The prevalence of cigarette smoking has decreased in the past 10 years, but 1 in 5 American adults aged 18 years and older, an estimated 45.3 million people, still consider themselves current smokers.³ According to data from the 2010 National Health Interview Survey and the 2010 Behavioral Risk Factor Surveillance System survey, smoking prevalence is higher among men (21.5%) than among women (17.3%), with the highest prevalence among adults aged 25 to 44 years (22.0%) and 45 to 64 years (21.1%).^3,4 Non-Hispanic Indians/Alaska Natives have the highest prevalence, followed by non-Hispanic whites and non-Hispanic blacks (31.4% vs 21.0% vs 20.6%). The prevalence of cigarette smoking is also related to socioeconomic factors; smoking is more common among those living below the poverty level than above the poverty level (28.9% vs 18.3%) and is associated with lower level of education attained.³ Among Americans who smoke, approximately 69% of smokers want to quit completely and 52% of smokers had attempted to quit in 2010.⁴

In addition to socioeconomic factors, there may also be a genetic influence on smoking behavior and nicotine dependence. A genetic variant of the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 was identified; it appears to have an effect on the quantity of cigarettes smoked per day and the risk for development of PAD in smokers of European descent.⁵ These results further support the established biologic relationship between smoking and arterial disease,⁶ but the threshold beyond which this relationship occurs is unknown.

Tar and Nicotine Content

Low-yield cigarettes that deliver less tar or nicotine in standardized machine measurements have been marketed by cigarette manufacturers as “light” or “ultralight” brands,⁷ but the existence of a nicotine or tar dose-response relationship is controversial with regard to risk of cardiovascular disease, and studies to date have provided conflicting results.⁸ One large epidemiologic study of more than 51,000 participants who were observed for 6 years found significantly fewer CAD-related deaths in participants who smoked cigarettes of low nicotine and tar content compared with those who smoked cigarettes of high nicotine and tar content (2.0-2.7 mg nicotine, 25.8-35.7 mg tar; 1007.5 deaths), with a mortality ratio of 0.83.⁸ Similarly, another prospective epidemiologic study consisting of 56,255 men observed for an average period of 13 years found that a 15-mg decrease in tar yield per cigarette resulted in a relative mortality of 0.77 for coronary heart disease and 0.86 for stroke.⁹ Two case-control studies have reported similar findings, with one study finding that a 5-mg decrease in tar yield resulted in a 13% reduction in cardiovascular disease risk¹⁰ and another finding that the risk of nonfatal myocardial infarction (MI) was 13% lower in people who smoke cigarettes with average tar yields of 7.5 mg versus those who smoke cigarettes with average tar yields of 13.3 mg.¹¹ Importantly, all of these studies noted that smokers of low-tar cigarettes had greatly increased rates of cardiovascular events compared with nonsmokers.^8–11

In contrast to the results of these studies, several studies found no relationship between nicotine and tar content and the risk of cardiovascular disease. Data from a male subset of the Framingham Heart Study showed that smokers of filtered cigarettes did not have lower rates of coronary events than smokers of unfiltered cigarettes.¹² In addition, two case-control studies of the impact of nicotine and carbon monoxide content of cigarettes on incident MI in men¹³ and women¹⁴ found that although the risk of MI increased with the number of cigarettes smoked, the risk did not vary according to the nicotine or carbon monoxide content. Finally, a case-control study of a subset of data from the second Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI-2) trial,¹⁵ consisting of 916 patients with acute MI and 1106 controls, found that although the relative risk of acute MI increased with the number of cigarettes smoked daily, there was no relationship between acute MI and the tar yield of cigarettes smoked (relative risk compared with nonsmokers: 3.8, 4.3, 3.2, and 3.7 for tar yields of <10, 10-15, >15-20, and >20 mg, respectively).¹⁶ Whereas it is unclear whether low-tar cigarettes are less detrimental than high-tar cigarettes in terms of cardiovascular risk, it is obviously certain that “no tar” (i.e., no smoking) is the best option for prevention of cardiovascular events.

