Vascular Medicine

http://vmj.sagepub.com/ Vascular damage from smoking: disease mechanisms at the arterial wall
Janet T Powell Vasc Med 1998 3: 21 DOI: 10.1177/1358836X9800300105 The online version of this article can be found at: http://vmj.sagepub.com/content/3/1/21

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8. Imperial College School of Medicine at Charing Cross Hospital. UK. nitric oxide. fibrinogen. The tar and nicotine content of cigarettes have been reduced substantially. attributable to the toxicity of absorbed products of tobacco combustion. must underlie. which on inhalation might injure the cells of the airways and alveoli. whilst other products (perhaps including nicotine) injure the arterial endothelium and promote atherogenesis. the powerful epidemiological evidence showing smoking as a potent. Absorbed nicotine stimulates the release of catecholamines. albeit to lesser extent. endothelium. lung cancer.2 In contrast. the concentration of DNA adducts in the vasculature of smokers is low. The tar content of cigarettes and vascular disease Identification of the cigarette components which. in large part. the effect of smoking to alter dietary habits and exercise tolerance will have indirect effects on the vasculature. Many of these effects are ameliorated by high concentrations of vitamin C. These injurious chemicals interfere with a variety of cellular and metabolic processes.6 Nicotine. including aromatic hydrocarbons. cause of vascular disease. UK Address for correspondence: Janet T Powell. in passive smokers. smoking Introduction Cigarette smoking is a common cause of premature death. the tobacco companies have accepted that ‘Smoking can seriously damage your health’ and there has been a drive to market safer cigarettes.5.Vascular Medicine 1998.sagepub. Department of Vascular Surgery. © Arnold 1998 Downloaded from vmj. acrolein and carbon monoxide. London W6 8RF. Continued stimulation of intimal cells by oxidized LDL leads to the development of atherosclerosis. with a lower tar and nicotine content. Free radicals and aromatic compounds diminish the endothelial synthesis of nitric oxide. when absorbed and metabolized.1. carbon monoxide and other products of tobacco combustion An indication of the variety of chemical products of tobacco combustion that are inhaled is given in Table 1. may damage the vasculature is important.9 The density of these and other nicotine receptors in the central nervous system is modulated by 1358-863X(98)VM210OA Department of Vascular Surgery.3 There is little evidence to suggest that those who smoke higher tar content cigarettes are at higher risk of either ischaemic heart disease or peripheral arterial disease than those who smoke low tar cigarettes. In addition. Cigarette smoking is the single most important risk factor for lung cancer.7–11 Nicotine binds to a subset of cholinergic receptors in the nucleus accumbens to trigger the release of dopamine. The combustion and partial combustion of tobacco in cigarettes yields hundreds of different chemicals. Professor of Cardiovascular Biology. whether from respiratory disease.com by guest on June 24. causing impaired endothelium-dependent relaxation of arteries. The association between smoking and lung cancer is readily appreciated. The addictive component is nicotine. the earliest clinical sign of endothelial dysfunction. Reluctantly. peripheral atherosclerosis and abdominal aortic aneurysm. 2013 . Smoking also potentiates thrombosis at the dysfunctional endothelium by increasing the concentration of plasma fibrinogen and altering the activity of platelets. The more cigarettes a person has smoked the higher the concentration of aromatic DNA adducts that are found in the lung. including the direct damage of cellular DNA. All these proatherogenic effects of smoking to injure the endothelium also are observed.5 However. smokers who inhale deeply appear to have an increased risk of both symptomatic peripheral arterial disease and abdominal aortic aneurysm.4. with consequent reduction in the average nicotine content from 2 mg to ෂ1 mg per cigarette. The average tar content of a cigarette has been reduced from 30 mg in 1970 to ෂ10 mg in 1997. 3: 21–28 Vascular damage from smoking: disease mechanisms at the arterial wall Janet T Powell Abstract: The products of tobacco combustion are absorbed into the systemic circulation. other cancers or cardiovascular disease. The pathways through which nicotine affects the release and turnover of neurotransmitters in the central nervous system are beginning to be unravelled. Imperial College School of Medicine at Charing Cross Hospital. The increased oxidation of low density lipoprotein (LDL) in smokers has synergistic effects to promote monocyte adhesion and monocyte migration into the subintimal space. Fulham Palace Road. aromatic amines.2 Different mechanisms. Smoking alters the shear forces and rheology at the endothelial surface and these changes enhance the effects of products of tobacco combustion to upregulate leucocyte adhesion molecules on the endothelial surface. Key words: atherosclerosis. London. but avoidable.

