Reduced vascular function, ventilatory efficiency and exercise capacity in young adult electronic cigarette users

Abstract

Background

Acute electronic cigarette (E-cigarette) use has shown adverse cardiorespiratory impacts similar to conventional cigarette (C-cigarette) smoking; however, its early effects remain unclear. We aimed to examine the early effects of E-cigarette use on systemic vascular function, cardiorespiratory responses to exercise and exertional symptoms in young adults.

Methods

75 healthy active young adults (18–30 years), divided into three age- and sex-matched groups (E-cigarette users, C-cigarette smokers and never-smoker controls; n=25 each, E-cigarette use or smoking duration ≥18 months), underwent an incremental cycle exercise test with standard metabolic, cardiorespiratory, blood lactate and sensory measurements. Brachial artery flow-mediated dilatation (FMD) was assessed using Doppler ultrasound. Blood samples were collected to assess vascular inflammatory markers.

Results

Cotinine (nicotine metabolite) levels were not different between E-cigarette users and C-cigarette smokers (80.7±33.0 versus 65.5±27.6 pg·mL⁻¹, p=0.2). At peak exercise, both E-cigarette users and C-cigarette smokers had lower exercise capacity, oxygen uptake, and ventilation compared with controls (182±31, 178±27 versus 219±43 watts; 35.1±6.4, 35.1±5.3 versus 41.2±5.9 mL·kg⁻¹·min⁻¹; 97.8±24.7, 98.9±21.6 versus 116.1±29.8 L·min⁻¹, respectively; all p<0.05). Furthermore, E-cigarette users and C-cigarette smokers demonstrated decreased exercise ventilatory efficiency, with higher ventilation, blood lactate, dyspnoea ratings and leg discomfort during submaximal exercise compared with controls. E-cigarette users and C-cigarette smokers showed lower FMD compared with never-smokers (4.7±3.0, 4.5±2.9 versus 8.1±3.5%, p<0.05), which was inversely associated with vascular cell adhesion molecule-1 and thrombospondin-2.

Conclusion

E-cigarette use and C-cigarette smoking were both associated with early detrimental effects on exercise capacity, ventilatory efficiency, systemic vascular function and amplified exertional symptoms.

Shareable abstract

In active, healthy young adults, electronic cigarettes and tobacco smoking each exhibited impaired resting systemic vascular function and exercise ventilatory responses, contributing to reduced exercise capacity and worse exertional symptoms https://bit.ly/48O4oeE

Introduction

Smoking, a common aetiological factor in several cardiovascular and respiratory diseases, is the most preventable cause of death. Electronic cigarette (E-cigarette) use (vaping) is advertised as a safe alternative to conventional cigarette (C-cigarette) smoking; however, recent evidence reveals a complex certainty [1]. The global prevalence of E-cigarette use has exponentially increased since their introduction in the mid-2000s, especially among young adults [2]; with >82 million people worldwide using E-cigarettes [3]. E-cigarettes were thought to produce fewer toxicants and deliver nicotine in a less harmful way than C-cigarette smoking [4]. While the addition of E-cigarettes to standard smoking cessation counselling shows some beneficial effects [5]; observational studies in the general population find weaker or no associations [6]. E-cigarette users also exhibit higher levels of disease outcomes in comparison with never-smokers, whereas the disease outcomes are equal to those of exclusive smokers [7]. Furthermore, concerns remain about their role as a gateway to nicotine addiction, especially among those who never smoked [8].

There is plenty of evidence regarding the short-term deleterious effects of E-cigarettes on cardiovascular and respiratory functions [9]. Acute exposure to E-cigarette aerosols induces oxidative stress, leading to reduced nitric oxide bioavailability and endothelial dysfunction, and increased arterial stiffness, posing significant vascular risks [10, 11]. Like C-cigarette smoking, E-cigarettes can lead to an immediate increase in heart rate and systolic blood pressure [12], due to reduced vagal activity and increased sympathetic predominance [13]. Moreover, E-cigarette use is also associated with increased airway flow resistance [10], accelerated lung function decline and progression of COPD [14].

