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Differential effects of heat-not-burn and conventional cigarettes on coronary flow, myocardial and vascular function


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We compared the effects of Heat-not-Burn cigarette (HNBC) to those of tobacco cigarette (Tcig), on myocardial, coronary and arterial function as well as on oxidative stress and platelet activation in 75 smokers. In the acute study, 50 smokers were randomised into smoking a single Tcig or a HNBC and after 60 min were crossed-over to the alternate smoking. For chronic phase, 50 smokers were switched to HNBC and were compared with an external group of 25 Tcig smokers before and after 1 month. Exhaled carbon monoxide (CO), pulse wave velocity (PWV), malondialdehyde (MDA) and thromboxane B2 (TxB2) were assessed in the acute and chronic study. Global longitudinal strain (GLS), myocardial work index (GWI), wasted myocardial work (GWW), coronary flow reserve (CFR), total arterial compliance (TAC) and flow-mediated dilation (FMD) were assessed in the chronic study. Acute HNBC smoking caused a smaller increase of PWV than Tcig (change 1.1 vs 0.54 m/s, p < 0.05) without change in CO and biomarkers in contrast to Tcig. Compared to Tcig, switching to HNBC for 1-month improved CO, FMD, CFR, TAC, GLS, GWW, MDA, TxB2 (differences 10.42 ppm, 4.3%, 0.98, 1.8 mL/mmHg, 2.35%, 19.72 mmHg%, 0.38 nmol/L and 45 pg/mL respectively, p < 0.05). HNBCs exert a less detrimental effect on vascular and cardiac function than tobacco cigarettes. Trial registration Registered on (NCT03452124, 02/03/2018).
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Scientic Reports | (2021) 11:11808 | 
Dierential eects of heat‑not‑burn
and conventional cigarettes
on coronary ow, myocardial
and vascular function
Ignatios Ikonomidis1*, Dimitrios Vlastos2, Gavriela Kostelli1, Kallirhoe Kourea1,
Konstantinos Katogiannis1, Maria Tsoumani3, John Parissis1, Ioanna Andreadou3 &
Dimitrios Alexopoulos1
We compared the eects of Heat‑not‑Burn cigarette (HNBC) to those of tobacco cigarette (Tcig), on
myocardial, coronary and arterial function as well as on oxidative stress and platelet activation in
75 smokers. In the acute study, 50 smokers were randomised into smoking a single Tcig or a HNBC
and after 60 min were crossed‑over to the alternate smoking. For chronic phase, 50 smokers were
switched to HNBC and were compared with an external group of 25 Tcig smokers before and after
1 month. Exhaled carbon monoxide (CO), pulse wave velocity (PWV), malondialdehyde (MDA) and
thromboxane B2 (TxB2) were assessed in the acute and chronic study. Global longitudinal strain (GLS),
myocardial work index (GWI), wasted myocardial work (GWW), coronary ow reserve (CFR), total
arterial compliance (TAC) and ow‑mediated dilation (FMD) were assessed in the chronic study. Acute
HNBC smoking caused a smaller increase of PWV than Tcig (change 1.1 vs 0.54 m/s, p < 0.05) without
change in CO and biomarkers in contrast to Tcig. Compared to Tcig, switching to HNBC for 1‑month
improved CO, FMD, CFR, TAC, GLS, GWW, MDA, TxB2 (dierences 10.42 ppm, 4.3%, 0.98, 1.8 mL/
mmHg, 2.35%, 19.72 mmHg%, 0.38 nmol/L and 45 pg/mL respectively, p < 0.05). HNBCs exert a less
detrimental eect on vascular and cardiac function than tobacco cigarettes.
Trial registration Registered on https:// clini caltr ials. gov/ (NCT03452124, 02/03/2018).
Smoking constitutes a major modiable risk factor for cardiovascular disease 1. e pathophysiological mecha-
nisms underlying its deleterious eects include arterial elasticity 2 and myocardial deformation impairment 3,
endothelial dysfunction 4, oxidative stress accentuation 2, and platelet activation enhancement 5. Carotid-femoral
pulse wave velocity (cfPWV) measurement allows a reproducible, non-invasive quantication of arterial stiness
6 with diagnostic 7 and prognostic value 8. In addition, total arterial compliance (TAC) represents a pulsatile
component of le ventricular (LV) aerload and quanties the compliance of the entire arterial system, with
signicant physiological and prognostic implications 9. Flow mediated dilation (FMD) of the brachial artery 10
evaluates endothelial function and predicts cardiovascular mortality. Every 1% improvement in FMD has been
associated with 13% reduction of the risk for cardiovascular events 11. Coronary ow reserve (CFR) as assessed
by echocardiography is marker of coronary microcirculatory function with predictive value for adverse cardio-
vascular outcome 12. Importantly, CFR may predict mortality and risk for myocardial infarction (MI) in patients
with normal or near-normal coronary arteries and preserved regional and global le ventricular function both at
rest and during stress 13. In this respect, smoking has been demonstrated to reduce CFR by 21% in asymptomatic
smokers without coronary artery disease 14. Global longitudinal strain (GLS) computation by speckle tracking
echocardiography is a standardized modality of myocardial deformation assessment 15. Myocardial work index
(MW) is a novel index of the ventricular-arterial interaction which combines longitudinal myocardial defor-
mation with dynamic non-invasive LV pressure measurements creating pressure–strain loops. us, this index
minimizes pitfalls of myocardial strain examination that derive from its load-dependent nature 16. Regarding
oxidative stress burden, plasma malondialdehyde (MDA) 17 and protein carbonyls (PC) 18 concentration serve
  
           
            
 *
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as widely used biomarkers, while plasma thromboxane B2 (TxB2) levels are associated with increased platelet
activation 19.
More than 5600 chemical components have been identied in traditional tobacco cigarettes, many of which
harmfully aect the cardiovascular system 20. In this respect, the development of potential reduced exposure
products (PREPs) has been suggested as a means to reduce the adverse eects associated with the use of tobacco
products 21. Although rst generation PREP use was, indeed, associated with reduced biomarkers of exposure
(BoE) levels, neither oxidative stress burden nor markers of inammation were improved 22. Heat-not-burn
cigarette (HNBC) has been developed as a new-generation non-combustible PREP 23. Early evidence suggests
that its use results in a signicantly reduced BoE levels in comparison with traditional combustible cigarettes
2431; however, this has not been consistently associated with cardiovascular function benets. On the one hand,
evidence has arisen that HNBC acutely impairs oxidative stress equilibrium, platelet activation, endothelial
function, and peripheral blood pressure to a lesser extent than traditional smoking 32. On the other hand, in rat
models, exposure to HNBC aerosol was as detrimental to FMD as cigarette smoke 33. us, the eects of HNBC
use on cardiovascular function have not been fully dened.
e aim of this study was to investigate the eects of HNBC on endothelial function, arterial stiness,
myocardial deformation, oxidative stress, and platelet activation both in an acute context and aer 1month of
switching to HNBC smoking, in comparison with traditional tobacco cigarette.
Study population. e mean age of the 50 participants was 48 ± 5years, 53% were female, and reported
smoking 27 ± 9 cigarettes per day per individual with a smoking history of 38 ± 18 pack-years. Tobacco smokers,
used as controls, had a mean age of 46 ± 14years, 53% were female and reported smoking 26 ± 8 cigarettes per
day per individual with a smoking history of 37 ± 19 pack-years. All subjects had similar baseline characteristics
in terms of arterial stiness, myocardial deformation, oxidative stress, and platelet activation status (Table1).
During the chronic study, only 3 of the 50 (6%) participants reported simultaneous use of IQOS with tradi-
tional cigarettes (< 5 per day). e remaining 47 participants successfully refrained from traditional cigarette
smoking and used HNBC exclusively during the 1-month follow-up period (17 ± 6 heets per day per individual).
No side-eects were reported. In the control group, smokers used 28 ± 8 Tcig per day per individual during one
Acute study. Vascular function. During the acute study, PWV was increased aer HBNC and Tcig smok-
ing compared to baseline (Table2, p = 0.04 and p = 0.005 respectively). However, Tcig smoking resulted in a
greater increase of PWV than HNBC pung (mean change 1.11m/s; 95% CI 0.35–1.18, p = 0.005 vs 0.54m/s;
95% CI 0.05–1.04, p = 0.03 respectively, dierence = 0.57m/s; 95% CI 0.005–1.131, p = 0.04) (Table2, Fig.1A,
Supplementary Fig.1). Furthermore, compared to baseline, Tcig smoking caused an increase in brachial systolic
blood pressure and heart rate (p = 0.03 and p = 0.02, respectively) while HNBC pung showed no signicant
changes on the above indices (p = 0.14 and p = 0.77) (Supplementary Fig.2).