There is little evidence to suggest that in man.16 Some of these nitrogen oxides interact with nicotine and other aromatic components to form nitrosonornicotine and other potentially carcinogenic compounds. Nitrosonornicotine smoking. The accumulating evidence that passive Downloaded from vmj. smoking is the principal risk factor for both abdominal aortic aneurysm and peripheral arterial disease.20.sagepub.14 The percentage substitution of haemoglobin with carbon monoxide in a smoker ranges from 2% to 10%.21 The Framingham Study.17 Vascular Medicine 1998. 3: 21–28 Passive smoking and vascular disease Society may countenance self-inflicted injury to the vasculature by smoking. Absorbed free radicals catalyse the oxidation of low density lipoprotein (LDL) to promote endothelial activation. although smoking cessation may reduce the likelihood of a fatal event.18.15 This erythrocytosis increases the viscosity of the blood and can impair the flow through capillaries. nicotine. although in animals the administration of intravenous nicotine has adverse effects on aortic endothelium.13.11 The release of dopamine and stimulation of a variety of neural pathways underlies the effect of smoking to alter mood and appetite. to reduce the vascular damage caused by smoking indicates that the generation of free radicals in products of tobacco combustion have an important role in the pathogenesis of vascular disease. 2013 . The extent of carboxyhaemoglobin formation depends on depth of inhalation and lung function in addition to the type and number of cigarettes smoked. with cell blebbing and detachment. In the peripheral nervous system. other critical risk factors including hyperlipidaemia.20. where it is absorbed by the haemoglobin on erythrocytes to form carboxyhaemoglobin. gangrene and impotence when the penile arteries are affected. These nitrates are absorbed into tobacco leaf and the yield of nitrate and nitrogen oxides from cigarettes is directly proportional to the nitrate content of the leaf.20. In contrast. platelets or leucocytes. Tobacco fields all too often are farmed intensively and the fields fertilized with nitrates. Smoking damage to umbilical arteries contributes to the low birth weight of children born to smoking mothers. In the alveolus. although any nitric oxide absorbed into the capillary at the alveolus also is likely to be rapidly absorbed by haemoglobin or plasma proteins.23 Nevertheless.22 JT Powell Table 1 A selection of the chemicals found in mainstream and sidestream tobacco smoke. Buerger’s disease is traditionally observed in young adult males and although uncommon in western Europe.19 The spectrum of vascular disease caused by smoking Epidemiological studies have provided clear evidence to associate smoking with almost all forms of arterial disease.31. inhaled carbon monoxide diffuses into the capillaries. a natural anti-oxidant. Mainstream smoke (cigarette smokers) Carbon monoxide Nitrogen oxides Hydrogen cyanide Ammonia Acetaldehyde Acrolein Benzene Benzanthracene Benzapyrene Toluene Phenol Cresols Acrylamide Nitrosonornicotine Nitrosoanatabine Sidestream smoke (passive smokers) Carbon monoxide Nitrogen oxides Hydrogen cyanide Ammonia Acetaldehyde Acrolein Benzene Benzanthracene Benzapyrene Nitric oxide is a free radical. vascular tone and lipid metabolism.22. Nitrogen oxides also can initiate free radical reactions. one of many absorbed by the smoker.27–29 When disease of the coronary or distal arteries is very severe. there are few associations between venous disease and smoking.34 No artery appears to be immune from the devastating effects of smoking. The effect of dietary supplementation with vitamin C. The earliest epidemiological studies to demonstrate the association between smoking and ischaemic heart disease included the Framingham Study and Sir Richard Doll’s classic study of British doctors. smoking initiates vasospasm causing digital blanching and penile artery vasospasm. it is very common in the Indian subcontinent.33. causing intermittent claudication. In contrast. with smoking increasing the risk of bypass graft occlusion. the plasma concentrations of these derivatives in smokers is too low to have therapeutic effect. adrenaline and noradrenaline. nicotine affects the release of the catecholamines. has