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UCSF public comment on PMI MRTP application: Evidence that IQOS hurts vascular fuction as much as a cigarette

Matthew Springer and his colleagues at UCSF have submitted this public comment to the FDA. The tracking number is 1k1-8zxa-mq9v and a PDF of the comment is available here

The evidence PMI presents in its MRTP application for IQOS is misleading and does not support the conclusion that IQOS will not harm endothelial function; independent research done in a more relevant physiological model shows that IQOS harms endothelial function as much as conventional cigarettes
Matthew L. Springer, Ph.D., Pooneh Nabavizadeh, M.D., and Leila Mohammadi, M.D., Ph.D. Department of Medicine, Division of Cardiology
Cardiovascular Research Institute
UCSF Tobacco Center of Regulatory Science
University of California, San Francisco
Docket Number: FDA-2017-D-3001
November 20, 2017

Philip Morris Products S.A. (PMP S.A.) modified risk tobacco product (MRTP) applications1-3 for its heat-not-burn product IQOS (also designated iQOS and THS2.2) in the United States claim that IQOS does not adversely affect the functioning of the vascular endothelium. The endothelium consists of cells lining arteries that play an important role in controlling normal functioning of arteries (vascular function). Abnormal endothelial function increases the risk of heart disease and heart attacks. The evidence that PMI presents is misleading and does not support the conclusion that IQOS will not harm endothelial function. In addition, new independent research done in a more relevant physiological model shows that IQOS harms endothelial function as much as conventional cigarettes.

This comment focuses on PMI’s assertion that IQOS aerosol exposure involves less cardiovascular risk than smoke exposure. PMI researchers have published studies that compare the effects of tobacco smoke and IQOS aerosol on various physiological systems at the cell, animal, and clinical levels (for example, Smith et al.4). The conclusions that they draw from these studies all point toward IQOS being substantially less harmful than cigarettes. However, some of the criteria used in these studies are incongruous with expected and established physiological assays.

In addition, PMI’s descriptions of their research findings in the MRTP application are worded to imply that IQOS is not harmful to vascular endothelial function known to be caused by tobacco smoke. However, this implication is unsupported because PMI has not performed the most physiologically relevant tests. PMI has not shown that IQOS aerosol exposure leads to less vascular endothelial dysfunction than cigarette smoke exposure.

Endothelial function assessed by arterial flow-mediated dilation (FMD) is a validated measure of cardiovascular health effects. FMD is the process by which arteries dilate (get larger) in response to increased blood flow.5, 6 The endo¬thel¬ial cells that line the arterial wall mediate blood flow to peripheral tissues and the heart by producing nitric oxide (NO) and other factors that lead to vasodilation. Endothelial cells sense increased blood flow because of increased friction of the liquid against the lining of the artery (shear stress) as blood flow velocity increases, and the cells respond by activating the enzyme endothelial nitric ox¬ide syn¬thase (eNOS), which creates NO, leading to FMD.

FMD is quantified by ultra¬sound in humans as the percent vasodilation of the arm’s brachial artery in res¬ponse to restoration of blood flow after transient occlusion.7 FMD is a well-established clinical prognostic indicator of endothelial function that is concordant with other measures of cardiovascular health such as risk of myocardial infarction.6-9 Brachial artery FMD correlates with endothelium-depen¬dent vasodilation of the coronary arteries10 and with a number of adverse cardiovascular outcomes including myocardial infarction and atherosclerosis11-13 that are increased by cigarette smoke. In a seminal pair of papers in the 1990s, David Celermajer and colleagues showed that both smoking and chronic exposure to secondhand smoke (SHS) impair FMD.14, 15 Juonala et al.16 reported that FMD was impaired in young adults whose parents were smokers 19-27 years earlier. Several groups including ours and our collabor¬ators have shown that a 30-minute exposure to SHS at real-world levels impairs FMD in humans.17-19 In a rat model of FMD, we have shown that exposure to realistic levels of sidestream smoke from tobacco cigarettes, filtered little cigars, and marijuana cigarettes with and without cannabinoids (but not exposure to clean air) impairs FMD, an effect that occurs after as little as one minute of exposure.20-22 In short, measurement of FMD is a common test to determine whether inhalation of aerosols leads to chronic or acute endothelial dysfunction, and FMD measurement is expected to be included in the basis of any claims that a tobacco product does not negatively impact endothelial function.

