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E-Cigarette Use and Subclinical Cardiac Effects
Florian Rader, MD, MS;a Mohamad A. Rashid, MBChB;a Trevor Trung Nguyen, BS;a
Eric Luong, MPH;a Andy Kim, BA;a a Elizabeth H. Kim, BA;a Robert Elashhoff, PhD;c
Katherine Davoren, MD, PharmD;b Norma B. Moy, BA;a Fida Nafeh, RDCS;a
C. Noel Bairey Merz, MD;a Joseph E. Ebinger, MD;a Naomi M. Hamburg, MD, MS;d
Jonathan R. Lindner, MDe Susan Cheng, MD, MMSc, MPHa
a Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA;
b Division of Nephrology, University of Massachusetts School of Medicine, Worchester, MA;
c University of California Los Angeles School of Public Health, Los Angeles, CA;
d Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA; and,
e Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR.
Correspondence: Florian Rader, MD, MSc, Smidt Heart Institute, Cedars-Sinai Medical
Center, Los Angeles, CA; phone (310) 423-3880; fax (310) 423-4627; [email protected];
and, Susan Cheng, MD, MMSc, MPH, Smidt Heart Institute, Cedars-Sinai Medical Center, Los
Angeles, CA; phone (310) 423-9680; fax (310) 423-9680; [email protected].
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2
ABSTRACT
BACKGROUND. Electronic (e-) cigarettes are marketed as a safer alternative to conventional
tobacco cigarettes. Although e-cigarettes contain a lower level of nicotine, the delivery method
involves delivering an aerosolized bolus of poorly-characterized ultrafine particles that have
unknown cardiovascular effects.
METHODS. We studied apparently adult volunteers, free of any chronic disease, including: non-
smoking controls, chronic e-cigarette users, and chronic tobacco cigarette smokers. After
overnight abstinence, we used myocardial contrast echocardiography to measure acute
increases in myocardial blood flow (MBF)induced by ischemic rhythmic handgrip stress, which
causes sympathetically-mediated increases in myocardial work and oxygen demand and, in
turn, shear stress, nitric oxide production, and coronary endothelial-dependent vasodilation.
RESULTS. In non-smoking controls, handgrip stress increased myocardial blood flow, reflecting
normal endothelial function. Chronic tobacco cigarette smokers demonstrated stress-induced
blunting in myocardial blood flow change, when compared to non-smoking controls. Chronic e-
cigarette smokers demonstrated a decrease, rather than increase, in myocardial blood flow
change.
CONCLUSION. Chronic e-cigarette users demonstrated substantially impaired coronary
microvascular endothelial function, even more pronounced than that seen in chronic tobacco
cigarette users. These findings suggest that chronic e-cigarette use leads to measurable and
persistent adverse vascular effects that are not directly related to nicotine.
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3
BACKGROUND
E-cigarette (vaping) devices continue to be perceived as a safer alternative to conventional
tobacco cigarettes. While providing variable and sometimes lower amounts of nicotine, e-
cigarettes rely on a battery-powered aerosolization method that involves delivering with each
inhalation a bolus of poorly-characterized small molecules (e.g. ultra-fine particles, heavy
metals, volatile organic compounds). Recent reports have now linked e-cigarette use with toxic
inhalation syndromes and risk for severe pulmonary disease.1 Beyond direct lung injury, inhaled
small molecules can rapidly cross the alveolar-capillary barrier and enter into the circulation,
potentially causing harm to other end-organs including the heart.
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4
METHODS
To understand the possible cardiac effects of e-cigarette use, we prospectively studied N=30
apparently healthy adults (mean age 28±4 years, 27% female) who were free of any chronic
disease including: self-reported non-smoking controls (n=10), chronic exclusive e-cigarette
users (n=10; mean e-cigarette use 3±2 years), and chronic exclusive tobacco cigarette smokers
(n=10; mean smoking history 8±2 years). The institutional review board of Cedars-Sinai Medical
Center approved all protocols, and each study participant provided written informed consent.
