Vascular Effects of E-Cigarettes

Overseen By Anna Reid-Stanhewicz, PHD

Age: 18 - 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: Anna Stanhewicz, PhD

Must not be taking: Antihypertensives, Statins, Stimulants, others

Disqualifiers: Cardiovascular, Metabolic, Skin diseases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

80 Participants Needed

Trial Summary

What is the purpose of this trial?

The use of electronic nicotine delivery systems, or e-cigarettes - colloquially referred to as "vaping" - in the United States has increased exponentially since their introduction to the US market in 2007. Prevalence of ever and current e-cigarette use is highest among teenagers and young adults with 16-28% of this population having reported vaping. While the majority of e-cigarette users are current tobacco smokers, 32.5% of current e-cigarette users are never- or former-smokers, representing a growing population of young adults who exclusively vape. While e-cigarettes have been marketed as a safer alternative to tobacco cigarettes, clinical studies examining these claims are limited. Cardiovascular disease (CVD) is the primary cause of premature death among tobacco cigarette smokers and reductions in vascular endothelial function, a significant predictor of future CVD, are detectible in otherwise healthy young adults who smoke. Despite the explosion in e-cigarette use among young adults, the health effects - especially the effects on mechanisms of vascular function - of these devices remain relatively unexplored. In this study, we use the blood vessels in the skin as a representative vascular bed for examining mechanisms of microvascular dysfunction in humans. Using a minimally invasive technique (intradermal microdialysis for the local delivery of pharmaceutical agents) we examine the blood vessels in a dime-sized area of the skin in otherwise healthy young (18-24yrs) chronic e-cigarette users. Local heating of the skin at the microdialysis sites is used to explore differences in mechanisms governing microvascular control. As a compliment to these measurements, we also draw blood from the subjects to measure circulating factors that may contribute to cardiovascular health and examine markers of inflammatory activation. We will also collect urine from female participants to measure estradiol.

Will I have to stop taking my current medications?

The trial requires that you do not currently use antihypertensive or cholesterol-lowering medications, so you would need to stop these if you are taking them. The protocol does not specify about other medications.

What data supports the effectiveness of the treatment involving e-cigarettes and chronic estrogen exposure?

The research indicates that e-cigarettes can effectively deliver nicotine, as shown by increased plasma nicotine levels in users. This suggests that e-cigarettes are efficient in delivering substances, which might imply potential effectiveness in delivering other treatments, such as chronic estrogen exposure, although direct evidence for this specific combination is not provided. ^{1 2 3 4 5}

How does the treatment involving chronic estrogen exposure, local heating, and L-NAME differ from other treatments for vascular effects of e-cigarettes?

This treatment is unique because it combines chronic estrogen exposure with local heating and L-NAME (a compound that inhibits nitric oxide production) to study their effects on vascular health, particularly in the context of e-cigarette use. Unlike other treatments, this approach specifically targets the microvascular function and endothelial response, which are crucial in understanding the vascular impact of e-cigarettes. ^{6 7 8 9 10}

Eligibility Criteria

This trial is for healthy young adults aged 18-24 who either have never used e-cigarettes or have been vaping regularly for at least 6 months. Participants should not have any cardiovascular, metabolic, skin diseases, obesity, high blood pressure, a history of smoking tobacco cigarettes or using illegal substances. Pregnant or breastfeeding individuals and those with allergies to latex or study drugs are also excluded.

Inclusion Criteria

I either have never used e-cigarettes or have been using them for over 6 months.

Exclusion Criteria

I have a history of heart, metabolic, or skin conditions.

Currently pregnant or breastfeeding

Body mass index >30 kg/m2

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Study Visit

Participants undergo intradermal microdialysis and local heating to examine microvascular function, with blood and urine samples collected

1 day

1 visit (in-person)

Follow-up

Participants are monitored for changes in microvascular function and estrogen exposure

1 month

Treatment Details

Interventions

• Chronic estrogen exposure
• Local heating + L-NAME

Trial Overview The study investigates how chronic e-cigarette use affects the blood vessels in young adults by comparing non-users to regular users. It involves local heating of the skin and administering L-NAME via microdialysis to test vascular function. Blood and urine samples will be collected from participants to analyze cardiovascular health markers and inflammation.