Oxidative stress and platelet activation. In the acute setting, Tcig caused a signicant MDA increase, in contrast
with the lack of increase of MDA levels aer HNBC pung (baseline: 1.34 ± 0.72 vs Tcig: 2.56 ± 0.85, p = 0.03,
vs HNBC: 1.28 ± 0.95nmol/L, p = 0.55) (Table2, Fig.1B, Supplementary Fig.3). us, MDA levels were found
lower aer HBNC than aer Tcig (p = 0.02). Additionally, the MDA increase caused by Tcig was signicantly
correlated with the respective increase in PWV (r = 0.825, p < 0.001).
PC levels were unchanged during the acute phase of the study (p for the overall model, p = 0.54, Table2).
Compared to baseline, acute Tcig smoking signicantly increased TxB2 concentration; TxB2 levels did
not change signicantly following HNBC pung (baseline: 378 ± 103 vs Tcig: 398 ± 105, p = 0.02, vs HNBC:
Table 1. Characteristics of the study cohort. SBP systolic blood pressure, DBP diastolic blood pressure, BMI
body mass index, BP blood pressure, CO exhaled carbon monoxide, CRP-hs C-reactive protein highly sensitive,
values are mean ± SD.
N = 50 Control
N = 25 p-value
Age (years) 48 ± 9 46 ± 11 0.7
Sex (female) 27 (53%) 14 (53%) 0.6
SBP (mmHg) 125 ± 15 121 ± 13 0.7
DBP (mmHg) 79 ± 10 76 ± 10 0.6
Heart rate (bpm) 66 ± 9 67 ± 8 0.8
BMI (kg/m2)27.2 ± 5.1 27.3 ± 5.2 0.9
CO (ppm) 14.9 ± 7.4 15.8 ± 4.9 0.7
Pack-years 38 ± 18 37 ± 19 0.3
LDL-cholesterol (mg/dl) 114 ± 22 118 ± 19 0.5
CRP-hs (mg/dl) 1.8 ± 0.4 1.9 ± 0.5 0.4
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362 ± 113pg/ml, p = 0.16). us, TXB2 levels were found lower aer HBNC than aer Tcig (p = 0.005) (Table2,
Fig.1C, Supplementary Fig.4).
CO exposure. In the acute phase, compared to baseline, exhaled CO levels were signicantly elevated aer
Tcig smoking but were not aected by HNBC pung (CO base: 14.9 ± 7.4 vs CO Tcig: 17.5 ± 7.8, p < 0.001, vs
CO HNBC: 14.2 ± 7.3ppm, p = 0.1) us, CO levels were found lower aer HBNC than aer Tcig (p < 0.001)
Chronic study. Vascular function. ere was a signicant interaction between changes of FMD, CFR,
TAC, central SBP and smoking status (HNBC or Tcig) at 1month (F = 5.6, p = 0.01; F = 7.1, p = 0.001; F = 6.8,
p = 0.001, and F = 5.4, p = 0.03, respectively).
FMD and CFR were both signicantly elevated within 1month of switching to HNBC compared to tobacco
smokers (dierence in FMD = 4.3%; 95% CI 1.23–7.51, p = 0.009; dierence in CFR = 0.98; 95% CI 0.23–1.80,
p = 0.02) (Table3, Figs.2A,B and 3, Supplementary Figs.5, 6).
Central SBP was significantly reduced in the HNBC group than in tobacco smoking group (differ-
ence = 10.4mmHg-1; 95% CI 3.05–17.88, p = 0.02). TAC was signicantly increased in the HNBC group than in
tobacco smoking group (dierence = 1.8mL/mmHg; 95% CI 0.3–3.5, p = 0.04). Compared to baseline, PWV, HR,
brachial SBP and DBP values were not reduced aer 1month of using HNBC (p > 0.05, Table3, Supplementary
Fig.7). Compared to baseline, no signicant changes were observed in all vascular markers within 1month in
the control group of tobacco smokers (p > 0.05, Table3).
Myocardial function. ere was a signicant interaction between changes of GLS, PWV/GLS, GWI, GWW,
GWE, and smoking status at 1month (HNBC or Tcig) (p < 0.05 for all comparisons).
GLS was improved in the HNBC compared to the control group at follow-up (dierence = 2.35%; 95% CI
0.23–4.48, p = 0.03) (Table3, Supplementary Fig.8).
PWV/GLS ratio, as a marker of ventricular-arterial interaction, was found to be improved within 1month
of switching to HNBC compared to conventional tobacco smoking (p = 0.03) (Table3).
Moreover, GWI and GWW were both reduced within one month of HNBC use compared to con-
ventional tobacco use (difference in GWI = 152mmHg%; 95% CI 81.74–224.05, p = 0.001; difference in
GWW = 19.72mmHg%; 95% CI 4.35–35.08 p = 0.014) (Table3, Fig.2C). e increase in TAC was signicantly
correlated with the decrease in GWI (r = 0.344, p = 0.03). Compared to baseline, all myocardial deformation
indices did not change signicantly in the control group of tobacco smokers at 1month (p > 0.05).
Oxidative stress and platelet activation. ere was a signicant interaction between changes of MDA, PC, TXB2
and smoking status (HNBC or Tcig) at 1month (F = 7, p = 0.01; F = 4.8, p = 0.04; and F = 6.8, p = 0.01 respectively).
MDA and PC concentration signicantly decreased in subjects switching to HNBC compared to tobacco
smokers (dierence MDA = 0.38nmol/l; 95% CI 0.10–0.66, p = 0.009; PC = 7.73nmol/mg protein; 95% CI
0.19–15.28, p = 0.04) (Table4, Supplementary Fig.9). Additionally, replacement of Tcig by HNBC caused a TxB2
reduction than tobacco smoking (dierence = 45pg/ml; 95% CI 5.28–86.31, p = 0.03) (Table2, Supplementary
Fig.10). None of the aforementioned parameters changed in the control group at 1month compared to baseline
(p > 0.05 Table4).
At follow-up, the measured decrease in plasma MDA levels was signicantly positively correlated with the
increase in FMD (r = 0.51, p = 0.03).
Table 2. Comparative acute eects of heat-not-burn cigarettes versus tobacco cigarette on arterial stiness,
oxidative stress, platelet activation, and exposure to CO in the acute study (n = 50). *p < 0.05 of the overall
model by ANOVA for the within subject eects of the tobacco products. p < 0.05 for the comparison of
variables between baseline and aer use of tobacco products by post hoc analysis using Bonferroni correction.
PWV carotid-femoral pulse wave velocity, CO carbon monoxide, HNBC heat-not-burn cigarette, MDA
malondialdehyde, TCig tobacco cigarette, TxB2 thromboxane B2, values are mean±SD.
Baseline Sham HNBC TCig
PWV (m/s) 9.7 ± 1.3 9.9 ± 1.7 10.2 ± 1.710.8 ± 2.4*
cSBP (mmHg) 121 ± 16 120 ± 15 119 ± 17.6 120 ± 17
Heart rate (bpm) 66 ± 9 66 ± 9 66 ± 8 70 ± 10*
SBP (mmHg) 125 ± 15 125 ± 16 128 ± 19 130 ± 19*
DBP (mmHg) 79 ± 10 78 ± 10 80 ± 11 82 ± 10
MDA (nmol/l) 1.34 ± 0.72 1.35 ± 0.83 1.28 ± 0.95 2.56 ± 0.85*
PC (nmol/mg protein) 15.7 ± 5.8 14.5 ± 4.9 12.8 ± 5.2 13.9 ± 5.6
TxB2 (ng/ml) 378 ± 103 375 ± 105 362 ± 113 398 ± 105*
CO (ppm) 14.9 ± 7.4 14.4 ± 3.8 14.1 ± 7.3 17.5 ± 7.8*
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Figure1. Acute eects of heat-not-burn pung versus tobacco cigarette smoking. Comparison between the
acute eects of heat-not-burn versus tobacco cigarette smoking on (A) arterial stiness, (B) oxidative stress
burden, and (C) platelet activation status. HBNC showed a smaller increase of PWV than tobacco cigarette.