Following overnight abstinence to ensure nicotine has cleared from their system (average half-
life=11 hours),2 all participants underwent myocardial contrast echocardiography (MCE)
perfusion imaging to quantify relative myocardial blood volume (MBVol), microvascular flux rate
(β), and blood flow (MBF) according to previously described methods3. Because conventional
tobacco cigarettes have been firmly established to cause both acute and chronic coronary
endothelial dysfunction and thereby initiating coronary atherosclerosis,4 MCE was used to
directly compare cigarette smoke and e-cigarette vapor exposure on coronary endothelial
function.5 Echocardiographic assessments were conducted before and after isometric handgrip
exercise (Figure 1),6 a standardized and reliable exercise stress protocol that leads to
sympathetically-mediated increases in myocardial work and oxygen demand (MVO2) and, in
turn, coronary endothelial-dependent vasodilation under normal conditions. Participants who
indicated regular use of both cigarettes and e-cigarettes (i.e. “dual users”) were placed into a
separate group which also completed the protocol. Their data was not included in this analysis
due to redundancy and time constraints.
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5
RESULTS
Normally, modest exercise stress induces physiologic increases in MBF through augmentation
in myocardial microvascular flux rate with relatively smaller degrees of increase in MBVol.
Accordinlgy, in non-smoking controls, exercise produced a statistically significant increase in
microvascular flux rate (median: 0.61pre-test vs. 1.14post-test s-1) and MBF (median: 84.3pre-test vs.
137.9post-test IU/s) (Table 1 and Supplementary Table). Exercise also increased MBF and flux
rate in tobacco users, albeit to a smaller degree than in normal controls; whereas no change in
perfusion was seen in e-cigarette users. These results indicate a significant degree of impaired
coronary endothelial function that is pronounced in chronic e-cigarette users.
To further examine whether changes in myocardial perfusion were different between groups, we
compared the percent change in MCE values between groups. The percent changes between
the post- and pre-test were compared, as opposed to the raw differences, to account for
differences in basal values. Indeed, we detected a significant difference in change of flux rate
and MBF between controls and e-cigarette users (Table 2 and Figure 2). In fact, differences
were even seen between tobacco users and e-cigarette users.
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6
DISCUSSION
Use of conventional combustible cigarettes has long been associated with vascular dysfunction
as well as incident cardiovascular disease. In this prospective study, we found evidence of
coronary microvascular endothelial dysfunction that was even worse in exclusive e-cigarettes
users than in exclusive combustible cigarette users. Importantly, these adverse cardiovascular
effects were seen to persist in apparently healthy young adult users. While the longer-term
cardiovascular consequences of e-cigarette remain unclear, our findings support the need for
further investigations into the safety profile of chronic e-cigarette use to better inform regulation
and policy.
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7
Disclosures
None.
Funding
This study was funded in part by an Exploratory/Developmental research grant TRDRP #22XT-
0017 from the California Tobacco-Related Disease Research Program, an unrestricted research
grant from Gilead Sciences, contracts from the National Heart, Lung and Blood Institutes N01-
HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, grants U01-64829, U01-HL649141,
U01-HL649241, R01-HL090957, R01-HL134168, R01-HL131532, R01-HL143227, R01-
HL078610 and R01-HL130046; and R03AG032631 from the National Institute on Aging, GCRC
grant MO1-RR00425 from the National Center for Research Resources, the National Center for
Advancing Translational Sciences Grant UL1TR000124, the Edythe L. Broad and the
Constance Austin Women’s Heart Research Fellowships, Cedars-Sinai Medical Center, Los
Angeles, California, the Barbra Streisand Women’s Cardiovascular Research and Education
Program, Cedars-Sinai Medical Center, Los Angeles, The Society for Women’s Health
Research (SWHR), Washington, D.C., the Linda Joy Pollin Women’s Heart Health Program, the
Erika Glazer Women’s Heart Health Project, and the Adelson Family Foundation, Cedars-Sinai
Medical Center, Los Angeles, California.