Little is known about the early impacts of E-cigarette use on cardiovascular function, exercise capacity, ventilatory efficiency, lung mechanics and exertional symptoms. E-cigarette use was recently shown to impair small airway function and ventilation (V′_E) distribution as assessed by the lung clearance index [15] and increase the risk of developing COPD [16]. Simovic et al. [17] also reported reduced cardiorespiratory fitness in young adults who regularly use E-cigarettes compared with healthy non-users. This study aimed to examine the early impacts of E-cigarette use on resting vascular function and cardiorespiratory and sensory responses during exercise in otherwise healthy active young adults who had never smoked and compare against those of tobacco-cigarette smokers and never-smoker controls. We hypothesised that E-cigarette users and C-cigarette smokers would each exhibit reduced resting vascular function relative to never-smokers, and that this, together with exercise ventilatory inefficiency and amplified dyspnoea, would be key determinants of decreased exercise tolerance.

Materials and methods

Participants

75 healthy, active young adults (18–30 years) were recruited and divided into three age- and sex-matched groups, 25 in each (16 males): 1) E-cigarette users, 2) C-cigarette smokers, and 3) never-smoker controls with no history of E-cigarette use. E-cigarette users and C-cigarette smokers must have been using only E-cigarette or C-cigarette for ≥18 months. None of the E-cigarette users had any history of using C-cigarettes or other substances, and conversely, those who smoked C-cigarettes had no history of using E-cigarettes or other substances. All participants had normal spirometry (forced expiratory volume in 1 s (FEV₁) ≥80% predicted, FEV₁/forced vital capacity >0.7 and both above the lower limit of normal) [18], no history of cardiovascular or respiratory diseases or any other conditions that could affect exercise or vascular function.

Study design

This cross-sectional study received ethical approval from the Manchester Metropolitan University (EthOS reference no. 57005). After providing informed consent, participants completed two visits within a week: visit 1 included eligibility screening, medical history, spirometry, maximal voluntary ventilation (MVV), maximal inspiratory and expiratory mouth pressures followed by an incremental cycle cardiopulmonary exercise test (CPET) with blood lactate, dynamic lung volumes and symptoms measurements; visit 2 included brachial artery flow-mediated dilatation (FMD) using Doppler ultrasound and venous blood samples to measure vascular inflammatory markers.

Procedures and analysis

A Vyntus CPX system (Jaeger Medical, Hochberg, Germany) was used for spirometry and MVV measurements according to the European Respiratory Society guidelines and standardised procedures [19]. Microspirometry (MicroMPM Spirometer, MD Spiro, Lewiston, ME, USA) was used to measure maximal mouth pressures. Participants completed incremental CPETs (20 W every 2 min) on an electronically braked cycle-ergometer (Ergoselect 5, Ergoline, Bitz, Germany) using a Vyntus CPX system as previously described [20]. Finger-prick blood samples were collected in the last 30 s of each exercise stage to measure blood lactate (Lactate Pro 2 analyser, Arkray, Kyoto, Japan). Inspiratory capacity (IC) manoeuvres were performed at rest, at each exercise stage and at peak exercise. Measurements of ventilatory efficiency during CPET included V′_E to carbon dioxide production ratio (V′_E/V′_CO2) at submaximal iso-workloads, V′_E/V′_CO2 nadir and V′_E−V′_CO2 slope. Participants rated the intensity of dyspnoea and leg discomfort during CPET using the modified 10-point Borg scale [21].

Brachial artery FMD was assessed using Doppler ultrasound (Terason uSmart 3300, TeraTech, Burlington, MA, USA) [22]. Brachial artery diameter and mean blood flow velocity were measured using a 7.5 MHz ultrasound linear probe at rest, during, and following 5 min of forearm occlusion. Venous blood samples were collected to assess full blood counts, and vascular inflammatory markers (e.g. interleukin-1 receptor antagonist (IL-1RA), vascular cell adhesion molecule 1 (VCAM-1), E-selectin and thrombospondin-2). To verify smoking status, cotinine, a nicotine metabolite, was measured in serum samples using ELISA (Abnova, KA0930, Taiwan). Participants were asked to refrain from E-cigarette use or C-cigarette smoking and to avoid caffeine, heavy meals, alcohol and vigorous exercise for at least 24 h before visits. The same investigator (RTJ) conducted all FMD tests and analyses, while the investigator (SJ) analysed the blood samples, with both being blinded to the group assignments.