Biology

The pathobiology of cigarette smoking has been extensively studied. Cigarette smoking mediates its adverse cardiovascular effects through deleterious effects on the artery wall, particularly the endothelium, along with effects on sympathetic tone, metabolism, and the coagulation and fibrinolytic systems (Box 27-1).^17–21 Despite extensive scientific knowledge, the precise component or components of cigarette smoke that lead to cardiovascular events is not known, although it is clear that both nicotine and carbon monoxide exposure are central.^19,22–24

Endothelial Effects

Cigarette smoking is associated with endothelial cell damage and altered endothelial function.¹⁷ Studies of umbilical artery samples derived from infants born to smoking mothers compared with nonsmoking mothers have shown extensive distortion of the normal arterial intima, including subendothelial edema, widening of intercellular junctions, distention of the endoplasmic reticulum, and thickening of the basement membrane.²⁵ Cigarette smoking increases platelet and leukocyte adhesion to the endothelial cells and increases permeability of the endothelial surface to fibrinogen.^17,23,26,27 Cigarette smoking alters normal endothelial cell function, including decreased nitric oxide bioavailability and impaired vascular tone.^28,29 Cigarette smoking is also associated with increased endothelial production of endothelin-1, a potent vasoconstrictor.³⁰ Even brief secondhand smoke exposure has been shown to cause vascular injury in healthy volunteers, including increased circulating markers of endothelial injury, impairment of chemotaxis of circulating endothelial progenitor cells, and impaired flow-mediated vasodilatation of the brachial artery.³¹ The effect of cigarette smoking on endothelial function is synergistic with the effect of hyperlipidemia²⁹ and may be ameliorated with statin treatment or antioxidants.^32–34 Endothelial dysfunction associated with smoking is also reversible with smoking cessation.²⁸ Cigarette smoking is a source of oxidative stress that potentiates endothelial dysfunction and is an important element of atherogenesis.^29,34–36

Hematologic Effects

In addition to its vascular effects, cigarette smoking induces a procoagulant state associated with abnormalities of platelet function, coagulation, and fibrinolysis. The hematologic effects of smoking may account for the epidemiologic association of tobacco and atherothrombotic events, especially MI. Smokers have increased platelet aggregation compared with nonsmokers, and the addition of nicotine to in vitro platelet assays has been associated with increased aggregation.^37–39 Smoking has been associated with multiple potentially prothrombotic abnormalities of the coagulation cascade, including fibrinogen and factor VII,^21,40,41 along with increased tissue factor expression within atherosclerotic plaques in animal models.⁴² Smoking is associated with abnormalities of the fibrinolytic system, the body’s endogenous mechanism of anticoagulation, including impaired release of tissue plasminogen activator.^43,44 Smoking increases blood viscosity in a dose-dependent manner that is reversible with smoking cessation.^45,46

Physiologic Effects

Cigarette smoking leads to additional adverse physiologic and metabolic effects that augment its detrimental impact on cardiovascular health. Smoking causes nicotine-mediated increase in sympathetic tone, which leads to increased heart rate, blood pressure, and myocardial oxygen demand along with peripheral vasoconstriction.^47–49 Smokeless tobacco, in the form of oral snuff, has been shown to have a similar effect on heart rate, blood pressure, and catecholamine levels in healthy volunteers.⁵⁰ Smokeless tobacco is associated with increased and more sustained blood levels of nicotine compared with cigarette smoke.⁵¹ Smoking increases markers of inflammation, including total white blood cell count^19,40 and C-reactive protein,⁵² and is associated with lower high-density lipoprotein and increased low-density lipoprotein, total cholesterol, and triglyceride levels compared with those of nonsmokers.^18,19 These effects are at least partially reversible with smoking cessation.^40,52 An association between smoking and insulin resistance has recently been identified, and it has been proposed that smokers most susceptible to the metabolic and cardiovascular consequences of smoking are those with coexisting insulin resistance.^53–55

