Cardiovascular Effects of Switching From Tobacco Cigarettes to Electronic Cigarettes

Background E-cigarette (EC) use is increasing exponentially worldwide. The early cardiovascular effects of switching from tobacco cigarettes (TC) to EC in chronic smokers is unknown. Meta-analysis of flow-mediated dilation (FMD) studies indicate 13% lower pooled, adjusted relative risks of cardiovascular events with every 1% improvement in FMD. Objectives This study sought to determine the early vascular impact of switching from TC to EC in chronic smokers. Methods The authors conducted a prospective, randomized control trial with a parallel nonrandomized preference cohort and blinded endpoint of smokers ≥18 years of age who had smoked ≥15 cigarettes/day for ≥2 years and were free from established cardiovascular disease. Participants were randomized to EC with nicotine or EC without nicotine for 1 month. Those unwilling to quit continued with TC in a parallel preference arm. A propensity score analysis was done to adjust for differences between the randomized and preference arms. Vascular function was assessed by FMD and pulse wave velocity. Compliance with EC was measured by carbon monoxide levels. Results Within 1 month of switching from TC to EC, there was a significant improvement in endothelial function (linear trend β = 0.73%; 95% confidence interval [CI]: 0.41 to 1.05; p < 0.0001; TC vs. EC combined: 1.49%; 95% CI: 0.93 to 2.04; p < 0.0001) and vascular stiffness (−0.529 m/s; 95% CI: −0.946 to −0.112; p = 0.014). Females benefited from switching more than males did in every between-group comparison. Those who complied best with EC switch demonstrated the largest improvement. There was no difference in vascular effects between EC with and without nicotine within the study timeframe. Conclusions TC smokers, particularly females, demonstrate significant improvement in vascular health within 1 month of switching from TC to EC. Switching from TC to EC may be considered a harms reduction measure. (Vascular Effects of Regular Cigarettes Versus Electronic Cigarette Use [VESUVIUS]; NCT02878421; ISRCTN59133298)

E lectronic cigarettes or E-cigarettes (EC) are gaining popularity worldwide as an alternative to smoking tobacco cigarettes (TC) with a 55% increase in users between 2013 and 2015 with growth in the United Kingdom occurring fastest in Europe (1). The prevalence of EC use in the United Kingdom and United States is around 6% (2), and 51% of users did so because they believed it to be less harmful than regular cigarettes (3). Observational 95% CI: 1.20 to 2.66) (4). Despite this, there remains little good quality evidence on the short-and longterm safety of these devices. Furthermore, conflicting advice from various public health bodies worldwide on the use of these devices has resulted in lack of clarity for policymakers as well as the public at large (5,6).
TC contain >7,000 chemicals, including exposing smokers to high levels of nicotine, carbon monoxide (CO), acrolein, and pro-oxidant compounds. Data from chemical analysis and toxicology studies suggest that exposure to toxic chemicals from EC is lower compared with exposure from TC (7,8). However, other studies have shown that there remains the presence of potentially harmful tobacco-specific alkaloids such as anabasine, myosmine, and b-nicotyrine in EC liquid cartridge samples tested (9). The impact of nicotine on vascular health is also unclear.
Nicotine may accelerate the atherogenic process by binding to high-affinity nicotinic acetylcholine receptor cell surface receptors (10). However, longerterm nicotine use appears not to accelerate atherogenesis but may contribute to acute cardiovascular events in the presence of cardiovascular (CV) disease (11). The early vascular impact of switching from TC to EC-nicotine versus EC-nicotine-free is not known.
Endothelial dysfunction is the earliest detectable change in vascular health, and, importantly, it has consistently been shown to be associated with CV risk and long-term outcomes (12,13). We measured endothelial function using flow-mediated dilatation (FMD) and arterial stiffness by pulse wave velocity (PWV), 2 validated and independent predictors of CV risk above and beyond traditional risk factors (14,15). We conducted the current trial to address specific questions on the early CV effects of switching from TC to EC and the impact of nicotine itself on any early vascular changes that might be seen.   BIOMARKERS. We measured oxidized low-density lipoprotein, high-sensitivity C-reactive protein, tissue plasminogen activator, and platelet activation inhibitor-1 at baseline and at 1 month. All biomarkers were measured by enzyme-linked immunosorbent assay at the Immunoassay Biomarker Core Laboratory, University of Dundee.