PMI’s studies of endothelial function are based on isolated cell properties in culture and on biomarkers, and do not directly test for endothelial dysfunction potentially caused by IQOS aerosol inhalation. PMI claims to have studied the relative effects of IQOS aerosol and cigarette smoke on mechanisms involved in endothelial function, with the conclusion that IQOS exposure is more benign than cigarette smoke exposure in this regard. Notably, PMI’s studies of endothelial functional properties are on the level of cell culture and address the integrity of endothelial cell monolayers and monocyte efflux as well as molecular changes.23, 24 Their rodent studies addressed long-term differences in atherosclerotic plaque. Their clinical investigations include measurements of soluble intercellular adhesion molecule-1 (sICAM-1) as a biomarker indicative of endothelial dysfunction.25 Importantly, neither their clinical nor animal studies include measurements of FMD.

Their published reports have been carefully worded to avoid saying that IQOS does not cause endothelial dysfunction, but the MRTP application makes the claim that the systems toxicology studies reported in the application “cover a variety of human-derived in vitro model systems comparing the impact of THS aerosol with that of cigarette smoke on vascular inflammation, endothelial dysfunction and airway epithelium toxicity” (PMP S.A. MRTP application Executive Summary, Section 2.7, page 11). The conclusion that IQOS aerosol induces less endothelial dysfunction is not supported by their studies.

FMD in rats exposed to undiluted IQOS aerosol is impaired to the same extent as in rats exposed to cigarette smoke. Our work26, 27 demonstrated that ten 5-second exposures of rats to IQOS aerosol over a 5 minute period substantially impaired FMD to the same extent as similar exposure to cigarette smoke. Our exposure conditions were designed to approximate the use of a single IQOS HeatStick, with identical exposure conditions for the cigarette exposures. To confirm that our exposure conditions were relevant to real-world use, we measured blood levels of nicotine immediately after and 20 minutes after the end of the brief exposure, and determined that the nicotine concentrations after one complete cigarette exposure period were comparable to the blood levels in humans after smoking a single cigarette.

This validated our conditions for inhalation of undiluted cigarette smoke by the rats, and by extension, the relevance of our comparable conditions for inhalation of IQOS aerosol.

These results were presented on November 14, 2017 at the American Heart Association annual Scientific Sessions. Their press release containing a more detailed description of these findings (attachment #1), as well as the poster presentation itself (attachment #2), are appended at the end of this comment after the references.

Conclusion. Unless PMI is able to provide results from humans or living animals showing that IQOS aerosol exposure leads to less vascular endothelial dysfunction than cigarette smoke exposure, PMI’s MRTP application should not claim nor imply that IQOS carries reduced risk for vascular endothelial function.


