Effects of tobacco cigarettes, e-cigarettes, and waterpipe smoking on endothelial function and clinical outcomes

Abstract

Tobacco smoking is a leading cause of non-communicable disease globally and is a major risk factor for cardiovascular disease (CVD) and lung disease. Importantly, recent data by the World Health Organizations (WHO) indicate that in the last two decades global tobacco use has significantly dropped, which was largely driven by decreased numbers of female smokers. Despite such advances, the use of e-cigarettes and waterpipes (shisha, hookah, narghile) is an emerging trend, especially among younger generations. There is growing body of evidence that e-cigarettes are not a harm-free alternative to tobacco cigarettes and there is considerable debate as to whether e-cigarettes are saving smokers or generating new addicts. Here, we provide an updated overview of the impact of tobacco/waterpipe (shisha) smoking and e-cigarette vaping on endothelial function, a biomarker for early, subclinical, atherosclerosis from human and animal studies. Also their emerging adverse effects on the proteome, transcriptome, epigenome, microbiome, and the circadian clock are summarized. We briefly discuss heat-not-burn tobacco products and their cardiovascular health effects. We discuss the impact of the toxic constituents of these products on endothelial function and subsequent CVD and we also provide an update on current recommendations, regulation and advertising with focus on the USA and Europe. As outlined by the WHO, tobacco cigarette, waterpipe, and e-cigarette smoking/vaping may contribute to an increased burden of symptoms due to coronavirus disease 2019 (COVID-19) and to severe health consequences.

Keywords: E-cigarette vaping; Endothelial function; Inflammation; Oxidative stress; Shisha/waterpipe smoking; Tobacco smoking.

Graphical Abstract

Figure 1

Hazard/odds ratio (HR/OR) or adverse effects (percentages) for smoking or vaping associated health risks or complications based on selected representative studies. All alphabetical cross references in this figure (^{a, b, c…}) are linked to literature reference numbers in the figure legend that can be found in the Supplementary material online with exactly identical numbering. Stroke source reports: a¹⁶⁵ (+++), b¹⁶⁶ (+), and c¹⁶⁷ (++). Perceived addictiveness source reports: d¹⁶⁸ (++). Percentages refer to the proportion of participants (PP) who believe that smoking/vaping is addictive. Chronic obstructive pulmonary disease (COPD) source reports: e¹⁶⁹ (++), f^170a (+++), and g^170b (++) Myocardial infarction source reports: h,¹⁷¹ i,¹⁷² and j¹⁷³ (++). Peripheral endothelial dysfunction source reports: k⁹⁴ (+) and l¹⁴³ (+). Percentages denote (k) relative difference in flow-mediated dilation (FMD) of the brachial artery in response to acute tobacco cigarette and e-cigarette use and (l) relative decrease in arterial forearm blood flow (FBF) in response to acute waterpipe smoking. Coronary artery disease source reports: m¹⁷⁴ (+++), n¹⁷⁵ (++), and o¹⁷³ (++). Lung cancer source reports: p¹⁷⁶ (+++) and q¹⁷⁷ (+++). Arterial stiffness source reports: r^178a (+) and s^178b (+). Percentages denote relative increase in augmentation index (AIx) measured by tonometry in response to chronic tobacco cigarette and e-cigarette use or acute waterpipe smoking. Erectile dysfunction source reports: t¹⁷⁹ (+++). NA means not available. + means medium (single cohort study <1000 subjects), ++ means good (single cohort study >1000 subjects) and +++ means strong (large scale meta-analysis) clinical evidence. Open access source for body image can be found at Pixabay (https://pixabay.com/de/photos/anatomie-mann-mensch-körper-haut-254129/). Note of caution: The presented values are based on selected representative studies with different quality levels of evidence highlighting the need for more research.

