Effect Comparison of E-Cigarette and Traditional Smoking and Association with Stroke—A Cross-Sectional Study of NHANES

Introduction: Tobacco use is one of the most significant risk factors for stroke. Besides traditional cigarettes and combustible products, the use of e-cigarettes and electronic nicotine delivery products has been widespread among young adults in the recent era. Furthermore, the trend of vaping has increased over the last decade. However, the relationship between e-cigarettes and stroke is largely unknown. The aim of this study was to evaluate the prevalence and identify the relationship between e-cigarette smoking and stroke. Methods: A cross-sectional study was performed using the NHANES database of the US population. Adults with a history of smoking were considered in our study and divided into three groups, e-cigarette users, traditional, and dual smokers. The Chi-squared test, Wilcoxon rank-sum test, and multivariable logistic regression analysis were used to identify the prevalence and association of e-cigarette consumption and stroke. Results: Out of a total of 266,058 respondents from 2015 to 2018, we found 79,825 respondents who smoked e-cigarettes (9.72%) or traditional (29.37%) or dual smoking (60.91%). Stroke prevalence among e-cigarette smokers was 1.57%. Stroke was more prevalent among traditional smokers than among e-cigarette smokers. (6.75% vs. 1.09%; p < 0.0001) E-cigarette smokers had early onset of stroke in comparison with traditional smokers. (median age: 48 vs. 59 years; p < 0.0001). Among females with stroke, the prevalence of e-cigarette use was higher in comparison with traditional smoking (36.36% vs. 33.91%; p < 0.0001). Among the stroke population, the prevalence of e-cigarette use was higher among Mexican-Americans (21.21% vs. 6.02%) and other Hispanics (24.24% vs. 7.70%) compared with traditional smoking (p < 0.0001). The regression analysis found higher odds of stroke history among e-cigarette users than traditional smokers [aOR: 1.15; 95% CI: 1.15–1.16)]. Conclusion: Though stroke was more prevalent in traditional smokers, the incidence of stroke was early-in-onset and was strongly associated with e-cigarette use compared to traditional smokers. We have also identified vascular effects of e-cigarettes components as possible triggers for the stroke.


Introduction
The prevalence, mortality, and disability-adjusted life years (DALYs) associated with stroke have steadily increased globally, from 1990 to 2019, reaching approximately 101 million (95% UI: 93.2 to 111 million); death from stroke has decreased over the past decade in the USA [1,2]. Stroke continues to be the fifth-leading cause of death [1]. Tobacco consumption is a major modifiable risk factor associated with stroke, CVD, and silent infarction [2,3] Globally, smoking is the second-leading cause of death and the leading cause of DALYs [2]. There are various forms of tobacco consumption [4], of which vaping is very popular among adolescents [5]. The popularity of vaping has sharply increased over the last two decades [2011: 1.5% to 2018: 20.8%] [2], and the most recent data shows that 20% of students in grades 7-12 are current vapers, and 34% have tried it at least once. Another study found a 112% increase in the rate of vaping among youth from 2017 to 2019 [6].
The few studies that have shown a positive association between the use of e-cigarettes and combustible cigarettes with vascular disorders were limited either by choosing specific target populations [5,7] or being not specific to stroke [7]. Parekh et al. showed that dual use of e-cigarettes and combustible cigarettes was associated with 2.9 times higher odds of stroke but no association between isolated e-cigarette use with stroke (0.69; 95% CI: 0.3-1.4) among the population of 18-44-year-olds [5]. Kaiser et al. showed that the use of nicotine and/or vaping leads to worsening outcomes in stroke, secondary to a state of glucose deprivation in the neurovascular unit, which augments neuronal damage and enhances ischemic brain injury [8]. The limited information on long-term health effects of e-cigarettes on CVD is one of the reasons why AHA maintains its stand on e-cigarette regulation and health care screening precisely like other forms of tobacco [9].
Hence, we aim to investigate the association of e-cigarettes and traditional smoking with ischemic stroke using the National Health and Nutrition Examination Survey (NHANES) among the general population of the USA. The risk of stroke incidence and hospitalizations due to tobacco consumption has increased among adults. However, the association between e-cigarette smoking and stroke development in this population remains unknown. This study aims to examine the effect of e-cigarettes and traditional smoking on stroke.

