Chronic E-Cigarette Use Impairs Endothelial Function on the Physiological and Cellular Levels.

BACKGROUND: The harmful vascular effects of smoking are well established, but the effects of chronic use of electronic cigarettes (e-cigarettes) on endothelial function are less understood. We hypothesized that e-cigarette use causes changes in blood milieu that impair endothelial function. METHODS: Endothelial function was measured in chronic e-cigarette users, chronic cigarette smokers, and nonusers. We measured effects of participants' sera, or e-cigarette aerosol condensate, on NO and H2O2 release and cell permeability in cultured endothelial cells (ECs). RESULTS: E-cigarette users and smokers had lower flow-mediated dilation (FMD) than nonusers. Sera from e-cigarette users and smokers reduced VEGF (vascular endothelial growth factor)-induced NO secretion by ECs relative to nonuser sera, without significant reduction in endothelial NO synthase mRNA or protein levels. E-cigarette user sera caused increased endothelial release of H2O2, and more permeability than nonuser sera. E-cigarette users and smokers exhibited changes in circulating biomarkers of inflammation, thrombosis, and cell adhesion relative to nonusers, but with distinct profiles. E-cigarette user sera had higher concentrations of the receptor for advanced glycation end products (RAGE) ligands S100A8 and HMGB1 (high mobility group box 1) than smoker and nonuser sera, and receptor for advanced glycation end product inhibition reduced permeability induced by e-cigarette user sera but did not affect NO production. CONCLUSIONS: Chronic vaping and smoking both impair FMD and cause changes in the blood that inhibit endothelial NO release. Vaping, but not smoking, causes changes in the blood that increase microvascular endothelial permeability and may have a vaping-specific effect on intracellular oxidative state. Our results suggest a role for RAGE in e-cigarette-induced changes in endothelial function.

Modeling Cardiovascular Risks of E-Cigarettes With Human-Induced Pluripotent Stem Cell-Derived Endothelial Cells.

BACKGROUND: Electronic cigarettes (e-cigarettes) have experienced a tremendous increase in use. Unlike cigarette smoking, the effects of e-cigarettes and their constituents on mediating vascular health remain understudied. However, given their increasing popularity, it is imperative to evaluate the health risks of e-cigarettes, including the effects of their ingredients, especially nicotine and flavorings. OBJECTIVES: The purpose of this study was to investigate the effects of flavored e-cigarette liquids (e-liquids) and serum isolated from e-cigarette users on endothelial health and endothelial cell-dependent macrophage activation. METHODS: Human-induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) and a high-throughput screening approach were used to assess endothelial integrity following exposure to 6 different e-liquids with varying nicotine concentrations and to serum from e-cigarette users. RESULTS: The cytotoxicity of the e-liquids varied considerably, with the cinnamon-flavored product being most potent and leading to significantly decreased cell viability, increased reactive oxygen species (ROS) levels, caspase 3/7 activity, and low-density lipoprotein uptake, activation of oxidative stress-related pathway, and impaired tube formation and migration, confirming endothelial dysfunction. Upon exposure of ECs to e-liquid, conditioned media induced macrophage polarization into a pro-inflammatory state, eliciting the production of interleukin-1ß and -6, leading to increased ROS. After exposure of human iPSC-ECs to serum of e-cigarette users, increased ROS linked to endothelial dysfunction was observed, as indicated by impaired pro-angiogenic properties. There was also an observed increase in inflammatory cytokine expression in the serum of e-cigarette users. CONCLUSIONS: Acute exposure to flavored e-liquids or e-cigarette use exacerbates endothelial dysfunction, which often precedes cardiovascular diseases.

Thirdhand Smoke at Philip Morris.

INTRODUCTION: Thirdhand cigarette smoke is the fraction of cigarette smoke that remains in the environment long after a cigarette is extinguished. METHODS: The Truth Tobacco Industry Documents collection at the University of California San Francisco was searched for information on thirdhand smoke. RESULTS: In 1991, scientists at Philip Morris Inc conducted some of the first studies on thirdhand cigarette smoke. For 110 days, 8 hours a day, they ran sidestream cigarette smoke through a 30 m3 room that contained carpet, curtain, and textured wallpaper. The room was ventilated with clean air every night. By comparing the chemicals in the air during the 8-hour smoking period and during the clean air ventilation period, they showed that some smoke chemicals persist in the air 12 hours after smoking. By extracting the nicotine and nitrosamines from samples of the carpet, curtain, and wallpaper, they found that high concentrations of nicotine and the carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) persisted in the room for more than 50 days; that surface chemistry affected nitrosamine concentrations; and that the concentration of NNK in the room, 110 days after the last cigarette was extinguished, could exceed the mass of NNK that entered the room as smoke. CONCLUSIONS: These data, from a controlled environment where the total number of cigarettes smoked is known, provide further evidence that cigarette smoke chemicals remain in the environment for months after smoking, that they reemit back into the air, and that they react to form new toxins and carcinogens. Smoke-free policies are the best method to reduce exposure to thirdhand smoke. IMPLICATIONS: This unpublished, original research from Philip Morris Inc demonstrates that majority of the nicotine and tobacco-specific nitrosamines in the secondhand smoke from each cigarette smoked indoors remains on indoor surfaces for months after the cigarette is extinguished. It also demonstrates that elevated concentrations of nicotine, ammonia, formaldehyde, and the gas-phase nitrosamine, N-nitrosopyrrolidine, can be found in the air for more than 12 hours after smoking; that surface chemistry affects nitrosamine formation and persistence; and that the amount of the carcinogenic nitrosamine NNK that persists months after smoking ends can exceed the amount that actually came out of the cigarettes.