Effect of Smoking Cessation

Whereas smoking has become an established risk factor for the development of atherosclerosis, there is some evidence that it continues to increase the biologic progression of atherosclerosis even after smoking cessation. Some studies, particularly of carotid intima-media thickness, suggest that cigarette smoking may be an independent predictor of atherosclerosis progression.^67,68 The Atherosclerosis Risk in Communities (ARIC) study observed 10,914 participants for longitudinal assessment of the relationship between smoking exposure and change in atherosclerosis, as measured by carotid intima-media thickness, during a period of 3 years.⁶⁸ After adjustment for demographic variables and cardiovascular risk factors, current smokers had a 50% increase in the progression of intima-media thickness relative to never-smokers (mean progression of 43.0 µm versus 28.6 µm for current smokers versus never-smokers). Former smokers had a 25% increase in the progression of atherosclerosis relative to never-smokers,⁶⁸ and after adjustment for the number of pack-years smoked, there was no difference in the progression of atherosclerosis between current and former smokers. The authors of the ARIC study indicated that this result suggests that smoking causes an irreversible and cumulative effect on the biology of atherosclerosis progression.⁶⁸ Within the ARIC cohort, environmental tobacco smoke exposure was also associated with increased progression of carotid intima-media thickness during the follow-up period.

The findings of the ARIC study are supported by an epidemiologic study of 744 older men living in western Australia.⁶⁹ Smoking was a primary risk factor associated with the development of PAD (current smoking odds ratio of 3.9 vs former smoking odds ratio of 2.0), with 32% of PAD attributable to current smoking. Interestingly, a further 40% of PAD was attributable to a history of past smoking among men who did not smoke currently.⁶⁹ This led the investigators to conclude that previous smoking among patients who quit continues to increase the risk of PAD.

There are conflicting data to suggest that smoking cessation decreases the risk for development of PAD. In a cross-sectional study of 2334 older (≥60 years) Chinese subjects who were screened for PAD by the Rose Claudication Questionnaire and the ankle-brachial index,⁷⁰ the odds ratio for PAD among current smokers versus never-smokers was 1.54 and 1.28 for former smokers versus never-smokers. Similar to the results of the ARIC study,⁶⁸ there was a dose-dependent relationship between the number of cigarettes smoked and risk of PAD. However, in contrast to the ARIC⁶⁸ and the western Australia⁶⁹ cohorts, the Chinese study found that smoking cessation dramatically reduced the risk of PAD, such that cessation for more than 10 years almost eliminated the excess risk associated with smoking.⁷⁰ This decrease in the risk of PAD with smoking cessation was reproduced in a study of 2517 Korean men aged 50 years or older.⁷¹ As expected, there was a graded relationship between smoking and PAD such that compared with never-smokers, the adjusted odds ratio of PAD for smokers of 0.1 to 20.0, 20.1 to 40.0, and more than 40.0 pack-years were 2.15 (1.06-4.38), 2.24 (1.08-4.65), and 2.93 (1.41-6.09), respectively. However, there was also an inverse relationship between years since tobacco cessation to risk of PAD such that the adjusted odds ratio of PAD for 11 to 20 and 21 or more years of smoking abstinence were 0.41 (0.19-0.86) and 0.49 (0.24-0.98) compared with current smokers.⁷¹

Although there may be some debate as to whether smoking cessation decreases the risk for development of PAD, it has been well established that continued smoking worsens the signs and symptoms of PAD. This was well demonstrated in a study that repeated ankle-brachial indices in 10 older (63 ± 10 years) chronic smokers with PAD (ABI = 0.64 ± 0.14) on smoking and nonsmoking days.⁷² The ankle-brachial index on the smoking day was significantly lower than on the nonsmoking day (0.55 ± 0.11 versus 0.64 ± 0.14; P = .008) owing to lower ankle systolic blood pressures.⁷² These results provide evidence of the acute physiologic effects of smoking on the peripheral circulation. The chronic arterial effects of tobacco have been demonstrated in multiple studies showing that current smokers with PAD have more severe claudication and inferior cardiorespiratory parameters at peak exercise than do former smokers.^73–75 In a study of 38 current smokers and 100 former smokers with claudication who were recruited to undergo exercise testing, current smokers had lower ankle-brachial indices, earlier time to onset and to maximal pain, and longer time to pain relief after exercise.⁷⁴ In addition, current smokers had lower peak oxygen uptake, lower heart rate, higher ventilation, and higher diastolic blood pressures than former smokers (all relationships compared with former smokers <.05). Of note, the finding of worsened exercise performance in current smokers versus former smokers was independent of the resting ankle-brachial index.⁷⁴

When current and former smokers were compared with nonsmokers in a study that exercised patients with intermittent claudication using the 6-minute walk test, nonsmokers walked significantly farther (P < .05) than either current or former smokers (413 ± 14 m vs 352 ± 7 m and 370 ± 7 m, respectively), but there was no difference in distance walked between smokers and former smokers.⁷⁶ Former smokers in this study self-reported abstinence for at least 12 months. These results again suggest that the effects of cigarette smoking on the biology of atherosclerosis in the peripheral vasculature may be only partially reversible.