Statistical analysis

We conducted an observational study with the main outcome measures of peak oxygen uptake (V′_O2peak) and brachial artery FMD. A sample size estimation of 23 participants per group was conducted based on a one-way ANOVA (three groups), with 90% power and α=0.05 (G*Power v.3.1). For V′_O2peak, an effect size of Cohen's f=0.42 was derived from a previously reported t-test effect size (Cohen's d=0.84 [17]), using the conversion f=d/2. For FMD, a Cohen's f=1.26 was applied [23]. A one-way ANOVA with Tukey post hoc test was used to determine between-group differences using SPSS (IBM, USA SPSS 29). In addition to group comparisons, multivariable linear regression models adjusting for age, sex and body mass index (BMI) as covariates were performed to explore the independent physiological predictors of V′_O2peak, exercise capacity, FMD and exercise ventilatory efficiency (General Linear Models, PROC GLM, SAS 9.4, SAS Institute, Cary, NC, USA). Reasons for stopping exercise were compared between groups using Fisher's exact test. Statistical significance was set at p<0.05, and data are presented as mean±sd.

Results

The three groups were well-matched for age, height, BMI, sex and weekly physical activity (table 1). E-cigarette users had significantly shorter duration of use than C-cigarette smokers (3.1±2.0 versus 5.1±3.7 years, p=0.02). Cotinine levels were not different between E-cigarette users and C-cigarette smokers (80.7±33.0 versus 65.5±27.6 ng·mL⁻¹, p=0.2). E-cigarette users reported vaping ≥5 times·day⁻¹ for approximately 3 min per episode, and C-cigarette smokers had a 1.8±1.4 pack-year smoking history. There were no differences between groups in spirometry, MVV, maximal mouth pressures, resting cardiovascular parameters and weekly alcohol use (table 1).

TABLE 1.

Participants’ characteristics (n=25 each group)

Variables	E-cigarette users	C-cigarette smokers	Never-smoker controls
Age, years (M:F)	22.8±2.5 (16:9)	23.0±2.8 (16:9)	23.0±2.8 (16:9)
Height, cm	176.1±7.8	174.3±6.9	174.5±8.1
Weight, kg	74.9±13.3	72.8±10.6	72.4±10.6
BMI, kg·m−2	24.0±3.0	23.9±3.0	23.7±2.6
Duration of use, years	3.1±2.0*	5.1±3.7#¶	0±0
Cotinine, ng·mL−1	80.7±33.0*	65.5±27.6#	0±0
Physical activity, min·week−1	199.4±44.3	214.4±48.6	219.8±44.1
Alcohol usage, units·week−1	15.9±8.9	17.1±11.4	12.1±10.3
Resting pulmonary function
FEV1, L (% predicted)	4.13±0.72 (98±11)	3.96±0.75 (98±10)	4.02±0.76 (101±12)
FVC, L (% predicted)	5.02±0.99 (102±13)	4.90±0.99 (101±10)	4.94±0.89 (103±8)
FEV1/FVC	0.83±0.05	0.81±0.06	0.81±0.06
FEF25–75, L·s−1	5.06±1.57	4.67±1.36	5.40±1.36
IC, L	3.78±0.77	3.75±0.76	3.82±0.73
MVV, L·min−1	150±34	142±23	157±33
MIP, cmH2O	107±20	99±26	111±22
MEP, cmH2O	115±21	104±27	116±21
Resting cardiovascular parameters
Heart rate, bpm	69±13	68±9	64±9
SBP, mmHg	120±14	123±12	120±15
MAP, mmHg	88±10	93±10	90±9
DBP, mmHg	72±10	78±11	74±10
Haemoglobin, g·dL−1	14.60±1.63	14.47±2.04	14.65±2.24

Data are presented as mean±sd. BMI: body mass index; C-cigarette: conventional cigarette; DBP: diastolic blood pressure; E-cigarette: electronic cigarette; F: female; FEF_25–75: forced expiratory flow between 25 and 75% of FVC; FEV₁: forced expiratory volume in 1 s; FVC: forced vital capacity; IC: inspiratory capacity; M: male; MAP: mean arterial pressure; MEP: maximum expiatory mouth pressure; MIP: maximum inspiratory mouth pressure; MVV: maximal voluntary ventilation; SBP: systolic blood pressure. *: p<0.05 E-cigarette users versus controls. ^#: p<0.05 C-cigarette smokers versus controls. ^¶: p<0.05 E-cigarette users versus C-cigarette smokers.

