Mary Rezk‐Hanna, PhD https://orcid.org/0000-0001-9926-5276 mrezk@ucla.edu, Rajat Gupta, MS https://orcid.org/0000-0003-2887-1935, Primadya Sakti, BS https://orcid.org/0009-0005-8606-8018, Chiao‐Wei Cheng, MPH, CPH https://orcid.org/0000-0003-4958-1152, Mary‐Lynn Brecht, PhD, Neal L. Benowitz, MD https://orcid.org/0000-0003-2041-8124, and Jesus A. Araujo, MD, PhD
https://doi.org/10.1161/JAHA.125.041217
Use of flavored electronic nicotine delivery systems (ENDS) has rapidly increased worldwide, particularly among youth.1 Unlike e‐cigarettes, e‐hookahs are a novel category of ENDS that are integrated into traditional waterpipes, allowing the aerosol to pass through water before inhalation. Evidence on the effects of ENDS on cardiovascular disease–related biomarkers is limited. Some laboratory studies suggest that vaping may increase cardiovascular disease risk,1 but the relative contributions of nicotine and flavored e‐liquid remain unclear.
We have previously demonstrated that, compared with vaping e‐hookah without nicotine, e‐hookah with nicotine acutely impaired endothelial function by reducing nitric oxide bioavailability and increasing reactive oxidative species production.2 We concluded that these effects were attributable to nicotine in the flavored liquid. However, we could not exclude the possibility that nonnicotine constituents are problematic. Herein, we investigated the contribution of nicotine in mediating the acute effects of e‐hookah vaping on selected cardiovascular disease–related biomarkers. To assess pro‐oxidative and proinflammatory effects, we measured plasma fibrinogen (a major plasma protein coagulation factor and marker of inflammation), paraoxonase‐1 activity (marker of oxidative stress), high‐density lipoprotein (HDL) antioxidant capacity determined by an HDL oxidant index, and plasma nicotine levels in healthy young adults before and after vaping e‐hookah with and without nicotine.
In a randomized crossover design, 16 habitual hookah smokers who do not smoke cigarettes (19% women; age, 26±1 years) completed three 30‐minute vaping sessions (nicotine‐containing, non–nicotine‐containing, sham as control) using an e‐hookah (Starbuzz E‐head) placed on a waterpipe, randomized using a computerized random number generator (M.R.H.) and separated by a ≥7‐day washout period. Inclusion criteria included having smoked hookah at least 12 times in the past 12 months, no cardiopulmonary disease by history/physical examination, blood pressure <140/90 mm Hg, body mass index ≥18.5 and <30 kg m2, and resting heart rate <100 beats/min. Exclusion criteria included having smoked cigarettes in the past 12 months or smoked >100 cigarettes in life, having smoked marijuana in the past 12 months or a positive urine tetrahydrocannabinol screen, taking prescription medication, pregnant or breastfeeding, and end‐expiratory carbon monoxide ≥10 ppm. Participants were recruited starting January 2020, and all sessions were completed by November 2022. All participants vaped the same fruit‐flavored liquid (Simply Mango) containing 50/50 propylene glycol/vegetable glycerin and 6 mg/mL or 0 mg/mL nicotine (Starbuzz Tobacco), following puffing parameters observed in natural settings (ie, ad libitum in hookah cafes: 3‐second puff at 20‐second intervals). The device power was set at 50 W on the basis of subjects' preference. Plasma biomarkers were measured before and within 10 minutes after vaping. The study was conducted at and approved by the University of California, Los Angeles, and informed written consent was obtained from participants. This trial followed the Consolidated Standards of Reporting Trials guidelines.
Plasma fibrinogen levels were determined using the Clauss clotting method. Assessment of paraoxonase‐1 activity, linked to HDL function, via its ability to hydrolyze paraoxon, and HDL antioxidant capacity was evaluated by measuring its inhibition of low‐density lipoprotein–induced oxidation of dihydrodichlorofluorescein, as detailed previously.3 Plasma nicotine was quantified using gas chromatography with nitrogen–phosphorus detection. A priori power calculation estimated a recruitment sample of 18 participants with paired observations to allow detection of medium‐to‐large effects of d=0.61 with power=0.80 and 2‐tailed α=0.05 when comparing from pre‐ versus postvaping outcomes for each condition. Two participants were excluded from analysis due to suboptimal data quality, resulting in an analysis sample of n=16, allowing detection of large effects of d=0.75 with power=0.80 and 2‐tailed α of 0.05 for paired comparisons. Because within‐participant change pre‐ versus postvaping met normality assumptions for each measure, we tested this change using paired t tests. Data were analyzed with condition assignments masked using subject ID codes; data are available from the corresponding author upon request.
E‐hookah vaping with nicotine increased plasma nicotine by 5.74 ng/mL (95% CI, 3.00–8.47; P<0.001), heart rate (+8‐bpm [95% CI, 1–14]; P=0.02), and mean arterial pressure (+6‐mm Hg [95% CI, 2–10]; P=0.01), while no changes were observed after vaping e‐hookah without nicotine. Vaping e‐hookah with or without nicotine increased plasma fibrinogen (+9.20‐mg/dL [95% CI, 3.33–15.07]; P=0.01; +12.50‐mg/dL [95% CI, 3.05–21.95]; P=0.01, respectively), with vaping without nicotine inducing greater, but not statistically significant, increases as compared with vaping with nicotine (Figure). No changes were observed in paraoxonase‐1 activity and HDL oxidative index. All parameters were unchanged after control. No adverse events were reported during the study sessions.
The acute hemodynamic effects observed after e‐hookah vaping align with the sympathomimetic effects of nicotine. While nicotine may exert anti‐inflammatory effects, through stimulation of the cholinergic immune system, nicotine may also exert proinflammatory effects through its role as a chemotactic agent on leukocytes.4 The significant acute increase in plasma fibrinogen after e‐hookah vaping without nicotine, indicates that nonnicotine components in the tested e‐hookah liquid contribute to increasing this acute‐phase reactant. Our findings align with a prior in vivo study showing that vaping other ENDS, such as e‐cigarettes, both with and without nicotine had detrimental effects on biomarkers of inflammation and oxidative stress.5 That study identified acrolein, a reactive aldehyde, as the likely causal agent for these adverse cardiovascular effects.5 Because acrolein derives mostly from vegetable glycerin heated at relatively high temperatures, we speculate that the preference among e‐hookah users to vape at higher wattages, as compared with e‐cigarette users, may increase acrolein production, exacerbating cardiovascular risk.
The lack of detectable effects on antioxidant parameters may be related to the single postexposure measurement. It is plausible that testing several hours later would reveal delayed effects on oxidative stress burden or prolonged effects on inflammation. Because the e‐hookah aerosol passes through water before inhalation, findings may not be generalizable to other ENDS that do not involve water exposure. The small sample size and the use of only 1 flavor limits the generalizability of our findings.
The main finding of this study is that acute e‐hookah vaping increases plasma fibrinogen levels, even without the presence of nicotine, implying an increased proinflammatory and procoagulant state. These findings enhance our understanding of the cardiovascular consequences of e‐hookah vaping, suggesting that nonnicotine vaping liquids have the potential to enhance cardiovascular disease risk. Given the lack of regulation on flavored ENDS, further regulatory scrutiny is warranted to mitigate cardiovascular harm, particularly among youth and young adults.
Sources of Funding
This study was funded by the University of California Tobacco‐Related Disease Research Program, University of California (#T30IP1013). Analytical chemistry and laboratory infrastructure at the University of California, San Francisco was supported by the National Institute of Drug Abuse (Grant P30 DA12393).
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