direct effects on the cells of the blood vessel wall interface. which also is caused by smoking. Once the vein is used as an arterial conduit it too becomes susceptible to smoking. The presence of carboxyhaemoglobin reduces the oxygen carrying capacity of the erythrocytes and often induces a compensatory erythrocytosis with increased haematocrit. ulcers.22 Smoking is associated with an increased risk of both atherothrombotic stroke and cerebral aneurysm. Smoking cessation is less effective as a treatment for ischaemic heart disease. bypass surgery using saphenous vein is considered.30 Even in subjects with apparently healthy arteries. peripheral vascular disease or abdominal aortic aneurysm. itself. it is unsurprising that smoking exacerbates Raynaud’s phenomenon. also have demonstrated an increased risk of stroke in smokers.com by guest on June 24.24–26 Peripheral arterial disease results from atherothrombosis of the distal aorta and its branches.32 Therefore. Although nitrosoalbumin derivatives have therapeutic effects as nitrite donors in the experimental situation. smoking is but one of the risk factors for both ischaemic heart disease and stroke. together with later studies. Smoking cessation is the most effective therapy for Buerger’s disease. Buerger’s disease is an inflammatory disease of the arteries. macrophage activation and the development of atherosclerosis in susceptible regions of the arterial tree. veins and nerves of the limbs. as is the activity of the dopamine metabolizing enzyme monoamine oxidase. hyperfibrinogenaemia and hypertension. the endothelium.12 This catecholamine release has important effects on cardiac function.

41 In young. again both in vivo and in vitro. it has remained the focus of this section. there is accumulating evidence to indicate that smoking disturbs the endothelial production of nitric oxide. monocyte adhesion and inhibit smooth muscle cell proliferVascular Medicine 1998. smokers these dilatations are reduced to 4% and 0% respectively. Several lines of evidence suggest that smoking impairs the production of nitric oxide by the endothelium. myristylation to transport the enzyme to the plasma membrane of cells. In the healthy adult. arterial dilation is the normal endothelium-dependent response after removal of an occluding tourniquet. In this respect smoking is both the disease and cause of the disease.45 In keeping with this observation. The endothelial production of nitric oxide can be augmented by a variety of physiological stimuli. active or passive. nitric oxide synthase.sagepub. The development of atherosclerotic lesions is a later event. Passive smoking also has been shown to be associated with impairment of dilatation of the brachial artery in reactive hyperaemia. The arterial dilatation of post-occlusive hyperaemia and the recruitment of capillaries in exercising skeletal muscle both depend on the release of nitric oxide from endothelium. healthy non-smoking adults the brachial and femoral arteries dilate by 11% and 4% respectively in response during reactive hyperaemia. This nitric oxide is synthesized by oxidation of l-arginine by an enzyme. Nitric oxide is considered to be the dominant local regulator of resting vasomotor tone. flavin adenine dinucleotide.com by guest on June 24. phosphorylation and the concentration of calcium in the cytosol of the endothelium. These in vivo findings are supported by in vitro findings showing that smoking impairs the endothelial nitric oxide production from saphenous vein rings and from platelets. The activity of this enzyme depends on several cofactors (including NADPH. The two best characterized endothelial vasodilators are nitric oxide (NO) and prostacyclin. being particularly susceptible to atherosclerosis. which can initiate free radical chain reactions. It is this effect to promote smooth muscle cell relaxation that is critical to the maintenance of normal vascular tone in healthy vessels.36 The synergistic effects of smoking and hypercholesterolaemia to potentiate endothelial dysfunction have been attributed to the ability of smoking to promote the oxidation of LDL.47 Since nitric oxide is the principal regulator of resting vascular tone. to promote vasoconstriction. Vasodilatory nitrate drugs. In normal.18 To summarize.43 When tetrahydrobiopterin concentrations are low the activation of nitric oxide synthase leads to the production of hydrogen peroxide. there is evidence from both in vivo and in vitro studies to suggest that the endothelial dysfunction associated with smoking is reversible. 