Tobacco Smoke and Endothelial Dysfunction: Role of Aldehydes?

Abstract

Purpose of Review

Tobacco smoking is the most significant modifiable risk factor in the development of cardiovascular disease (CVD). Exposure to mainstream cigarette smoke (MCS) is associated with CVD through the development of endothelial dysfunction, a condition characterized by an imbalance of vasoactive factors in the vasculature. This dysfunction is thought to be induced in part by aldehydes generated at high levels in MCS.

Recent Findings

Electronic cigarettes (e-cigs) may also pose CVD risk. Although the health effects of e-cigs are still largely unknown, the presence of aldehydes in e-cig aerosol suggests that e-cigs may induce adverse cardiovascular outcomes similar to those seen with MCS exposure.

Summary

Herein, we review studies of traditional and emerging tobacco product use, shared harmful and potentially harmful constituents, and measures of biomarkers of harm (endothelial dysfunction) to examine a potential and distinct role of aldehydes in cardiovascular harm associated with cigarette and e-cig use.

Introduction

Tobacco smoking is the most significant modifiable risk factor in the development of cardiovascular disease (CVD) [1]. The Centers for Disease Control and Prevention reports that despite declining usage, tobacco use still remains the leading cause of preventable death both nationally and globally [1]. Cigarettes contain numerous toxic compounds, many of which could contribute to disease development [2]. Brook et al. [3] propose three likely mechanisms by which air pollutants such as mainstream cigarette smoke (MCS) contribute to the development of CVD: (1) an imbalance in the autonomic nervous system, (2) translocation of particles into the circulation, and (3) the development of systemic oxidative stress and inflammation within the vasculature. Although these are likely serial pathways rather than three separate and parallel pathways, a primary outcome of each mechanism is the development of endothelial dysfunction. The endothelium plays a critical role in the regulation of vascular tone and in the production of a variety of vascular mediators [4]. Endothelial dysfunction is characterized by an imbalance of vasoactive factors in the vasculature, particularly a decreased level of the vasodilator nitric oxide (NO) [5]. The onset of endothelial dysfunction is considered one of the earliest changes in the development of CVDs [6] and, in relation to smoking, it is a result of decreased NO bioavailability [5, 7] (Fig. 1a, Table 1).

Fig. 1.

Comparisons of mainstream cigarette smoke and electronic cigarette aerosol. Mainstream cigarette smoke (MCS) and electronic cigarette (e-cig) aerosol show a number of shared cardiovascular health outcomes, but measures of specific biomarkers of harm have not been studied after exposure to e-cig aerosol (a). These health effects are, at least in part, likely induced by shared constituents of MCS and e-cig aerosol, particularly shared constituent aldehydes (b). CAC circulating angiogenic cell, E-cig electronic cigarette, FMD flow-mediated dilation, MCS mainstream cigarette smoke, NO nitric oxide, OS oxidative stress, PG propylene glycol, ROS reactive oxygen species, VG vegetable glycerin

Table 1.

Epidemiological and experimental studies of the unique and shared cardiovascular health effects of mainstream cigarette smoke (MCS) and electronic cigarette (e-cig) aerosol