All biomarkers are impaired following Tcig smoking, in contrast with HNBC pung. PWV carotid-femoral
pulse wave velocity, HNBC heat-not-burn cigarette, MDA malondialdehyde, Tcig tobacco cigarette, TxB2
thromboxane B2, SE Standard Error.
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CO exposure. ere was a signicant interaction between changes of CO and smoking status (HNBC or
Tcig) at 1month (F = 8.5, p = 0.001). Compared to baseline, CO measurements were reduced aer switching to
HNBC (p < 0.001), while remaining unchanged in controls subjects (p = 0.2) (dierence in CO between groups:
10.42ppm; 95% CI 3.07–17.76, p = 0.007) (Table4).
In the acute crossover phase of this study, it was demonstrated that a single HNBC pung resulted in a smaller
increase of pulse wave velocity compared to tobacco cigarette smoking and was not associated with further
impairment of oxidative stress and platelet activation or increased exposure to CO, compared to baseline. Con-
versely, acute smoking of a tobacco cigarette had detrimental eects on the examined markers of vascular func-
tion, oxidative stress, and platelet activation. Furthermore, in the chronic phase of this study, switching from
Tcig to HNBC for 1month was associated with improvement in endothelial function, coronary ow reserve,
arterial compliance, and myocardial work, as well as with reduction of oxidative stress burden, platelet activation,
and exposure to CO. ese changes were not evident in the parallel control group of subjects who continued
smoking tobacco cigarettes for a month. Interestingly, the reduction in oxidative stress burden aer switching
to HNBC was associated with the respective improvement of endothelial function, while the increase in arterial
compliance was associated with the concomitant reduction of myocardial work.
Arterial elasticity is impaired in the context of both acute and chronic smoking, as assessed by carotid to
femoral PWV 2,34. e use of electronic cigarettes has shown less detrimental eects on arterial elasticity com-
pared to smoking tobacco cigarettes 2. Increased arterial stiness has been shown to be reversible, albeit aer a
considerable period of abstinence from smoking, spanning from 2 to 10years 2,3437. To our knowledge, this is
Table 3. Arterial elasticity, myocardial deformation, endothelial function, and ventricular-arterial coupling
progression aer 1month of switching from tobacco cigarette smoking to heat-not-burn product pung
(n = 50) compared to tobacco cigarette smokers (n = 25). *p < 0.05 for interaction with group, derived from post
hoc analysis by ANOVA. HNBC heat-not-burn cigarette, TCig tobacco cigarette, CFR coronary ow reserve,
PWV carotid-femoral pulse wave velocity, FMD ow-mediated dilation, GCW constructive myocardial work,
GLS global longitudinal strain, GWE myocardial work eciency, GWI global myocardial work index, GWW
wasted myocardial work, values are mean±SD.
Group Baseline One month p-value
Body weight (kg) HNBC 76.9 ± 2.4 77.1 ± 1.9 0.7
Tcig 80.9 ± 3.4 80.5 ± 3.5 0.8
PWV (m/s) HNBC 9.7 ± 1.3 10.1 ± 1.5 0.3
Tcig 9.7 ± 1.6 10.2 ± 2.3 0.4
Central SBP (mmHg) HNBC 121 ± 16 112 ± 17* 0.02
Tcig 121 ± 16 123 ± 15 0.3
TAC (ml/mmHg) HNBC 19.1 ± 4.2 20.9 ± 5.2* 0.03
Tcig 17.6 ± 8.4 17.5 ± 7.6 0.2
Heart rate (bpm) HNBC 66 ± 9 65 ± 8 0.4
Tcig 67 ± 8 68 ± 8 0.8
SBP (mmHg) HNBC 125 ± 15 126 ± 16 0.9
Tcig 121 ± 13 122 ± 13 0.9
DBP (mmHg) HNBC 79 ± 10 78 ± 9 0.7
Tcig 76 ± 10 76 ± 10 0.9
GLS (%) HNBC − 19.9 ± 2.3 − 20.9 ± 2.5* 0.002
Tcig − 19.7 ± 1.3 − 20 ± 0.7 0.3
FMD (%) HNBC 7.8 ± 4.3 12.1 ± 4.2* 0.01
Tcig 7.9 ± 3.9 8.3 ± 3.5 0.6
CFR HNBC 2.4 ± 0.6 3.5 ± 0.8* < 0.001
Tcig 2.5 ± 0.2 2.6 ± 0.2 0.2
PWV/GLS HNBC − 0.5 ± 0.1 − 0.48 ± 0.08* < 0.001
Tcig − 0.49 ± 0.1 − 0.51 ± 0.1 0.4
GWI (mmHg%) HNBC 1949 ± 315 1828 ± 320* 0.01
Tcig 1954 ± 290 1986 ± 290 0.1
GCW (mmHg%) HNBC 2214 ± 339 2156 ± 385 0.1
Tcig 2202 ± 379 2180 ± 356 0.3
GWW (mmHg%) HNBC 80 ± 55 65 ± 37* < 0.001
Tcig 74 ± 33 78 ± 42 0.09
GWE (%) HNBC 95.8 ± 2.3 96.4 ± 1.8 0.1
Tcig 95.5 ± 2 95 ± 2 0.5
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Figure2. Progression of coronary ow reserve, ow mediated dilation, and myocardial work within 1month
of follow-up. Replacement of Tcig smoking with HNBC pung for 1-month results in coronary and peripheral
endothelial function improvement, along with wasted myocardial work reduction. CFR coronary ow reserve,
FMD ow-mediated dilation, GWW global wasted work, SE Standard Error.
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the rst study to demonstrate that acute HNBC pung is associated with a smaller increase of PWV compared
to tobacco smoking. HNBC pung increases nicotine blood levels. Nicotine activates the sympathetic nerv-
ous system by acting via splanchnic nerves to the adrenal medulla and stimulates the release of epinephrine 38.
Acute elevation of nicotine levels has been linked to endothelial dysfunction 39 leading to reduced nitric oxide
release and thus contributes in addition to increased sympathetic activity to increased vascular tone. ese
mechanisms likely underlie the increase of PWV aer acute HNBC pung. Conversely, the deleterious acute
eects of smoking a tobacco cigarette on arterial stiness were in line with the respective oxidative stress burden
accentuation, underlining their interplay in our acute study 2,40. TAC constitutes an index of arterial compliance
of the entire arterial tree and entails physiologic and prognostic signicance 9. To our knowledge, this is the rst
study to highlight that replacement of Tcig with a HNBC results in improved TAC and central SBP, suggesting
a less detrimental eect of this novel smoking product on le ventricular aerload. e discrepancy between
Figure3. Coronary ow of le anterior descending artery at rest (le panel) and aer adenosine infusion (right
panel) for calculation of coronary ow reserve. Coronary ow of le anterior descending artery at rest (le
panel) and aer adenosine infusion (right panel) for calculation of coronary ow reserve at baseline (A) and
aer switching to HNBC for one month (B). e coronary ow reserve increased from 2.5 to 3.1 aer 1month
of switching from tobacco cigarette to HNBC.
Table 4. Progression of exposure to CO, oxidative stress burden, and platelet activation aer 1month of
switching from tobacco cigarette smoking to heat-not-burn product pung. *p < 0.05 for interaction with
group, derived from post hoc analysis by ANOVA. CO carbon monoxide, MDA malondialdehyde, PC protein
carbonyls, TxB2 thromboxane B2values are mean ± SD.
Group Baseline Follow-up p-value
CO (ppm) HNBC 14.9 ± 7.4 6.7 ± 6.4* < 0.001
Tcig 15.8 ± 4.9 17.4 ± 4.8 0.3
MDA (nmol/l) HNBC 1.34 ± 0.72 1.11 ± 0.95* 0.01
Control 1.43 ± 0.9 1.45 ± 0.83 0.3
PC (nmol/mg protein) HNBC 15.7 ± 5.8 9 ± 4.4* 0.04
Control 16.1 ± 8.8 17.2 ± 3.3 0.3
TxB2 (pg/ml) HNBC 378 ± 103 323 ± 137* 0.01
Control 417 ± 24 407 ± 16 0.4
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lack of improvement of PWV and increase of TAC in our study may be explained by the dierent vascular beds
these indices represent. On the one hand, PWV assesses the aortoiliac segment of the arterial tree 41; on the
other hand, TAC incorporates the eects of the large, central, elastic arteries as well as the small, peripheral,
muscular arteries 9. us, improved arterial compliance of the peripheral arterial system could improve TAC,
without aecting PWV.