Details of Data
The National Health and Nutrition Examination Survey (NHANES) is a populationbased cross-sectional survey study program designed to assess the health and nutritional status of adults and children in the United States. NHANES is a part of the National Center for Health Statistics (NCHS) and the Centers for Disease Control and Prevention (CDC). The NHANES includes socio-demographic, dietary, examination, lab findings, and healthrelated questions. The dataset is available at the CDC website https://www.cdc.gov/nchs/ nhanes/about_nhanes.htm, accessed on 30 August 2021, and details of the respondents are de-identified, so institutional IRB was not required.

Demographic Characteristics of the Study Population
A cross-sectional retrospective population-based study was performed using the NHANES database 2015-2018 of the US. Participants 18 or older with a history of smoking were considered in our study and divided into three groups, exclusive e-cigarette users, traditional smokers, and dual (e-cigarette + traditional) smokers. The confirmed history of stroke among all three groups was extracted.
Exclusive e-cigarettes, vaping, or electronic nicotine delivery systems (ENDS) use was defined by "SMQ900" (Ever used an e-cigarette?) and "SMQ905" (During the past 30 days, how many days have you used an e-cigarette?). Exclusive traditional smoking was defined by either "SMQ020" (Smoked at least 100 cigarettes in life) or "SMQ040" (Do you now smoke cigarettes?). Dual smokers were defined by respondents who responded "yes" to both e-cigarettes and traditional smoking. Stroke was defined by "MCQ160f" (Has a doctor or other health professional ever told you had a stroke?) and "MCQ180f"-(Age when told you had a stroke?).
We have included socio-demographic variables like age, race, annual household income, and comorbidities like diabetes, cholesterol, hypertension, depression, obesity, cancer, substance abuse (marijuana, cocaine/heroin/methamphetamine, illegal injectable drug), alcohol use (median average # of drinks/day and binge drinking (women: 4 or more and men: 5 or more drinks/day in past 12 months), and preventive aspirin use. We have collected data on high blood pressure on two occasions, recent systolic and diastolic blood pressure, body mass index (BMI), S. cholesterol, S. LDL, S. TG, and HbA1C.

Outcomes
The primary aim of this study is to evaluate the prevalence of e-cigarette, traditional, and dual smokers among respondents with a history of stroke. The secondary aim of this study is to evaluate the odds of different methods of nicotine consumption among respondents with a history of stroke. We have also evaluated the odds of e-cigarette use in the past 30 days among the population having a history of stroke.

Statistical Analysis
We analyzed the data using SAS software (Version 9.4, SAS Institute Inc., Cary, NC, USA). We performed univariate analysis to find out socio-demographic characteristics of the respondents with different methods of nicotine consumption among the stroke population, using Chi-square for categorical variables and a t-test and Wilcoxon ransom test for continuous variables. Multivariable logistic regression models were generated to calculate the odds of e-cigarettes among the stroke population in comparison with traditional smokers after adjusting for confounding variables. There was no pre-decided sample size calculation. p-value < 0.05 was considered significant, and an adjusted odds ratio (aOR) with a 95% confidence interval (95% CI) was calculated.
In regression analysis, the models were adjusted with socio-demographic variables, like age, gender, and annual household income, and comorbidities, like diabetes, cholesterol, hypertension, depression, cancer, substance abuse (marijuana, cocaine/heroin/methamphetamine, illegal injectable drug), alcohol use (median average # of drinks/day and binge drinking (women: 4 or more and men: 5 or more drinks/day in past 12 months), and preventive aspirin use. We collected data on high blood pressure on two occasions, recent systolic and diastolic blood pressure, and body mass index (BMI).