1. Reuters. Philip Morris seeks U.S. approval to market alternative cigarette (12/6/16; accessed 6/9/17). 2016; Available from:
2. Altria Group. Altria’s Statement on Philip Morris International’s MRTP Application Submission with the FDA (12/6/16; accessed 5/5/17). 2016; Available from:
3. U.S. Food and Drug Administration. Philip Morris Products S.A. Modified Risk Tobacco Product (MRTP) Applications (5/24/17; accessed 6/9/17). 2017; Available from:
4. Smith MR, Clark B, Ludicke F, Schaller JP, Vanscheeuwijck P, Hoeng J, Peitsch MC. Evaluation of the Tobacco Heating System 2.2. Part 1: Description of the system and the scientific assessment program. Regul Toxicol Pharmacol 2016;81 Suppl 2:S17-S26
5. Pyke KE, Tschakovsky ME. The relationship between shear stress and flow-mediated dilatation: implications for the assessment of endothelial function. J Physiol 2005;568(Pt 2):357-69 (PMC 1474741)
6. Flammer AJ, Anderson T, Celermajer DS, Creager MA, Deanfield J, Ganz P, Hamburg NM, Luscher TF, Shechter M, Taddei S, Vita JA, Lerman A. The assessment of endothelial function: from research into clinical practice. Circulation 2012;126(6):753-67 (PMC 3427943)
7. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, Deanfield JE. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992;340(8828):1111-5
8. Widlansky ME, Gokce N, Keaney JF, Jr., Vita JA. The clinical implications of endothelial dysfunction. J Am Coll Cardiol 2003;42(7):1149-60
9. Nabel EG, Selwyn AP, Ganz P. Large coronary arteries in humans are responsive to changing blood flow: an endothelium-dependent mechanism that fails in patients with atherosclerosis. J Am Coll Cardiol 1990;16(2):349-56
10. Anderson TJ, Uehata A, Gerhard MD, Meredith IT, Knab S, Delagrange D, Lieberman EH, Ganz P, Creager MA, Yeung AC, Selwyn AP. Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol 1995;26(5):1235-41
11. Yeboah J, Crouse JR, Hsu FC, Burke GL, Herrington DM. Brachial flow-mediated dilation predicts incident cardiovascular events in older adults: the Cardiovascular Health Study. Circulation 2007;115(18):2390-7
12. Yeboah J, Folsom AR, Burke GL, Johnson C, Polak JF, Post W, Lima JA, Crouse JR, Herrington DM. Predictive value of brachial flow-mediated dilation for incident cardiovascular events in a population-based study: the multi-ethnic study of atherosclerosis. Circulation 2009;120(6):502-9 (PMC 2740975)
13. Yeboah J, Sutton-Tyrrell K, McBurnie MA, Burke GL, Herrington DM, Crouse JR. Association between brachial artery reactivity and cardiovascular disease status in an elderly cohort: the cardiovascular health study. Atherosclerosis 2008;197(2):768-76
14. Celermajer DS, Adams MR, Clarkson P, Robinson J, McCredie R, Donald A, Deanfield JE. Passive smoking and impaired endothelium-dependent arterial dilatation in healthy young adults. N Engl J Med 1996;334(3):150-4
15. Celermajer DS, Sorensen KE, Georgakopoulos D, Bull C, Thomas O, Robinson J, Deanfield JE. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation 1993;88(5 Pt 1):2149-55
16. Juonala M, Magnussen CG, Venn A, Gall S, Kahonen M, Laitinen T, Taittonen L, Lehtimaki T, Jokinen E, Sun C, Viikari JS, Dwyer T, Raitakari OT. Parental smoking in childhood and brachial artery flow-mediated dilatation in young adults: the Cardiovascular Risk in Young Finns study and the Childhood Determinants of Adult Health study. Arterioscler Thromb Vasc Biol 2012;32(4):1024-31
17. Kato T, Inoue T, Morooka T, Yoshimoto N, Node K. Short-term passive smoking causes endothelial dysfunction via oxidative stress in nonsmokers. Can J Physiol Pharmacol 2006;84(5):523-9
18. Heiss C, Amabile N, Lee AC, Real WM, Schick SF, Lao D, Wong ML, Jahn S, Angeli FS, Minasi P, Springer ML, Hammond SK, Glantz SA, Grossman W, Balmes JR, Yeghiazarians Y. Brief secondhand smoke exposure depresses endothelial progenitor cells activity and endothelial function: sustained vascular injury and blunted nitric oxide production. J Am Coll Cardiol 2008;51(18):1760-71
19. Frey PF, Ganz P, Hsue PY, Benowitz NL, Glantz SA, Balmes JR, Schick SF. The exposure-dependent effects of aged secondhand smoke on endothelial function. J Am Coll Cardiol 2012;59(21):1908-13
20. Pinnamaneni K, Sievers RE, Sharma R, Selchau AM, Gutierrez G, Nordsieck EJ, Su R, An S, Chen Q, Wang X, Derakhshandeh R, Aschbacher K, Heiss C, Glantz SA, Schick SF, Springer ML. Brief exposure to secondhand smoke reversibly impairs endothelial vasodilatory function. Nicotine Tob Res 2014;16(5):584-90 (PMC 3977486)
21. Liu J, Wang X, Narayan S, Glantz SA, Schick SF, Springer ML. Impairment of endothelial function by little cigar secondhand smoke. Tob Regul Sci 2016;2(1):56-63 (PMC 4703945)
22. Wang X, Derakhshandeh R, Liu J, Narayan S, Nabavizadeh P, Le S, Danforth OM, Pinnamaneni K, Rodriguez HJ, Luu E, Sievers RE, Schick SF, Glantz SA, Springer ML. One minute of marijuana secondhand smoke exposure substantially impairs vascular endothelial function. J Am Heart Assoc 2016;5(8) e003858. (PMC 5015303)
23. Poussin C, Laurent A, Peitsch MC, Hoeng J, De Leon H. Systems toxicology-based assessment of the candidate modified risk tobacco product THS2.2 for the adhesion of monocytic cells to human coronary arterial endothelial cells. Toxicology 2016;339:73-86
24. van der Toorn M, Frentzel S, De Leon H, Goedertier D, Peitsch MC, Hoeng J. Aerosol from a candidate modified risk tobacco product has reduced effects on chemotaxis and transendothelial migration compared to combustion of conventional cigarettes. Food Chem Toxicol 2015;86:81-7
25. Ludicke F, Picavet P, Baker G, Haziza C, Poux V, Lama N, Weitkunat R. Effects of Switching to the Menthol Tobacco Heating System 2.2, Smoking Abstinence, or Continued Cigarette Smoking on Clinically Relevant Risk Markers: A Randomized, Controlled, Open-Label, Multicenter Study in Sequential Confinement and Ambulatory Settings (Part 2). Nicotine Tob Res 2017; Epub ahead of print April 21, 2017
26. Nabavizadeh P, Liu J, Ibrahim S, Springer ML. Impairment of Endothelial Function by Inhalation of Heat-Not-Burn Tobacco Aerosol (conference abstract). Circulation 2017;136:A16035
27. Nabavizadeh P, Liu J, Ibrahim S, Derakhshandeh R, Springer ML. Inhalation of heat-not-burn tobacco aerosol impairs vascular endothelial function (poster presentation Nov 14, 2017). American Heart Association Scientific Sessions, Anaheim, CA 2017

