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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; florian.rader@cshs.org;

and, Susan Cheng, MD, MMSc, MPH, Smidt Heart Institute, Cedars-Sinai Medical Center, Los

Angeles, CA; phone (310) 423-9680; fax (310) 423-9680; susan.cheng@cshs.org.

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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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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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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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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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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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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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REFERENCES

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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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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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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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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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