The VESUVIUS (Vascular Effects of Regular
OUTCOMES. The primary outcome was defined as the change in FMD among the TC group and the ECnicotine and EC-nicotine-free arms as a linear contrast. Secondary outcomes included change in FMD, PWV, augmentation index at 75 beats/min, heart rate, blood pressure, and biomarkers (oxidized low-density lipoprotein, high-sensitivity C-reactive protein, tissue plasminogen activator, and platelet activation inhibitor-1) for the TC, EC-nicotine, and EC-nicotine-free arms. As the parallel control arm expressed a preference to not be randomized, a propensity score was created with the binary outcome of randomized versus nonrandomized using logistic regression and subsequently used as an adjustment covariate in the regression models to allow for potential bias. Variables included in the propensity score included demographic data, blood pressure, CO levels, all measured biomarkers, FMD and vascular stiffness parameters, and smoking history (Online Table 1).
All analyses were conducted in SAS version 9.4 (SAS Institute Inc., Cary, North Carolina).

RESULTS
A total of 145 patients were recruited into the trial  p < 0.0001) and separately between TC and ECnicotine and between TC and EC-nicotine-free ( Table 2). There was no statistically significant difference in FMD change between the EC-nicotine and EC-nicotine-free arms ( Table 2, Central Illustration).
The interaction term between treatment and sex for the primary outcome of FMD change was statistically significant (p ¼ 0.009), therefore the subgroup analyses was performed by sex. The improvement in FMD was seen in both males and females for TC versus EC comparisons but significantly greater improvement in vascular function was seen in females who switched from TC to EC ( Table 3).
As expected, exhaled CO levels were high at baseline and comparable among the 3 arms of the study (Table 1). However, at the end of study, those with the There was no significant trend in difference among the 3 arms for other secondary outcomes including PWV, heart rate, and biomarkers of inflammation and platelet reactivity ( Table 5). However, the interaction terms between treatment and smoking pack-years were significant for PWV (p ¼ 0.016) and heart rate (p ¼ 0.003).
Therefore, a subgroup analysis was done for these outcomes by smoking pack-years.

VASCULAR STIFFNESS AND BLOOD PRESSURE.
Smokers who smoked #20 pack-years also demon-     Third, switching to EC from TC may benefit females more than males and this is also seen in females who were less compliant (dual use). However, this was a subgroup analysis of our data and should be interpreted with caution. Nevertheless, female smokers face more health risks than male smokers do; they are more likely to develop lung cancer (21) and are almost twice as likely to have a myocardial infarction as a result of their smoking (22). The worrying trend worldwide of increased TC prevalence among women (23) suggests that further measures are urgently required to reduce harms associated with TC.
Therefore, the switch to EC may be considered a vascular harms reduction measure for both sexes but Adjusted mean percentage change in forearm flow-mediated dilation with 95% confidence intervals for subjects on electronic cigarettes (EC), EC-nicotine, and ECnicotine-free. In addition to these findings, we found a reduction in resting heart rate in the >20 pack-years cohort who switched to EC. The association between resting heart rate and CV events is well known (26,27)    Abbreviations as in Tables 1 and 2. when both products were accompanied by behavioral support.
STUDY LIMITATIONS. This was a single-center study. We could not perform a full 3-arm randomized controlled design as it was unethical for participants who wished to quit smoking to be allocated to the smoking arm. We created a propensity score as an adjustment covariate in the regression models to allow for any potential bias and the results remained consistent. Baseline characteristics of the cohorts were also comparable. The duration of effect tested was deliberately short as the primary purpose of the study was to investigate whether there were early vascular benefits from switching from TC to EC and the results are reassuring. However, longer follow-up is required to determine whether males also benefit to the same level as females do and whether these changes seen are sustained and to assess the impact of nicotine in EC.