Flow-mediated dilation and inflammatory markers

The three groups have had similar baseline brachial artery diameters, but FMD was reduced in E-cigarette users and C-cigarette smokers compared with controls (4.7±3.0, 4.5±2.9 versus 8.1±3.5%, respectively, both p<0.05) (table 2 and figure 1). Thrombospondin-2 was greater in E-cigarette users and C-cigarette smokers versus controls (4.44±2.93, 3.94±1.67 versus 2.14±1.38 ng·mL⁻¹, respectively, both p<0.05) (table 2). Compared with controls, IL-1RA was higher in C-cigarette smokers and VCAM-1 was higher in E-cigarette users (table 2). Further blood results are shown in supplementary tables S1 and S2.

TABLE 2.

Flow-mediated dilation characteristics and vascular inflammatory markers

Variables	E-cigarette users	C-cigarette smokers	Never-smoker controls
Flow-mediated dilation	(n=24, 8F)	(n=23, 8F)	(n=24, 8F)
Baseline diameter, mm	3.99±0.61	4.05±0.77	3.92±0.62
Peak diameter, mm	4.18±0.69	4.23±0.79	4.24±0.69
Time-to-peak diameter, s	53.17±24,72	64.43±27.95	58.17±21.26
SRAUC, s−1	14 235±4799	16 652±7199	18 402±9570
Absolute FMD, mm	0.19±0.13*	0.18±0.10#	0.31±0.17
FMD, %	4.70±3.03*	4.53±2.86#	8.12±3.74
Vascular inflammatory markers	(n=22)	(n=19)	(n=22)
IL-1RA, pg·mL−1	150.7±35.8	190.6±89.5#	133.5±67.9
VCAM-1, ng·mL−1	363.0±105.0*	331.3±77.4	279.4±90.7
E-selectin, pg·mL−1	13.2±5.6	14.5±6.9#	11.7±5.4
Thrombospondin 2, ng·mL−1	4.2±2.9*	3.7±2.0#	2.2±1.3

Data are presented as mean±sd, except where indicated. C-cigarette: conventional cigarette; E-cigarette: electronic cigarette; FMD: flow-mediated dilation; IL-1RA: interleukin-1 receptor antagonist; SR_AUC: shear rate area under the curve; VCAM-1: vascular cell adhesion molecule 1. *: p<0.05 E-cigarette users versus controls. ^#: p<0.05 C-cigarette smokers versus controls.

FIGURE 1.

Individual baseline brachial artery diameter and maximum brachial artery diameter (a), delta brachial artery diameter (maximum–baseline) (b), and brachial artery flow-mediated dilation (FMD) (c) in electronic (E)-cigarette users (black circles/bars), conventional (C)-cigarette smokers (grey circles/bars) and healthy never-smoker controls (open circles/bars). Data are presented as mean±sem. *: p<0.05 E-cigarette users versus controls. ^#: p<0.05 C-cigarette smokers versus controls.

Measurements during incremental CPET

E-cigarette users and C-cigarette smokers achieved lower peak workloads and V′_O2peak compared with controls (table 3 and figure 1a). There were no between-group differences in mechanical efficiency (W/V′_O2peak). Anaerobic threshold (AT) occurred at a significantly lower workload and V′_O2 level in both E-cigarette users and C-cigarette smokers compared with controls (119±23, 114±20 versus 147±32 watts; and 1.83±0.43, 1.77±0.34 versus 2.09±0.46 L·min⁻¹, respectively, all p<0.05). However, these values corresponded to similar percentages of peak workloads and V′_O2peak in all three groups (p>0.05). Yet E-cigarette users and C-cigarette smokers both exhibited an accelerated increase in lactate levels compared with controls throughout submaximal exercise (figure 2b). There were no differences between groups in heart rate and O₂ pulse (figure 2c,d) nor the chronotropic response index (CRI).

TABLE 3.