Participant Groups

Group I: Young Women using E-cigarettes Experimental Treatment 2 Interventions

Young women chronically use e-cigarettes

Group II: Young Men using E-cigarettes Experimental Treatment 1 Intervention

Young men chronically use e-cigarettes

Group III: Healthy Young Women Experimental Treatment 2 Interventions

Young women who do not use e-cigarettes

Group IV: Healthy Young Men Experimental Treatment 1 Intervention

Young men who do not use e-cigarettes

Who Is Running the Clinical Trial?

Anna Stanhewicz, PhD

Lead Sponsor

Trials

12

Recruited

460+

Findings from Research

Identifying selective biomarkers for electronic nicotine delivery systems (ENDS) is challenging because their aerosols do not contain unique substances, making it hard to distinguish ENDS use from other tobacco or environmental sources.

The study introduces two new LC-MS/MS methods to measure specific tobacco alkaloids and metabolites that can help confirm the use of conventional tobacco products, which can improve the accuracy of assessing ENDS exposure and dual use with traditional cigarettes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Minor Tobacco Alkaloids as Biomarkers to Distinguish Combusted Tobacco Use From Electronic Nicotine Delivery Systems Use. Two New Analytical Methods. Jacob, P., Chan, L., Cheung, P., et al.[2022]

In a study involving 45 participants (22 cigarette smokers and 23 ENDS users), higher concentrations of protonated nicotine and increased device power led to greater plasma nicotine delivery, indicating that both factors significantly affect nicotine absorption.

ENDS users experienced higher nicotine delivery compared to cigarette smokers, and they also took longer and larger puffs, suggesting that device design and liquid formulation play crucial roles in user experience and nicotine intake.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interactive effects of protonated nicotine concentration and device power on ENDS nicotine delivery, puff topography, and subjective effects. Eversole, A., Budd, S., Karaoghlanian, N., et al.[2023]

A new method for self-administering vaporized nicotine in rats shows that both male and female rats can consistently engage in nicotine vapor self-administration, indicating its potential for studying nicotine's effects.

The study found that while male rats achieved similar blood levels of nicotine's metabolite, cotinine, from vapor as from intravenous administration, female rats had lower cotinine levels with vapor, highlighting significant sex differences in nicotine intake and response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotine e-cigarette vapor inhalation and self-administration in a rodent model: Sex- and nicotine delivery-specific effects on metabolism and behavior. Lallai, V., Chen, YC., Roybal, MM., et al.[2022]

In a study involving 32 participants (19 exclusive ENDS users and 13 dual users), it was found that lower nicotine concentrations combined with higher device power settings led to increased abuse liability, as users worked harder for puffs in the low nicotine/high watt condition.

Limiting nicotine concentration alone may not effectively reduce the risk of abuse associated with electronic nicotine delivery systems, as users may compensate by increasing device power to achieve desired nicotine delivery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The interaction of nicotine concentration and device power on electronic nicotine delivery system (ENDS) abuse liability among exclusive ENDS users and dual users of ENDS and combustible cigarettes. Hoetger, C., Bono, RS., White, AM., et al.[2022]

The study successfully developed an e-cigarette nicotine delivery system that produced effects similar to subcutaneous nicotine injection in both female and male mice, demonstrating its efficacy in delivering pharmacologically active doses of nicotine.

Sex differences were observed in the effects of nicotine, with females experiencing greater hypothermia from aerosol exposure and males from injection, while females consistently had higher nicotine and cotinine levels in plasma and brain, regardless of the administration route.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Delivery of nicotine aerosol to mice via a modified electronic cigarette device. Lefever, TW., Lee, YO., Kovach, AL., et al.[2019]

In a study involving 22 healthy volunteers, inhaling electronic cigarette aerosol with nicotine significantly increased both platelet and fibrin-rich thrombus formation shortly after exposure, indicating a potential risk for vascular health.