Results
Out of 266,058 respondents from 2015 to 2018 in the NHANES survey, we found 79,825 respondents who smoked e-cigarettes or traditional smoking or dual smoking, after excluding patients with age < 18 years and admissions with missing data for age, gender, or ethnicity. Out of 79,825 respondents, 7756 (9.72%) were e-cigarette smokers, 23,444 (29.37%) were dual smokers, and 48,625 (60.91%) were traditional smokers. The overall prevalence of stroke was 5.41%(n = 4194) among various types of smokers. The overall prevalence of stroke among e-cigarette smokers was 1.57%, among traditional smokers was 78.04%, and among dual smokers was 20.39%. Stroke was more prevalent among traditional smokers than e-cigarette and dual smokers (6.75% vs. 1.09% vs. 3.72% p < 0.0001). E-cigarette smokers have an early onset of stroke compared to dual and traditional smokers, respectively (median age in years: 48 vs. 50 vs. 59; p < 0.0001) ( Table 1).

Multivariable Logistic Regression Showing Association between Stroke and Smoking Habits
In multivariable logistic regression analysis, after adjusting for socio-demographic characteristics and comorbidities, the odds of having a history of stroke was higher among e-cigarette in comparison with traditional smokers (adjusted odds ratio (aOR): 1.15; 95% CI: 1.15-1.16; p < 0.0001). Dual smoker respondents had 14% higher odds of stroke history in comparison with traditional smokers (aOR: 1.14; 95% CI: 1.14-1.15; p < 0.0001). Respondents who smoked e-cigarettes in the last 30 days were also associated with higher odds of stroke prevalence in comparison to non-e-cigarette smokers in the last 30 days (aOR: 1.14; 95% CI: 1.14-1.15; p < 0.0001) ( Table 3).