Measurements at the peak of incremental cycle exercise (n=25 each group)

Variables	E-cigarette users	C-cigarette smokers	Never-smoker controls
Work rate, watts	182±31*	178±27#	219±43
V′O2, L·min−1	2.60±0.62*	2.55±0.53#	2.99±0.64
Mechanical efficiency, %	23.4±3.1	23.6±3.2	24.3±2.6
V′O2, mL·min−1·kg−1 (% predicted)	35.1±6.4* (80±14*)	35.1±5.3# (80±13#)	41.2±5.9 (94±13)
V′E, L·min−1	97.8±24.7*	98.9±21.6#	116.1±29.8
V′E/MVV, %	67±13	71±15	74±14
V′E/V′CO2	33.9±6.3	36.3±5.7	34.8±6.9
HR, beats·min−1 (% predicted)	180±12 (94±6)	179±14 (93±7)	184±13 (96±7)
Chronotropic response index	0.97±0.11	0.98±0.09	0.98±0.08
O2 pulse (V′O2/HR), mL·beat−1	14.4±3.4	14.3±3.1	16.2±3.0
Fb, breaths·min−1	41±9	44±8	46±9
VT, L	2.5±0.5	2.4±0.5	2.6±0.6
IC, L	3.6±0.7	3.4±0.5	3.7±0.8
VT/IC, %	71±11	69±9	72±13
IRV, L	1.1±0.5	1.1±0.4	1.1±0.6
RER	1.12±0.09	1.11±0.06	1.10±0.08
Blood lactate, mmol·L−1	13.0±3.0	11.7±3.5	12.0±3.5
Dyspnoea, Borg units	7.6±1.9	7.4±2.2	7.4±2.1
Leg discomfort, Borg units	9.3±0.9	8.6±1.6	8.6±1.6

Data are presented as mean±sd. C-cigarette: conventional cigarette; E-cigarette: electronic cigarette; F_b: breathing frequency; HR: heart rate; IC: inspiratory capacity; IRV: inspiratory reserve volume; MVV: maximal voluntary ventilation; RER: respiratory exchange ratio; V′_CO2: carbon dioxide production; V′_E: minute ventilation; V′_O2: oxygen uptake; V_T: tidal volume. *: p<0.05 E-cigarette users versus controls. ^#: p<0.05 C-cigarette smokers versus controls.

FIGURE 2.

Cardiometabolic responses to incremental cycle exercise in electronic (E)-cigarette users (black circles), conventional (C)-cigarette smokers (grey circles) and healthy never-smoker controls (open circles). Data are presented as mean±sem. The vertical lines in (a) show differences in work rate. *: p<0.05 E-cigarette users versus controls. ^#: p<0.05 C-cigarette smokers versus controls.

Peak V′_E was lower in both E-cigarette users and C-cigarette smokers than in controls (97.8±24.7, 98.9±21.6 versus 116.1±29.8 Lmin⁻¹, both p<0.05) (figure 3a). V′_E, V′_E/V′_CO2 and breathing frequency were higher and end-tidal carbon dioxide (P_ETCO2) was lower in both E-cigarette users and C-cigarette smokers compared with controls at submaximal exercise (figure 3b–d). Tidal volume, IC, and inspiratory reserve volume were similar across groups at iso-submaximal workloads (figure 3e,f). Furthermore, V′_E/V′_CO2 was higher and P_ETCO2 was lower in both E-cigarette users and C-cigarette smokers compared with controls at iso-percentage of maximum workload (figure 4). V′_E/V′_CO2 nadir was also higher in E-cigarette users and C-cigarette smokers compared with controls (29.2±2.6, 29.9±2.0 versus 27.3±2.2; both p<0.05). The V′_E–V′_CO2 slope was significantly steeper in C-cigarette smokers and marginally steeper in E-cigarette users compared with controls (34.9±5.7, 33.1±4.9 versus 30.0±4.2; p<0.05, p=0.05, respectively). Borg scores for dyspnoea and leg discomfort were significantly higher in E-cigarette users and C-cigarette smokers than in controls at iso-workloads (figure 5a,b) and at iso-ventilation levels (figure 5c,d). The slopes of dyspnoea and leg discomfort versus workload and ventilation were also steeper in E-cigarette users and C-cigarette smokers than in controls (supplementary material). Leg discomfort was more frequently reported as the dominant symptom at the end of exercise in all three groups (p>0.05).

