Ricerc@Sapienza

The randomized trial hereby proposed has many uniquely innovative features.
1. Being a randomized trial, this controlled prospective study will provide the most internally valid scientific testing of our chosen hypothesis. In a scientific arena dominated mostly by observational and retrospective studies, thus at high risk of selection, performance, adjudication and attrition bias, our project thus appears quite impactful and will be less suitable to criticism from tobacco company-affiliated researchers and stakeholders.(1) In particular, despite the small sample, the size of the
study will be adequate to test adequately differences in the primary endpoint when comparing invasive effects of modified risk products (MRP).
2. Our focus on coronary flow reserve (CFR) and ancillary measures of the functional severity of a coronary stenosis such as fractional flow reserve and instantaneous wave-free ration, on top of quantitative coronary angiography and Thrombolysis in Myocardial Infarction frame count is completely unprecedented in users of MRP, and while we may guess that prior findings on the vascular effects of MRP of tobacco exploiting non-invasive measurements will be confirmed in our study, this remains to be
proven, but of key scientific and clinical relevance.(2-3)
3. Our aim at comparing the two leading prototypical MRP, ie JUUL, as electronic vaping cigarette (EVC), and IQOS, as heat-not-burn cigarette (HNBC), is unprecedented, as no other study to date has ever compared in prospective fashion this novel devices. This is most important as JUUL represents the US leader in EVC, but has been questioned in terms of safety given its very high nicotine content and appeal to teenagers, while IQOS is the global leader in HNBC, and its usage has been recently approved in the United States as well (while both are already available for routine use in Italy and Europe at large).(4)
4. Our focus on chronic smokers of traditional combustion cigarettes (TCC), who actually have established coronary atherosclerosis as demonstrated by invasive coronary angiography, represent a total novelty for a prospective, randomized trial, and our findings will forcefully shape and guide future research on MRP in chronic smokers in the secondary prevention setting of cardiovascular disease.(5) Yet, restriction of inclusion to smokers only will reinforce the need to consider MRP such as
EVC or HNBC mainly as an alternative to TCC, thus discounting any promoting effort for their use among non-smokers.
5. Our integrative approach boosting on a plethora of secondary and ancillary endpoints will provide a veritable mine of pathophysiologic insights on the coronary, cardiac, vascular, systemic and environmental effects of acute use of MRP in general, on EVC and HNBC in particular, and also on any difference between the two. In particular, we will be able to test whether EVC and HNBC have any effect, and if so, any differential one, on several dimensions of cardiovascular and systemic physiology. In addition, by analyzing their correlation and association, we will be able to explore potential clustering features among such effects (eg correlation between pro-inflammatory and oxidative effects). Finally, the appraisal of environmental contamination simultaneously with coronary and systemic responses will permit the precise analysis of the association between smoking patterns, biologic responses and environmental pollution.
6. The choice of multisite blood draws, able to generate veritable gradients of measurements from arteries to coronary sinus and femoral vein, in particular represents an almost unheard approach, which, combined with the selective inclusion of patients with right coronary dominance and left coronary lesions ,will inform on intracoronary and intracardiac gradients in oxidative stress, redox reserve, inflammation, and myocardial injury.(6) This approach, while technically demanding, can be safely implemented, and will provide for the first time ever in the literature a glimpse at the coronary-specific and cardiac-specific effects of using MRP such as EVC and
HNBC.
7. Last, but not least, this study will be totally independent from any tobacco company sponsorship or influence. In a scientific scenario in which independence from bias is crucial to validly and objectively inform patients, physicians, and stakeholders, this methodological choice will be a key adjunctive strength of our work. In addition, this premise is key to motivate public academic institutions such as Sapienza University of Rome to fund independent high-quality research such as the one hereby
proposed.(7)

References
1. Ling et al. Tob Control 2019;28:289-96.
2. Petraco et al, Circ Cardiovasc Interv 2014;7:492-502.
3. Garrone et al. J Interv Cardiol 2009;22:527-36.
4. Chu et al. J Adolesc Health 2018;63:582-86.
5. Bhatta et al, J Am Heart Assoc 2019;8:e012317.
6. Buffon et al, New Engl J Med 2002;347:5-12.
7. Glantz. JAMA Netw Open 2019;2:e191032.