Alessandra Caporale1, Shampa Chatterjee2, Michael C Langham1, Wensheng Guo3, Frank Leone4, Andrew Strasser5, and Felix W Wehrli1
1Radiology, Laboratory for Structural, Physiologic and Functional Imaging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States, 2Physiology, Institute for Environmental Medicine, Perelman School of Medicine, Philadelphia, PA, United States, 3Biostatistics and Epidemiology, Perelman School of Medicine, Philadelphia, PA, United States, 4University of Pennsylvania Medical Center, Pulmonary, Allergy & Critical Care Division, Philadelphia, PA, United States, 5Psychiatry, Center for Interdisciplinary Research on Nicotine Addiction, Philadelphia, PA, United States
Synopsis
The vascular effects of e-cigarette use were investigated in young
adults (19-35 years). Blood draws and 3T-MRI data were collected from seven
e-cigarette users, seven smokers, thirty nonsmokers, the latter replicating
the measurements after one nicotine-free e-cigarette vaping session. MRI-protocol
measured peripheral vascular reactivity in response to cuff-induced ischemia, quantifying
femoral artery luminal flow mediated dilation (FMDL), blood flow
velocity, venous saturation (SvO2).
FMDL decreased by 33% acutely after vaping, consistent with 20%
NOx reduction and elevated inflammation (C-reactive protein increased by 95%). Reactive
hyperemia was blunted as a chronic effect of both smoking and vaping, paired
with anomalous biomarkers.
Introduction
Electronic cigarette
(e-cig) use, or vaping, has increased alarmingly among teenagers, with one
vaper in five high school students, according to recent surveys[1]. Rather than being harmless water vapor, e-cig
aerosol contains heavy metals, ultra-fine particles, free radicals, toxicants
and carcinogens[2-4], and when inhaled in
the presence of nicotine, it is known to cause acute endothelial dysfunction[5]. Previously, we investigated whether e-cig
aerosol inhalation, in the absence of nicotine, had acute and detrimental effects
on the vascular endothelium, and we were able to quantify these effects using a
battery of quantitative MRI parameters (qMRI)[6].
Briefly, in nonsmokers after a
single episode of vaping, peripheral vascular reactivity (PVR) was
significantly impaired in the femoral vessels, with reduced arterial blood flow
velocity (BFV) peak and upslope during reactive hyperemia, decreased luminal
flow mediated dilation, and a drop in venous oxygen saturation (SvO2)[6]. In this work, we examined the relation
between qMRI and biomarkers of oxidative stress and inflammation extracted from
the blood serum of non-smokers, after acute exposure to non-nicotinized e-cig
aerosol. In addition, we compared PVR measurements and serum markers between
the non-smokers group and a small group of newly recruited smokers and e-cig
users, to observe the effect of chronic exposure to e-cig aerosol or
conventional smoke on the vascular endothelium. Methods
Single
users of either conventional cigarette (smokers) or e-cig (vapers), with a
history of smoking/vaping of at least one year (Figure 1A) were recruited. Smokers and e-cig users underwent a
single blood draw followed by a three-step MRI
protocol (Figure 1B-D) performed at
3T (Siemens Prisma). Non-smokers only were subjected to an e-cig challenge
entailing vaping a nicotine-free e-cig (16 puffs, 3s each; qMRI reported in [6]). The present study encompasses results
of the first part of the MRI
protocol only, quantifying PVR to cuff-induced ischemia. A
sphygmomanometer cuff (Hokanson, Bellevue, Wash) was placed proximal to the
superficial femoral vessels. After a baseline
period (2 min) the cuff was inflated quickly for 5 min to 210–220 mmHg,
allowing 5 min of recovery, post-deflation (Figure 2A). An eight-channel extremity transmitter-receiver coil
(Invivo, Pewaukee, Wis) was used for the MRI scans (sequence details in [6]). The red and blue blocks in Figure 2B-C represent the time-resolved
acquisition of blood flow velocity (BFV), and venous oxygen saturation (SvO2)
measurement via MRI susceptometry[7], at baseline. Immediately after cuff release, BFV
and SvO2 were resolved dynamically during the same TR cycle, at
reactive hyperemia (Figure 2D). At
rest and additional three time points post cuff release the arterial lumen was
measured with high resolution rapid vessel-wall imaging (Figure 2E) to quantify luminal flow mediated dilation (FMDL)
as the fractional change in arterial lumen. Concentrations of nitric oxide
metabolites (NOx) and C-reactive protein (CRP), markers of oxidative stress and
inflammation, respectively, were measured via ELISA and colorimetric assays of
serum. Post vs pre-e-cig vaping differences in the serum biomarkers and qMRI
were evaluated with Hotelling’s T2 test, together with Pearson’s
correlation coefficients between qMRI and serum biomarkers. Differences between
the three groups of non-smokers (before e-cig vaping), smokers and vapers were
assessed by means of Dunnett’s test, considering non-smokers as the comparison group. Results and Discussion
Serum markers and most of the qMRI-metrics of PVR showed significant alterations post vs pre (nicotine-free) e-cig vaping (Figure 3). FMDL was impaired by over 30% (P<0.0001), together with NOx reduction (-20%, from 35.3 to 28.2 µmol/L; P<0.005). This could result from enhanced reactive oxygen species formation upon exposure of the vascular endothelium to nicotine-free e-cig aerosol[8], limiting NO bioavailability. There was large inter-subject variability of the inflammatory burden in the circulating serum, expressed by CRP. Pre-vaping, non-smokers with lower CRP levels showed larger FMDL, consistent with prior findings[9]. Post-vaping, CRP almost doubled (+95%, from 428.6 to 835.6 ng/ml; P<0.005), and measures of dynamic oxygen saturation (SvO2) were altered, including lower pre-cuff SvO2b, increased overshoot and shorter washout time (Tw). Reactive hyperemia was blunted acutely in nonsmokers post-vaping, as indicated by reduced peak velocity (VP), upslope (HI), and area under the hyperemic curve, (AUCa); reduced VP and HI were found also in e-cig vapers, as well as smokers (Figure 4), the latter confirming previous findings[7]. Preliminary results of comparison among the three groups (Figure 5), show that NOx bioavailability was significantly reduced after chronic exposure to e-cig aerosol (with nicotine). Systemic inflammation was higher in smokers, with CRP levels comparable between vapers and the nonsmokers’ group. In distinction, RI was increased similarly in smokers and vapers, suggesting greater vascular resistance, which may be due to increased blood viscosity. Reactive hyperemia AUC was significantly lower in smokers than in non-smokers (P<0.05) and trended towards lower values in vapers, as well as did hyperemic peak (VP). Conclusions
E-cig inhalation elicits
acute endothelial dysfunction in healthy nonsmoking adults and triggers an
inflammatory response, even in the absence of nicotine. Chronic exposure to e-cig aerosol for more than one year
seems to reduce the bioavailability of NO, increase vascular resistance, and
to alter peripheral vascular reactivity, comparably to tobacco smoking, albeit
without increasing noticeably serum CRP levels. The results in smokers and vapers need to
be interpreted with caution given the limited sample size. Acknowledgements
This study was supported by the National Institutes of Health, National Heart, Lung, and Blood Institute (R01 HL109545, R01HL139358).References
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