Augmentation of oxidative stress is a key pathophysiological mediator of cardiovascular harm caused by acute
and chronic smoking 2,34. MDA is the product of cellular membrane phospholipids peroxidation and thus a valid
and reproducible marker of lipid peroxidation 17. PCs represent an irreversible form of protein modication that
are formed early during oxidative stress conditions, are relatively stable in contrast to lipid peroxidation products,
are not a result of one specic oxidant, and thus they are considered a sensitive and reproducible marker of total
protein oxidation 18. In our previous studies, both MDA and PCs were increased in smokers and their levels were
reduced either aer nicotine replacement treatment or varenicline use in medically-assisted smoking cessation
programs 34 or aer switching to electronic cigarette smoking. 2,42. us, plasma concentrations of MDA 17 and
PC 18 are valid markers of oxidative stress burden related to tobacco smoking. Recently, evidence has arisen that
acute HNBC pung is less detrimental to oxidative stress equilibrium compared with Tcig smoking, as assessed
by Nox2-derived peptide, vitamin E, and HBA levels 32. Similarly, our study demonstrated that MDA levels
were not elevated acutely aer using an HNBC, in contrast with Tcig use. Furthermore, in our chronic study, we
demonstrated reduced MDA and PC levels within 1month of replacing Tcig with HNBC.
Increased platelet activation plays a signicant role in promoting atherosclerosis and thrombotic complica-
tions, and is enhanced by Tcig smoking 5. A recent study suggests that HNBC invokes platelet activation to a
lesser degree than Tcig, as evident by comparatively lesser increase in soluble CD40 ligand and soluble P-selectin,
as markers of platelet activation 32. Plasma TxB2 is a valid marker of platelet activation 19. In agreement with the
aforementioned study 32, in our acute study, we did not detect signicant changes in plasma TxB2 acutely aer
HNBC pung compared to baseline. Conversely, we observed the increasedTXB2 levels aer Tcig smoking.
Further expanding on this nding, plasma TxB2 levels were signicantly reduced aer 1month of HNBC use
while no changes were observed in the parallel group of tobacco smokers in the same period.
Exhaled CO levels constitute a widely used marker of acute smoking status 43. In addition, inhaled CO has
been associated with endothelial damage and pathological capillary permeability 34. A recent study investigating
the BoE footprint of HNBC highlighted that exhaled CO levels within 5days of switching from Tcig to HNBC
are equal to those measured aer total abstinence from tobacco products 24. Similarly, in our study, acute HNBC
use did not increase exhaled CO levels, while CO levels were signicantly reduced at the 1-month follow-up
examination, approaching though the levels previously reported for passive-smokers 24,43. is nding suggests
that some of the HNBC users were substantially exposed to passive smoking in their family and/or working
environment despite adherence to HNBC use during the chronic study.
Endothelial dysfunction is a prominent end-point of the pathophysiological cascades activated by Tcig smok-
ing 4. In this regard, FMD and CFR evaluation reecting endothelial and coronary microcirculatory function
respectively, possess unequivocal diagnostic and prognostic value 10,12. Early investigation of the interaction
between HNBC and endothelial function has not produced consistent results. On the one hand, acute HNBC
pung has been shown to impair FMD to a lesser extent than Tcig 32. On the other hand, an animal model study
recognised HNBC and Tcig as equally detrimental on endothelial function 33. Our study found a signicant
increase in FMD aer switching to HBNC use for 1month, in accordance with recently published evidence of
FMD improvement aer replacing TCig smoking with electronic-cigarette vaping 44. Interestingly, FMD improve-
ment was positively correlated with MDA reduction at 1month, suggesting the contribution of reduced oxidative
stress to improvement of endothelial function. Furthermore, the current study is the rst to our knowledge that
has demonstrated a signicant improvement in CFR within 1month of switching to HNBC. Studies strongly
support the independent prognostic value of a reduced CFR for adverse cardiovascular outcome 13.
Novel markers of ventricular arterial-interaction incorporate measurements of aerload in the investigation of
myocardial function using speckle tracking echocardiography; the shortcomings of ejection fraction assessment
and the diagnostic pitfalls arising from the load-dependent nature of global longitudinal strain estimation are
overcome. us, a non-invasive and more clinically feasible method of myocardial work estimation is provided by
constructing longitudinal myocardial strain-pressure curves using speckle tracking imaging 16. In our study myo-
cardial eciency was improved aer switching to HNBC for one month, as shown by the respective improvement
of the GLS 11 and the reduction of the myocardial work index (GWI), global wasted myocardial work (GWW)
and the increase of the global myocardial work eciency (GWE) as assessed by the respective strain-pressure
curves. Interestingly, improved GWI was associated with increasing TAC values us, the reduction of GWI aer
switching to HNBC may be attributed to the reduction of LV aerload as indicated by the concomitant reduction
of central SBP and increase of TAC at one month. Furthermore, the observed improvement of the ratio PWV/
GLS aer one month of HNBC use also suggests an improvement in ventricular-arterial interaction 11. us, in
our study we observed that the improvement of vascular function and oxidative stress, likely on the grounds of
reduced CO exposure, evolved in parallel with the improvement of myocardial work eciency aer switching
from the traditional tobacco smoking to HNBC for one month. Alternatively, a potential reduction in the blood
nicotine levels aer switching to HNBC from Tcig smoking may have also accounted for the improvement of
cardiac and vascular markers in our chronic study.
In an elegant study by Frati etal. 45, the use of unsupervised machine learning techniques identied dierent
clusters of individuals within a larger study cohort with a similar within each cluster but dierent among clusters
responses to HNBC or e-cigarette smoking for various vascular and biochemical markers. e identication of
clusters of subjects with favorable or unfavorable responses to novel smoking products for surrogate markers of
cardiovascular function may facilitate the denition of the potential individual specic features of cardiovascular
safety of these smoking products.
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Design. Our study was an acute independent, randomised, cross-over trial followed by a chronic case control
follow-up study.
According to our initial Study design, (, NCT03452124) the primary outcome for the acute
study was the eect of HNBC in comparison to Tcig on PWV, while primary outcome for the chronic study was
the eect of use of HNBC for one month in comparison to Tcig smoking for the same period on LV deforma-
tion. e study was approved by the Attikon University Hospital scientic ethics committee (Approval number:
2874/06-12-17), funded by the Hellenic Society of Lipidology of Atherosclerosis and Vascular Disease. e
study was conducted according to the Declaration of Helsinki and written informed consent was provided by
the participants. Our study was registered on https:// clini caltr ials. gov/, NCT03452124, 02/03/2018.
Study population. Out of 95 screened smokers attending the Attikon University Hospital smoking ces-
sation unit, 50 current smokers (age: 48 ± 5years, 53% female, 27 ± 9 cigarettes/day, 29 ± 9 pack-years) and 25
controls smokers (age: 46 ± 14years, 53% female, 26 ± 8 cigarettes/day, 30 ± 8 pack-years) with no intention to
quit smoking were included in our study (Fig.4). Smoking status was veried by way of self-reported smoking
burden per day and exhaled carbon monoxide (eCO) concentration measurement [parts per million (ppm),
Bedfont Scientic, Maidstone, Kent UK] (exclusion criteria: < 5 cigarettes per day end exhaled CO < 10ppm).
Exclusion criteria included history of cardiovascular disease, hepatic or renal failure, active neoplasia, alcohol
abuse, psychiatric illness, pregnancy, breastfeeding, cigar smoking, or the presence of any additional risk fac-
tor for cardiovascular disease (dyslipidaemia: total cholesterol > 200mg/dl or the use of cholesterol-lowering
agents; hypertension: blood pressure > 140/90mmHg or use of anti-hypertensive drugs; diabetes mellitus: fast-
ing plasma glucose > 125mg/dl or use of antidiabetic drugs).
Study protocol. Our study included an acute and a chronic phase. e acute phase of the study entailed
an initial sham smoking session of inhaling on a non-lighted cigarette for 7min, simulating the mean duration
Figure4. Flow chart of the study population. HNBC heat-not-burn cigarette, TCig tobacco cigarette.
