Acute cardiovascular effects of 4th generation electronic cigarettes and combusted cigarettes: implications for harm reduction

Abstract

The health consequences associated with using electronic cigarettes (ECs) are of great public interest because of their potential role in smoking cessation. In 110 participants, including 41 nonusers, 34 people who exclusively use ECs (EC group), and 35 people who smoke tobacco cigarettes (TCs) including 12 dual users (collectively called the TC-D group), the heart rate (HR), blood pressure (BP), and heart rate variability (HRV) were compared at baseline. People in the EC or the TC-D groups were also compared after using a 4th generation EC with or without nicotine, a TC with or without nicotine (TC-D group only), and a straw-control. Baseline HR, BP, and HRV parameters were not different among the EC, the TC-D, and nonuser groups. In people who exclusively use ECs, acute nicotine-EC use increased HR and BP, and produced changes in HRV patterns suggestive of increased cardiac sympathetic influence. In people in the TC-D group, BP increased similarly after acutely smoking a nicotine-TC or a nicotine-EC. However, the increase in HR was significantly greater after smoking a TC compared with the nicotine-EC despite similar acute increases in plasma nicotine. Overall, all exposures containing nicotine significantly increased HR and BP in both cohorts when compared with non-nicotine exposures. Since acute EC use 1) produces an abnormal HRV pattern associated with increased cardiac sympathetic tone in people who chronically use ECs, and 2) similar hemodynamic increases compared with acute TC smoking in people who chronically smoke TCs including dual users, the role of ECs as part of a harm reduction strategy is questioned.

NEW & NOTEWORTHY We found that nicotine, not the non-nicotine constituents in tobacco cigarette (TC) or electronic cigarette (EC) emissions, may be the instigator of the acute, potentially adverse, changes in hemodynamics and heart rate variability (HRV) that were recorded several minutes after tobacco product use. Furthermore, acute EC use produced an abnormal HRV pattern associated with increased cardiac risk in people who chronically smoke ECs and produced similar hemodynamic increases compared with acute TC use in people who chronically smoke TCs, including people who are dual users.

INTRODUCTION

Combusted tobacco cigarette (TC) smoking is the leading preventable cause of premature death in the United States, accounting for ∼480,000 deaths annually (1). Individuals who smoke TCs are at significantly greater risk of developing cancers of the lung, mouth, stomach, cervix, and kidneys among many others (1). Furthermore, TC smoking substantially increases the risk of acute cardiovascular events such as myocardial infarction, stroke, and sudden death (2). Due to detrimental health effects of chronic TC smoking, there is great public health interest in developing effective smoking cessation strategies (3).

Electronic cigarettes (ECs) have been promoted as a safer alternative to smoking TCs (4). However, in the absence of long-term studies, it remains controversial whether ECs are safer compared with TCs, and could play a role in a harm reduction strategy (5, 6). Prior research has shown that, in people who use ECs compared with people who smoke TCs, levels of toxicants and carcinogens are significantly lower, if present at all, with one exception—nicotine (7). Nicotine, the highly addictive constituent in tobacco, activates the sympathetic nervous system to acutely increase heart rate (HR), blood pressure (BP), and myocardial contractility, and may precipitate vasospasm (2). Animal models have also shown nicotine to have proarrhythmic and proatherogenic effects (8–10). Importantly, although little is known about the effects of the non-nicotine constituents in EC emissions, in preclinical studies, even the ECs without nicotine have been shown to be proarrhythmic (9).

Although HR and BP can be directly monitored using a noninvasive BP monitor, cardiac sympathetic and parasympathetic activity can be estimated by analyzing an individual’s heart rate variability (HRV) (11). HRV parameters reflect sympathetic-vagal balance and declines have been associated with increased risk of cardiovascular events, even in individuals without known heart disease (12–14). Previous studies have reported an altered sympathetic-vagal cardiac ratio in individuals who smoke TCs and in those who use ECs (15, 16).

One factor increasing the difficulty in measuring the long-term health consequences of ECs compared with TCs is the staggering pace of innovation in the EC industry. ECs were introduced during the mid-2000s and have dramatically evolved throughout the past decade, changing from the original, disposable “cigalike” products to the modern rechargeable devices called “mods,” which are modifiable. Individuals are able to customize their choice in e-liquid solution, heating temperature, nicotine yield, and puff volume (17). At present, the most widely used EC is the 4th generation pod EC, in which a unique chemical formulation of nicotine, nicotine salts, permits very high concentrations of nicotine to be released with each puff. Fourth-generation devices, such as the JUUL, deliver higher levels of nicotine at faster rates compared with older generation devices, with similar pharmacokinetics as TCs. Acute hemodynamic and sympathomimetic effects of earlier generation ECs compared with combusted TCs were significantly less, but acute hemodynamic and sympathomimetic effects of the 4th generation ECs have not yet been compared with TCs (18).

