Cigarette smoking is intimately (Fig. 30–7) involved in development and progression of cardiovascular disease. Cigarette smoke is a mixture of more than 5000 toxic chemicals17 and 1015 to 1017 free radicals.18,19 It is conventionally divided in two chemically different phases: a tar phase and a gas phase.20 The tar or particulate phase is material that is trapped when the smoke steam is passed through the glass-fiber (cigarette) filter. The cigarette filter retains 99.9% of all particles of greater than 0.1 μm. Nicotine is a major chemical component of the particulate phase of cigarette smoke.21 The gas (or vapor) phase consists of the material that passes through the cigarette filter.21 The common chemical components of the gas phase include carbon monoxide (CO), acetaldehyde, formaldehyde, acrolein, nitrogen oxides, and carbon dioxide. Both phases are high in reactive oxygen species (ROS).22 Despite the presence of multitude of constituents in both phases, only three constituents (ie, nicotine, CO, and ROS) have been shown to play a role in the initiation and progression of cardiovascular disease.23
Schematic representations of pathways linking cigarette smoking with development and progression of cardiovascular disease. α1, α1-adrenergic receptor; β1, β1-adrenergic receptor; ANGII, angiotensin II; AT1, angiotensin II type 1 receptor; BH4, tetrahy-droxybiopterin; BP, blood pressure; cGMP, cyclic guanosine monophosphate; eNOS, endothelial nitric oxide synthase; CO, carbon monoxide; COX-2, cyclooxygenase-2; HDAC, histone deacetylase; IL, interleukin; IP3, inositol trisphosphate; MAPK, mitogen-activated protein kinase; NE, norepinephrine; NO, nitric oxide; NOX, NADPH oxidase; ROS, reactive oxygen species; sGC, soluble guanylate cyclase; TNFα; tumor necrosis factor α; TXA2, thromboxane A2; VWF, von Willebrand factor.
Cigarette smoke affects various cell lines and acts through several pathophysiological mechanisms.24,25,26,27,28,29 These mechanisms include, but are not limited to, hemodynamic changes, cardiac remodeling, inflammation, endothelial dysfunction, thrombosis, and changes in glucose and lipid metabolism. The central role in the cigarette smoking–related cardiovascular pathogenesis belongs to oxidative stress. Most of the molecular changes associated with cigarette smoking are triggered by high concentration of oxidizing chemicals inhaled by smokers with the cigarette smoke.
The net effect of various endogenous chemicals from cigarette smoke, such as oxidative free radicals and nicotine, together with inflammatory molecules and endogenous-produced ROS released by activated inflammatory cells, is disruption of cardiovascular homeostasis leading to hemodynamic changes, endothelial dysfunction, inflammation, thrombosis and plaque progression, and abnormalities in lipid and glucose metabolism.19
Nicotine from cigarette smoke is the major culprit for hemodynamic changes caused by cigarette smoking. It is a strong sympathomimetic drug that stimulates release of catecholamines from the adrenal medulla and local sympathetic neurons.25 Via sympathetic stimulation, nicotine leads to an increase in cardiac contractility, acute and chronic increase in heart rate up to 7 to 10 beats per minute,25 and elevation in systolic blood pressure up to 5 to 10 mm Hg from baseline.23 Interestingly, a large study using mendelian randomization selecting genes associated with smoking heaviness to overcome the observational nature of studies did not find any relationship with hypertension, and it hypothesized that a lower body mass index among smokers may be nullifying adverse effects of smoking on blood pressure.30 The study did find an important relationship between smoking and higher heart rate.