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of a traditional cigarette smoking. In the acute phase, the participants were thereaer randomised into either
a tobacco cigarette (Tcig) smoking session, using a single mainstream Tcig [Marlboro Red, Papastratos-Philip
Morris International (PMI), Athens, Greece], or a single HEETS stick (PMI, amber avour) pung session
(HNBC) using a commercially available HNBC (IQOS, PMI). Randomization was performed by an attending
research nurse using a table of random numbers as reproduced from the online randomization soware http://
www. graph pad. com/ quick calcs/ index. cfm, as previously published 45. Proper use of IQOS device was demon-
strated by a qualied research nurse, who also served as a supervisor during the HNBC pung session. Aer
a washout period of 60min, the subjects were crossed over to the alternative session (Tcig or HNBC, Fig.5).
Vascular studies and blood sampling were completed during 20-min at baseline before initiation of smoking and
within the wash-out period. e decision about the washout period duration was based on evidence that the
acute eects of a smoking on arterial function resolve within 60min 41.
For the chronic phase, all participants of the acute phase, were instructed to replace Tcig smoking with HNBC
pung for 1month and were compared with an external group of 25 Tcig smokers, with no intention to quit
smoking, (2:1 ratio) before and aer 1month.
Exhaled CO, arterial elasticity and blood sampling for oxidative stress and platelet activation, which were
assessed at baseline, aer each smoking session of the acute phase and at the chronic phase. Endothelial function,
coronary ow reserve and myocardial deformation were assessed at baseline and aer 1month, in the chronic
study. Arterial elasticity, myocardial, endothelial function examinations were executed by a single, blinded-
to-treatment and to values of measured biomarkers, operator. In the acute study the time elapsed between
smoking (Tcig or HNBC) and assessment of vascular markers was approximately 10min. For the chronic study,
participants were instructed to abstain from smoking (Tcig or HNBC) in the morning before the vascular and
echocardiography assessment. HNBC adherence was assessed by asking the participants to answer a question-
naire regarding the daily use of HNBC sticks as well as by measurement of the exhaled CO in each participant
during a clinic visit at days 15 and 30 of the chronic study. e HNBC sticks were provided to the participants by
the investigators at baseline and at day 15 during a clinic visit and aer the participant had returned the empty
boxes of the used HNBC sticks.
Endothelial function. Brachial artery FMD was ultrasonically assessed in line with published methodol-
ogy recommendations 17 and expressed as the percent increase of the baseline arterial diameter. Intra-observer
variability of the brachial artery diameter was 0.1 ± 0.12mm.
Coronary ow reserve. CFR was measured by transthoracic Doppler echocardiography, analysing colour-
guided pulse-wave Doppler signals derived from long axis apical projections. e maximal velocity end veloc-
ity–time integral in the distal le anterior descending artery were recorded at rest and following intravenous
adenosine administration, according to published methodology 46 and quantied as the ratio of hyperaemic to
resting maximal diastolic velocity. Coronary ow reserve assessment of le anterior descending artery was fea-
sible in all subjects of the study, though in 3 out of 75 participants, we had to use intravenous contrast (Sonovue,
Bracco, Italy) to improve Doppler imaging of the coronary ow.
Arterial stiness. Carotid-to-femoral PWV was estimated according to a previous published methodology
(Complior, Alam Medical, Vincennes, France) 40, by computing the ratio of the distance between the carotid and
femoral pulse palpation site to the pulse wave transit time (m/s). e Cointra-observer variability was 6%, in
Figure5. Acute phase protocol. Following an initial sham smoking session, subjects were randomised to either
a heat-not-burn or traditional cigarette smoking session; following a washout period of 60min, they were
crossed-over to the alternative smoking session. Each session was followed by a vascular stiness examination
and blood-sampling for oxidative stress and platelet activation assessment. Exam examination, HNBC heat-not-
burn cigarette, TCig tobacco cigarette.
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accordance with existing evidence in similar studies 34. Total arterial compliance (TAC) was evaluated utilising
the stroke volume (SV) to pulse pressure (PP) ratio (SV/PP), based on the two-element Windkessel model 9; SV
measurements were derived from two-dimensional echocardiography.
In the acute and chronic study assessment of vascular markers (FMD, PWV and PP) was performed in a
random order.
Myocardial deformation. Myocardial deformation was assessed by way of 2-dimensional strain measure-
ment, with speckle-tracking analysis by dedicated soware (Echopac 203, GE Horten Norway). LV apical 2-,
3-, and 4-chamber views at ≥ 50 frames per second frame rate were acquired and the global longitudinal strain
(GLS) was calculated from the respective apical views, applying previously published methodology 17,34. PWV/
GLS ratio (− m/s%) was calculated as a marker of ventricular arterial interaction 36.
Myocardial work. Myocardial work (MW) was estimated by combining echo-derived le ventricular (LV)
strain with brachial blood pressure to construct LV strain-pressure curves non-invasively, following recently
published methodology 16. Brachial cu systolic pressure measurements provide the peak systolic LV pressure
value, which is combined with the input of valvular timing events that dene isovolumetric and ejection phases,
allowing the construction of an LV pressure curve. is is combined with LV strain data into a pressure-strain
loop (PSL), the area within which represents MW. Global MW index (GWI) is dened as the work within the LV
PSL from mitral valve closure to mitral valve opening, while constructive MW (GCW) is the component of MW
that contributes to LV ejection. On the contrary, wasted MW (GWW) is the work wasted as myocyte lengthen-
ing during systole, which does not contribute to LV ejection. MW eciency (GWE) is dened as the ratio of
GCW to the sum of GCW and GWW [GWE = GCW/(GCW + GWW)].
Oxidative stress. A commercially available spectrophotometry kit (Oxford Biomedical Research, Roches-
ter Hills, Mich, colorimetric assay for lipid peroxidation; measurement range 1–20nmol/l) was used to deter-
mine plasma MDA levels. Plasma PC levels were measured by spectrophotometrical assessment of 2,4-dinitro-
phenylhydrazine PC derivatives, as previously published 40, and results were expressed as nmol/mg protein. For
MDA and PC, the intra-assay variability was 3.39% and 4.52%, respectively and the inter-assay variability was
4.75% and 5.93%, respectively.
In the chronic study two-dimensional echocardiography preceded the coronary ow reserve assessment,
aer completion of vascular studies.
Platelet activation. A commercially available ELISA kit was used to measure blood levels of romboxane
B2 (romboxane B2 EIA Kit Cayman Ann Arbor MI USA) with an assay range 1.6–1000pg/ml.
Statistical analysis. We used the soware STATA v.11 and SPSS v.22 in order to procced to data analysis.
We used Shapiro–Wilk test to examine if values had normal distribution, and Levene test for evaluating data
homoscedasticity, as it was previously published 34. Non-parametric variables were transformed into rank for
analysis. Two tailed tests with p < 0.05 were used during data acquisition. ANOVA (general linear model, SPSS
22, SPSS Inc, Chicago, Ill) for repeated measurements was applied for analysis of the examined indices of vas-
cular, myocardial, and endothelial function, as well as biochemical markers (at baseline, aer each smoking
session, and at the 1-month follow-up examination) with the parameter of time used as a within-subject factor.
e Greenhouse–Geisser correction was used when the sphericity assumption, as assessed by Mauchly’s test,
was not met. We used parametric (Pearson r) and non-parametric (Spearman rho) correlation coecients to
examine cross-sectional associations. Multiple comparisons of baseline values of study markers to values aer
sham, Tcig or HNBC in the acute study were performed with Bonferroni correction. A p-value of < 0.05 was
considered statistically signicant. e ordering of intervention (begin with HBNC versus begin with Tcig) and
the brachial systolic blood pressure (SBP) were included as covariates in the model and the respective p-value for
their interaction with the overall model was calculated. T-test was performed to compare the absolute or percent
changes of the parameters evaluated in the chronic phase of the study. Inter- and intra-observer variabilities (%)
of vascular, myocardial function, and biochemical markers were calculated as the SD of the dierences between
the rst and second measurements, and expressed as a percentage of the average value in 30 healthy volunteers.
Power analysis. For the acute study, we planned a study of a continuous response variable from matched
pairs of study subjects (HNBC and Tcig users). In a pilot study of ten smokers randomised to HNBC or Tcig and
then crossed-over to the alternate smoking (Tcig or HNBC) the dierence in the PWV of matched pairs aer
HNBC and Tcig smoking was normally distributed with standard deviation 1.3 and the true dierence in the
mean PWV of the matched pairs aer HBNC and Tcig smoking was 0.54m/s. us, we needed to study 47 pairs
of subjects to be able to reject the null hypothesis that this response dierence in PWV aer HNBC and Tcig is
zero with probability (power) 0.8. e Type I error probability associated with this test of this null hypothesis
is 0.05.