In this study, we compared the acute hemodynamic and HRV effects of a 4th generation, pod EC device to acute TC smoking. In addition, to determine the contribution of nicotine compared with non-nicotine constituents in these emissions in inducing changes in hemodynamic and HRV parameters, ECs without nicotine and TCs without nicotine (research cigarette) were also used. We hypothesized that nicotine, as well as non-nicotine constituents in TC smoke, but not in EC emissions, would contribute to acute cardiovascular effects.

MATERIALS AND METHODS

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Study Population

The study population consisted of healthy male and female participants between the ages of 21 and 45 yr. Participants were categorized into three groups: 1) nonusers, 2) people who exclusively use ECs (≥12 mo), and 3) people who smoke tobacco cigarettes (TCs) (≥12 mo). Individuals who used both TCs and ECs (dual users; D) were included with the people who exclusively smoke TCs, and this combined group is collectively called the TC-D group. Former EC or TC users who had quit smoking for at least 1 yr before were considered nonusers. All participants were only eligible if they had no known health problems, such as high blood pressure, heart disease, diabetes, obesity [≤30 kg/m² body mass index], were not diagnosed with depression, anxiety, or any other mental illness, were not taking prescription medications (excluding oral contraceptives), not pregnant (which was verified at each visit by a urine pregnancy test), had two or fewer alcoholic drinks per day, and did not use cannabis, which was verified by self-report and confirmed by urine toxicology testing. Participants were not eligible if they used other nicotine replacement therapies or if they were exposed to secondhand smoke more than once a week. The experimental protocol was approved by the Institutional Review Board at the University of California, Los Angeles (UCLA), and written informed consent was obtained from each participant. This study was registered on ClinicalTrials.gov with the unique identifier: NCT03916341. H.R.M. had full access to all the data in the study and took responsibility for its integrity and the data analysis.

Study Design

Baseline comparison study.

Baseline heart rate, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and HRV at their first experimental session were compared among nonusers, people who exclusively use ECs, and people who smoke TCs including dual users (TC-D group).

Randomized crossover study.

People who exclusively use ECs underwent three experimental sessions in random order: 1) a straw-control, 2) an EC with 5% nicotine (EC5), or 3) an EC with 0% nicotine (EC0) at a given visit. People who smoke TCs, including dual users, underwent four experimental sessions in random order: 1) a straw-control, 2) an EC5, 3) a commercially available tobacco cigarette with nicotine (TCN), or 4) a research tobacco cigarette without nicotine (TC0).

Exposures

The straw-control used in the study was a plastic soda straw. The EC5 device was a JUUL with a standard 5% menthol pod. The EC0 device was an Ezee E-Cigarette with a 0% menthol cartridge attachment. People in the TC-D group smoked their own brand of TC. The TC0 was obtained from the Food and Drug Administration (Spectrum 20 Class A cigarette).

Nicotine and Cotinine Plasma Levels

Before and after each intervention, blood was drawn and sent to the UCLA Clinical Laboratory for measurement of plasma nicotine and cotinine levels.

Heart Rate Variability

An electrocardiogram (ECG) was recorded for 5 min at baseline and after the acute exposure in the supine position. Leads II and V1 of the 5-min ECG recordings were used for analysis using commercially available software (LabChart 8, ADInstruments) for HRV in the frequency domain and time domain. In the frequency domain, HRV is divided into three components: low frequency (LF, 0.004–0.15 Hz) likely reflecting both sympathetic and vagal activity and/or baroreflex function (19, 20), high frequency (HF, 0.15–0.4 Hz) indicative largely of cardiac vagal nerve activity (11, 21), and the log of the LF-to-HF ratio (LF/HF), which may be indicative of overall sympathetic to vagal balance, but this assumption is controversial and far from secure (11, 22). HRV was analyzed in normalized units to correct for differences in total power. In the time domain analysis, the standard deviation of RR intervals (SDRR) and the root mean square of successive RR interval differences (RMSSD), both of which decrease with a decrease in relative parasympathetic dominance (11), were reported.

Blood Pressure and Heart Rate

Systolic blood pressure (SBP), diastolic BP, mean blood pressure (MAP), and heart rate (HR) were measured after a 10-min rest period in the supine position at baseline, and after a 5-min rest period following each exposure, with a noninvasive BP monitor (Casmed 740, Avante Health Solutions and the Capsule Smart Linx Vitals Plus) according to American Heart Association guidelines (23). The same approach to BP measurement was followed in all groups pre-/postexposure, including sham (straw-control) smoking.