Type	Pollutant	Findings	Reference(s)
Human	MCS	Increased WBCs	Pedersen et al. [8], Higuchi et al. [9]
		Decreased CACs	Kondo et al. [10]
		Increased sICAM-1	Conklin et al. [11••], Scott and Palmer [12], Delgado et al. [13]
		Increased CRP	Conklin et al. [11••]
		Decreased NO	Marchio et al. [5], Carnevale et al. [7]
		Decreased FMD	Cui et al. [6], Messner and Bernhard [14], Fetterman et al. [15•], Conklin et al. [11••]
		Increased ROS and OS	Morris et al. [16], Marchio et al. [5]
		Increased platelet activation and aggregation	Conklin et al. [11••], Nocella et al. [17]
		Increased atherosclerosis	Marchio et al. [5]
	E-cig aerosol	Decreased FMD	Kuntic et al. [18]
		Increased ROS and OS	Carnevale et al. [7], Moheimani et al. [19]
		Increased platelet activation and aggregation	Nocella et al. [17], Qasim et al. [20], Hom et al. [21]
Murine	MCS	Increased ROS and OS	Kim et al. [22]
	E-cig aerosol	Decreased FMD	Rao et al. [23••], Caporale et al. [24•]
		Increased ROS and OS	Sussan et al. [25], Espinoza-Derout et al. [26]
		Increased atherosclerosis	Espinoza-Derout et al. [26]
Aerosol	MCS	Increased ROS and OS	Zhao and Hopke [27], Valavanidis et al. [28]
Aerosol	E-cig aerosol	Increased ROS	Lerner et al. [29]
Cells	E-cig aerosol	Decreased NO	Fetterman et al. [15•]

CACs circulating angiogenic cells, CRP C-reactive protein, E-cig electronic cigarette, FMD flow-mediated dilation, MCS mainstream cigarette smoke, NO nitric oxide, OS oxidative stress, ROS reactive oxygen species, sICAM-1 soluble intercellular adhesion molecule-1, WBCs white blood cells

Decreased levels of NO are linked to excess production of reactive oxygen species (ROS). ROS are oxygen-containing, highly reactive molecules, many of which are endogenously produced by normal cellular metabolism [30]. At basal levels, ROS are shown to mediate physiological processes, but exposures to pollutants or toxicants can lead to increased production of ROS [31•], inducing oxidative stress [30, 32]. Thus, increased ROS and the resulting oxidative stress are linked to a number of negative health outcomes [30, 32, 33], including CVD [30, 33]. Studies show MCS to be both a source of ROS [27, 28, 34] and a promoter of ROS production [16, 22], and the ROS-induced decrease in NO bioavailability is a central mechanism by which MCS likely contributes to endothelial dysfunction and, subsequently, the development of CVD.

Clinically, endothelial function is often measured noninvasively by flow-mediated dilation (FMD) [35], and several studies associate decreased FMD with smoking and endothelial dysfunction [6, 11••, 14, 15•]. Furthermore, Cui et al. [6] show that current smokers have diminished FMD compared with never smokers, and there is a dose- and duration-dependent effect of smoking on impaired FMD. Kondo et al. [10] find that circulating angiogenic cells (CACs)—a stem cell population partly responsible for repair of the injured endothelium—are restored with smoking cessation but decrease again upon resuming cigarette use. Studies also show that exposure to secondhand smoke (SHS) induces endothelial dysfunction [14], further indicating the significance of MCS in this early and critical stage of CVD development. Markers of endothelial dysfunction are increased in the plasma of cigarette users, with smokers showing increased levels of soluble intercellular adhesion molecule 1 (sICAM-1) [11•, 12, 13], although the relationship between soluble vascular adhesion molecule 1 (sVCAM-1) and smoking is less well defined [12, 13, 36].

Electronic Cigarettes and Endothelial Dysfunction

The use of traditional cigarettes is well established as a Framingham CVD risk factor through mechanisms such as endothelial dysfunction. However, the emergence of new tobacco products requires research into the cardiovascular effects of these devices, particularly to determine whether these are “harm reduction” products as advertised compared with traditional cigarettes. Electronic nicotine delivery systems (ENDS) generate an inhalable aerosol via by heating a solution known as an e-liquid. E-liquids are composed of a ratio of propylene glycol (PG) and vegetable glycerin (VG), a wide range of nicotine levels (0–6%) [37-39], and flavor additives [25, 40, 41••]. The most commonly used ENDS are electronic cigarettes (e-cigs) [40, 42, 43]. Usage of ENDS has increased dramatically over the past several years, with a significant rise in the use of e-cigs [44, 45], especially among youth and young adults [46].