For the chronic study, we planned a study of a continuous response variable from independent control (Tcig
smokers) and experimental subjects (HNBC users) with 0.5 control(s) per experimental subject. In a pilot study
of 10 HNBC and 5 Tcig smokers the response for the GLS within each subject group was normally distributed
with a standard deviation of 3.1% and the true dierence of GLS means between the HNBC and Tcig smok-
ers was 2.3%. us, we needed to study at least 50 experimental and 25 control subjects to be able to reject the
null hypothesis that the population means of the HNBC and Tcig smoking groups are equal with a probability
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(power) of 0.8. e Type I error probability associated with this test for this null hypothesis is 0.05, as previously
published 34.
Ethical approval. It was approved by the Attikon University Hospital scientic ethics committee (Approval
number: 2874/06-12-17), registered on https:// clini caltr ials. gov/ (NCT03452124, 25/02/2018). e study was
conducted according to the Declaration of Helsinki and written informed consent was provided by the partici-
Study limitations
Our study was a single centre study. Its design does not permit to explore denite causative associations among
changes in oxidative stress, vascular and myocardial function markers. We should also acknowledge as a study
limitation the lack of measurement of cotinine blood or urine levels to appraise for the actual number of products
smoked by our study participants and to clarify whether dierences in circulating nicotine levels in addition to
dierences in CO production aer HNBC and Tcig smoking mediate the observed dierences of cardiovascular
markers in our study. Long term follow-up is needed to assess whether the observed improvement in vascular
and myocardial function, aer switching to HBNC, is associated with reduced cardiovascular events. Cluster
analysis using unsupervised machine learning techniques to identify subgroups of participants with favourable
or unfavourable responses to HNBC use for the measured vascular, cardiac and biochemical markers was not
Acute HNBC pung showed a less detriment eect on arterial elasticity compared to Tcig and did not cause a
further augmentation of oxidative stress burden, platelet activation, and exposure to CO compared to baseline,
in contrast to acute smoking of tobacco cigarette. Switching from Tcig to HNBC for one month resulted in
improved endothelial function, oxidative stress burden as well as in reduction of platelet activity and exposure
to CO, while caused an improvement in coronary ow reserve and myocardial work eciency compared with
tobacco smoking.
Data availability
e datasets generated during and/or analysed during the current study are available from the corresponding
author on reasonable request. Anonymised data are only available upon request from the authors.
Received: 21 April 2020; Accepted: 17 May 2021
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Author contributions
I.I. contributed to the study design, data analysis and writing of the manuscript. D.V. contributed to data analysis
and writing of the manuscript. G.K. contributed to patient recruitment, and randomization. Ka.K. contrib-
uted to patient recruitment and study design. Ko.K. performed echocardiographic studies and respective data
analysis. M.T. and I.A. performed the bio markers measurement and analysis. D.A. and J.P. critically reviewed
Content courtesy of Springer Nature, terms of use apply. Rights reserved
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the manuscript and contributed to the scientic analysis of the results. All authors discussed the results and
contributed to the nal manuscript.
e study was funded by Special Account for research Grants (11645) of the National and Kapodistrian University
of Athens without any direct or indirect support from Tobacco Company.
Competing interests
e authors declare no competing interests.
Additional information
Supplementary Information e online version contains supplementary material available at https:// doi. org/
10. 1038/ s41598- 021- 91245-9.
Correspondence and requests for materials should be addressed to I.I.
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... In this prospective observational cross-sectional study, chronic smoking of both TCCs and HNBCs was associated with reduced endothelial function, increased oxidative stress, and platelet activation, in accordance with previous studies (Figure 4) [19,[21][22][23]. However, since this was a sex-focused sub-study intended to unveil sex-related differences concerning different smoking habits, we deeply analyzed gender-related differences with respect to redox state, platelet aggregation, and vascular function. ...
Full-text available
Smoking is still a major cardiovascular risk factor, despite many public awareness campaigns and dedicated interventions. Recently, modified risk products (MRP), e.g., heat-not-burn cigarettes (HNBCs), have been introduced as surrogates of traditional combustion cigarettes (TCCs). Although these products are promoted as healthier than TCCs, few studies have been conducted to assess it. This work is a sex-focused sub-study of a prospective observational study in which apparently healthy chronic TCC smokers were age-matched with regular HNBC users. Blood samples were collected for biochemical assays and blood pressure and flow-mediated dilation (FMD) were measured. Out of 60 subjects, 33 (55%) were women, and 27 (45%) men, with 11 (33%) vs. 9 (33%) non-smokers, respectively, 10 (30%) vs. 10 (37%) TCC smokers, and 12 (36%) vs. 8 (30%) HNBC smokers (p = 0.946). Bivariate and multivariable analyses showed no statistically significant between-sex differences in NO, H2O2, sCD40L, sNox2-dp, sP-selectin, platelet aggregation, cotinine or FMD, overall, in non-smokers, in TCC smokers, or in HNBC smokers (all p > 0.05). HNBCs appeared safer than TCCs when focusing on Nox2-dp (p = 0.026) and sP-selectin (p = 0.050) but had similar levels of the other measured markers. In conclusion, HNBCs have similar detrimental effects on women and men’s oxidative stress (H2O2: p = 0.49; sNox2-dp: p = 0.31) and platelet activation (sP-selectin: p = 0.33; platelet aggregation p = 0.87).
... In anderen Studien wurde für Tabakerhitzer eine geringere Schädlichkeit als für herkömmliche Zigaretten festgestellt. Beim Umstieg von Tabakzigaretten auf Tabakerhitzer verbessere sich die Endothelfunktion, sinke die Belastung durch oxidativen Stress und verringere sich die Thrombozytenaktivität und die CO-Belastung [35]. Zwar würden auch Tabakerhitzer oxidativen Stress und entzündliche Reaktionen verursachen, aber erst nach viel intensiverer Exposition [32]. ...
The use of inhaled psychotropic substances is widespread in our society. In addition to the wide variety of tobacco-containing smoking products, e‑cigarettes, cannabis, sniffing substances, cocaine and heroin are consumed by inhalation. While the harmful effects of most tobacco-containing smoking products on the lungs have been sufficiently researched, there is still a lack of scientifically sound evidence for many other substances consumed by inhalation. In particular, for novel products, such as e‑cigarettes and tobacco heaters, there is a lack of independent standardized data demonstrating reduced health risk as a result of lower exposure to harmful substances. Clear conclusions are also currently not possible for the long-term effects of cannabis use on the lungs and respiratory tract. For the inhaled use of cocaine and heroin, on the other hand, considerable damage to the lungs can be documented, especially in the case of extensive and chronic use.
... showing its less impactful effects compared to conventional cigarette smoking on the outcomes of oxidative stress, platelet activation and blood pressure [10,11]. ...
Full-text available
Objective: To critically assess the methodological characteristics and quality of interventional clinical trials investigating the effects of heated tobacco products (HTPs). Data sources: Web of Science (Core collection and MEDLINE), Scopus, MedRxiv, and ICTRP trial databases and transnational HTP manufacturer online publication libraries were searched for clinical trials on HTPs published between January 2010 and April 2022. Study selection: Interventional clinical trials of any design, in which at least one group of adult participants used a currently marketed HTP, were selected by two reviewers with good or very good agreement. Data extraction: Data relating to trial characteristics and effects of intervention on primary outcomes were extracted using a predesigned form. Risk of bias was assessed using Cochrane's Risk of Bias tool v1. Data synthesis: 40 trials were included, 29 of which were tobacco industry affiliated. Methodological characteristics, such as registration, design, setting, comparator interventions, participants, outcomes and analyses, varied between trials, though there were few significant differences between industry-affiliated and independent trials. Of the 40 trials, 33 were judged to be at high risk of bias and 6 at unclear risk of bias. Trial findings were not significantly associated with either affiliation or risk of bias. Conclusions: The conduct and reporting of HTP interventional clinical trials were poor in many respects and limited to investigating effects of short-term exposure. These trials fall short of what is needed to determine whether HTPs are beneficial to public health, meaning they may not be a sound basis for tobacco control policy decisions.