Experimental Session

Studies were conducted between 8:00 am and 2:00 pm to avoid the potential influence of circadian rhythm on autonomic tone. Participants were instructed to abstain from smoking, ingesting caffeine, or exercising for at least 12 h before their visit. Participants were also asked to abstain from eating or drinking (except water) 6 h before their visit. During the visit, participants were in a supine position in a quiet, temperature-controlled (21°C) room in the Human Physiology Laboratory at the UCLA Clinical and Translational Research Center. Participants were not allowed to use their cell phones or talk during data acquisition. The participant was instrumented, blood was drawn, and after a 10-min rest period, blood pressure and heart rate were measured. An ECG was then recorded for 5 min for later analysis for HRV. The participant was then detached from the ECG electrodes and led down a short corridor to a smoking patio, where they underwent their assigned exposure (straw-control, EC5, EC0, TCN, or TC0). A uniform vaping protocol was enforced to ensure a similar “dose” among interventions. Participants were instructed to take a 3-s puff every 30 s for up to 15 min when given a straw, EC5, or EC0. If the participants used a TCN or TC0, they were instructed to finish the entirety of the cigarette (usually within 10 min). Immediately after vaping or smoking, the participant returned to the examination room, was repositioned in the supine position, and after a 5-min rest period, heart rate and blood pressure were measured. An ECG was then recorded for 5 min, blood was drawn, and the study was concluded.

Statistical Analysis

A Fisher’s exact test was used to compare differences in sex, race, and education levels among each group.

An unpaired parametric one-way analysis of variance (ANOVA) was used to compare the differences in HR, BP, and components of HRV among each group at their first visit to establish a baseline. Multiple comparison tests were conducted with a Tukey correction to compare differences in mean among each group. The same statistical tests were utilized to compare differences in the change of plasma nicotine level after vaping an EC5 between people who smoke exclusively ECs and people in the TC-D group.

Parametric unpaired t tests were conducted to compare differences in plasma cotinine levels between people who vape exclusively ECs and people in the TC-D group at their first visit. Parametric unpaired t tests were also used to compare the change in plasma nicotine level after vaping an EC5 and smoking a TCN in people in the TC-D group.

A parametric mixed-effects model ANOVA was used to compare differences in the change in HR, BP, and components of HRV after each exposure for a single group. A mixed-effects model was used because not every participant completed all interventions. Multiple comparison tests were conducted with a Tukey correction to compare differences in mean between each exposure.

Pearson correlations were calculated by analyzing the correlation between the change in HR, BP, and components of HRV and the change in plasma nicotine level.

Normal quantile plots (data not shown) were examined, and the Shapiro–Wilk statistic was computed to confirm that the model residual errors followed the normal distribution on the appropriate original or log scale. Statistical significance was determined when P ≤ 0.05. Pearson correlation strength was determined as the following: negligible (r = 0.00–0.10), weak (r = 0.10–0.39), moderate (r = 0.40–0.69), strong (r = 0.70–0.89), or very strong (r = 0.90–1.00) (24).

All statistical tests and figures were conducted using GraphPad Prism 9. All estimates of variability are presented as standard deviations unless otherwise stated.

RESULTS

Study Population

One hundred ten (110) participants, including 41 nonusers, 34 people who exclusively use ECs, and 35 people who smoke TCs, including 12 dual users (collectively called the TC-D group), participated in the study. Study population characteristics are shown in Table 1. There were no significant differences in age, sex, and body mass index among groups. Plasma cotinine levels were similar between people who exclusively use ECs and people in the TC-D group (129 ± 162 ng/mL vs. 90 ± 105 ng/mL, P = 0.25). Although participants were instructed to abstain from vaping or smoking for 12 h before a visit, baseline plasma nicotine levels were greater than 4 ng/mL in 22 of 287 visits, suggestive of more recent use. We have included those data points into our analysis as the removal of those visits did not change the statistical significance of any of our findings.

Table 1.

Study population

	Nonusers	EC	TC-D	P Value
	n = 41	n = 34	n = 35
Mean age, yr	24.44 ± 3.55	23.29 ± 2.65	24.24 ± 2.71	0.34
Sex (M/F)	20/21	17/17	14/21	0.65
Cotinine, ng/mL	–	129 ± 162	90 ± 105	0.25
Race				0.32
African American	0	1	1
Asian	15	9	10
Hispanic	6	3	2
White (non-Hispanic)	12	18	19
Other/Unknown/Mixed	8	3	3
Education				1.0
In college or more	41	34	35
No college	0	0	0
Height, in.	1.71 ± 0.08	1.72 ± 0.10	1.71 ± 0.10	0.97
Weight, lb	66.4 ± 11.9	68.0 ± 12.3	64.9 ± 10.8	0.55
BMI, kg/m2	22.35 ± 3.15	22.94 ± 2.72	21.75 ± 2.38	0.21

Values are represented as means ± SD. BMI, body mass index; EC, people who use electronic cigarettes; NA, not applicable; TC-D, people who smoke tobacco cigarettes, including dual users.