The net result is increased myocardial oxygen demand that can predispose individuals to myocardial ischemia. In long-term smokers with coronary artery disease, cigarette smoking causes coronary vasoconstriction. Smoking-induced coronary vasoconstriction can be prevented with the α-adrenergic blocker phentolamine and potentiated with the β-blocker propranolol, suggesting that the α-adrenergic pathway is the main mechanism of smoke-related cardiac hemodynamic changes.24 CO is another component of cigarette smoke that has been implicated in cigarette smoke–induced hemodynamic changes. By binding to hemoglobin, CO reduces the oxygen-carrying capacity of hemoglobin, resulting in relative hypoxemia and subsequent dilation of coronary arteries.31 However, this increase in coronary blood flow is lower than required to keep up with nicotine-mediated increased sympathetic drive toward the heart. A combination of nicotine-induced increased oxygen demands on one side, and CO-associated reduced oxygen availability on the other side, may lower the threshold for angina onset in smokers.32
Cigarette smoking–induced endothelial dysfunction is an important factor in coronary hemodynamic disturbances and the progression of atherosclerosis. Endothelium is an active regulator of the vascular tone through the release of nitric oxide (NO), prostacyclin, tissue plasminogen activator (tPA), and plasminogen activator inhibitor-1.23 Endothelium-dependent vasodilation in coronary and peripheral vessels is diminished in smokers when compared to nonsmokers. The primary mechanism by which smoking leads to vascular and endothelial dysfunction is thought to be suppression of endothelial nitric oxide synthase (eNOS) expression and subsequent decreased bioavailability of NO caused by oxidant chemicals from cigarette smoke.33 NO is synthesized by eNOS when L-arginine is transformed to L-citrulline in the presence of oxygen, and cofactors such as calmodulin, tetrahydroxybiopterin (BH4), and reduced nicotinamide adenine dinucleotide phosphate.26 The main role of endothelial NO is vasodilation and increased blood flow. However, NO also participates in various vascular functions such as inhibition of platelet aggregation and adhesion, inhibition of leukocyte adhesion, and reduction of smooth muscle proliferation.26 Therefore, deficiency of NO participates in initial phases of plaque formation and atherosclerosis pathogenesis. Biomolecular pathways behind decreased NO production in endothelial cells caused by smoking-related oxidative stress are complex and involve several different components of the cigarette smoke, such as free radicals, ROS, and reactive aldehydes. Free radicals from cigarette smoke oxidize and deplete BH4 in vascular endothelial cells, an important cofactor of eNOS, resulting in uncoupling of eNOS and production of superoxide anions (O2) instead of NO.26 Another mechanism by which oxidative stress affects endothelium-mediated vasodilation is direct degradation of NO by oxidant chemicals from inhaled cigarette smoke. If vitamin C is administered to smokers, it may reverse endothelial-mediated vasodilation, thus providing additional support that pathogenesis of endothelial dysfunction caused by smoking involves oxygen-derived free radicals from cigarette smoke.34 Chronic application of nicotine decreases the bioavailability of endogenous NO by producing superoxide anions and impairs vasodilation of pial vessels.35
Cigarette smoking has been shown to promote a prothrombotic state through several mechanisms. These mechanisms include alterations in platelet activity as well as alterations in antithrombotic and prothrombotic factors, including fibrinolytic factors and platelet-mediated pathways.20,36
Once atherosclerotic plaque is formed, its vulnerability for rupture depends on the amount of its lipid content, thickness of the fibrous cap, size of its necrotic core, the rate of plaque progression,37 recruitment of inflammatory cells, and intraplaque hemorrhage.38 Smokers are shown to have higher extracellular content in their plaque39 and lower activity of n-prolyl-4-hydroxylase,40 a key enzyme in arterial wall collagen metabolism that could contribute to thinning of the fibrous cap in the atherosclerotic plaque of smokers. Furthermore, cigarette smoking leads to increased activity of matrix metalloproteinases (MMPs) involved in degradation of extracellular matrix proteins within atherosclerotic plaque.41 Taken together, most of pathologic changes associated with highly vulnerable plaque and plaque rupture37 are potentiated by smoking.38 Moreover, cigarette smoke accelerates biopathological pathways, such as platelet activation and aggregation, that occur after plaque rupture. Platelets isolated from smokers have shown to exhibit an increased spontaneous and stimulated aggregation compared to nonsmokers.42 Not only does smoking decrease endothelial NO production, it also leads to diminished bioavailability of platelet-derived NO and decreased platelet sensitivity to NO.28,29,43 Both mechanisms promote platelet activation and adhesion, making smokers’ platelets more thrombogenic. In addition to impaired NO release from platelets, cigarette smoke also triggers the release of thromboxane A2, a potent vasoconstrictor, and inhibits coronary endothelial release of prostacyclin, a potent vasodilator and inhibitor of platelet aggregation.24 Cigarette smoking exposure has also been related to different clot dynamics that are more resistant to thrombolysis compared with clots of nonsmokers.38 An increased level of circulating von Willebrand factor, an important ligand of platelet binding, has been demonstrated in smokers compared to nonsmokers.44,45 Furthermore, cigarette smoking is associated with increased concentration of fibrinogen46,47; increased expression of tissue factor that contributes to thrombosis after plaque rupture48; and reduced basal production of tPA,33 which is an essential regulator of plasminogen-plasmin transformation. Lower level of activated plasmin leads to diminished lysis of fibrin and propagation of thrombus. As previously mentioned, CO from cigarette smoke causes relative hypoxemia, which compensatory leads to increase in the number (and mass) of erythrocytes in the circulation which increases blood viscosity.31 An increased blood viscosity may mildly increase predisposition to thrombosis and atherosclerotic plaque formation.
