Impact of cigarette smoke on pulmonary vein and artery volumes in those with current and former smoking status: a quantitative computed tomography analysis

Extract

Cigarette smoke affects the small pulmonary vasculature through mechanisms involving endothelial dysfunction, oxidative stress, inflammation, smooth muscle proliferation, and fibrosis, some of which are more acute and others more chronic [1]. These changes contribute to various lung diseases, including COPD, emphysema and pulmonary hypertension, and also increase the risk of cardiovascular complications such as right-sided heart failure [2].

Shareable abstract

Cigarette smoking is related to increased small pulmonary vein and artery volumes. These findings highlight the potential of CT imaging to assess smoking-related vascular changes in diseases like COPD and pulmonary hypertension. https://bit.ly/4ljnU6q

To the Editor:

Cigarette smoke affects the small pulmonary vasculature through mechanisms involving endothelial dysfunction, oxidative stress, inflammation, smooth muscle proliferation, and fibrosis, some of which are more acute and others more chronic [1]. These changes contribute to various lung diseases, including COPD, emphysema and pulmonary hypertension, and also increase the risk of cardiovascular complications such as right-sided heart failure [2].

Despite extensive evidence of cigarette smoke-induced vascular remodelling, few studies have separately quantified the impact on pulmonary veins versus arteries [3, 4]. This study aims to fill that gap by exploring whether vascular alterations are related to the extent of tobacco smoke exposure and whether these changes differ between venous and arterial compartments. Outside the lungs, studies on the retinal veins found that current smokers have wider retinal venules and that chronic smoking induces inflammation and endothelial dysfunction, leading to retinal vein dilation [5]. Therefore, we hypothesise that current smokers will exhibit increased volumes in small pulmonary veins compared to former smokers, with changes potentially increasing with higher smoking intensity expressed in pack-years. By using a commercially available system for quantitative analysis of chest computed tomography (CT) and a large set of participants from the COPDGene study, we investigated the effects of cigarette smoke on small pulmonary vein versus artery volumes in individuals who were currently smoking and those who had quit.

We included COPDGene study participants (ClinicalTrials.gov: NCT00608764) for whom demographic data, clinical data and CT scans qualified for analysis were available. Baseline data was collected in 2008–2011 [6]. All subjects provided written informed consent.

Details on data collection and CT scan protocols have been described in the study protocol [6]. Pack-years and smoking status were self-reported with questionnaires. All quantitative CT analyses were performed using Thirona's lung quantification platform, LungQ (Thirona B. V., The Netherlands, https://www.thirona.eu). The CT-based artery-vein phenotyping analysis has been described previously [3]. For each subject, we quantified small vein or artery volume as the accumulated volume of all venous or arterial branches with a diameter <1 mm, divided by body surface area (BSA) (calculated according to the DuBois method (BSA in m²=0.007184·height in cm^0.725·weight in kg^0.425) to accommodate for inherent differences in body size (sensitivity analysis with only height yielded similar but slightly weaker mortality associations in previous work).

Data were analysed using R version 4.3.3 (R Foundation for Statistical Computing, Vienna, Austria).

Analysis of covariance, adjusted for age, gender, race, body mass index, forced expiratory volume in 1 s % predicted, modified Medical Research Council dyspnoea score, 6 min walking distance, bronchial wall thickness (using Pi10), %emphysema (%low attenuation area 950) and Global Initiative for Chronic Obstructive Lung Disease spirometry stage were used to compare adjusted means between never-smokers and current/former smokers. Multivariable linear regression models were used to examine associations of CT-based small pulmonary vein and artery volumes with smoking status and with pack-years, adjusting for previously mentioned parameters and additionally for the presence of severe exacerbations and coronary calcium score (modified Agatston). Furthermore, models were corrected for pixel spacing, CT scanner model and study centre. The partial R² was used to quantify the proportion of variance in the outcome (small pulmonary vein or artery volume) attributable to smoking status, while accounting for the number of pack-years and vice versa.

We analysed 8931 subjects, with a mean age of 60.0±9.0 years; 4221 (47.3%) were female. About half of the participants (50.7%) were current smokers, with a mean cumulative smoking history of 44.5±25.0 pack-years. Former smokers had a smoking history of 43.5±23.6 pack-years. 4046 (45.3%) had COPD. Mean small vein volume was 2.71±0.55 mL·m⁻² and mean small artery volume was 3.88±0.90 mL·m⁻². 374 never-smokers were included with a mean age of 59.9±9.4 years; 213 (57%) were female.

Never-smokers had a mean small vein volume of 2.69±0.44 mL·m⁻² and a mean small artery volume of 3.80±0.82 mL·m⁻². Former smokers had a mean small vein volume of 2.77±0.54 mL·m⁻² and a mean small artery volume of 3.88±0.84 mL·m⁻²; current smokers had a mean small vein volume of 2.66±0.55 mL·m⁻² and a mean small artery volume of 3.89±0.96 mL·m⁻² Using the adjusted analysis of covariance model, we observed that mean small pulmonary vein and artery volumes were significantly higher in current smokers compared to never-smokers (p <.001 and p <.001, respectively). There were no significant differences between former compared to never-smokers.