Baseline Hemodynamics and HRV

At their first visit, there were no differences in heart rate, SBP, DBP, MAP, LF, HF, LF/HF, SDRR, and RMSSD among nonusers, people in the EC group, or in the TC-D group (Table 2).

Table 2.

Baseline hemodynamic and heart rate variability values

	Nonusers	EC	TC-D	P Value
	n = 41	n = 34	n = 35
Heart rate, beats/min	64.8 ± 9.1	65.3 ± 12.2	62.3 ± 10.4	0.45
SBP, mmHg	108.6 ± 9.1	107.8 ± 8.3	106.7 ± 8.0	0.61
DBP, mmHg	63.2 ± 7.6	64.5 ± 7.7	62.9 ± 7.2	0.66
MAP, mmHg	78.0 ± 8.1	78.3 ± 7.6	77.2 ± 7.5	0.82
LF, nu	44.2 ± 21.2	37.8 ± 21.2	36.1 ± 15.8	0.18
HF, nu	54.4 ± 20.4	59.7 ± 19.8	60.0 ± 14.6	0.37
log (LF/HF)	−0.1 ± 0.4	−0.2 ± 0.4	−0.3 ± 0.4	0.25
SDRR, ms	61.7 ± 22.0	64.4 ± 21.6	64.9 ± 24.8	0.81
RMSSD, ms	53.8 ± 20.5	62.5 ± 27.5	70.4 ± 37.3	0.06

DBP, diastolic blood pressure; EC, people who use electronic cigarettes; HF, high frequency; LF, low frequency; log (LF/HF), log of the LF-to-HF ratio; MAP, mean arterial pressure; nu, normalized units; RMSSD, root mean square of successive RR interval differences; SBP, systolic blood pressure; SDRR, standard deviation of RR intervals; TC-D, people who smoke tobacco cigarettes, including dual users.

Crossover Study

EC group.

Five participants did not complete the straw-control exposure, four did not complete the EC5 exposure, and five did not complete the EC0 exposure.

Changes in hemodynamics and HRV.

In the people who exclusively use ECs, the acute rise in plasma nicotine was 10.23 ± 6.37 ng/mL after acutely using the EC5. Heart rate, SBP, DBP, and MAP significantly increased following EC5 exposure compared with EC0 or straw exposure in people who exclusively use ECs (Fig. 1).

Figure 1.

Change in hemodynamics after acute exposure to either a straw, an electronic cigarette (EC) with 5% nicotine (EC5), or an EC with 0% nicotine (EC0) in people who exclusively use ECs. Heart rate (A) significantly increased after using an EC5 (8.1 ± 8.1 beats/min, n = 31) compared with an EC0 (−0.4 ± 5.5 beats/min, n = 33) and a straw-control (−1.5 ± 4.7 beats/min, n = 30). Systolic blood pressure (B) significantly increased after using an EC5 (10.5 ± 9.3 mmHg, n = 31) compared with an EC0 (5.0 ± 6.2 mmHg, n = 33) and a straw-control (3.0 ± 8.8 mmHg, n = 30). The change in diastolic blood pressure (C) was only greater after using an EC5 (7.1 ± 6.7 mmHg, n = 31) compared with an EC0 (2.6 ± 5.9 mmHg, n = 33), but not the straw-control (3.2 ± 8.8 mmHg, n = 30). Mean arterial pressure (D) significantly increased after using an EC5 (7.8 ± 5.9 mmHg, n = 31) compared with an EC0 (3.8 ± 5.1 mmHg, n = 33) and a straw-control (2.3 ± 6.5 mmHg, n = 30). Means were compared among groups using parametric mixed-effects model ANOVA controlling for visit. Values are depicted with the mean, (horizontal line within the box), 25–75% (lower and upper borders of the box) and whiskers to notate the minimum and maximum values. BPM, beats per minute; BP, blood pressure. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001.

There were also significant differences among exposures in the change in HRV when measured in both the frequency and time domains. In the frequency domain, HF decreased significantly, whereas LF/HF increased after using an EC5 compared with straw-control (Fig. 2). For time domain measurements, both SDRR and RMSSD decreased significantly after using an EC5 compared with the straw-control and EC0 (Fig. 2).

Figure 2.