Ankle Pressure

One of the first studies to examine the relationship between smoking cessation and improvement in ankle-brachial indices and maximum treadmill walking distance included 62 patients (124 limbs) with intermittent claudication.⁷⁷ Ankle-brachial indices were recorded every 3 months at rest and after treadmill exercise; participants were categorized into those who continued to smoke after the first test or quit smoking after the first test and continued to abstain until after the last test. Ankle-brachial indices were unchanged in the group who continued to smoke (0.82 ± 0.20 at test 1, 0.78 ± 0.19 at test 3; P = .13) but significantly improved in those who quit smoking after the first test (0.71 ± 0.18 at test 1, 0.82 ± 0.19 at test 3; P = .001). Similarly, maximum treadmill walking distance did not change among those who continued to smoke (230.4 ± 96.3 m at test 1, 254.2 ± 102.6 m at test 3; P = .179) but significantly increased (214.7 ± 87 m at test 1, 300.9 ± 129.9 m at test 3; P = .018) in those who quit smoking.⁷⁷

Amputation Rate and Graft Patency

Continued tobacco smoking increases the likelihood of amputation among patients with PAD.⁸¹ Amputation rates are significantly associated with smoking intensity, as was shown in a study of 125 post-revascularization patients who were characterized as either moderate smokers (<15 cigarettes daily) or heavy smokers (≥15 cigarettes daily).⁸¹ During the subsequent 3 years, the amputation rate was 2% in moderate smokers and 21% in heavy smokers (P < .001).⁸¹ The alarming rate of amputation in heavy smokers after revascularization may have been related to increased graft failure in patients who continue to smoke even after surgery. A meta-analysis of 19 studies (10 prospective, 9 retrospective) of the effects of smoking and smoking cessation on lower extremity bypass patency rates showed a twofold to threefold increase in the risk of graft failure among patients who smoked versus nonsmokers.⁷⁹ Furthermore, heavy smokers had decreased patency compared with moderate smokers, and patients who quit smoking from the time of bypass surgery had patency rates similar to those of never-smokers.

Survival

Finally, smoking cessation is associated with improved survival among patients with PAD, as has been demonstrated in multiple epidemiologic studies.^75,80 One of the first studies to investigate the survival benefit of smoking cessation compared with continued smoking among patients with severe, symptomatic PAD found that patients who quit smoking had twice the survival rate at 5 years compared with those who continued to smoke (66% vs 36%; P < .01).⁸⁰ Similarly, a study of 343 smokers and former smokers (quit within 6 months of study enrollment) with intermittent claudication who were observed for 10 years found a significant improvement in the rates of MI (11% vs 53%; P < .05) and cardiac death (6% vs 43%; P < .05) among former smokers compared with active smokers, respectively.⁷⁵ In contrast to the previous study, however, the differing rates of survival at 10 years of follow-up (46% in smokers vs 82% in former smokers; P = .076) were not statistically significant until after 1 year, suggesting that the effect of smoking cessation on survival may not be immediately apparent.⁷⁵

The Nurses Health Study reported the effects of smoking cessation on mortality among 104,519 female participants.⁸² This prospective observational study with 24 years of follow-up, including 12,483 deaths, found that compared with never-smokers, current smokers had a twofold to threefold risk of all-cause mortality (hazard ratio, 2.81), and the risk increased with the number of cigarettes smoked.⁸² There was a 13% reduction in the risk of all-cause mortality for former smokers 5 years after quitting compared with continued smoking, and the excess risk for all-cause mortality for current smokers decreased to the level of never-smokers 20 years after quitting. There was a more rapid decline in the risk for vascular disease–related mortality in the first 5 years after quitting compared with other causes of death, including lung disease and cancer, such that 61% and 42% of the mortality benefit of quitting for coronary and cerebrovascular disease, respectively, occurred in the first 5 years of smoking cessation. Finally, 64% and 28% of deaths among current and former smokers, respectively, were attributable to cigarette smoking.⁸²