In sex-stratified analyses, both male and female current smokers exhibited significantly higher small pulmonary vein and artery volumes compared to former smokers within their respective sex groups: small vein volume was 0.08 mL·m⁻² (2.6%, p<0.001) higher for female current smokers and 0.10 mL·m⁻² (3.2%, p<0.001) higher for male current smokers; small artery volume was 0.34 mL·m⁻² (8.8%, p<0.001) higher for female current smokers and 0.31 mL·m⁻² (8.0%, p<.001) for male current smokers. In the non-stratified model, pack-years explained 1.0% of the variance in the model with small pulmonary veins and 1.7% in the models with pulmonary arteries, with higher smoking intensity being associated with higher small vessel volumes. Smoking status explained 0.8% of the variance in the model with small pulmonary veins and 3.8% in the model with small pulmonary arteries. Figure 1 shows the association of pack-years with small vein and artery volume stratified by smoking status, derived from the multivariable regression model.

FIGURE 1.

Adjusted association between a) small pulmonary vein and b) small artery volume with pack-years smoked, stratified by former smokers (dark red, dark blue) and current smokers (light red, light blue). Note that the adjusted association between pack-years and small pulmonary vein and artery volumes is strong until about 50 pack-years, after which the association weakens. Also, current smokers have higher absolute volumes in both veins and arteries.

In this large cohort of current and former smokers, we found that both acute and chronic smoking are significantly associated with slightly higher (2.9% for veins, 8.5% for arteries) CT-quantified small pulmonary vein and artery volumes. These associations were robust to adjustment for demographic factors, technical parameters and surrogate markers for cardiovascular disease. Sex-stratified analyses further revealed that the association between current smoking and increased small pulmonary vascular volumes was consistent in both males and females.

Previous in vivo measurements on pulmonary vascular morphology showed that cigarette smoke exposure is associated with higher blood vessel volumes and vascular remodelling, but no distinction could be made between the small arteries and veins [1]. Although more focus has traditionally been on the arteries due to their role in pulmonary hypertension, cigarette smoke also affects the small pulmonary veins, leading to fibrosis and impaired blood returning to the heart, exacerbating conditions like COPD and pulmonary fibrosis [7]. Indeed, our group previously found that a higher small vein volume was associated with mortality in smokers with and without COPD [3]. We have now demonstrated that both the veins and arteries are associated with smoking, with a stronger association for the arteries in those who continue to smoke compared to those who have quit.

In small pulmonary arteries, smoking-induced oxidative stress triggers smooth muscle proliferation, resulting in vascular remodelling, contributing to increased pulmonary vascular resistance and hypertension. This process is exacerbated by the activation of molecular pathways like the Ras-ERK signalling cascade, which promotes pathological changes in the vessel wall, such as increased wall thickness and fibrosis [8]. Similar chronic processes of vascular remodelling are also a possible explanation for the higher volumes of small pulmonary veins. As shown in figure 1, chronic smoking (measured by pack-years) is associated with higher venous and arterial volumes, with a plateau after approximately 50 pack-years. Similarly, studies on the retinal venules describe that chronic smoking induced inflammation, and endothelial dysfunction can cause microvascular damage leading to venular dilation [3].

Additionally, the effects of current smoking also seem to affect small vessel volumes. Figure 1 illustrates that the volumes are higher in current compared to former smokers, showing that current smoking is associated with higher venous and arterial volumes. Indeed, a study of the retinal vessels found that current smoking was a major determinant of dilated retinal venules [5].

Another critical event in smoking-induced pulmonary vascular disease is apoptosis of endothelial cells [9]. Research demonstrates that cigarette smoke increases the methylation of key genes regulating mitochondrial function, leading to increased apoptosis rates in pulmonary endothelial cells [10]. This cell loss impairs the integrity of the pulmonary vasculature, potentially causing fluid leakage into the perivascular space, which could lead to increased small vascular dimensions and the development of diseases like COPD.

Altogether, these studies suggest that the effects of cigarette smoke on pulmonary veins and arteries are both acute and chronic and multifaceted, involving oxidative damage, inflammatory responses and direct cellular injury, which together contribute to smoking-related chronic lung diseases. Our study is not able to evaluate the contribution of individual biological pathways, but our findings suggest that automated quantitative CT analysis may provide an opportunity to capture changes in small arteries and veins in vivo. The <1 mm vessels are at the resolution limit of the scans, however, similar effects were observed at 2 mm and 3 mm cut-offs. Therefore, we think that resolution issues do not explain our findings. Such in vivo CT measurements could be of value in research focusing on therapies to counteract the effects of cigarette smoke, such as antioxidants or gene-modifying treatments [11]. The observation that small artery volume exceeded small vein volume for vessels <1 mm likely reflects intrinsic differences in the peripheral pulmonary vascular architecture, as arteries tend to have a denser branching pattern and higher number of terminal branches at this small calibre level, despite veins being larger at more proximal levels.

In conclusion, this large study of current and former smokers found that both the number of pack-years and smoking status were associated with increased small pulmonary vein and artery volumes. Further research is necessary to determine whether quantitative CT analysis may have a role in evaluating smoking-related pulmonary vascular pathology.