Change in heart rate variability (HRV). HRV was compared in the frequency domain and time domain after acute exposure to either a straw (n = 29), an electronic cigarette (EC) with 5% nicotine (EC5; n = 30), or an EC with 0% nicotine (EC0; n = 29) in people who exclusively use ECs. In the frequency domain, the change in low frequency (LF, A) did not differ among the exposures, straw [−3.7 ± 11.8 normalized units (nu)] vs. EC5 (5.5 ± 15.3 nu) vs. EC0 (−0.3 ± 14.8 nu). After using an EC5 compared with a straw-control, the high frequency (HF, B) decreased (−4.9 ± 15.7 vs. 5.0 ± 13.0 nu) but the change was not different from that following the EC0 (0.5 ± 13.4 nu) and the log of the LF-to HF ratio (C) increased (0.1 ± 0.3 vs. −01 ± 0.2) but again the change was not different from that following the EC0 (−0.01 ± 0.28). In the time domain, after using an EC5 compared with the EC0 and straw-control, the standard deviation of RR intervals (SDRR, D) decreased (−14.1 ± 18.6 ms vs. 3.8 ± 15.4 ms vs. 2.18 ± 10.9 ms, respectively) and root mean square of successive RR interval differences (RMSSD, E) decreased (−14.3 ± 21.2 ms vs. 4.1 ± 16.6 ms vs. 1.5 ± 14.3 ms, respectively). Means were compared among groups using a parametric mixed-effects model ANOVA and are depicted with the mean, (horizontal line within the box), 25–75% (lower and upper borders of the box) and whiskers to notate the minimum and maximum values. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001.

Crossover Study

TC-D group.

Three participants did not complete the straw-control exposure, six did not complete the EC5 exposure, one did not complete the TCN exposure, and four did not complete the TC0 exposure.

Changes in hemodynamics and HRV.

In people who chronically smoke TCs, including 12 dual users, the acute rise in plasma nicotine was similar after acutely smoking a TCN and using the EC5 (8.50 ± 5.28 ng/mL vs. 8.66 ± 5.65 ng/mL, P = 0.95). Heart rate and blood pressure increased significantly only after exposures containing nicotine (EC5 and TCN), not after straw-control or TC0 (Fig. 3). Interestingly, despite a similar rise in plasma nicotine after acute TCN and EC5 use, the increase in HR was significantly greater after smoking the TC compared with using the EC5 (Fig. 3A).

Figure 3.

Change in hemodynamics after acute exposure to either a straw, an electronic cigarette (EC) with 5% nicotine (EC5), a tobacco cigarette (TC) with nicotine, or a TC without nicotine in people who smoke TCs including dual users. Heart rate (HR, A) increased significantly after using an EC5 (7.3 ± 8.6 beats/min, n = 29) and tobacco cigarette with nicotine (TCN) (12.6 ± 9.8 beats/min, n = 34) but not after straw-control (−1.3 ± 5.2 beats/min, n = 32) or tobacco cigarette without nicotine (TC0) (−0.03 ± 6.9 beats/min, n = 31). The increase in HR was significantly greater following the TCN vs. the EC5. Systolic blood pressure (BP) (B) increased significantly after using an EC5 (12.4 ± 10.3 mmHg, n = 29) and TCN (12.0 ± 7.0, n = 34) but not after straw-control (3.4 ± 5.7 mmHg, n = 32) or TC0 (3.4 ± 5.6 mmHg, n = 31). Diastolic blood pressure (C) increased significantly after using an EC5 (8.3 ± 10.0 mmHg, n = 29) and TCN (8.3.0 ± 7.0, n = 34) compared with straw-control (2.1 ± 5.6 mmHg, n = 32) and TC0 (1.8 ± 5.2 mmHg, n = 31). Mean arterial pressure (D) increased significantly after using a TCN (10.0 ± 6.5, n = 34) compared with straw-control (3.4 ± 4.9 mmHg, n = 32) or TC0 (2.7 ± 5.0 mmHg, n = 31), and was not different from the increase after EC5 (9.0 ± 12.8 mmHg, n = 29). Means were compared among groups using a parametric mixed-effects model ANOVA controlling for visit. Values are depicted with the mean, (horizontal line within the box), 25%–75% (lower and upper borders of the box) and whiskers to notate the minimum and maximum values. BPM, beats per minute. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001.

There were no significant differences in changes in heart rate variability among exposures in people in the TC-D group (Fig. 4).

Figure 4.