Cigarette smoking is a major risk factor for the development of cardiovascular disease (CVD). Cigarette smoke contains toxicants that cross the alveolar barrier into the blood stream and elicit systemic oxidative stress and inflammatory responses, which can lead to an abnormal lipid profile and affect normal vascular functions. These changes predispose smokers to the development and progression of atherosclerosis, leading to various types of CVDs, such as ischaemic heart disease, cerebrovascular disease, peripheral artery disease, and aortic aneurysm. While the best choice a smoker can make is to stop smoking altogether, unfortunately not all smokers make that choice. In recent years, alternative products to cigarettes have been developed to offer a better alternative to continuing to smoke. However, new products representing a better alternative must be scientifically substantiated to understand how they present less risk to users compared with cigarettes. This literature review summarises the results of in vitro, in vivo, and clinical studies that, taken together, show the CVD risk reduction potential of switching from cigarette smoking to these smoke-free products.
Heated tobacco products represent a novel category of tobacco products in which a tobacco consumable is heated to a temperature that releases nicotine from the tobacco leaf but not to a temperature sufficient to cause combustion. Heated tobacco products may therefore have the potential to be a less harmful alternative for adult smokers that would otherwise continue to smoke conventional cigarettes. Given the rapid development of this product category, the aim of this review was to examine the available peer-reviewed scientific evidence related to heated tobacco products and highlight any research gaps. In recent years, manufacturers of heated tobacco products have published a number of studies on their respective heated tobacco products. Whilst there is limited research that is independent of commercial interests, the available scientific evidence indicates that heated tobacco products produce a much simpler aerosol than conventional cigarette smoke, with fewer and substantially lower levels of harmful toxicants. Toxicology assessments indicate these reductions in aerosol toxicants translate to reduced biological effects. Biomarker and clinical data from studies in which product use is controlled within a clinical setting, indicate changes in biomarker levels and clinical end-points similar to observations in cessation studies, indicating the potential for reduced harm. The scientific evidence also indicates that exposure of non-users to emissions from heated tobacco products in indoor environments is significantly reduced compared to exposure resulting from smoking conventional cigarettes. Overall, the available scientific evidence indicates that heated tobacco products hold promise as a less harmful alternative to conventional cigarettes, but more independent data is required to validate industry findings. As a growing product category, epidemiological studies and independent population modelling studies are outstanding, and empirical data on how dual tobacco product category use by consumers affects their risk profile is lacking.
Full-text available
Purpose of Review Modified risk products (MRP) are promoted as a safer alternative to traditional combustion cigarettes (TCC) in chronic smokers. Evidence for their lower hazardous profile is building, despite several controversies. Yet, it is unclear whether individual responses to MRP differ among consumers. We hypothesized that different clusters of subjects exist in terms of acute effects of MRP. Recent Findings Pooling data from a total of 60 individuals, cluster analysis identified at least three clusters (labelled 1 to 3) of subjects with different electronic vaping cigarettes (EVC) effects and at least two clusters (labelled 4 to 5) of subjects with different heat-not-burn cigarettes (HNBC) effects. Specifically, oxidative stress, platelet aggregation, and endothelial dysfunction after EVC were significantly different cluster-wise (all p < 0.05), and oxidative stress and platelet aggregation after HNBC were significantly different (all p < 0.05). In particular, subjects belonging to Cluster 1 appeared to have less detrimental responses to EVC usage than subjects in Cluster 2 and 3, as shown by non-significant changes in flow-mediated dilation (FMD) and less marked increase in Nox2-derived peptide (NOX). Conversely, those assigned to Cluster 3 had the worst reaction in terms of changes in FMD, NOX, and P-selectin. Furthermore, individuals belonging to Cluster 4 responded unfavorably to both HNBC and EVC, whereas those in Cluster 5 interestingly showed less adverse results after using HNBC than EVC. Results for main analyses were consistent employing different clusters, tests, and bootstrap. Summary Individual responses to MRP differ and smokers aiming at using EVC or HNBC as a risk reduction strategy should consider trying different MRP aiming at finding the one which is less detrimental, with subjects resembling those in Cluster 1 preferably using EVC and those resembling Cluster 5 preferably using HNBC.
Full-text available
Background: E-cigarette (EC) use is increasing exponentially worldwide. The early cardiovascular effects of switching from tobacco cigarettes (TC) to EC in chronic smokers is unknown. Meta-analysis of flow-mediated dilation (FMD) studies indicate 13% lower pooled, adjusted relative risks of cardiovascular events with every 1% improvement in FMD. Objectives: This study sought to determine the early vascular impact of switching from TC to EC in chronic smokers. Methods: The authors conducted a prospective, randomized control trial with a parallel nonrandomized preference cohort and blinded endpoint of smokers ≥18 years of age who had smoked ≥15 cigarettes/day for ≥2 years and were free from established cardiovascular disease. Participants were randomized to EC with nicotine or EC without nicotine for 1 month. Those unwilling to quit continued with TC in a parallel preference arm. A propensity score analysis was done to adjust for differences between the randomized and preference arms. Vascular function was assessed by FMD and pulse wave velocity. Compliance with EC was measured by carbon monoxide levels. Results: Within 1 month of switching from TC to EC, there was a significant improvement in endothelial function (linear trend β = 0.73%; 95% confidence interval [CI]: 0.41 to 1.05; p < 0.0001; TC vs. EC combined: 1.49%; 95% CI: 0.93 to 2.04; p < 0.0001) and vascular stiffness (-0.529 m/s; 95% CI: -0.946 to -0.112; p = 0.014). Females benefited from switching more than males did in every between-group comparison. Those who complied best with EC switch demonstrated the largest improvement. There was no difference in vascular effects between EC with and without nicotine within the study time frame. Conclusions: TC smokers, particularly females, demonstrate significant improvement in vascular health within 1 month of switching from TC to EC. Switching from TC to EC may be considered a harms reduction measure. (Vascular Effects of Regular Cigarettes Versus Electronic Cigarette Use [VESUVIUS]; NCT02878421; ISRCTN59133298).
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Background Little clinical research on new‐generation heat‐not‐burn cigarettes (HNBC) in comparison with electronic vaping cigarettes (EVC) and traditional tobacco combustion cigarettes (TC) has been reported. We aimed to appraise the acute effects of single use of HNBC, EVC, and TC in healthy smokers. Methods and Results This was an independent, cross‐over, randomized trial in 20 TC smokers, with allocation to different cycles of HNBC, EVC, and TC. All participants used all types of products, with an intercycle washout of 1 week. End points were oxidative stress, antioxidant reserve, platelet activation, flow‐mediated dilation, blood pressure, and satisfaction scores. Single use of any product led to an adverse impact on oxidative stress, antioxidant reserve, platelet function, flow‐mediated dilation, and blood pressure. HNBC had less impact than EVC and TC on soluble Nox2‐derived peptide (respectively, P=0.004 and 0.001), 8‐iso‐prostaglandin F2α‐III (P=0.004 and <0.001), and vitamin E (P=0.018 and 0.044). HNBC and EVC were equally less impactful than TCs on flow‐mediated dilation (P=0.872 for HNBC versus EVC), H2O2 (P=0.522), H2O2 breakdown activity (P=0.091), soluble CD40 ligand (P=0.849), and soluble P‐selectin (P=0.821). The effect of HNBC and, to a lesser extent EVC, on blood pressure was less evident than that of TC, whereas HNBC appeared more satisfying than EVC (all P<0.05). Conclusions Acute effects of HNBC, EVC, and TC are different on several oxidative stress, antioxidant reserve, platelet function, cardiovascular, and satisfaction dimensions, with TCs showing the most detrimental changes in clinically relevant features. Clinical Trial Registration URL: Unique identifier: NCT03301129.