2013 . binding readily to proteins with active Fe2+ centres. with compensatory increase in production of the vasoconstrictor thromboxanes. These in vivo tests of endothelial function are based on our increasing knowledge of the factors that regulate normal vascular tone and which may be perturbed by smoking.39 Once atherosclerosis narrows the arterial lumen and disrupts the anti-thrombotic properties of the vessel wall. normally has a very short halflife. thrombosis at the diseased arterial wall may trigger acute cardiovascular events. Nitric oxide. including an increase in blood flow. with packets of NO being produced at regular intervals. In disease. with the magnitude of the impairment related directly to the amount of exposure to tobacco smoke. apparently healthy.38 with endothelial dysfunction being the earliest detectable sign of endothelial injury. whilst the responses to nitrates are preserved. the vasoconstrictor response is soon counterbalanced by the local release of vasodilators from endothelium. with consequent systemic release of adrenaline and noradrenaline. with some vessels. perhaps through an aromatic product of tobacco combustion inhibiting one of the biosynthetic enzymes. to predispose to the development of atherosclerosis (Figure 1).35 should spearhead new legislation to restrict smoking in all public areas. Vascular pathology The earliest injurious effects of smoking can be detected as abnormal vasodilator responses of the brachial or femoral arteries. a molecule containing an electron with unpaired spin.43. to show that prostacyclin production is impaired in smokers. Hence. The activation of this enzyme causes the release of cyclic GMP to trigger smooth muscle relaxation and prevent platelet aggregation respectively. who does not usually smoke. flavin mononucleotide and tetrahydrobiopterin). Regulation of vascular tone The inhalation of cigarette smoke results in the rapid absorption of nicotine. There is also considerable evidence.42 a topic to be revisited (see below).40 Smoking facilitates every facet of this disease process and it is this that will be considered in some detail. provide nitric oxide directly to the vascular smooth muscle cells to bypass the endothelium and stimulate endothelium-independent vasorelaxation. even within 12 months of smoking cessation.41 This loss of endothelium-dependent responses is probably the earliest manifestation of injury to the endothelium caused by smoking. These catecholamines bind to ␣1-adrenergic receptors on vascular smooth muscle to cause muscle contraction and vasoconstriction. the effects of nitric oxide to prevent platelet aggregation. including guanylate cyclase in smooth muscle and platelets.48 Cellular events in the development of atherosclerotic or inflammatory vascular disease Impaired production of vasodilators nitric oxide and prostacyclin is but one manifestation of injury to the endothelium Downloaded from vmj. high concentrations of the antioxidant vitamin C improve the endothelial dysfunction observed in the brachial artery and forearm vessels of smokers. leading to oxidative vascular injury.36 Injury to the endothelium is considered to be the earliest forerunner of atherosclerosis. 3: 21–28 ation assume greater importance. How many smokers read this journal? Do not despair.Vascular damage from smoking 23 smoking increases a person’s risk of ischaemic heart disease by one-quarter. which is expressed constitutively. including the distal aorta.37. such as sodium nitroprusside and glyceryl trinitrate. These responses to hyperaemic flow and nitrate vasodilators have been used as the basis of an in vivo assessment of endothelium-dependent responses. The accumulating evidence to associate passive smoking with an increased risk of vascular disease comes from both epidemiological studies and direct studies of endothelial function in passive smokers.44 The in vitro evidence indicates that the biosynthetic pathway to provide the nitric oxide synthase cofactor tetrahydrobiopterin is impaired in smokers.46.

