associations represent a cause-effect relationship between the exposure of vaping and development of cardiovascular and respiratory disease requires inferences far beyond the data of the studies presented in this thesis. Our findings provide the preliminary evidence which supports the harm reduction role of e-cigarettes when used as a temporary short-term smoking cessation intervention. Although our findings suggest that e-cigarettes may be less harmful, it is important to recognise that our research findings also suggest that e-cigarette use may not be devoid from cardiovascular risk and the implications of these findings on long-term health need further exploration