Acknowledgements
We dedicate this work to memory of Dr. Ronald G. Victor, MD, to whom we are indebted for his
pioneering investigations in cardiovascular physiology.
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8
REFERENCES
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JG, Mikosz CA and Meiman J. Pulmonary Illness Related to E-Cigarette Use in Illinois and
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Benowitz NL, Tashkin DP, Elashoff RM, Lindner JR and Victor RG. Acute Effect of Hookah
Smoking on the Human Coronary Microcirculation. Am J Cardiol. 2016;117:1747-54.
4. Morris PB, Ference BA, Jahangir E, Feldman DN, Ryan JJ, Bahrami H, El-Chami MF,
Bhakta S, Winchester DE, Al-Mallah MH, Sanchez Shields M, Deedwania P, Mehta LS, Phan
BA and Benowitz NL. Cardiovascular Effects of Exposure to Cigarette Smoke and Electronic
Cigarettes: Clinical Perspectives From the Prevention of Cardiovascular Disease Section
Leadership Council and Early Career Councils of the American College of Cardiology. J Am Coll
Cardiol. 2015;66:1378-91.
5. Lindner JR. Molecular imaging of cardiovascular disease with contrast-enhanced
ultrasonography. Nat Rev Cardiol. 2009;6:475-81.
6. Jake Samuel T, Beaudry R, Haykowsky MJ, Sarma S, Park S, Dombrowsky T, Bhella
PS and Nelson MD. Isometric handgrip echocardiography: A noninvasive stress test to assess
left ventricular diastolic function. Clin Cardiol. 2017;40:1247-1255.
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The copyright holder for this preprintthis version posted January 18, 2020. .https://doi.org/10.1101/2020.01.16.20017780doi: medRxiv preprint
9
Figure 1. Endothelial-Dependent Coronary Vasodilation Quantified by Myocardial
Contrast Echocardiography Before and After Static Handgrip Stress. In Panel A,
myocardial contrast echocardiography images are shown for a 30 year old healthy non-smoker.
After destruction of microbubbles at pulse interval 0, the septal myocardium (arrow) has
increased opacification at all post-destructive time intervals during static handgrip at 33%
maximal voluntary contraction, indicating increased perfusion. In this participant, both
microvascular flux rate and especially the plateau video intensity of the post-destructive time-
intensity plot, which represents myocardial blood volume, are clearly increased during static
handgrip. Time plots show increase in myocardial blood volume (A) by 21%, microvascular flux
rate (β) by 65%, and myocardial blood flow (A x β) by 99%. In Panel B, myocardial contrast
echocardiography images are shown for a 33 year old apparently healthy e-cigarette user. After
destruction of microbubbles at pulse interval 0, we would expect the septal myocardium to
opacify similarly to what was seen in the non-smoker; however, it remains dark after
microbubble destruction, indicating an impairment of endothelial dependent vasodilation and,
thus, perfusion. Time plots show a decrease during static handgrip in myocardial volume by 6%,
microvascular flux rate by 25%, and myocardial blood flow by 30%.
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Figure 2. Change in Myocardial Blood Flow Fofllowing Standardized Stress.
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Table 1. Pre- and Post-Stress Myocardial Blood Flow and Related Measures
GroupMyocardial
Blood Mean ± SD Median Q1 Q3 IQR Mean ± SD Median Q1 Q3 IQR p-value
Volume (IU) 136 ± 19 131 121 154 33 139 ± 21 143 128 154 26 0.76 a
Flux Rate (s-1) 0.69 ± 0.23 0.61 0.57 0.77 0.2 1.11 ± 0.33 1.14 0.8 1.38 0.57 0.002 *
Flow (IU/s) 95 ± 42 84 67 104 37 153 ± 50 138 112 184 72 0.002 *
Volume (IU) 155 ± 13 153 146 164 18 148 ± 26 150 140 168 28 0.846
Flux Rate (s-1) 0.62 ± 0.17 0.61 0.5 0.68 0.18 0.83 ± 0.24 0.9 0.69 0.97 0.27 0.006 *
Flow (IU/s) 97 ± 31 93 73 109 36 126 ± 47 134 105 154 49 0.027
Volume (IU) 139 ± 18 139 124 152 28 137 ± 21 142 119 148 29 0.492
Flux Rate (s-1) 0.59 ± 0.08 0.57 0.53 0.62 0.09 0.55 ± 0.1 0.55 0.52 0.62 0.11 0.492
Flow (IU/s) 82 ± 20 77 74 91 17 76 ± 18 79 62 90 28 0.432
a Based on a normal approximation, due to tie in ranks
Pre-test Post-test
Control
Tobaccousers
E-Cigusers
* Denotes statistically significant changes from pre- to post- test at the alpha = 0.01 level
Wilcoxon Signed-Rank tests with exact p-values were run to compare post- and pre-test values.