Discussion
Although stroke was more prevalent in traditional smokers, our cross-sectional study found that e-cigarette smokers had an early onset of stroke compared to traditional and dual smokers. Furthermore, the odds of having a history of stroke was 1.15 times higher among e-cigarette and 1.14 times higher in dual smokers compared to traditional smokers. These findings have clear implications in helping physicians, healthcare policymakers, and tobacco product regulatory authorities to call for strict new regulations on e-cigarette access, sales, and marketing.
Tobacco consumption, a known modifiable risk factor, is associated with stroke and cardiovascular disease, including myocardial infarction [10,11]. Although death from stroke has decreased in the last decade, the use of tobacco products such as e-cigarettes and vaping has trended upward in the last two decades [12]. According to the World Health Organization 2018, vaping has increased from around 7 million users in 2011 to 41 million in 2018, with a projection of more than 55 million by 2021 [13]. Globally, tobacco consumption is worth an estimated $19.3 billion, up from around $7 billion five years ago, of which the US is one of the biggest markets [14]. Prior studies have shown that e-cigarettes are less harmful than tobacco cigarettes and can help smokers quit or reduce tobacco use [15][16][17][18][19]. But our study reveals that e-cigarette users had higher odds of stroke than traditional smokers. In addition, we found that dual smokers (e-cigarette plus traditional) had 14% higher odds of stroke than traditional smokers alone. The higher odds of stroke in dual smokers suggest that e-cigarettes may have an additive effect on traditional smokers. The additive effect may be attributed to e-cigarette ingredients other than nicotine, like carbonyls, including aldehydes such as formaldehyde, acetaldehyde, and acrolein; fine and ultrafine particulate matter (PMs); benzene; toluene; ethylbenzene; and xylenes (BTEX) [8,[20][21][22][23]. Parekh et al. also found higher odds of stroke among the young adult population (18-44 years) secondary to the additive effect of e-cigarettes (aOR: 2.91) on current or former traditional smokers (sole combustible cigarette OR: 1.83), without establishing a relationship between sole e-cigarette use and stroke [5].
Long-term exposure to higher nicotine levels is known to increase the risk of atherosclerosis and further promote stroke risk [11,24]. According to Kaiser et al., e-cigarettes, like traditional smoking, can cause a loss of blood-brain barrier (BBB) integrity and vascular inflammation [25]. Several studies have documented the detrimental effect of non-nicotinic ingredients of e-cigarettes on cerebral and cardiovascular systems (Table 4). Acrolein and PM inhalation from smoking and ambient air pollution have previously been reported to have various deleterious effects on the vascular system, including increasing blood pressure; increasing vascular injury by impairing vascular repair capacity; and increasing the risk of thrombosis and atherosclerosis due to endothelial dysfunction, dyslipidemia, and platelet activation [11,[26][27][28][29][30][31][32][33][34]. Kuntic et al. found that E-cigarette vapor exposure increases vascu-lar, cerebral, and pulmonary oxidative stress through toxic aldehyde(acrolein)-mediated NOX-2-dependent mechanisms [35]. A few studies have reported that e-cigarette use negatively impacts heart rate and blood pressure [36][37][38][39]. In addition, E-cigarettes cause endothelial cell dysfunction, vascular injury, and oxidative stress, which play important roles in the pathogenesis of stroke [40,41]. Furthermore, e-cigarette vapor extracts (toxic chemical, fine particulate matter: 2.5 µm and smaller, and nicotine) were found to enhance platelets' activation (aggregation-adhesioninflammation), which potentiates the atherosclerosis process [42]. S. Hom et al. found that e-vapor extracts have the same effect on the vascular system as traditional tobacco products, including myocardial infarction and stroke, and they noticed that it is fine particulate matter (PMs), not nicotine or toxic combustion products, that activates the hemostatic system/platelet activation. Thus, it is plausible that just reducing exposure to the fine particulate matter may reduce some of the risks associated with CVD development [42]. Acute and chronic effects of e-cigarette extract as a possible risk factor and trigger for the stroke were summarized in Figure 1 and described in detail in Table 5. Table 5. Acute and chronic effects of e-cigarettes as a possible risk factor and trigger for stroke.

Acute Direct Effect
Kuntic et al. [35] E-cigarette product acrolein (reactive aldehydes) mediated NOX-2-driven oxidative stress and cerebrovascular inflammation Caporale et al. [43] Transient impairment of cerebrovascular reactivity and endothelial function Sifat et al. [8] Induces a state of glucose deprivation at the neurovascular unit, leading to enhanced ischemic brain injury and/or stroke risk

Acute Indirect Effect
Antoniewicz et al., Mitchelle et al. [44,45] Increased HR; increased arterial stiffness is an independent risk factor for cardio and cerebrovascular events such as myocardial infarctions and stroke Nocella et al. [46] Increase the soluble CD40L and P-selectin; enhance platelet aggregation Boas et al. [47] Activation of splenocardiac axis (increase oxidative stress and increase sympathetic activity) Carnevale et al. [40] Increase oxidative stress and endothelial dysfunction by increasing soluble NOX-mediated peptides and decreasing NO bioavailability and vitamin E

Chronic Direct Effect
Kuntic et al. [35] Endothelial dysfunction and narrowing of vessels Kaisar et al. [25] Alter blood-brain barrier (BBB) permeability and vascular inflammation Qasim et al. [48] In mice, alter physiological hemostasis and increase the risk of thrombogenic events; platelet activation   Table 5. Acute and chronic effects of e-cigarettes as a possible risk factor and trigger for stroke.