Figure 2

Effects of different forms of smoking and vaping on endothelial function in human subjects and antioxidant interventions. (A) Left, Vitamin C treatment markedly improves endothelium-dependent vasodilation to acetylcholine in chronic smokers while having no significant effect on the dose–response curve of control subjects. Mean ± SEM responses of forearm blood flow to intra-arterial acetylcholine in control subjects (n = 10) and chronic smokers (n = 10) with and without concomitant administration of vitamin C. *Significant difference in the overall dose–response relationship compared with control subjects with and without vitamin C and with smokers with vitamin C. Adopted from ref. with permission of the publisher. Copyright © 2000, Wolters Kluwer Health. Right, Effect of BH4 on ACh-induced vasodilation in chronic smokers. BH4 significantly improved ACh-mediated vasodilation in chronic smokers but failed to change the ACh dose–response relationship in control subjects (not shown). Data are presented as mean ± SEM. *Significant differences in the overall dose–response vs. saline treatment. Adopted from Ref. with permission of the publisher. Copyright © 2000, Wolters Kluwer Health. (B) Left, Individual and mean percentage changes before and after 30 minutes of charcoal-heated hookah smoking. Middle, Individual and mean percentage changes before and after 30 min of electrically heated hookah smoking. Right, Individual and mean percentage changes before and after smoking 1 cigarette. The circles with bars reflect the overall mean ± SEM. *P < 0.05 (pre- vs post-exposure). FMD indicates flow-mediated dilation. Adopted from ref. with permission of the publisher. Copyright © 2000, Wolters Kluwer Health. (C) Systolic BP (Left) and PWV (Right) responses. Each line represents response defined as net TC/EC smoking effect minus sham procedure effect at each time point. BL means baseline; NS means non-significant. The P-values refer to the composite effect of TC/EC at 5 and 30 min vs. sham during the whole study duration. The composite effect of TC/EC vs. sham was determined by using mean pressure as covariate. *TC vs. sham, ^¶EC at 5 min vs. sham, ^†EC at 30 min vs. sham, **P < 0.001, PWV change between EC 5 min session and sham session after 15 min smoking using the Student’s t-test for paired measures. Adopted from ref. with permission of the publisher. © 2016 by the American College of Cardiology Foundation.

Figure 3

Chronic and acute effects of different forms of smoking and vaping on endothelial function in animals. (A) B-mode Doppler ultrasound in vivo data from the carotid artery of mice under anaesthesia (inhaled isoflurane) before, during (at ∼4.5 months), and after 8 months of chronic exposure to electronic cigarette (E-cig) vapour and reference tobacco (3R4F) cigarette smoke. Left: significant increase in arterial stiffness [measured as pulse wave velocity (PWV)] for E-cig and 3R4F groups following 8-month exposure. Right: significantly greater change in PWV (translating to greater arterial stiffness) after 8 months in E-cig- and 3R4F-exposed than control (air-exposed) mice. Slight, non-significant, rise in PWV in control mice following 8 months is consistent with the normal aging effect. n = 5–8 mice/group. *P < 0.05 vs. air. (B) Ex vivo dose–response curves for phenylephrine (Left) and methacholine (Right), obtained from thoracic aorta ring segments following 8 months of exposure to E-cig vapour, reference tobacco (3R4F) cigarette smoke, and filtered air. α-Adrenergic vasoconstrictor response was greater (Left), while the endothelium-mediated vasodilatory response was impaired (Right), following 8 months of exposure to E-cig vapour and 3R4F cigarette smoke. Response to sodium nitroprusside was not altered or different between groups (not shown). n = 5 mice/group. *P < 0.05 vs. air. Adopted from ref. with permission of the publisher. Copyright © 2018, The American Physiological Society. (C) FMD was impaired by acute exposure to JUUL aerosol, previous generation e-cig aerosol, and Marlboro Red cigarette smoke. FMD after 5 min of exposure is shown. Coloured lines denote individual rats. Horizontal black bars denote the mean of the respective groups. P-values are derived from paired two-tailed t-tests. (D) Serum levels (ng/mL) of nicotine and cotinine from sera collected after 20 min of exposure. *P < 0.001 compared to air group. ^§  P < 0.001 compared to JUUL. ‘Previous Gen’ means previous generation. Adopted from ref. Permission granted by Tobacco Regulatory Science Group to use figures. Rao P, Liu J, Springer ML. JUUL and combusted cigarettes comparably impair endothelial function. Tob Regul Sci 2020;6:30-37.

Figure 4

Effects of different forms of smoking and vaping as summarized from human and animal studies. The major toxicants (red, blue and green = high quantity, black = intermediate quantity, grey = trace amounts) for tobacco cigarette and waterpipe smoking as well as e-cigarette vaping are listed. The molecular link of these toxicants on major damage markers reported for the different forms of smoking and vaping with respect to oxidative stress is shown on the left side. The effects of these toxicants on endothelial (vascular) function are summarized in the inserted scheme (modified from ref. with permission). The associated adverse health effects as well as antioxidant interventions are also shown.

Figure 5

Overview on global regulations on e-cigarette products sales (A) and on European regulations on tobacco product advertising (B). Maps were created using data from www.globaltobaccocontrol.org, www.tobaccocontrollaws.org and https://ggtc.world (last accessed 31/05/2020).