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Background Heated tobacco products (also called ‘heat-not-burn’ products) heat tobacco at temperatures below that of combustion, causing nicotine and other compounds to aerosolise. One such product, IQOS from Philip Morris International, is being marketed internationally with claims of harm reduction. We sought to determine whether exposure to IQOS aerosol impairs arterial flow-mediated dilation (FMD), a measure of vascular endothelial function that is impaired by tobacco smoke. Methods We exposed anaesthetised rats (n=8/group) via nose cone to IQOS aerosol from single HeatSticks, mainstream smoke from single Marlboro Red cigarettes or clean air for a series of consecutive 30 s cycles over 1.5–5 min. Each cycle consisted of 15 or 5 s of exposure followed by removal from the nose cone. We measured pre-exposure and postexposure FMD, and postexposure serum nicotine and cotinine. Results FMD was impaired comparably by ten 15 s exposures and ten 5 s exposures to IQOS aerosol and to cigarette smoke, but not by clean air. Serum nicotine levels were similar to plasma levels after humans have smoked one cigarette, confirming that exposure conditions had real-world relevance. Postexposure nicotine levels were ~4.5-fold higher in rats exposed to IQOS than to cigarettes, despite nicotine being measured in the IQOS aerosol at ~63% the amount measured in smoke. When IQOS exposure was briefer, leading to comparable serum nicotine levels to the cigarette group, FMD was still comparably impaired. Conclusions Acute exposures to IQOS aerosol impairs FMD in rats. IQOS use does not necessarily avoid the adverse cardiovascular effects of smoking cigarettes.
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Use of intima-media thickness in the assessment of the development of preclinical atherosclerosis R.N.N. Najafov
We examined the effects of electronic cigarette on platelet and vascular function after 4 months of use compared to tobacco smoking. Forty smokers without cardiovascular disease were randomized to smoke either conventional cigarettes or an electronic cigarette (nicotine concentration of 12 mg/ml). At baseline and after four months, we measured a) platelet function by Platelet Function Analyzer PFA-100 and Light Transmission Aggregometry, b) pulse wave velocity, c) plasma malondialdehyde levels as oxidative stress index and d) the exhaled CO level. After 4 months, continuation of conventional cigarette smoking further impaired platelet function compared to vaping as assessed by PFA (mean increase 27.1 vs 11.6 s, p for interaction = 0.048) and by LTA (decline 24.1 vs 9.4%, p for interaction = 0.045). Conversely, compared to smoking, vaping resulted in greater reduction of exhaled CO (6.9 ppm vs 2.6, p for interaction < 0.001), improvement of PWV (decrease of 0.8 m/s vs increase of 0.8 m/s, p for interaction = 0.020) and reduction of MDA (reduction 0.13 vs increase 0.19 nmol/L, p for interaction = 0.035). Switching to electronic cigarette for 4 months has a neutral effect on platelet function while it reduces arterial stiffness and oxidative stress compared to tobacco smoking.
Chest pain in patients without obstructive coronary artery disease has been realized as a frequent problem encountered in clinical practice. Invasive flow investigations have suggested that up to two-thirds of patients with nonobstructive coronary atherosclerosis may have microvascular dysfunction (MVD). Positron emission tomography myocardial perfusion imaging in conjunction with tracer-kinetic modeling enables the concurrent quantification of myocardial blood flow (MBF) in milliliters per minute per gram of tissue. This allows the assessment of hyperemic MBFs and myocardial flow reserve for the noninvasive identification and characterization of MVD as an important functional substrate for angina symptoms amenable to intensified and individualized medical intervention with nitrates, calcium-channel blockers, statins, angiotensin-converting enzyme inhibitors, and/or angiotensin II type 1 receptor blockers. Recent investigations suggest that cardiac magnetic resonance and computed tomography may also be suitable for the noninvasive detection of MVD. Whether intensified and individualized treatment related improvement or even normalization of hyperemic MBF and/or myocardial flow reserve may lead to a persistent reduction in angina symptoms and/or improved cardiovascular outcome as compared to standard care, deserves further testing in large-scale randomized clinical trials.
Introduction: IQOS is an emerging heated tobacco product marketed by Philip Morris International (PMI). Because the tobacco in IQOS is electrically heated and not combusted, PMI claims that it generates significantly lower toxicant levels than combustible cigarettes. To date, a few independent studies have addressed IQOS toxicant emissions, and none have reported reactive oxygen species (ROS), and the form of the nicotine emitted by the device. Methods: In this study, IQOS aerosol was generated using a custom-made puffing machine. Two puffing regimens were used: Health Canada Intense and ISO. ROS, carbonyl compounds (CCs), and total nicotine and its partitioning between free-base and protonated forms were quantified in the IQOS aerosol by fluorescence, high-performance liquid chromatography, and gas chromatography, respectively. The same toxicants were also quantified in combustible cigarette aerosols for comparison. In addition, propylene glycol and vegetable glycerin were also measured in the IQOS tobacco and aerosol. Results: IQOS and combustible cigarettes were found to emit similar quantities of total and free-base nicotine. IQOS total ROS (6.26 ± 2.72 nmol H2O2/session) and CC emissions (472 ± 19 µg/session) were significant, but 85% and 77% lower than levels emitted by combustible cigarettes. Conclusions: IQOS emits harmful constituents that are linked to cancer, pulmonary disease, and addiction in cigarette smokers. For a given nicotine intake, inhalation exposure to ROS and CCs from IQOS is likely to be significantly less than that for combustible cigarettes. Implications: IQOS is PMI's new heated tobacco product. PMI claims that because IQOS heats and does not burn tobacco it generates low toxicant yields. We found that one IQOS stick can emit similar free-base and total nicotine yields as a combustible cigarette. A pack-a-day equivalent user of IQOS may experience significant inhalation exposure of ROS and CCs compared to background air. However, substituting IQOS for combustible cigarettes will likely result in far lower ROS and carbonyl inhalation exposure for a given daily nicotine intake.
Background Arterial elastance to left ventricular elastance ratio assessed by echocardiography is widely used as a marker of ventricular‐arterial coupling. Materials and methods We investigated whether the ratio of carotid‐femoral pulse wave velocity, as a marker of arterial stiffness, to global longitudinal strain, as a marker of left ventricular performance, could be better associated with vascular and cardiac damage than the established arterial elastance/left ventricular elastance index. In 299 newly‐diagnosed untreated hypertensives we measured, carotid‐femoral pulse wave velocity, and carotid intima‐media thickness, coronary‐flow reserve, arterial elastance/left ventricular elastance, global longitudinal strain, and markers of left ventricular diastolic function (E/A and E’) by echocardiography. Results Pulse wave velocity‐to‐global longitudinal strain ratio (PWV/GLS) was lower in hypertensives than controls (‐0.61±0.21 vs ‐0.45±0.11m/sec%, p<0.001). Low PWV/GLS values were associated with carotid‐intima media thickness>0.9mm (p=0.003), E/A≤0.8 (p=0.019) and E’≤9 cm/sec (p=0.002) and coronary‐flow reserve<2.5 (p=0.017), after adjustment for age, sex and mean arterial pressure. Low PWV/GLS was also associated with increased left ventricular mass and left atrial volume in the univariate (p=0.003 and p=0.038) but not in the multivariate model. In hypertensives, there was no significant association of arterial elastance‐to‐left ventricular elastance index with carotid intima media thickness, coronary flow reserve, E/A, E’, or left atrial volume with the exception of an inverse association with left ventricular mass (p=0.027). Conclusions Pulse wave velocity‐to‐global longitudinal strain ratio but not the echocardiography‐derived arterial elastance‐to left ventricular elastance index is related to impaired carotid‐intima media thickness, coronary‐flow reserve and diastolic function in hypertensives. This article is protected by copyright. All rights reserved.
Aims: Non-invasive left ventricular (LV) pressure-strain loop (PSL) provides a novel method of quantifying myocardial work (MW) with potential advantages over conventional global longitudinal strain (GLS) by incorporating measurements of myocardial deformation and LV pressure. We investigated different patterns of LV PSL and global MW index (GWI) in patients with hypertension (HTN) and dilated cardiomyopathy (CMP). Methods and results: Seventy-four patients underwent transthoracic echocardiography and strain analysis before coronary angiography. Patients were divided into three groups: control, HTN, and CMP. GWI was calculated as the area of the LV PSL as a product of strain × systolic blood pressure. MW efficiency (GWE) is derived from the percentage ratio of constructive work (GCW) to sum of constructive work (GCW) and wasted work (GWW). Influences of HTN and LV function on its relationship with MW were evaluated. GLS and LV ejection fraction were preserved in the HTN group with no difference from controls. GWI was significantly higher in moderate to severe HTN patients (P = 0.004) as a compensatory mechanism to preserve LV contractility and function against an increase in afterload. GWE was preserved in HTN patients due to the proportional increase in GCW and GWW. GLS, GWI, and GWE were significantly reduced in CMP (P < 0.05), with a trend in rightward shift and reduction in the LV PSL. Conclusion: GWI is a potential new technique that allows better understanding of the relationship between LV remodelling and increased wall stress under different loading conditions.