2013 . Firm adhesion is then mediated by distinctive protein adhesion molecules on the endothelium (e. healthy endothelium has antiadhesive properties and the continued synthesis of nitric oxide is important in this respect. This increase in calcium concentration stimulates the synthesis of nitric oxide from l-arginine by the enzyme nitric oxide synthase (NOS).54 The concentration of leucocyte adhesion molecules (ICAM-1 and VCAM-1) on the endothelial surface also is regulated by changes in haemodynamic forces.50 Chemoattractants recruit the leucocytes to the endothelial surface. Nitric oxide is no longer available to stimulate endothelium-dependent relaxation.g. The lipid peroxides avidly bind to available nitric oxide. caused by smoking. endothelial expression of the potent monocyte chemoattractant MCP-1 (monocyte chemoattractant protein-1) is regulated by shear stress. adhesion and migration of monocytes into the subendothelial space (Figure 2). This invisible endothelial dysfunction leads directly to the recruitment of monocytes/macrophages into the arterial intima. in normal healthy endothelium the expression of adhesion molecules. 3: 21–28 shown that smoke condensate causes a rapid increase in expression of both ICAM-1 and VCAM-1 on the surface of the cultured cells.37. Using endothelial cells isolated and cultured from human umbilical vein it has been Vascular Medicine 1998. including intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM1).52 The cells have become activated and are poised to ‘grab’ any rolling leucocytes. The normal. The haemodynamic changes induced by smoking appear likely to favour the upregulation of both MCP-1 and VCAM-1. The classic response to injury hypothesis of the development of atherosclerosis has been described elegantly by Ross. The synthesis of nitric oxide also is reduced to decreased synthesis of tetrahydrobiopterin. The increased concentration of cyclic GMP triggers smooth muscle relaxation.sagepub. The increased concentration of blood-borne free radicals accelerates cellular lipid peroxidation.com by guest on June 24.38 In response to injury the adhesive properties of the endothelium change in a manner that supports the recruitment.24 JT Powell Figure 1 Smoking impairs endothelium-dependent relaxation of vessels.49 Leucocyte recruitment at the vessel wall is a multistep process. smoking is likely to effect more extensive changes of the endothelial surface than can be observed non-invasively with changes in brachial or femoral artery diameter in response to hyperaemic flow. (Left) The immediate response of healthy endothelium to an increase in blood flow (and other physiological stimuli) is an increase in intracellular calcium. on the endothelium is very low. There is evidence to indicate that endothelial cells Downloaded from vmj. itself synthesized in endothelium. Again. More extensive arterial injury leads to endothelial denudation. important in the recruitment of monocyte/macrophages.55 Similarly. (Right) Smoking limits the endothelial synthesis of nitric oxide in two (or more) ways. The nitric oxide diffuses out of the endothelium to bind to the Fe2+ in the haem moiety of guanylate cyclase to stimulate the synthesis of cyclic GMP. This migration of monocytes is orchestrated by cytokines and fuelled by the oxidation of LDL. smoking alters the haemodynamic forces at the blood–endothelial surface. where they roll along the endothelium with loose interactions between proteins and glycoproteins on the two cell types. ICAM-1 and VCAM-1) and activated integrins on the leucocyte. Therefore.53 In addition.15.51 With the diminished production of endothelial nitric oxide in smokers (see above) these anti-adhesive properties are lost. Yet again vitamin C may have beneficial effects to prevent the increased adhesiveness of monocytes in smokers. both directly and indirectly through effects on blood rheology. Essential cofactors for this activity include tetrahydrobiopterin.

Vascular Medicine 1998.57 Again. 2013 . myocardial infarction and stroke. macrophages and smooth muscle cells proliferate. The variety of free radicals generated by tobacco combustion exacerbate this process further by provoking the oxidation of LDL. which show that platelets isolated Downloaded from vmj. These cells also engulf oxidized LDL. continuously stimulated by smoking. The cholesterol crystals of the atherosclerotic plaque are the gravestones of these cells. has pleiotropic effects to exacerbate the cellular changes critical to the development of atherosclerosis.49 This atherosclerotic lesion is both living and dying.Vascular damage from smoking 25 Figure 2 Smoking stimulates monocyte adhesion. which may stabilize the atherosclerotic plaque. The atherosclerotic lesion has started to develop. As discussed above. The altered shear stress at the endothelial surface induced by smoking and the absorbed products of tobacco combustion have synergistic effect to increase the expression of leucocyte adhesion molecules (ICAM-1 and VCAM-1) on endothelium.59 Both