At least two major findings are derived from this large-scale prospective study conducted among initially healthy women. First, smoking is a potent risk factor for the occurrence of symptomatic PAD, even after accounting for a number of established risk factors and markers of subclinical inflammation. Second, smoking cessation is associated with a substantial reduction in the risk of PAD, highlighting the importance of efforts to promote smoking cessation.
While prior prospective studies consistently showed an increased risk of PAD among smokers, few analyses specifically assessed smoking as main exposure variable and the strength of the relationship varied widely across reports, with relative risks for current smoking ranging from 1.6 – 10.2 (8
). Our data represent one of the strongest associations for current smoking reported thus far, a finding which may be explained by our focus on symptomatic as opposed to subclinical disease (9
) and our evaluation in an exclusively female, otherwise relatively young and low risk population. Even within this relatively homogenous population, the risk of PAD associated with smoking is higher among younger, premenopausal women. A higher relative risk conferred by current smoking among younger and relatively low risk individuals has been previously reported with regard to myocardial infarction where the odds ratio for non fatal myocardial infarction was 3.53 (3.23–3.86) in younger as compared to 2.55 (2.35–2.76) in older individuals (P
for interaction <0.001) (24
). Whether the strength of the association is also influenced by gender should be assessed in other mixed-gender cohorts.
We also demonstrate a strong dose response relationship between life-long smoking exposure and subsequent PAD, confirming prior studies that were suggestive of such an association (10
). While our data show no particular threshold below which smoking does not confer an increased risk, a particularly steep risk increase emerged among women who indicated at least 10 pack years of smoking exposure, underscoring the importance of smoking as a determinant of PAD and a priority for intervention.
Also of importance from a public health perspective is our finding that smoking cessation is associated with a dramatic reduction in incident PAD. Prior investigations in this context have focused on total cardiovascular morbidity and mortality. For example, in the Nurses’ Health Study, the risk of vascular death among women who stopped smoking was gradually reduced with an increasing duration of smoking abstinence and reached the relative risk of never smokers after approximately 20 years (7
). While we also found a gradual decrease in risk with an increasing duration of smoking abstinence, even women who had quit smoking >20 years prior to enrolling in our study had a higher risk of developing symptomatic PAD than never smoking women. This residual risk may relate to chronic adverse effects of smoking on the peripheral vasculature. Still, for patients and their physicians, the current findings suggest that long-term smoking cessation substantially reduces the risk of symptomatic PAD. However, the residual PAD risk even among smokers who have been abstinent for at least 20 years underscores the importance of primary efforts for smoking prevention.
There was no strong confounding of the adverse effects of smoking by any of the traditional risk factor variables included in the multivariable models. Adding high-sensitivity C-reactive protein and sICAM-1 as markers of subclinical inflammation somewhat attenuated the coefficients for actively smoking women () suggesting that these factors may in part mediate the adverse smoking effects. Nevertheless, despite multivariable adjustment, we found that the increased risk associated with smoking remains largely unexplained, which is consistent with one of the few prior studies on this issue (13
Strengths of the present study include the prospective design, large sample size, long-term follow-up with a large number of confirmed endpoints, and the homogeneity of our study participants, which may reduce confounding. Our results should also be considered in the context of several potential limitations. First, our study included mainly Caucasian women, and our findings may not be generalizable to other groups. Second, as our study is observational, unmeasurable or residual confounding may be present. Third, the use of symptomatic PAD as the primary a priori
end point by definition excludes subclinical disease, which may have otherwise been detected through abnormal pulse examination or ankle-brachial index (25
). However, we believe our data to be not only relevant from a mechanistic perspective but also of clinical importance, because claudication and revascularization of an ischemic limb are the principal clinical manifestations of PAD. Importantly, events included in this analysis were confirmed by a validated claudication questionnaire, cardiovascular physician interview and medical record review. Our focus on symptomatic disease may also have reduced the likelihood of endpoint misclassification, as would the characteristics of our study population. Participants were health professionals and therefore less likely to encounter barriers to medical care, which may otherwise have led to misdiagnosis or underdiagnosis among all smoking exposure groups. Whether or not women with PAD are more likely to have atypical leg symptoms or more often be asymptomatic is controversial (26
), especially as some studies suggest a lower (less stringent) ABI cut-off for PAD diagnosis may be more appropriate for women (28
). Nonetheless, if smoking is even modestly associated with PAD, misclassification of women with atypical PAD symptoms as non-cases would, if anything, tend to bias our results towards the null by including relatively more smokers in the non-PAD group. Finally, in this study we did not consider exposure to second-hand smoke, which has been shown to be an important risk factor for PAD in women (30
In conclusion, this large prospective study underscores the importance of smoking as a risk factor for the development of symptomatic PAD. While this association appears partly mediated by inflammation, the majority of excess risk conferred by smoking remains unexplained. Although smoking cessation dramatically reduces the risk of PAD, an increased disease risk remains even among long term abstinent women, highlighting the importance of both prevention of smoking initiation and efforts to promote long-term abstinence.