Heat-not-burn tobacco products may be ‘not so hot’ at protecting blood vessel function
Tuesday News Tip Poster Presentation T1051 Session: AT.APS.28.

Embargoed until time 12 p.m. PT/ 3 p.m. ET, Tuesday, Nov. 14, 2017
This news tip contains updated study information not reflected in the abstract.

ANAHEIM, California, Nov. 14, 2017 — Heat-not-burn devices may eliminate users’ exposure to tobacco smoke, but the vapor they produce has the same negative impact on blood vessel function as smoking, according to a preliminary animal study presented at the American Heart Association’s Scientific Sessions 2017, a premier global exchange of the latest advances in cardiovascular science for researchers and clinicians.

Heat-not-burn products are not new, but have been recently updated and test marketed in several countries outside the United States with greater success. Despite tobacco industry claims of heat-not-burn products being less harmful than regular cigarettes, the health effects of the devices are still unproven, according to researchers.

Heat-not-burn devices raise the temperature of tobacco enough to release nicotine-containing vapor but not enough to burn, avoiding smoke exposure. To test the devices’ ability to reduce harm, researchers assessed whether exposure to the vapor affects the ability of rats’ blood vessels to widen when there is increased blood flow – a measure of blood vessel health that is impaired with exposure to smoke from cigarettes, small cigars and marijuana.

Researchers found:
• After ten 15-second exposures over five minutes to the vapor from iQOS, a heat-not-burn device that has been test-marketed in several countries, blood vessel function decreased by 58 percent.
• Similarly, after ten 5-second exposures over five minutes to iQOS vapor, blood vessel function decreased by a similar amount, 60 percent.
• The reduction was comparable to that induced by cigarette smoke (57 percent for the 15-second exposures, 62 percent for the 5-second exposures).
• Exposure to clean air had no impact on blood vessel dilation.
• The amount of nicotine in the rats’ blood after exposure to cigarette smoke was similar to the amount in blood after humans have smoked one cigarette, confirming that the exposure conditions were relevant to the real world. However, the amount of nicotine in the blood after exposure to iQOS vapor was substantially higher (70.3 nanogram/milliliter for iQOS, 15.0 nanogram/milliliter for cigarettes).

Using heat-not-burn products may not avoid the adverse cardiovascular effects of smoking cigarettes.

The research was conducted by Pooneh Nabavizadeh, M.D. in a group led by Matthew L. Springer, Ph.D. Other contributors were Jiangtao Liu, M.D., Sharina Ibrahim, B.Sc. and Ronak Derakhshandeh, M.S.

The study was funded by the National Heart, Lung, and Blood Institute at the National Institutes of Health and the U.S. Food and Drug Administration Center for Tobacco Products. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the FDA.

Presentation Location: Basic Science Section, Science and Technology Hall

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