these changes. thromboxane A2. Hence. observed in vivo. The endothelium becomes leaky. the latter secreting a connective tissue matrix. which acts as a mitogen for smooth muscle cells. Smoking has particular effects on platelets and coagulation factors. the anti-oxidant vitamin C has been found to interrupt this process. appear to be initiated by instability in the atherosclerotic plaque to favour the development of an acute thrombus. In response to the elaboration of growth factors and cytokines. to form foam cells. which promote the development of thrombosis. The alterations of shear stress induced by smoking also may stimulate the release of monocyte chemoattractants.sagepub. which occludes the vessel locally or more distally by embolization. There is a shortened half-life of platelet survival in the apparently healthy smoker. which activates the migrated monocyte/macrophages to release cytokines and growth factors to attract more cells (smooth muscle cells and macrophages) to migrate and proliferate in the intima.58 Through analysis of urinary prostanoid metabolites it has been demonstrated that chronic smoking causes an increase in the principal platelet product of arachidonic acid metabolism. through its ability to modulate nitric oxide production. Thrombosis at the injured vessel wall Critical atherosclerotic events. are ‘lost’ into the circulation in response to smoking. by diminishing the oxidation of LDL. permitting the entry of oxidized LDL (oxLDL). smoking may initiate endothelial denudation. The very avidity of these cells in taking up oxidized LDL fuels the cycle of inflammatory cytokine release. exposing the underlying matrix to promote platelet adhesion and diminish the amount of platelet nitric oxide production to remove protection against aggregation. but also eventually causes cell death. alter haemodynamic forces at the vessel wall.com by guest on June 24. 3: 21–28 increase the adhesivity of endothelium and generate free radicals to promote the oxidation of LDL. Reduced nitric oxide synthesis also increases the adhesiveness of the endothelium. would suggest that smoking is associated with a heightened sensitivity of platelets to activation and aggregation.19 Smoking.56 The exposed collagen of the subendothelial matrix supports platelet adhesion and aggregation. migration and activation. The aggregated platelets secrete potent paracrine factors including platelet derived growth factor (PDGF). smoking has initiated a self-propagating pathway of disease and destruction. taken up through the now leaky endothelium. With the migration of monocytes into the intima and the secretion of smooth muscle cell mitogens the scene has been set for the development of a traditional atherosclerotic lesion. These findings contrast with in vitro experiments.

All the scientific evidence suggests that a high intake of vitamin C can ameliorate or abolish the smoking-induced endothelial dysfunction and the imbalance in anti-oxidants.63 Both factor VII and fibrinogen are critical to the development of fibrin clot on the surface of damaged endothelium and atherosclerotic plaque.64. long before acute thrombosis on the damaged vessel becomes problematic.62 Fibrinogen also is a risk factor for other forms of vascular disease. with a rare polymorphic variant of the endothelial nitric oxide synthase gene (ecNOS4a) are over-represented in patients found to have severe stenotic lesions on coronary artery angiography.78.sagepub. rather than Mediterranean south-east Europe.com by guest on June 24. inflammatory cell recruitment and the development of the atherosclerotic plaque.75 Smokers Vascular Medicine 1998. However. such as the possible effects of carbon monoxide on endothelial permeability and vasospasm or interactions between smoking and homocysteine. The author would like also to acknowledge all those whose work she has read.30. Equally. There is. Perhaps the answer to this paradox is to be found in the interaction of smoking with genes. the most significant effects of smoking being found in north-west Europe. Smoking increases the plasma concentration of fibrinogen but appears to have little effect on the concentration of factor VII. even teenage smokers. There is strong evidence to suggest that the dietary habits of smokers are different from those of non-smokers. The interaction between polymorphisms in the apolipoprotein and cholesterol ester transfer protein genes has important effects. 