E-cig use is commonly cited as a means of smoking cessation or as a healthier alternative to traditional tobacco smoking [25, 40, 42, 43, 45, 47••]. This latter claim is largely due to the fact that e-cigs do not contain actual tobacco leaf, nor does their use involve combustion [42, 48]. However, the true health effects of these devices are still largely unknown (Fig. 1a, Table 1). Early studies of the health effects of e-cigs show increased reports of cracked teeth and tongue and/or inside-cheek pain in adolescent e-cig users [49] and increased reports of dry mouth, sore throat, and acute cough in never-smokers and of acute cough in smokers with and without a history of respiratory disease [50]. Other studies show significantly increased airway resistance [51, 52] and impaired mesenchymal stem cell differentiation [53]. Studies in humans also show increases in markers of oxidative stress after vaping [7, 19], and studies of e-cig aerosol show that it contains measurable ROS [29]. Clinically, measures of endothelial function in e-cig users show that acute exposure causes a significant decrease in FMD [7] as well as an increase in arterial stiffness parameters [18]. Vlachopoulos et al. [54] demonstrate increases in arterial blood pressure and aortic stiffness as measured by carotid-femoral pulse-wave velocity in young e-cig users. Furthermore, as few as ten puffs of e-cig aerosol is enough to increase levels of CACs in healthy volunteers [55], an indicator of altered endothelial function. Additionally, an early study of adult e-cig users (both tank and cartridge styles) shows significantly decreased levels of sICAM-1 compared with adult smokers, although the comparability of these levels with nonsmokers was not tested [56].

Studies in rodents also demonstrate that the cardiovascular system is sensitive to e-cig generated aerosols. For example, chronic e-cig exposures in mice increase aortic stiffness and impair aortic endothelial function in female C57BL/6 mice [57] and enhance cardiac dysfunction and atherosclerotic development and increase oxidative stress in apolipoprotein-E knockout mice [26]. An acute e-cig aerosol exposure from either a JUUL device or from an earlier generation e-cig shows impaired endothelial function as measured by FMD in both male and female rats [23••]. Furthermore, female rats exposed to e-cigs during pregnancy show decreased circulation in both the maternal uterine and fetal umbilical cords, indicating potential development of negative health effects in the next generation related to maternal e-cig use while pregnant, an outcome similar to that seen with the use of traditional cigarettes during pregnancy [58].

As many e-cig users make use of flavor additives, additional studies have focused on potential adverse effects induced by e-cig flavorings. Many of the flavorings used to flavor e-cig liquids come from food flavorings that are deemed by the Flavor and Extract Manufacturers Association as “generally regarded as safe” (GRAS) for ingestion but never tested for inhalation [59]. In microwave popcorn production plant workers, inhalation of aerosolized diacetyl, a GRAS flavoring for ingestion, is associated with the development of bronchiolitis obliterans [60]. Thus, there is warranted concern that similar pulmonary diseases may arise with use of flavored e-cig liquids [61]. Fetterman et al. [15•] find that endothelial cells isolated from nonsmokers and exposed to menthol or eugenol, two flavorings used to provide mint and clove flavor profiles, respectively, in culture have decreased levels of NO production. Additional flavors also impair NO production in endothelial cells as well as induce inflammation [15•].

Shared Biomarkers of Harm

Based on the literature, it appears likely that shared constituents are responsible for many of the shared adverse cardiovascular health outcomes associated with exposures to MCS or to e-cig aerosol (Fig. 1 a and b, Tables 1 and 2). As previously mentioned, exposure to both MCS and e-cig aerosol induce oxidative stress [7, 16, 19, 22, 27-29, 34] and contribute to the development of endothelial dysfunction [6, 14, 15•]. Additionally, comparisons between e-cig users and nonusers in the 2016 and 2017 National Health Survey reveal that e-cig users have a higher incidence of stroke [73], similar to the increased risk of stroke in smokers compared with nonsmokers [74, 75]. MCS-induced atherosclerosis and hypertension are linked with thrombosis [17, 76], and recent studies of e-cigs show similar levels of platelet activation and aggregation in response to exposure [17, 20, 21]. However, many changes in biomarkers of harm that are induced by MCS exposure have not been thoroughly measured in response to e-cig aerosol exposure. Although several epidemiological studies find increased levels of leukocytes in cigarette smokers [8, 9], a change likely indicative of the persistent inflammation induced by MCS [8, 9, 77], the effects of e-cigs on hematological measures still are not well defined. Additionally, although a study of acute e-cig exposure shows increased levels of CACs [55]—similar to what has been shown with acute exposure to MCS [78]—there has been no chronic study of e-cig exposure to determine whether this increase persists.

