What's So Passive About Passive Smoking?: Title and subTitle BreakSecondhand Smoke as a Cause of Atherosclerotic Disease

Cigarette smoking represents the single most important preventable cause of death in the United States.¹ Studies that document the effect of cigarette smoke on the progression of the atherosclerotic process add to the overwhelming evidence that tobacco smoke is an atherogenic agent. The morbidity and mortality secondary to tobacco smoke have been dismissed by the tobacco industry because smokers have a choice in whether they smoke and are generally aware of the risks associated with smoking. However, this argument does not extend to the millions of people who are exposed to tobacco smoke not as active smokers but by inhalation of environmental tobacco smoke (ETS). The public health impact of ETS is thought to be considerable. Of the estimated 480000 smoking-related deaths that occur every year in the United States, 53000 have been attributed to ETS, making passive smoke the third leading preventable cause of death, after active smoking and alcohol use.² Recent epidemiologic evidence shows that never smokers exposed to ETS have an increased risk not only of lung cancer but also of cardiovascular disease (CVD). Two recent prospective trials^{3 - 4} and meta-analyses^{2 ,5} estimate the relative risk for CVD at 1.2 to 1.3 for individuals exposed to ETS. Of the deaths caused by ETS, the number of deaths from heart disease is about 3 times the number of noncardiac deaths.²

Yet, the mechanisms by which ETS causes CVD and the implications for the reversibility of this disease have been less well defined. In this issue of THE JOURNAL, Howard et al⁶ compare the effects of active smoking, ETS, and absence of exposure to any tobacco smoke on the progression of carotid artery atherosclerosis, using carotid intimal-medial thickness (IMT) assessed by B-mode ultrasound as a surrogate end point. In their study of 10914 participants from the Atherosclerosis Risk in Communities study who were followed up over 3 years, Howard et al⁶ found that exposure to active smoke increased IMT progression by 50%, an expected result. In addition, ETS exposure was associated with an increase in IMT of 20%, or 6.7 µm, an effect that was similar to the progression of atherosclerosis observed in former smokers. These differences remained after adjustment for multiple risk factors. This new evidence from a large, longitudinal study suggests that exposure to ETS contributes significantly to an increased rate of atherosclerotic progression. Several important questions emerge from this study.

First, is IMT and its progression a valid surrogate marker for advancing atherosclerotic disease? Ample evidence suggests that measurement of IMT by B-mode ultrasound is a marker for atherosclerotic disease. Increased carotid artery IMT has correlated with risk factors for cardiovascular disease^{7 - 9} and with increased prevalence of atherosclerosis involving other arteries.¹⁰ Its use in prospective trials to study atherosclerotic progression has become common.^{7 ,11} To date, only 2 studies have demonstrated an association between increased carotid IMT and increased risk of cardiovascular disease. In 1991, Salonen and Salonen¹² studied the carotid arteries of more than 1000 Finnish men using ultrasound. They found that the maximal IMT of the common carotid arteries was associated with an increased risk of acute coronary events; for each millimeter of increase in the IMT, the risk increased 2.14-fold. More recently, Bots et al¹³ found that the risk for myocardial infarction increased by 43% for every increase of 0.163 mm of carotid artery IMT (1 SD). Both of these studies found a positive correlation between an increased carotid IMT at baseline and the risk for a future cardiovascular event.

In a novel application of this technology, Howard et al⁶ used serial ultrasonography to associate change in carotid IMT with exposure to cigarette smoking and ETS. Their prospective results cannot be directly compared with previous cross-sectional data. These investigators found a small but real increase in the carotid artery IMT of 6.7 µm in subjects exposed to ETS, but they provide little information as to the degree of increased risk of cardiovascular events that can be attributed to changes in IMT of this magnitude. However, what is most striking about the study by Howard et al⁶ is that the change in carotid artery IMT after exposure to secondhand smoke is a surprisingly large fraction of the change observed in current smokers (20% vs 50%). Active smoking, in turn, was the strongest promoter of atherosclerotic progression. Given what is known about the increased risk of cardiovascular events associated with active smoking, it is difficult to ignore the magnitude of IMT change associated with exposure to ETS documented in this study.