FIGURE 3.

Ventilatory and breathing pattern responses to incremental cycle exercise in electronic (E)-cigarette users (black circles), conventional (C)-cigarette smokers (grey circles) and healthy never-smoker controls (open circles). Data are presented as mean±sem. V′_E/V′_CO2: ventilatory equivalent for carbon dioxide; P_ETCO2: end-tidal carbon dioxide tension; TLC: total lung capacity. *: p<0.05 E-cigarette users versus controls. ^#: p<0.05 C-cigarette smokers versus controls.

FIGURE 4.

Ventilatory efficiency at iso-percentage of maximum workload in electronic (E)-cigarette users (black circles), conventional (C)-cigarette smokers (grey circles) and healthy never-smoker controls (open circles). Data are presented as mean±sem. V′_E/V′_CO2: ventilatory equivalent for carbon dioxide; P_ETCO2: end-tidal carbon dioxide tension. *: p<0.05 E-cigarette users versus controls. ^#: p<0.05 C-cigarette smokers versus controls.

FIGURE 5.

Exertional dyspnoea intensity and leg discomfort are shown relative to work rate (a,b) and ventilation (c,d) in electronic (E)-cigarette users (black circles), conventional (C)-cigarette smokers (grey circles) and healthy never-smoker controls (open circles). Data are presented as mean±sem. *: p<0.05 E-cigarette users versus controls. ^#: p<0.05 C-cigarette smokers versus controls.

Multivariable regression analyses

In the whole sample, multivariable linear regression models (supplementary table S3) identified a higher V′_E/V′_CO2 nadir, lower shear rate, elevated E-selectin concentrations, and a steeper dyspnoea slope as significant independent predictors of reduced V′_O2peak (p<0.01, R²=0.58). For peak workload, steeper dyspnoea slopes and lower shear rate were the strongest predictors (p<0.001, R²=0.57). Higher VCAM-1 (p=0.04), and thrompsopndin-2 (p=0.01) levels were inversely associated with reduced FMD, while IL1RA was significantly associated with increased V′_E–V′_CO2 slope (p=0.02) (supplementary figure S1). Supplementary table S4 shows the Pearson correlation matrix of key physiological and inflammatory markers.

Discussion

This study comprehensively characterises the early detrimental effects of E-cigarette use on cardiorespiratory, ventilatory, and sensory responses to exercise and resting vascular functions among young adults in comparison with C-cigarette smokers and healthy never-smoker controls. Our results showed that both active young vapers and cigarette smokers exhibit impaired vascular function (reduced brachial artery FMD), diminished cardiorespiratory fitness (lower peak workloads and V′_O2peak), increased ventilatory and metabolic demands and reduced exercise ventilatory efficiency (higher V′_E/V′_CO2) with excess symptoms of dyspnoea and leg discomfort during exercise, in the absence of mechanical ventilatory constraints, compared with controls. Reduced vascular function and ventilatory inefficiency, observed in otherwise healthy young adults, may represent early warning signs for future cardiopulmonary diseases, highlighting the potential risk of E-cigarette use.

Impact of vaping on vascular functions

E-cigarettes were thought to be significantly less cytotoxic and emit fewer harmful substances compared with C-cigarettes [4]. Improvements in endothelial function and vascular stiffness were also reported among C-cigarette smokers within a month of switching to E-cigarettes [24]. This provided support for the purported health harm reduction role of E-cigarettes and their benefits in smoking cessation [5]. Yet several studies have shown that E-cigarette use also triggers oxidative stress, systemic inflammation, increased arterial stiffness and vascular endothelial cellular death [10, 11].