Chronic vascular inflammation mediated by cigarette smoking may play an important role in the progression of atherosclerosis.49 The exact molecular-pathogenic mechanisms by which smoking induces vascular inflammation are not completely established. Nonetheless, the role of several proinflammatory cytokines as well as activation and interaction between leukocytes and endothelial cells is well recognized in this process. Smoking increases the peripheral leukocyte count by 20% to 25%50 and promotes leukocyte adhesion to endothelial cells within the blood vessel wall, starting an initial inflammatory step in atherosclerosis.51 One of the proposed biochemical pathways that links cigarette smoking to vascular inflammation is enhanced expression of soluble vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin, which leads to increased leukocyte-endothelial cell interaction.52 Increased levels of multiple proinflammatory markers have been associated with smoke exposure; these include C-reactive protein, cytokines such as the interleukins (ILs) IL-1β and IL-6, and tumor necrosis factor-α (TNF-α).27 It has been shown that cigarette smoking induces release of proinflammatory cytokines in macrophages53 and lymphocytes by activation of NF-κB and post-translational modification of histone deacetylase.49 Free radicals in cigarette smoke in synergy with inflammatory cytokines (IL-1β and TNF-α), present in the serum of smokers, increase the activity of nicotinamide adenine dinucleotide phosphate oxidase within endothelial cells, leading to generation of superoxide anion and induction of cyclooxygenase-2 (COX-2) expression via the p38 mitogen-activated protein kinase (MAPK)/Akt pathway.27 COX-2 induces production of prostanoids, which diffuse toward endothelial cells and attenuate vasodilation by decreasing the activity of soluble guanylate cyclase and production of cyclic guanosine monophosphate (cGMP).54
Smoking has been associated with left ventricular hypertrophy and left atrial enlargement in animal models.55,56 Smokers exhibit higher level of activation of MMPs that degrade elastin and collagen in the extracellular matrix. Within myocardium, increased MMP activity leads to breakdown of the supporting fibrillary collagen and ventricular wall thinning.57 Smoke-related ROS stimulate fibroblasts to proliferate and induce myocardial cell apoptosis, leading to cardiac fibrosis and remodeling.58 Cigarette smoking–induced cardiac remodeling has also been linked to increased activation of MAPKs by either norepinephrine (NE), which is increased in smokers’ serum, or directly by free radicals from cigarette smoke.57 Within the heart, NE can lead to myocyte hypertrophy by binding to α1-adrenergic receptors or apoptosis by binding to β1-adrenergic receptors.59 Nicotine increases the expression of angiotensin-converting enzyme and production of angiotensin II,60 which has an important role in cardiac remodeling through stimulation of hypertrophic gene program within cardiomyocytes as well as through stimulation of fibroblast proliferation within myocardium.
Multiple studies have demonstrated that cigarette smoking enhances atherosclerosis at least in part by altering the lipid profile. Cigarette smoking lowers serum high-density lipoprotein (HDL), but it increases triglycerides, cholesterol, and low-density lipoprotein (LDL).61 More importantly, smokers have higher levels of oxidized LDL, which is involved in pathogenesis of atherosclerosis.62 Exposure of human plasma to cigarette smoke causes oxidative modification of plasma LDL that is actively taken up by the macrophages and forms foam cells in the culture.62 In addition to this, smoking increases hepatic lipase activity, which leads to production of small dense LDLc and small dense HDLc. First, LDLc has toxic effects on endothelium and promotes release of even more ROS. Second, HDLc has no protective antiatherogenic effects, which are normally attributed to HDL.63 A nicotine-induced increase in circulating catecholamines induces lipolysis and release of plasma-free fatty acids.23,64
Cigarette smoking increases the risk of development of diabetes mellitus type 2.65 A dose-response relationship has been found between the smoking and the incidence of diabetes mellitus in both men and women.66 Data from the Cancer Prevention Study have shown that there is a 45% higher diabetes rate among smokers than among men who had never smoked. Higher levels of HbA1C have been found in smokers with diabetes as compared to nonsmokers with diabetes. Smoking also increases requirements for insulin and causes insulin resistance in nondiabetics.67 Studies have also shown increased risk of microvascular complications of diabetes such as diabetic neuropathy and faster progression of renal disease.68 There has been a debate about whether possible weight gain associated with quitting smoking is associated with increased risk, too.69 Although confounding in observational studies makes it difficult to test this relationship further, the increased risk of weight gain after cessation ameliorates with duration of smoking cessation.69 The pathogenesis of smoking and glucose metabolism is not well understood, but nicotine appears to have central role in this process.19,70 Nicotine stimulates cathecholamine release from the adrenal medulla and sympathetic nervous system, which may lead to insulin resistance. It also increases the release of corticosteroids, which are known hyperglycemic hormone.23