Author + information
- Thomas Rasmussen, MD†∗ (, )
- Daria Frestad, MD†,
- Lars Køber, MD, DMSc†,
- Jesper Holst Pedersen, MD, DMSc‡,
- Laura Hohwü Thomsen, MD§,
- Asger Dirksen, MD, DMSc§ and
- Klaus Fuglsang Kofoed, MD, DMSc†⋮
- †Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- ‡Department of Thoracic Surgery, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- §Department of Pulmonary Medicine, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
- ⋮Department of Radiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- ↵∗Department of Cardiology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2012 Copenhagen Ø, Denmark
To the Editor:
Smoking has a major negative impact on global health. The adverse effects of smoking continuation relative to smoking cessation on coronary atherosclerosis are not well elucidated. The aim of this study was in a cohort of long-term smokers to assess the effects of continued smoking on the development and progression of subclinical coronary artery calcification (CAC) over time.
A total of 1,265 current or previous smokers 50 to 70 years old with at least 20 pack-years and without coronary artery disease (CAD) were recruited from the Danish Lung Cancer Screening Trial, a randomized controlled trial initiated in 2004. All participants completed questionnaires on smoking annually as well as undergoing multidetector computed tomography (MDCT) for a period of 4 years. Only continuous smokers or ex-smokers without CAD events during the study period were included. Continuous smokers were categorized as light (1 to 17 cigarettes per day) and heavy smokers (>17 cigarettes per day). Volumetric CAC scores were measured at baseline and after 4 years. CAC development, so-called incident CAC (CACi) and CAC progression (CACp) were analyzed as proposed by McEvoy et al. (1). CACp was defined according to Hokanson et al. (2). Multivariable logistic regression was used to determine associations between clinical variables and CACi and CACp. Interaction analyses between clinical parameters and CAC at baseline were included in the analysis of CACp to account for potential change in effect dependent of CAC at baseline. Statistical analyses were performed using SAS for Windows, version 9.1 (SAS Institute, Cary, North Carolina).
Baseline characteristics included 45% women, with a median age of 57 years and 34 pack-years. The frequency of CACi was higher in continued smokers compared to ex-smokers and showed a dose-response relationship with respect to extent of smoking (Fig. 1A). Participants in whom CACi was observed (n = 173) were older (57 vs. 56 years of age, p = 0.008) and were more likely to be male (52% vs. 40%, p < 0.01) and to be treated with antihypertensive agents (17% vs. 9%, p < 0.01), statins (8% vs. 3%, p < 0.01), and/or antidiabetic agents (5% vs. 1%, p < 0.001). Similarly, participants with CACi had more pack-years at study inclusion (35 vs. 31 years, p < 0.001). Age, male gender, and continued heavy smoking compared to ex-smoking were found to be independently associated with an increased risk of CACi (Fig. 1C). There was no interaction between pack-years and years of smoking cessation. The frequency of CACp (n = 481) was higher in continued smokers compared to ex-smokers and showed a dose-response relationship with respect to extent of smoking (Fig. 1B). Furthermore, participants with CACp were more likely to be older (59 vs. 57 years of age, p < 0.0001) and male (66% vs. 48%, p < 0.0001), and have hypertension (21% vs. 10%, p < 0.0001), hypercholesterolemia (12% vs. 4%, p < 0.0001), or diabetes (4% vs. 1%, p < 0.001) requiring treatment. Participants with CACp had higher baseline CAC scores compared to participants without CACp (median volumetric CAC 31 vs. 0, p < 0.0001). Furthermore, participants with CACp had more pack-years (56 vs. 33 years, p < 0.0001). Male gender, medical treatment of hypertension, and diabetes in addition to continued heavy smoking when compared to ex-smoking were found to be independently associated to CACp (Fig. 1D). There were no interactions between smoking and clinical parameters.
This is the first longitudinal study to report the deleterious effects of smoking continuation in long-term smokers with regard to subclinical CAD.
One previous study found that age >40 years, smoking, and diabetes were predictive of converting from CAC = 0 to CAC >0 during a 5-year period, which is in correlation with our results (3). Earlier studies have sought to evaluate the effect of smoking and smoking cessation on CAC cross-sectionally, although the effect measured was in a population level rather than in an individual level. A substudy of the Heinz Nixdorf Recall Study sought to evaluate the effect of smoking in accumulation of CAC (4). Based on findings they hypothesized that smoking cessation by the age of 45, 55, and 65 years was associated with a CAC score at the age of 75 years that would have been reached 9, 6, and 3 years earlier, respectively, had smoking been continued. Although, these statistically modeled results are not directly comparable to our study, the conclusion was concordant. In the CARDIA study (5), risk factors for the prediction of CACi 15 years after baseline were studied in a young cohort. Being a current smoker at baseline was independently associated with CACi. However, the study could not document an association between a 15-year change in smoking habit and CACi. Our study population was older, smoking habits were recorded in much greater detail and frequencies and quantitative levels of CAC were by far higher than in the CARDIA study, which might explain the discrepant results.
The following limitations should be taken into account. Our study is only representative of current or former long-term smokers. MDCT was performed without electrocardiography gating. However, previous comparisons of CAC obtained by gated versus ungated MDCT have shown a high degree of concordance. According to study design we did not measure cardiovascular outcomes but rather the rate of CAC development and progression. Furthermore, participants who developed manifest CAD during the study period, possibly representing a group with higher rates of CACp, were excluded.
In long-term smokers without known CAD continuation of smoking is associated with more frequent development (odds ratio: 1.65; 95% confidence interval: 1.05 to 2.65) and more aggressive progression (odds ratio: 1.47; 95% confidence interval: 1.06 to 2.04) of CAC. These findings support smoking cessation in long-term smokers irrespective of the number of previous pack-years to reduce the extent of CAC accumulation and thus potentially to reduce the subsequent risk of CAD events.
The authors thank the investigators, staff, and participants of the Danish Lung Cancer Screening Trial for their valuable contributions.
Please note: Dr. Rasmussen was supported by an unrestricted grant from AstraZeneca AB and the Danish Heart Foundation. Dr. Køber has received speaker honorarium from Servier. Dr. Pedersen served on the advisory board for Roche Diagnostics in 2012 for a special issue of Lung Cancer Screening. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. The DLCST (Danish Lung Cancer Screening Trial) trial was funded in full by a governmental grant by the Danish Ministry of Health and Prevention from 2004 to 2011. Danish Lung Cancer Screening Trial [DLSCT]; NCT00496977.
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