In this study of over 1,500 active smokers, both carotid plaque and CIMT were associated with increasing age, BMI, small LDL, and pack-years of smoking. The association between smoking burden and carotid plaque presence was stronger in women than in men. Increasing CIMT additionally was associated with male sex, non-white race, systolic blood pressure, and total HDL. The relationship between smoking burden (pack-years) and higher CIMT is consistent with a previous report from the Atherosclerosis Risk in Communities (ARIC) study.6
However, data regarding smoking in ARIC were ascertained two decades ago, participants in the ARIC study on average were a decade older than in our study, and were in a narrower age range (45–65 years old). We studied a modern set of active smokers across a wide range of ages (18–79 years old), and looked at the effect of smoking burden after controlling for lipoprotein measurements, which are more strongly associated with CIMT than lipids.18
Furthermore, we evaluated physiological markers of smoking such as cotinine and measures of nicotine dependence, alcohol consumption, personality, and affect disorders, which may be more common among current smokers.
Several of the findings in this study are unique. Because of the large sample size and evaluation of multiple descriptors of smoking burden, we were able to determine that of the smoking-related variables, current pack-years was most strongly associated with both carotid plaque presence and CIMT, even after controlling for the effects of age. In this cohort, current pack-years and age were the strongest predictors of both CIMT and carotid plaque presence, supporting the dose-response relationship previously observed between cigarette smoking and CVD incidence, suggesting that increased atherosclerotic burden contributes to the increased CVD risk observed in smokers.1,3
Several studies have supported the hypothesis that smoking interacts with other risk factors in a multiplicative fashion, further increasing CVD risk, even in young adults.1,19
In our study, another important finding was the interaction between smoking burden and female sex. Although men had a significantly higher smoking burden, the effect of increasing pack-years of smoking on the development of carotid plaque was stronger in women than in men. The observation that female smokers are at increased CVD risk is supported by previous research which demonstrated that smoking had a stronger association with coronary heart disease incidence in women compared to men.20
This study emphasizes the importance of targeting smoking cessation interventions and avoidance messages towards women.
Smoking is associated with low HDL-c and hypertriglyceridemia.21
However, this study demonstrated that direct lipoprotein measurements were more strongly associated with subclinical carotid atherosclerosis than their corresponding lipid measurements and lipid ratios. Small LDL and total HDL particle concentrations were independently associated with higher CIMT, and small LDL particles were independently associated with carotid plaque presence, a more advanced stage of subclinical atherosclerosis. LDL-c levels tend not to be increased in smokers, but smoking does shift the LDL particle size to the smaller, more atherogenic lipoprotein subtype.21
As expected, small LDL, rather than LDL-c, total LDL particles, or LDL size had the strongest association with carotid atherosclerosis of the LDL-related variables. In this context, BMI also was associated with increasing CIMT and carotid plaque presence. The relationship of BMI to CIMT is an expected finding, since obesity also is associated with low HDL and small LDL particles.22
Although BMI was an inverse predictor of carotid plaque presence in the multivariable model, the relationship was weak, of borderline statistical significance, and added only a minimal amount of predictive value to the regression model (adjusted R2
=0.184 without BMI, adjusted R2
=0.188 with BMI). Furthermore, the area under the curve for BMI was only 0.499. Because the presence of plaque was consistent across all quintiles of BMI and BMI was positively correlated with small LDL particles (r=0.215, p<0.001) which strongly predicted carotid plaque presence, we believe that the relationship between BMI and carotid plaque in smokers is confounded by small LDL particles. If small LDL particles are not present, then the negative metabolic effects of increased BMI on atherosclerosis are less likely to be seen.
Inventories regarding personality and affect were not associated with carotid atherosclerosis in our study. Previous research has not shown a direct relationship between positive and negative affect and coronary artery disease.23
However, certain emotions may be confounders of atherosclerosis development and CVD events.24
This was a cross-sectional study of individuals who chose to participate in a smoking cessation intervention study; therefore, our findings may not be generalizable to all smokers. However, over 70% of current smokers plan to quit smoking in the next year.25
Although significant efforts were made to target recruitment of non-white subjects, non-whites comprised only approximately 16% of the study cohort. It is possible that there are racial differences in associations with carotid atherosclerosis among smokers. Data about family history of premature CVD and physical activity were not available for analysis. Uncontrolled hypertension was an exclusion criterion, which restricted the range to evaluate blood pressure and its relationship to carotid atherosclerosis. Inclusion of individuals with higher blood pressures may have demonstrated a stronger association of blood pressure with CIMT and/or plaque. Menopausal status was not known; however, 69% of the women were under 50 years old, and <1% were on estrogen therapy. Therefore, the use of hormone replacement therapy should not affect the results of this study. Finally, data were not available for biomarkers that may affect atherosclerosis among smokers, such as fibrinogen and inflammatory cytokines.