In the current study, serum levels of cotinine (a nicotine metabolite) were not different between E-cigarette users and C-cigarette smokers (table 1). It is well acknowledged that nicotine exposure via C-cigarette smoking, or E-cigarette use can lead to disruptions in lung endothelial microvasculature through oxidative stress and inflammation [25]. The vapour produced from E-cigarettes (containing acrolein and formaldehyde) increases pro-inflammatory cytokines, inhibits endothelial nitric oxide synthase (NOS), reduces vascular endothelial growth factor and nitric oxide bioavailability, impairing endothelial function and promoting atherogenesis [11, 23]. The expression of VCAM-1 is canonically induced by pro-inflammatory cytokines in the endothelium of blood vessels (enhanced vascular inflammation) [26]. In addition, thrombospondin-2 can promote vascular inflammation and potentially contribute to the pathological processes of various cardiovascular diseases [27]. The similar overexpression of VCAM-1 and thrombospondin-2 in vapers and smokers (table 2) may indicate that E-cigarette use and C-cigarette smoking have comparable effects in promoting vascular inflammation, and triggering atherosclerosis and adverse cardiovascular events [28, 29]. The reduced FMD% and elevated vascular inflammation and thrombosis biomarkers in vapers and smokers (table 2) also support the notion of increased systemic vascular resistance [30], attenuate endothelium-dependent vasodilator response [11] and diminished endothelial function in healthy young E-cigarette users [23]. Our results showed that increased vascular inflammatory markers, in conjunction with impaired vascular function, correlated with reduced cardiorespiratory fitness in vapers and smokers (supplementary tables S3 and S4).

Cardiorespiratory responses during exercise

Cardiorespiratory fitness relies on the integrated capacity of cardiovascular, pulmonary and musculoskeletal systems to supply and utilise oxygen. The novelty of the current study lies in showing that regular E-cigarette use has a similar early detrimental impact on exercise capacity, V′_O2peak (figure 2a), and cardiorespiratory and metabolic responses during exercise as C-cigarette smoking. Reduced exercise capacity and V′_O2peak in C-cigarette smokers without airflow limitation are associated with reduced left ventricular function and stroke volume, increased carboxyhaemoglobin and impaired gas exchange, thus hindering oxygen delivery [31, 32]. There is scarce evidence on the impact of E-cigarette use on the cardiorespiratory responses during exercise [17]. While there is some evidence that E-cigarettes use can impair cardiac geometry and function, affecting oxygen delivery during exercise [17, 33]; the similar heart rate and O₂ pulse responses from rest to peak exercise (figure 2c,d) and CRI among all groups rule out impaired central haemodynamics as main contributing factor to reduced exercise capacity in the vapers and smokers groups. Nevertheless, pulmonary vascular dysfunction in vapers may disrupt ventilation–perfusion matching before alterations in small airways, and increase ventilation–perfusion inequalities, similar to those seen in early-stage COPD [34, 35]. Moreover, endothelial impairment, as indicated by reduced FMD and elevated systemic inflammatory markers in E-cigarette and C-cigarette groups (table 2), can significantly compromise peripheral vascular function, reduce muscle perfusion and affect oxygen delivery during exercise.

C-cigarette smoking can additionally induce oxidative fibre atrophy, increased percentage of muscle fibres with high glycolytic capacity and lactate dehydrogenase activity, and diminished vascular endothelial function (via reduced NOS expression) [36]. Also, E-cigarette exposure can increase oxidative stress and mitochondrial damage in the skeletal muscle [37]. In addition, nicotine, present in E-cigarette aerosol, can impair skeletal muscle force production independent of muscle atrophy due to impaired excitation-contraction coupling [38]. Reduced skeletal muscle force production, combined with impaired mitochondrial oxidative capacity and an elevated reliance on glycolysis, would contribute to reduced muscle fatigue resistance and a faster rise in blood lactate, leading to a lower AT, reduced exercise capacity and heightened leg discomfort during exercise [39], consistent with our findings in E-cigarette and C-cigarette groups (figures 2a,b and 5b). Therefore, these differences in cardiorespiratory fitness in vapers and smokers could be attributed to changes in vascular and skeletal muscle functions as there were no differences in baseline physical activity levels.

Exercise ventilatory efficiency and dyspnoea

A higher V′_E/V′_CO2 nadir and V′_E–V′_CO2 slope have been identified as prognostic markers for all-cause mortality across the spectrum of COPD severity [40]. The V′_E–V′_CO2 slope is influenced by changes in arterial CO₂ and the fraction of physiological dead space to tidal volume during exercise [40]. In agreement with our previous findings in middle-aged smokers without airflow limitations [39], young active C-cigarette smokers in this study showed increased V′_E and breathing frequency, with higher V′_E/V′_CO2 nadir, lower P_ETCO2 and a steeper V′_E–V′_CO2 slope during exercise than healthy never-smokers, without drastic changes in lung mechanics (figure 3). Reduced ventilatory efficiency in young smokers in the current study is likely linked to increased dead space, due to increased pulmonary endothelial dysfunction and ventilation–perfusion inequalities secondary to nicotine-induced sympathetic stimulation, and early metabolic acidosis [35, 39, 41].