2013 .66–68 Hence. Therefore it is not surprising that there are several Scottish studies to show that smoking is associated with a reduced intake/plasma concentration of antioxidants and unsaturated fatty acids.76 These findings are probably only the tip of an iceberg: the environmental–genotype interactions may predict which smokers will develop early onset and severe vascular disease.61 The identification of increased plasma concentrations of fibrinogen and factor VII as major risk factors for ischaemic heart disease must be credited to the Northwick Park Heart Study. promoting the adhesion of leucocytes to activated endothelium and stimulating the release of inflammatory cytokines (MCP-1 an IL-8) from cultured endothelial cells. given the diverse mechanisms whereby smoking potentiates the development of vascular disease it is difficult to envisage the production of a safe cigarette.80. including the occlusion of venous bypass grafts and restenosis after coronary artery angioplasty. Other factors influencing the toxic effects of smoking on the vasculature With the number of toxins delivered into the lungs and absorbed into the circulation of cigarette smokers it is surprising that some committed smokers live so long in apparent rude good health.79 The altered dietary patterns of smokers also are likely to favour large swings in insulin secretion. Smokers eat less frequently than non-smokers and eat more sugar and animal fat than non-smokers. the meta-analyses show that cholesterol concentrations are raised in smokers.74.81 These cumulative interactions between diet and smoking all feedback on the mechanisms discussed above to favour the development of endothelial dysfunction. increasing recognition is being given to the role of fibrin(ogen) as an inflammatory mediator. an important factor in the development of atherosclerosis. but not cited.82–84 Until evidence becomes available the best advice to a smoker remains ‘stop smoking’. Genetic background There is accumulating evidence for strong smoking–genotype interactions.69 As the atherosclerotic disease progresses from fatty streak to raised lesion. the effect of smoking to increase plasma fibrinogen concentrations and activate platelets in vivo is important in accelerating all future stages of disease progression.77 Smokers have a lower intake of polyunsaturated fat and anti-oxidant vitamins than nonsmokers.71–73 In the presence of specific genotypes. with its exposed tissue factor.64 The role of fibrinogen to increase blood viscosity is well established. diet and other lifestyle factors. where all the vascular toxins had been removed. no evidence from clinical trials that vitamin C (or vitamin E) supplementation reduces cardiovascular events. Diet Demographic evidence underscores the contribution of diet to the development of atherosclerosis.65 Cessation of smoking is associated with a slow but steady reduction of plasma fibrinogen concentrations. smoking acts to increase the plasma concentration of cholesterol and lower the concentration of high density lipoprotein. There is no doubt that smoking damages the vasculature. as yet. 3: 21–28 Downloaded from vmj. Other evidence shows that persons of specific fibrinogen genotype.70 Therefore. This role of fibrinogen as an inflammatory mediator might underlie the recently reported association between fibrinogen concentration and intimal thickening of the carotid arteries. the increased flow through stenotic areas exacerbates the deposition of both platelets and fibrinogen at the apex of the stenosis. both changes being pro-atherogenic. achieving a reduction of ෂ5% after 5 years of abstinence. Other aspects of smoking toxicity. in the presence of endothelial dysfunction. Conclusion This review has focused on how smoking impacts on and potentiates the mechanisms at three separate stages of the development of vascular disease (atherosclerosis): 1) endothelial dysfunction 2) monocyte recruitment and development of the plaque 3) thrombosis at the damaged vessel wall.70 Fibrin(ogen) deposition is also prominent in the thrombus area so often observed adjacent to discrete stenoses. who choose to smoke.26 JT Powell from smokers have a diminished sensitivity to activation in response to agonists such as ATP.60.77 Within Europe there will be a gradient in these differences. Further. the action of smoking to increase plasma fibrinogen concentrations will favour the recruitment of inflammatory cells into the vessel wall to stimulate the development of atherosclerosis. will show accentuated elevation of plasma fibrinogen concentrations.

114: 454–60. 10 Benwell MEM. 315: 717–20. Grundy SM. Tognoni G. Voldby B. 39 Strong JP. Poulter NR. Yano K. 3: 21–28 Downloaded from vmj. Intimal ultrastructure of human umbilical arteries. 36 Celermajer DS. Peto R. IARC Sci Publ 1991. Yin Y. Magyarosy I. Preussmann R. 314: 488–500. Br Med J 1989. Circulation 1996. 37 Ross R. Atherosclerosis 1996.Vascular damage from smoking 27 References 1 Phillips DH. Dain R. 3 Kiryluk S. Arterioscler Thromb Vasc Biol 1996. Powell JT. Riemersma RA et al. 46 Celermajer DS. ˇ´ 45 Cosentino F. 81: 341–47. 44 Ichiki K. Sorensen KE. 8 Benwell MEM. 347: 31–36. Lancet 1994. J Neurochem 1988. Haugartner J. Lancet 1992. Powell JT. Folts JD. Miller RH. Haapanen A et al. 382: 255–57. Tanda G. 119: 139–50. Stewart CM. 129: 41–48. Santoro L. Orzi F.com by guest on June 24. 11: 487–92. 65: 485–87. J Smoking Relat Dis 1995. 11: 135–41. 2013 . Smoking impairs the activity of endothelial nitric oxide synthase in saphenous vein. Role of oxidized LDL. 36: 579–89. 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