Impact of Tobacco Smoking and Smoking Cessation on Cardiovascular Risk and Disease

Christopher Bullen


Expert Rev Cardiovasc Ther. 2008;6(6):883-895. 

In This Article


Cigarette smoke is a complex mix of more than 4000 chemicals,[41] including polycyclic aromatic hydrocarbons and oxidant gases that are known to be cardiotoxins. However, the nature and relative toxicity of many of these chemicals is still poorly understood.[42] It is not surprising, therefore, that the pathways linking smoking with cardiovascular disease have not yet been fully elucidated. As understanding of these complex mechanisms and their relative importance increases, so too does the prospect of developing new approaches to prevention and treatment. We first consider the role of nicotine, as it can perhaps lay claim to being the most well-known, but also the most misunderstood, constituent of cigarette smoke.


Nicotine is a sympathomimetic chemical that promotes the release of catecholamines and other neurotransmitters acting centrally and peripherally. In addition to its cardiovascular effects such as elevated heart rate, blood pressure and cardiac output,[42] nicotine has metabolic effects, in particular increased lipolysis. Lipolyis leads to increased levels of circulating free fatty acids and glycerol in the blood and the resulting increase in fat metabolism drives a demand for more oxygen, leading to increased coronary blood flow and myocardial oxygen uptake.[43] Inhaled nicotine from cigarette smoke is delivered rapidly in high concentrations in the arterial blood to the heart. The rapidity of absorption and the peak arterial blood concentrations are determinants of the magnitude of at least some of the cardiovascular effects of nicotine. In healthy smokers, these cardiovascular and metabolic effects are unlikely to be hazardous. However, in people with established coronary artery disease there is a theoretical increase in risk of a cardiac event since, unlike exercise-induced sympathetic activity, nicotine-induced sympathetic activity leads to greater myocardial oxygen demand without a concomitant increase in organ blood flow and with an increase in vasoconstriction, including constriction of the coronary vessels disease.[43] These effects could potentially trigger symptoms of ischemia in such smokers. One might also expect that the hemodynamic effects of nicotine would contribute to endothelial damage and accelerate the progression of atherosclerosis.[44]

In fact, the clinical evidence does not support a major role for nicotine in cardiovascular disease. Studies of smokeless tobacco users shed some light. Smokeless tobacco users absorb the same amount of nicotine as cigarette smokers, but are not exposed to tobacco combustion products. Nicotine absorbed from cigarette smoke is more rapidly absorbed and rapidly attains peak arterial concentrations compared with nicotine absorbed slowly from smokeless tobacco, given an equivalent daily exposure. However, smokeless tobacco produces sympathomimetic effects similar to those produced by smoked tobacco.[45,46] The key difference is that smokeless tobacco does not lead to the inflammatory reaction seen in smokers, nor does it produce the endothelial dysfunction, platelet activation or evidence of oxidant stress believed to be fundamental to pathogenesis.[47] Rather, it is the other constitutents of cigarette smoke that are responsible for the prothrombotic and atherogenic changes underlying cardiovascular disease. The contribution of nicotine to aggravating myocardial ischemia, smoking-related atherosclerosis and cardiovascular disease is of little clinical importance.[48,49] The crucial role that nicotine plays in cardiovascular disease is in initiating and maintaining tobacco dependence, thereby exposing smokers to the other far more hazardous components of tobacco smoke.[43]

Carbon Monoxide

Another constituent of cigarette smoke implicated in the pathway from smoking to cardiovascular disease is carbon monoxide (CO).[48] Inhaled CO binds swiftly to hemoglobin, reducing not only oxygen-carrying capacity but also inhibiting oxygen release from hemoglobin that is not directly bound to CO. Carboxyhemoglobin levels in smokers average 5%, but may be as high as 10%, compared with levels of only 0.5–2% in nonsmokers. The resulting relative hypoxemia leads to a compensatory increase in red cell mass and in blood viscosity. CO may also increase the occurrence of ventricular arrhythmias. Early studies reporting evidence of direct effects of CO on atherosclerosis and thrombus formation have not been confirmed by more recent work.[43]