E-cigarette users also showed increased ventilatory requirements during exercise as C-cigarette smokers (figure 3a), which could be attributed to increased ventilation–perfusion heterogeneity [34]. Poor ventilatory efficiency (higher V′_E/V′_CO2) in E-cigarette users, as shown at submaximal iso-workloads or at a given percentage of maximum workload (figures 3b and 4c), could also be linked to decreased FMD secondary to the oxidative and pro-inflammatory conditions [42], and may explain the higher exertional dyspnoea at lower submaximal exercise intensities compared with controls (figure 5a). While increased submaximal V′_E during exercise may compensate for any possible gas exchange derangements and maintain appropriate oxygenation [34, 35], this will be at the cost of increased work of breathing [20] and may lead to intensified dyspnoea responses during exercise (figure 5a,c). Of note, mechanical ventilatory limitation (tidal volume constraints) was not a predominant mechanism for higher ratings of dyspnoea or exercise intolerance in both E-cigarette and C-cigarette groups (figure 3e,f). However, impaired gas exchange and higher lactate could stimulate peripheral chemoreceptors and may result in increased ventilatory drive and higher V′_E and perceived dyspnoea during submaximal exercise [43]. Thus, higher ventilatory requirements and dyspnoea ratings in vapers and smokers could be associated with airway inflammation and resultant ventilation inhomogeneity, early metabolic acidosis, and elevated ventilation–perfusion inequalities in the absence of overt respiratory mechanical limitations [15, 35, 39].

Limitations

The novelty of the current study lies in having well-matched and well-characterised groups who have similar lifestyles (caffeine and alcohol consumption) and physical activity levels (amount/form of exercise); however, the cross-sectional methodology may limit causal inferences. While the frequency of E-cigarettes use per week was calculated, there was a wide range of e-liquid composition and nicotine amounts in vaping devices, which made it difficult to assess the history and load of E-cigarette usage precisely [34]. The C-cigarette smokers have a slightly longer duration of usage with a low pack-year history (1.8±1.4 pack-years); however, blood cotinine levels were comparable between E-cigarette and C-cigarette groups (table 1). This may suggest that E-cigarette users were predominantly using high-nicotine pod devices, and both groups had a similar nicotine exposure regardless of smoking load and duration.

Lung diffusing capacity (D_LCO) was not measured in the current study. Yet, we have previously shown reduced D_LCO and an inverse correlation between V′_E/V′_CO2 and D_LCO in smokers with normal spirometry [39]. Low D_LCO in C-cigarette smokers was previously shown to be linked with peripheral endothelial dysfunction and decreased FMD [42]. As E-cigarette users exhibited similar findings of reduced FMD and high V′_E/V′_CO2, we anticipate that E-cigarette users may also show a reduced D_LCO compared with never-smoker controls, likely due to pulmonary microvascular loss [15].

Physical activity levels were assessed using the International Physical Activity Questionnaire [44]; however, there were no evaluations of physical activity conducted using a multisensor accelerometer. In previous research, we demonstrated that daily step count, basal metabolic rate, and physical activity levels did not differ significantly between smokers with normal spirometry and never-smoking healthy controls [39]. Therefore, it is unlikely that we would identify differences in physical activity levels among the otherwise healthy, active young adults who participated in our study, even with the use a multisensor accelerometer.

Conclusion

Like tobacco smoking, E-cigarette use was accompanied by detrimental effects on resting vascular function, ventilatory efficiency, cardiorespiratory fitness and exertional symptoms of dyspnoea and leg discomfort among young adults. Further mechanistic studies are crucial to understand the medium/long-term consequences of E-cigarette use on cardiovascular, respiratory and skeletal muscle functions. Overall, our findings provide critical information to the general community, healthcare providers, medical trusts and regulatory authorities about the potential early risks associated with E-cigarette use, especially in the alarming number of young adults who never smoke and choose to consume these products.

Supplementary material

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Supplementary material

00425-2026.SUPPLEMENT