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o reuse allowed w
ithout permission.
(which w
as not certified by peer review) is the author/funder, w
ho has granted medR
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he copyright holder for this preprintthis version posted January 18, 2020. .
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medR
xiv preprint
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Table 2. Change Between Pre- and Post-Stress Myocardial Blood Flow and Related Measures Across User Groups
MyocardialBlood
Mean ± SD Median Q1 Q3 IQR Mean ± SD Median Q1 Q3 IQR Mean ± SD Median Q1 Q3 IQR
Controls
vs.Tobacco users
Controlsvs.
E-cig users
Tobaccovs.
E-cig users
Volume (IU) 2.7 ± 12.7 0.1 -2.9 11.4 14.3 -4.3 ± 16.8 -3.9 -7.2 8.3 15.5 -0.9 ± 9.2 -2.3 -7 3.5 10.5 0.353 0.529 0.971
Flux Rate (s- 66.8 ± 42.8 71.5 27.3 92.2 64.9 34.7 ± 28.3 42.4 13.4 54.4 41.1 -4.7 ± 20.9 -0.3 -24.5 5.3 29.8 0.105 < 0.001 * 0.005 *Flow (IU/s) 72.1 ± 53.2 67.8 30.5 98.4 67.9 30.5 ± 40.9 30.1 6.5 50.3 43.8 -5.8 ± 20.8 -4.2 -20.3 5 25.3 0.089 < 0.001 * 0.023
Controls Tobacco users E-cig users p-values
* Denotes a statistically significant difference between in MB measurement between the two groups at an alpha = 0.01 level
Wilcoxon Rank-Sum tests with exact p-values were run to compare percent changes between groups.
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o reuse allowed w
ithout permission.
(which w
as not certified by peer review) is the author/funder, w
ho has granted medR
xiv a license to display the preprint in perpetuity. T
he copyright holder for this preprintthis version posted January 18, 2020. .
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medR
xiv preprint
14
Supplementary Table 1. Summary of Wilcoxon Signed-Rank Test Between Pre- and Post-Stress Myocardial Blood Measurements
Within Groups
GroupMyocardial
Bloodn Mean Rank Sum of Ranks n Mean Rank Sum of Ranks Ties p-value
Volume (IU) 5 4.8 24 5 6.2 31 1 0.76 a
Flux Rate (s-1) - - - 10 5.5 55 0 0.002 *
Flow (IU/s) - - - 10 5.5 55 0 0.002 *
Volume (IU) 6 5.0 30 4 6.3 25 0 0.846
Flux Rate (s-1) 1 2.0 2 9 5.9 53 0 0.006 *
Flow (IU/s) 2 3.0 6 8 6.1 49 0 0.0273
Volume (IU) 6 5.8 35 4 5.0 20 0 0.492
Flux Rate (s-1) 5 7.0 35 5 4.0 20 0 0.492
Flow (IU/s) 6 6.0 36 4 4.8 19 0 0.432
* Denotes statistically significant changes from pre- to post- test at the alpha = 0.01 levela Based on a normal approximation, due to tie in ranks
Negative Ranks Positive Ranks Test Statistics
Controls
Tobaccousers
E-Cigusers
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