Change in heart rate variability (HRV) (frequency domain and time domain) after acute exposure to either a straw (n = 32), an electronic cigarette (EC) with 5% nicotine (EC5; n = 29), a tobacco cigarette (TC) with nicotine (TCN; n = 32), or a TC without nicotine (TC0; n = 31) in people who smoke TCs including dual users. Change in HRV (frequency domain), including low frequency (LF, A) did not differ after acute exposure to either a straw [0.9 ± 13.2 normalized units (nu), n = 32], an EC with 5% nicotine (EC5; 6.0 ± 16.3 nu, n = 29), a TC with nicotine (2.0 ± 15.7 nu, n = 32), or a TC without nicotine (−1.4 ± 11.0 nu, n = 31). Change in high frequency (HF) (frequency domain) (B), did not differ after acute exposure to either a straw (−0.6 ± 11.7 nu, n = 32), an EC with 5% nicotine (−4.4 ± 15.7 nu, n = 29), a TC with nicotine (−2.0 ± 15.0 nu, n = 32), or a TC without nicotine (1.3 ± 10.5 nu, n = 3). Change in log of LF-to-HF ratio (LF/HF; frequency domain) (C) did not differ after acute exposure to either a straw (0.01 ± 0.3, n = 32), an EC with 5% nicotine (0.1 ± 0.3, n = 29), a TC with nicotine (0.05 ± 0.3, n = 32), or a TC without nicotine (−0.02 ± 0.2, n = 31). Change in HRV (time domain), including standard deviation of RR intervals (SDRR, D) did not differ after acute exposure to either a straw (0.4 ± 14.3 ms, n = 32), an EC with 5% nicotine (−5.8 ± 17.4 ms, n = 29), a TC with nicotine (−6.3 ± 15.8 ms, n = 32), or a TC without nicotine (1.6 ± 15.5 ms, n = 31). Change in root mean square of successive RR interval differences (RMSSD) (time domain) (E) did not differ after acute exposure to either a straw (−2.0 ± 18.0 ms, n = 32), an EC with 5% nicotine (−8.5 ± 23.5 ms, n = 29), a TC with nicotine (−7.8 ± 19.7 ms, n = 32), or a TC without nicotine (1.4 ± 23.4 ms, n = 31). Means were compared among groups using a parametric mixed-effects model ANOVA controlling for visit. Values are depicted with the mean, (horizontal line within the box), 25%–75% (lower and upper borders of the box) and whiskers to notate the minimum and maximum values.

Correlation between Change in Hemodynamics and HRV versus Change in Plasma Nicotine Levels

When the EC group and the TC-D groups were combined after EC5 or TCN exposures, changes in HRV (n = 89) and all hemodynamic variables (n = 94), except diastolic BP, were correlated with the change in nicotine (Table 3).

Table 3.

Correlation of change in nicotine with changes in hemodynamics and heart rate variability

	Combined	EC	TC-D:EC5	TC-D:TCN
	n = 89	n = 28	n = 29	n = 34
Heart rate, beats/min	r = 0.52, P < 0.0001	r = 0.65, P < 0.0001	r = 0.58, P = 0.001	r = 0.48, P = 0.004
SBP, mmHg	r = 0.29, P = 0.005	r = 0.28, P = 0.13	r = 0.37, P = 0.048	r = 0.27, P = 0.12
DBP, mmHg	r = 0.19, P = 0.07	r = 0.34, P = 0.06	r = 0.10, P = 0.61	r = 0.18, P = 0.32
MAP, mmHg	r = 0.31, P = 0.003	r = 0.35, P = 0.05	r = 0.40, P = 0.04	r = 0.26, P = 0.14
LF, nu	r = 0.22, P = 0.04	r = 0.11, P = 0.56	r = 0.30, P = 0.12	r = 0.25, P = 0.17
HF, nu	r = −0.23, P = 0.03	r = −0.12, P = 0.54	r = −0.30, P = 0.11	r = −0.24, P = 0.19
ln (LF/HF)	r = 0.24, P = 0.02	r = 0.12, P = 0.54	r = 0.29, P = 0.12	r = 0.30, P = 0.09
SDRR, ms	r = −0.29, P = 0.01	r = −0.19, P = 0.33	r = −0.41, P = 0.03	r = −0.20, P = 0.27
RMSSD, ms	r = −0.28, P = 0.01	r = −0.07, P = 0.74	r = −0.48, P = 0.008	r = −0.26, P = 0.16

Combined, both people the EC group and the TC-D group; DBP, diastolic blood pressure; EC, people who use electronic cigarettes; HF, high frequency; LF, low frequency; log (LF/HF), log of the LF-to-HF ratio; MAP, mean arterial pressure; nu, normalized units; RMSSD, root mean square of successive RR interval differences; SBP, systolic blood pressure; SDRR, standard deviation of RR intervals; TC-D, people who smoke tobacco cigarettes, including dual users.