Table 2.

Unique and shared constituents of mainstream cigarette smoke (MCS) and electronic cigarette (e-cig) aerosol

Mixture	Constituent	Reference(s)
MCS	Formaldehyde	Kaden et al. [62], Baker [63]
	Acetaldehyde	WHO [64]
	Crotonaldehyde	van Andel et al. [65]
	Acrolein	Alwis et al. [66]
	Nicotine	US FDA [2]
	Metals	US FDA [2]
	PM	UD FDA [2]
E-cig aerosol	Formaldehyde	Conklin et al. [37], Ogunwale et al. [41••], Rubinstein et al. [67]
	Acetaldehyde	Conklin et al. [37], Ogunwale et al. [41••], Rubinstein et al. [67]
	Acrolein	Conklin et al. [37], Ogunwale et al. [41••], Rubinstein et al. [67], Goniewicz et al. [68]
	Nicotine	Conklin et al. [37], Hutzler et al. [38], Goniewicz et al. [39], Mobarrez et al. [69]
	Metals	Hess et al. [70], Olmedo et al. [71], National Academies [47••]
	PM	Lee et al. [72], National Academies [47••]
	PG:VG	Conklin et al. [37], Bertholon et al. [40]
	Flavorings	Bertholon et al. [40], Ogunwale et al. [41••]

E-cig electronic cigarette, MCS mainstream cigarette smoke, PG:VG propylene glycol:vegetable glycerin, PM particulate matter, US FDA US Food and Drug Administration, WHO World Health Organization

Shared Biomarkers of Exposure: Are Aldehydes Responsible for Tobacco-Related Endothelial Dysfunction?

More studies have focused on the potential toxicity of the components within the aerosol produced by e-cigs. These analyses reveal that the aerosol, like MCS, contains many harmful or potentially harmful constituents (HPHCs), including particulate matter (PM) [47••, 72], metals [47••, 70, 71], nicotine, and volatile organic compounds, including many aldehydes [67, 72, 79] (Fig. 1b, Table 2). Aldehydes are compounds with a terminal carbonyl group (–CHO), and they can be classified as saturated, unsaturated, or aromatic. Unsaturated aldehydes contain one or more carbon-carbon double bond, which increase their reactivity compared with saturated aldehydes [80]. These compounds are generally ubiquitous in the natural environment, and many are found in foods and drinks, including meats, cheeses, fried foods, bread, and beer and other alcohols [81]. However, the majority of environmental aldehydes are generated from anthropogenic sources, including combustion sources (e.g., diesel and gasoline exhaust, industrial emissions, MCS, and SHS) and also from various consumer products and building materials that leach aldehydes [81]. Additionally, as they are linked with a number of negative health effects [62, 64, 82, 83], aldehydes from both ambient and personal exposure sources (e.g., MCS, SHS, occupational exposures, personal hobby exposures) present potential health risks.

Because of their pervasiveness and their documented toxicity, four specific aldehydes have been identified as significant contributors to disease risk and development: the saturated aldehydes formaldehyde and acetaldehyde and the unsaturated aldehydes acrolein and crotonaldehyde. These aldehydes are found in high levels in MCS [62-66, 81, 84, 85], and research shows that acrolein in particular is responsible for the majority of the CVD risk related to MCS [86, 87]. Previous studies demonstrate that acrolein can induce vascular injury by impairing vascular repair capacity, as well as by increasing the risk of thrombosis and atherosclerosis, a possible result of endothelial dysfunction, dyslipidemia, and platelet activation [88-92]. Acrolein, formaldehyde, and acetaldehyde are all also detected in e-cig aerosols [41••, 48, 67, 68, 79, 93], with generation related to PG and/or VG [37]. Levels of unsaturated aldehydes, however, are typically much lower in e-cigs than in MCS and much lower compared with generated levels of saturated aldehydes. Crotonaldehyde generation is primarily a product of tobacco combustion, whereas little to none is formed in aerosols of different e-liquids [37, 41••].

