Cardiovascular Disease Risk of Nicotine and Tobacco Products

Cigarettes

Smoking cigarettes affects multiple forms of CVD. The risk of CVD due to smoking is in general lower than the risk of lung cancer. Individuals who smoke have a 9- to 10-fold higher risk of developing lung-cancer, and a 4-fold higher risk of COPD. In contrast, the relative CVD risk varies from 1.3 to 4. Nonetheless, smokers are at a particularly high risk of developing abdominal aortic aneurysm, atrial fibrillation, heart failure, peripheral artery disease (see Classic References, Price et al.) and sudden cardiac death. Patients with diabetes who smoke are also at greater risk as are individuals who continue to smoke after a cardiovascular procedure such as percutaneous coronary intervention or coronary artery bypass surgery. The relative risk (RR) for different cardiovascular conditions is shown in Table 28.1 . In many cases, the effects of smoking appear to be dose-dependent; the relative risk (RR) of peripheral artery disease among heavy smokers is 3.94 in heavy smokers, but 1.87 to 1.70 in moderate smokers. Similarly, it has been reported that the risk of nonfatal acute myocardial infarction (MI) (odds ratio [OR] = 2.95) increases by 5.6% for every additional cigarette smoked.

Although the adverse health effects of smoking are widely recognized, there is surprising lack of understanding of the mechanisms by which smoking impairs cardiovascular health and the specific harmful or potentially harmful substances (HPHCs) in tobacco smoke responsible for cardiovascular injury have not been clearly identified. Nonetheless, extensive evidence suggests that one of the key targets of smoking is the endothelium. In humans, smoking acutely causes endothelial cell damage (see Classic References, Blann et al.), diminishes endothelium-mediated relaxation, and long-term smoking is associated with impaired endothelium-dependent relaxation in conduit and coronary arteries (see Classic References, Barua et al. and Campisi et al.). These changes have been linked to a decrease in the bioavailability of nitric oxide in smokers. Smoking-induced vascular dysfunction not only affects blood pressure regulation, but by altering the integrity of the vessel wall, it promotes the formation of atherosclerotic lesions as well. It has been found that cigarette smoking is an independent predictor of new coronary lesion formation and that smoking is associated with a consistent increase in intimal-medial thickness of the carotid artery.

In addition to its hemodynamic and vascular effects, smoking could promote atherosclerosis also by affecting lipid metabolism. Many studies have shown that compared with nonsmokers, smokers have higher levels of serum cholesterol, triglycerides, and low-density lipoprotein (LDL)-cholesterol, but lower levels of high-density lipoprotein (HDL)-cholesterol (see Chapter 27 ). But, because smoking is also associated with nutritional changes, it is unclear whether the changes in lipid profile are a direct effect of smoking or dietary differences between smokers and nonsmokers. The high-triglyceride/HDL ratio in smokers has been suggested to be related to insulin resistance; however, the relationship between smoking and diabetes is complex, and the effects of smoking on diabetes seem to vary with race and smoking intensity, but mild-to-moderate insulin resistance may be a key link between cigarette smoking and CVD.

Cigarette smoking can also increase the risk of CVD by affecting thrombosis and coagulation. Smokers have higher circulating levels of fibrinogen, and platelets isolated from smokers show increased aggregation (see Chapter 95 ). Smoking also affects tissue factor (TF) and TF pathway inhibitor-1, and it increase blood viscosity, red blood cell counts, and hematocrit, thereby creating a prothrombotic state, which could increase the acute thrombotic responses upon plaque rupture. In women, smoking has been associated with sudden cardiac death due to plaque erosion leading to the formation of a large occlusive thrombus (see Chapter 91 ).

Despite extensive descriptions of the cardiovascular effects of smoking, the process that contributes to changes in vascular function, thrombosis, lipid metabolism, and atherogenesis in smokers remains unclear, and the specific constituents and chemicals that induce such injury have not been identified. Cigarette smoke, as well as smoke from combustible and HTPs, contains fine particulate matter (PM), which may be responsible for the cardiovascular risk of smoking. Indeed, a large body of work has shown that exposure to ambient air PM leads to many of the cardiovascular changes seen with smoking, which suggests that adverse cardiovascular effects of smoking, at least in part, may be attributable to PM exposure. In addition to PM, both particulate and gaseous phases of tobacco smoke contain high levels of free radicals ; some of them are particularly long-lived and may be responsible for extensive tissue damage, oxidative stress, and inflammatory responses associated with smoking.

Cardiovascular injury caused by smoking may also be related to the gaseous phase of tobacco smoke. Tobacco smoke contains 3000 to 7000 different chemicals, many of which react avidly with a wide range of biomolecules. These chemicals include tobacco-specific nitrosamines, metals, gases such as carbon monoxide, and volatile organic compounds (VOCs) such as acrolein, formaldehyde, 1,3-butadiene, benzene, and acrylonitrile. The specific toxicologic profile of each of these chemicals remains uncertain and the contribution of each of these chemicals to the overall toxicity of cigarette smoke has not been well documented. Nevertheless, theoretical hazard estimates based on the toxicologic properties of individual constituents and their relative abundance in cigarette smoke suggest that a major portion of the toxicity of cigarettes could be attributed to VOCs such as acrolein. This is significant because many of the newer tobacco products (e.g., e-cigarettes) do not generate high levels of tobacco-specific nitrosamines or carbon monoxide, but they do produce VOCs such as acrolein, which may be responsible for the residual toxicity associated with these products.

Even though combustion products, gases, and trace metals in tobacco smoke have received the most attention from toxicologists, the role of nicotine could not be entirely discounted. Because by itself nicotine is well tolerated and is often used for smoking cessation, it is widely believed that nicotine is relatively innocuous. This belief is fueled in part by the often-repeated phrase that “people smoke for nicotine, but they die from tar” (see Classic Reference, Russell). Nonetheless, nicotine is a potent sympathomimetic drug, which upon binding to very specific cholinergic receptors in nervous tissue elicits a wide range of metabolic and physiologic responses that could significantly affect vascular function, cardiac contractility, and lipid metabolism as shown in Fig. 28.2 . These changes, brought about by acute nicotine delivery, could increase the risk of arrhythmias, plaque rupture, and sudden cardiac death.