When the EC group was analyzed separately after EC5 exposure (n = 31), the increase in heart rate, but not the other hemodynamic or HRV variables, was correlated with the change in nicotine. When the TC-D group was analyzed separately after EC5 (n = 29) exposure, the increase in HR and the decline in two HRV variables indicative of vagal tone, SDRR and RMSSD, were correlated with the increase in plasma nicotine. When the TC-D group was analyzed separately after TCN exposure (n = 34), only the increase in HR was correlated with the increase in plasma nicotine (Table 3 and Supplemental Figs. S1–S3).

DISCUSSION

This study adds to the existing literature by the exclusive use of the 4th generation pod EC device, the type of device currently in greatest use in the community, in our experimental sessions. Furthermore, uniquely, in addition to an EC without nicotine exposure, a non-nicotine TC exposure was also included, allowing the cardiovascular effects of nicotine versus non-nicotine constituents in emissions from ECs and TCs to be determined. Specifically, research cigarettes with negligible nicotine were obtained from the FDA. The primary new findings in this study are that 1) in people who exclusively use ECs, acute nicotine-EC use increases HR and BP, and produces changes in the HRV pattern associated with increased cardiac sympathetic activity, compared with straw-control and non-nicotine EC use. 2) In people who smoke TCs including dual users, following similar exposures to EC or TC emissions (as estimated by similar rises in plasma nicotine levels), BP increased similarly and significantly after each exposure compared with control and to the no-nicotine research TC. Interestingly, the increase in HR was significantly greater following acute TC use compared with acute nicotine-EC use, and the increases in HR after both exposures containing nicotine were significantly greater than following the straw-control and the no-nicotine TC exposure. In individuals who smoke TCs including dual users, patterns of HRV did not change after any exposure compared with straw-control. In correlation analyses of the people who use tobacco products, acute changes in plasma nicotine were correlated with increases in HR and BP, and correlated with changes in HRV. Collectively, these findings are consistent with the notion that nicotine, not non-nicotine constituents in emissions from TCs or ECs, is the instigator of the acute, potentially adverse, changes in hemodynamics and HRV that accompany tobacco product use.

These findings are similar to those in our prior report of healthy people who were nicotine-naïve, in which early generation (cigalike and pen-like) EC devices were used. Only acute use of an EC with nicotine, not an EC without nicotine, led to changes in hemodynamics and HRV (25), implicating nicotine as the instigator. Interestingly, the findings in the current study differ from our prior acute exposure study conducted in people who chronically and exclusively use ECs (26). Early generation (cigalike and pen-like) devices were used in most of the acute exposure studies in that report. Although acute EC use with nicotine, but not without nicotine, increased BP and HR in that study, there was no change in the HRV parameters. One explanation for the finding that the EC with nicotine in the current study but not in the prior study altered the HRV parameters in chronic EC users could be that the acute increase in plasma nicotine following EC exposure was approximately twofold greater in the current study (4.67 vs. 10.23 ng/mL). Differences in EC topography are an unlikely the explanation for this greater increase in plasma nicotine levels in the current study since the EC puffing topography was the same; in fact, the exposure duration was actually shorter in the current study, 15 min compared with 30 min in the prior study (26). Importantly, however, in the current study, all participants used the 4th generation pod-like device, with its more efficient delivery of nicotine. Although we must be cautious in comparing findings between these different studies, it is interesting to note that the increase in BP and HR was also greater after using the 4th-generation pod-like device compared with the earlier-generation devices.

Increased sympathetic tone, either acute or chronic, is associated with increased cardiovascular risk (15, 27, 28). This observation is the rationale for the recommendation to use β-adrenergic blockers for several cardiovascular conditions, including heart failure, tachyarrhythmias, and coronary artery disease. In addition, acute increases in sympathetic nerve activity, for example, induced by use of psycho-motor stimulants (cocaine or methamphetamines), are associated with increased risk for myocardial infarction, stroke, and lethal arrhythmias (29). Although the acute increase in sympathetic tone, HR, and BP following exposures to ECs and TCs is orders of magnitude smaller than after these drugs of misuse, these changes are unlikely to be completely harmless. In fact, TC smoke is thought to act as a pharmacological “trigger” for adverse cardiovascular events since the risk of cardiovascular events, including sudden death, begins to decline toward that of a nonsmoker soon after smoking cessation (30–33). Since 34 million adult Americans currently smoke TCs, even small sympathomimetic effects have important public health implications and should not be ignored. Since our findings support the notion that the sympathomimetic and hemodynamic effects of TCs or ECs are driven by the nicotine in each product, this finding challenges the concept that ECs would be an effective long-term harm reduction strategy to decrease cardiovascular risk from smoking.