A second question to consider is what is the mechanism of action through which ETS causes these vascular changes. Evidence concerning the mechanisms for plausible causal pathways between ETS and atherosclerosis progression has been described.¹⁴ In healthy adults, exposure to ETS resulted in increased blood levels of sloughed endothelial cells , indicating damage to the arterial endothelium. Celermajer et al¹⁵ demonstrated evidence for endothelial dysfunction after exposure to cigarette smoke. Acute effects on endothelial cells may be responsible for the ability of ETS to lower the threshold for angina and cardiac ischemia, as has been demonstrated in clinical studies.¹⁶

While endothelial dysfunction and damage may be reversible, they also constitute the initial stage of atherosclerotic plaque formation. Platelets, which also have increased aggregation because of smoke, are thought to adhere to subendothelial connective tissue exposed by endothelial denudation, initiating the smooth muscle proliferation that leads to atherosclerotic plaque formation. Previous prospective studies have demonstrated causal relationships between firsthand smoke exposure and atherosclerotic progression. For example, Waters et al¹⁷ followed coronary disease progression with serial angiography in smokers and nonsmokers and found that over 2 years the mean narrowing of the minimal lumen diameter of all coronary lesions was 0.15 mm in smokers, more than twice the rate in nonsmokers (0.07 mm). In addition, new coronary artery lesions developed in more than half of smokers, compared with less than one quarter of nonsmokers. The Kuopio Atherosclerosis Prevention Study¹⁸ documented an increased rate of carotid IMT progression in smokers vs nonsmokers, with rates of progression especially high in those patients with increased IMT at baseline. The study by Howard et al⁶ implicates not only active smoking but also ETS as a cause for atherosclerotic progression, implying that persons exposed to ETS may be left with residual disease and residual risk. The chronic nature of the atherosclerotic disease is suggested by their additional finding that former smokers had progression of their IMT at a rate 24% greater than never smokers, which is similar to those exposed to ETS.

What are the implications of these findings for cardiovascular epidemiology, clinical practice, and public heath? Epidemiologic studies have attributed approximately 50% of all coronary disease and stroke to the known major cardiovascular risk factors, one of which is cigarette smoking.¹⁹ Most multivariate equations to predict CVD risk have not included ETS, and previous studies have rarely collected data on ETS. In addition, ETS may act synergistically with other risk factors such as diabetes and hypertension, as demonstrated by Howard et al,⁶ to further increase risk. Finally, ETS exposure may help explain some of the unaccounted for risk in individuals with a family history of CVD with an early age of onset. People with premature cardiac and cerebrovascular events have an increased prevalence of smoking, and their close relations, therefore, are much more likely to have a history of exposure to ETS.

Among the implications for clinical practice is that the tobacco history should include questions about ETS exposure. While ETS exposure is difficult to quantify, qualitative assessment should suffice. Given the evidence that irreversible changes may be caused by ETS, history of exposure to second-hand smoke should enter into our assessment of a patient's cardiovascular risk and probably his or her oncologic risk as well.²⁰ Avoiding ETS should be given the same priority that is given to smoking cessation as a way to prevent disease, especially among persons with existing CVD, diabetes, hypertension, and other cardiovascular risk factors.

The study by Howard et al⁶ also has obvious implications for public health. The findings suggest that ETS has about 34% of the impact on atherosclerotic progression that occurs with active smoking, which is compatible with the relative risk of 1.3 found in epidemiologic studies.^{2 ,5} Moreover, the evidence that ETS may initiate a long-term irreversible process adds to the mandate to avoid smoke exposure from the start. While many states have clean air legislation, and the Occupational Safety and Health Administration as proposed rules for making workplaces smoke free, many public places and millions of households remain smoke filled in the United States, with increasingly less control of ETS in most foreign countries. The huge number of potential exposures allows a relatively small increase in relative risk to become a potentially large source of preventable disease. The study by Howard et al⁶ certainly suggests that when a person finishes work in a smoke-filled office, factory, or restaurant he or she goes home with more than just the smell of cigarette smoke on their clothes.

Not much is passive about "passive smoke." However, what is passive is our lack of recognition of the importance of passive smoke as a CVD risk factor, our oversight in not asking patients about this exposure, and our lack of advocacy for clean air as a way to help prevent chronic disease.