Acute Direct Effect
Kuntic et al. [35] E-cigarette product acrolein (reactive aldehydes) mediated NOX-2-driven oxidative stress and cerebrovascular inflammation Caporale et al. [43] Transient impairment of cerebrovascular reactivity and endothelial function Sifat et al. [8] Induces a state of glucose deprivation at the neurovascular unit, leading to enhanced ischemic brain injury and/or stroke risk Acute Indirect Effect Antoniewicz et al., Mitchelle et al. [44,45] Increased HR; increased arterial stiffness is an independent risk factor for cardio and cerebrovascular events such as myocardial infarctions and stroke Nocella et al. [46] Increase the soluble CD40L and P-selectin; enhance platelet aggregation Boas et al. [47] Activation of splenocardiac axis (increase oxidative stress and increase sympathetic activity) In our study, among respondents with a history of stroke, males had higher use of e-cigarettes in comparison to females. However, among females with stroke, the prevalence of e-cigarette use was higher in comparison with traditional smoking. This study reveals that the stroke population with coexisting conditions like congestive heart failure, depression, and hypertension had higher odds of e-cigarette utilization compared to traditional smoking. Previous studies have also reported a strong association between e-cigarette use and level of stress, depression, CHF, and hypertension [26,28,31,53]. Our study also reports that the prevalence of marijuana or hashish, cocaine, heroin, methamphetamine, and injectable illegal drug abuse was higher among e-cigarette users than traditional smoking.
Secondly, we have also evaluated the odds of e-cigarette use in the last 30 days in stroke population. In the VESUVIUS study, George et al. reported short-term beneficial effects from switching to e-cigarette smoking on vascular function and found a significant improvement in endothelial function and vascular stiffness in e-cigarette smokers who had switched from traditional smoking to e-cigarette smoking within the last 30 days [54]. However, in contrast, we found higher odds of stroke prevalence compared to non-ecigarette smokers in respondents who smoked e-cigarettes in the previous 30 days. This results from the acute harmful effects of e-cigarettes on vascular function, including high blood pressure and heart rate, increased arterial stiffness, endothelial dysfunction, and increased cerebrovascular oxidative stress [40,[43][44][45]. This finding of our study is limited by the fact that 'non-e-cigarette smokers in the last 30 days' could have smoked e-cigarettes outside the last 30 days of the time frame, and stroke could occur before smokers switch from traditional smoking.

Strength and Limitations
Our study has several limitations. First, because of the study's cross-sectional design, causal inferences may be limited, with the possibility of reverse temporality, as we considered isolated e-cigarettes smokers separate from traditional and dual smokers (history of traditional and e-cigarette smoking at least once). We have assumed that isolated e-cigarette smokers, as mentioned in the survey, never had a history of traditional smoking. So if they had a stroke, they would not start or switch their form of smoking. Thus, this stroke episode happened after e-cigarettes had started. Secondly, the study cannot determine the amount or type of e-cigarette use, timing, frequency, nature of stroke, stroke severity, or timing. We could not evaluate the role of e-cigarettes as a trigger of stroke. This survey study also has respondents and recall bias due to limited responses from survey respondents. Despite major limitations, NHANES data represent a diverse sample of the US population, covering populations of all ages, sex, race, and socioeconomic status from all geographic distributions.

Future Directions
We propose more studies to evaluate the short-and long-term effects of e-cigarette ingredients, including but not limited to acetaldehyde, acrolein, fine and ultrafine PMs, and BTEX on cardio and cerebrovascular systems. The use of e-cigarettes might be more harmful to the female and Hispanic population, so more awareness should be created among these sub-groups of the population. Future guidelines for the quantification of e-cigarettes in regards to cardio and cerebrovascular risk stratification may provide additional insight to mitigate the burden.

Conclusions
Stroke is more prevalent in traditional smokers than among e-cigarette users, but we found that the incidence of stroke was early in onset in e-cigarette smokers compared to traditional smokers. There were higher odds of stroke prevalence for those who smoked ecigarettes in the last 30 days compared to non-e-cigarette smokers in the last 30 days. More prospective studies are needed to evaluate the long-term effects and safety of e-cigarettes to mitigate the risk of cardio and cerebrovascular disorders.

Conflicts of Interest:
The authors declare no conflict of interest.