We were surprised by the finding that the increase in HR was greater following TC smoking compared with EC use despite the similar increase in plasma nicotine. We postulate that the non-nicotine constituents in TC smoke contributed to this greater increase in HR. Although this explanation is not supported by the finding that the non-nicotine TC did not increase HR, it is possible that there is a synergistic or unmasking effect of nicotine and non-nicotine constituents in smoke. Preclinical studies have reported synergistic or additive effects between various constituents in emissions from electronic cigarettes, including nicotine, acrolein, and menthol flavorings, all of which are also found in tobacco cigarette smoke (9); additional studies conducted in humans would be necessary to explore this possibility.

When people who chronically use ECs acutely used a nicotine-EC in our study, changes in HRV were recorded that mimic those associated with increased cardiac sympathetic activity and adverse cardiovascular effects. This raises concerns about the long-term safety of ECs in chronic EC users, specifically as part of a harm reduction strategy. Surprisingly, in our study, when people who chronically smoke TCs including dual users acutely used a nicotine-EC or a commercial TC, there was no significant change in HRV parameters compared with straw-control or no-nicotine TC. One is tempted to hypothesize an alerting response, with its accompanying increases in sympathetic outflow, in addicted TC smokers eager to smoke a cigarette were provided a TC, even one without nicotine. The fact that the non-nicotine TC, which looks and feels just like a commercial cigarette, elicited a similar effect on HRV as the nicotine-containing exposures seems to support this hypothesis. That there was no difference between the exposures and the straw-control is more difficult to explain, but perhaps the tactile and behavioral aspects of puffing on an empty straw were sufficient to replicate the pharmacological effects of the inhaled emissions. Further studies may be best used to investigate this interesting but perplexing finding. In the TC-D group, only the change in nicotine delivered by the EC5 device, not the TCN, was weakly correlated with the change in HRV, although the increase in HR was correlated with the increase in nicotine after using either nicotine-containing product. We were also surprised that in the correlation analysis of people who exclusively use ECs, the change in nicotine was only correlated with change in HR, not changes in HRV or other hemodynamic variables. These findings may be explained by insufficient power, and warrant further study in a larger group.

Again, the finding that acute EC use in people who chronically use ECs produces a pattern in HRV consistent with increased sympathetic activity coupled with the findings that the hemodynamic effects of acute EC use are similar to those associated with acute TC use, supports the notion that if ECs are used as part of a smoking cessation strategy, they should be used for the shortest duration possible. They are not harmless.

Limitations

Although we used a 4th generation pod device for these studies, we only used one brand and flavor. There are many 4th generation devices on the market. This lack of a standardized product makes it difficult to effectively quantify the EC burden as each product may deliver nicotine at different dosages. Additional studies are warranted using other 4th generation devices. The history of EC and TC use was self-reported by our participants and is difficult to verify or standardize. We overcame this challenge by measuring plasma cotinine levels as an objective, shared indicator for smoking burden that can be compared between cohorts. The plasma cotinine levels for both people who exclusively use ECs and people in the TC-D group were low on average, indicating that our participants were light users. There was a delay from tobacco product exposure to postexposure recording of HR, BP, and HRV in our protocol, so early and transient changes in these variables induced by nicotine-free tobacco products may have been missed. Nonetheless, since this delay was likely between 10 and 15 min, any changes in hemodynamics would have been quite transient, with uncertain clinical significance. Twelve people who use both ECs and TCs were included with the people who smoke tobacco cigarettes, allowing a larger group for the acute exposure comparisons. Unfortunately, too few individuals who use both types of tobacco products were enrolled to allow a separate analysis as a distinct group. Although acutely using an EC induced potentially adverse acute changes in HRV in people who use ECs chronically, the duration of these changes and their clinical implications remains to be investigated.

Summary

In summary, these findings support the notion that nicotine, not non-nicotine constituents in emissions from TCs or ECs, is the instigator of the acute, potentially adverse, changes in hemodynamics and HRV that accompany tobacco product use. If ECs are used as part of a smoking cessation strategy, they should be used for the shortest duration possible. They are not harmless.

DATA AVAILABILITY

The data that support this study are available at https://doi.org/10.6084/m9.figshare.24719670.

SUPPLEMENTAL DATA

Supplemental Figs. S1–S3: https://doi.org/10.6084/m9.figshare.24939735.

GRANTS

This work was supported by Tobacco-Related Diseases Research Program T29IP0319 and by the NIH National Center for Advancing Translational Science (UCLA CTSI) under Grant No. L1TR001881.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

H.R.M. conceived and designed research; R.N., I.R., K.L., and J.M. performed experiments; R.N. analyzed data; R.N. and H.R.M. interpreted results of experiments; R.N. prepared figures; R.N. and H.R.M. drafted manuscript; I.R., K.L., and J.M. edited and revised manuscript; R.N., I.R., K.L., J.M., and H.R.M. approved final version of manuscript.