The same exposure also reduced the capacity for microvascular dilation, suggesting that nicotine in e-cigarettes can negatively impact blood vessel function, while no significant effects were observed with nicotine-free aerosol.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Electronic Cigarette Vaping with Nicotine Causes Increased Thrombogenicity and Impaired Microvascular Function in Healthy Volunteers: A Randomised Clinical Trial. Lyytinen, G., Brynedal, A., Anesäter, E., et al.[2023]

In a study involving 40 healthy adults (20 smokers and 20 nonsmokers), both e-cigarettes and traditional cigarettes significantly increased oxidative stress and decreased endothelial function, as measured by flow-mediated dilation (FMD).

However, e-cigarettes appeared to have a lesser impact on certain oxidative stress markers compared to traditional cigarettes, suggesting they may be somewhat less harmful in the short term, although both still have negative vascular effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute Impact of Tobacco vs Electronic Cigarette Smoking on Oxidative Stress and Vascular Function. Carnevale, R., Sciarretta, S., Violi, F., et al.[2017]

A study using intravital microscopy on anesthetized mice showed that both electronic cigarette (E-cig) aerosol and traditional cigarette smoke caused similar vasoconstriction responses in skeletal muscle, indicating that E-cigs may not be safer for vascular health than regular cigarettes.

The research found that the vasoconstriction effect was not dependent on nicotine and was consistent regardless of the e-liquid's base solution composition, suggesting that harmful components other than nicotine in both E-cigs and cigarettes contribute to adverse vascular effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotine and Microvascular Responses in Skeletal Muscle from Acute Exposure to Cigarettes and Vaping. Pitzer, CR., Aboaziza, EA., O'Reilly, JM., et al.[2023]

Inhaling aerosol from nicotine-free e-cigarettes significantly impaired endothelial function in healthy nonsmokers, as evidenced by reduced luminal flow-mediated dilation and other markers of vascular reactivity, based on a study of 31 participants.

The study found that even without nicotine, e-cigarette aerosol can lead to transient changes in vascular health, suggesting potential long-term risks that warrant further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute Effects of Electronic Cigarette Aerosol Inhalation on Vascular Function Detected at Quantitative MRI. Caporale, A., Langham, MC., Guo, W., et al.[2020]

In a study involving 16 young, healthy participants, vaping electronic cigarettes with either 0% or 5.4% nicotine did not result in significant changes to heart rate, blood pressure, or vascular functions over a 2-hour period.

The findings suggest that, at least in the short term, vaping does not have acute adverse effects on vascular health in tobacco product naïve individuals, challenging the perception that e-cigarettes are inherently harmful compared to traditional tobacco cigarettes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vascular effects of a single bout of electronic cigarette use. Cossio, R., Cerra, ZA., Tanaka, H.[2021]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Minor Tobacco Alkaloids as Biomarkers to Distinguish Combusted Tobacco Use From Electronic Nicotine Delivery Systems Use. Two New Analytical Methods. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Interactive effects of protonated nicotine concentration and device power on ENDS nicotine delivery, puff topography, and subjective effects. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Nicotine e-cigarette vapor inhalation and self-administration in a rodent model: Sex- and nicotine delivery-specific effects on metabolism and behavior. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

The interaction of nicotine concentration and device power on electronic nicotine delivery system (ENDS) abuse liability among exclusive ENDS users and dual users of ENDS and combustible cigarettes. [2022]

5. Ireland pubmed.ncbi.nlm.nih.gov

Delivery of nicotine aerosol to mice via a modified electronic cigarette device. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Electronic Cigarette Vaping with Nicotine Causes Increased Thrombogenicity and Impaired Microvascular Function in Healthy Volunteers: A Randomised Clinical Trial. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Acute Impact of Tobacco vs Electronic Cigarette Smoking on Oxidative Stress and Vascular Function. [2017]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Nicotine and Microvascular Responses in Skeletal Muscle from Acute Exposure to Cigarettes and Vaping. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Acute Effects of Electronic Cigarette Aerosol Inhalation on Vascular Function Detected at Quantitative MRI. [2020]

10. Australia pubmed.ncbi.nlm.nih.gov

Vascular effects of a single bout of electronic cigarette use. [2021]