The most important mechanism implicated in initiating acute cardiovascular events is the development of a hypercoagulable state leading to thrombosis.[50] Epidemiologic studies indicate that cigarette smoking increases the risk of AMI and sudden cardiac death, mediated by thrombosis, much more than it increases the risk of angina pectoris, which is caused primarily by hemodynamic factors.[50] Cigarette smoking contributes to thrombosis by promoting platelet activation and aggregation and through stimulating prothrombotic changes in clotting factors.[51] Levels of circulating fibrinogen, one of the strongest predictors of coronary events, are increased in smokers.[52,53] Increases in fibrinogen levels act in tandem with the increased red cell mass from long-term CO exposure, increasing blood viscosity and enhancing platelet activation, which, in turn, promotes atherogenesis.[53,54] Fibrinogen may also contribute to atherosclerosis through a direct effect on platelets.[54] Tissue factor (TF), another link in the chain, is present in atherosclerotic plaques and may promote plaque thrombogenicity and possibly thrombus propagation where there is existing atherosclerosis.[55] Sambola et al. found that smoking increases plasma levels of TF in smokers who smoke ten cigarettes or more per day with a smoking history of 10 or more years, within 2 h after smoking just two cigarettes.[55]

Oxidant Gases

Oxidative stress, the oxidation of lipids, proteins and DNA leading to cellular damage, is now known to be a pivotal factor in atherogenesis.[8,43] It occurs when there is an imbalance between production of oxidants and endogenous protective antioxidants, such as nitric oxide (NO), a key factor in regulating normal vascular tone.[56] Cigarette smoke is not only a rich source of oxidant chemicals, such as hydrogen peroxide, peroxynitrite and superoxide,[56] but also stimulates the generation of oxidants in vivo.[56] Furthermore, oxidant chemicals increase the destruction of ‘protective' antioxidants in smokers, but this is reversible with administration of antioxidants such as vitamin C.[57] Antioxidants have been shown to reverse endothelial dysfunction,[58] and reduce inflammation[59] and other adverse changes associated with cigarette smoking.[60–62] Oxidation of LDL may also promote atherosclerosis. Smokers have higher levels of oxidized LDL, which is taken up preferentially by macrophages, a pivotal step in the development of foam cells that are found in atherosclerotic lesions.[63,64]

Oxidants in cigarette smoke also decrease NO release and bioavailability.[56] Barua et al. took serum from nonsmokers and current smokers who had abstained from smoking for a 6–8-h period and incubated it with human umbilical vein endothelial cells (HUVECs). After 12 h, HUVECs incubated with current smoker's serum showed significantly lower basal NO production compared with HUVECs incubated with nonsmoker's serum, suggesting that smoking is associated with reduced basal NO production.[65] Celer-majer et al. found a significant association of cigarette smoking with impaired endothelium-dependent vasodilation of different blood vessels, one of the earliest effects of the various risk factors for atherosclerosis.[66] This occurs before changes in the blood vessel walls are evident and appears to be a consequence of smoking-induced impairment of endothelial NO release.[67,68] NO also plays a role in regulating platelet activation and recruitment into aggregates and at normal levels inhibits smooth muscle cell proliferation and adhesion of monocytes to the endothelium. Thus, the impaired endogenous NO release seen in smokers may contribute to both acute cardiovascular events and accelerated atherogenesis.[67,68]

Smoking also promotes a chronic inflammatory state. Cigarette smoking is consistently associated with increased circulating neutrophil counts.[69] For example, Lavi et al. found that current smokers with no evidence of coronary artery disease have significantly increased white blood cell counts compared with nonsmokers.[70] Epidemiological studies have shown that elevated white blood cell counts are associated with a greater long-term cardiovascular risk.[71,72] Neutrophils may promote cardiovascular disease by releasing oxidant chemicals, proteases and leukotrienes[73] that, in turn, cause endothelial cell injury and the aggregation and activation of platelets.

The effects of these complex interdependent pathphysiological processes are also evident in studies tracking the development of atherosclerosis in smokers and nonsmokers. Serial quantitative coronary arteriography has demonstrated that active smoking promotes the formation of new lesions and accelerates progression of existing coronary artery disease [74]; Howard et al. found active smoking to be associated with increased progression of carotid atherosclerosis, as assessed by carotid ultrasound to evaluate carotid intima–medial thickness, in over 10,000 participants.[75]


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