Furthermore, nicotine is known to play a role in the vascular effects of tobacco products. The presence of nicotine in traditional cigarettes, in addition to serving as the addictive component of these products, is linked with the development of CVD, especially atherosclerosis [2]. Nicotine induces the release of catecholamines, causes hemodynamic changes (increases in heart rate and blood pressure, vasoconstriction of vascular beds), and produces endothelial dysfunction [94]. An early study focusing on the cardiovascular effects induced by e-cigs shows that nicotine is responsible for changes in blood pressure, heart rate, and arterial stiffness due to exposure [95]. E-cig aerosol containing 2.4% nicotine significantly increases atherosclerotic lesions compared with saline aerosol treatment in apolipoprotein-E knockout mice [96]. Similarly, as few as 30 puffs of nicotine-containing e-cig aerosol causes increased formation of platelet-derived extracellular vesicles and increased expression of P-selectin, a marker of platelet activation, and expression of CD40, a marker of inflammation [69]. However, Caporale et al. [24•] demonstrate that exposure to aerosol from nicotine-free e-cigs adversely impacts endothelial function in healthy never-smokers, although this change is transient. These preliminary findings may suggest that other constituents within e-cig aerosol may independently contribute to the development of adverse cardiovascular outcomes that have been associated with e-cig use, although additional studies are needed to further explore this hypothesis and its underlying mechanisms.

Conclusions

The use of traditional cigarettes has been clearly demonstrated to increase an individual’s risk of CVD. With the introduction of new tobacco delivery systems such as e-cigs, the potential for the incidence of tobacco-related health problems in a new generation has become a worldwide concern. Although additional studies are still needed to gain a better understanding of the cardiovascular effects of e-cig use, the current literature provides evidence suggesting that e-cigs are capable of inducing many of the same adverse cardiovascular outcomes seen with MCS exposure. Furthermore, the evidence of shared constituent aldehydes—aldehydes associated with CVD—seems to suggest that these aldehydes are, at least in part, playing a role in the development of these conditions. Exposure to both MCS and e-cig aerosol are linked to endothelial dysfunction, potentially related to acrolein, as this unsaturated aldehyde has been measured in both MCS and e-cig aerosol at levels capable of producing injury within the vasculature. Nicotine is likely another contributing factor to these effects, but additional studies are needed to clarify the cardiovascular effects of e-cig constituents such as aldehydes independent of nicotine. As the use of tobacco continues to be the most significant modifiable risk factor for the development of CVD, it is imperative to better understand how individual constituents such as aldehydes that are found in both MCS and e-cig aerosol contribute to disease in order to decrease the global health burden of these products.

Abbreviations

CAC

Circulating angiogenic cell

CRP

C-reactive protein

CVD

Cardiovascular disease

E-cig

Electronic cigarette

ENDS

Electronic nicotine delivery systems

FMD

Flow-mediated dilation

GRAS

Generally regarded as safe

HPHCs

Harmful or potentially harmful constituents

MCS

Mainstream cigarette smoke

NO

Nitric oxide

OS

Oxidative stress

PG

Propylene glycol

PM

Particulate matter

ROS

Reactive oxygen species

SHS

Secondhand smoke

sICAM-1

Soluble intercellular adhesion molecule 1

sVCAM-1

Soluble vascular adhesion molecule 1

US FDA

US Food and Drug Administration

VG

Vegetable glycerin

WBCs

White blood cells

WHO

World Health Organization