Nicotine Addiction and Coronary Artery Disease

Current Pharmaceutical Design, 2010, 16, 000-000

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Nicotine Addiction and Coronary Artery Disease: Impact of Cessation Interventions Oliver Gaemperli1 Riccardo Liga1,2 Paul Bhamra-Ariza1 and Ornella Rimoldi1,3 1

MRC Clinical Sciences Centre and National Heart and Lung Institute, Hammersmith Hospital, Imperial College, London, United Kingdom, 2Scuola Superiore Sant’Anna, Pisa, 3CNR, Institute of Clinical Physiology, Pisa, Italy Abstract: Cigarette smoking is the leading preventable cause of death worldwide, and a considerable proportion of smoking-related fatalities are attributable to coronary artery disease (CAD). The detrimental effects of smoking span all stages in the development of CAD ranging from the early functional alterations in the endothelium and the microcirculation to the late clinicopathological manifestations of atherosclerotic plaques. Smoking results in the generation of free radicals and increased oxidative stress which plays a central role in the pathogenetic mechanisms leading to atherosclerotic disease. It causes reduced nitric oxide bioavailability and lipid peroxidation which are crucial initial steps of plaque formation. Furthermore, smoking enhances leukocyte and platelet activation and promotes local and systemic inflammation, which contribute to plaque progression and maturation. Finally, alterations in fibrinolytic and prothrombotic factors create a pro-thrombogenic environment which harbours the risk of plaque rupture and thrombosis. In smokers, the cessation of smoking is the most important intervention for cardiovascular risk reduction. Total mortality can be reduced by 36% which is comparable to established modern secondary preventive therapies. Nonetheless, non-aided cessation attempts are notoriously poor with a success rate of less than 10%. Patient counselling and pharmacological therapies are important aides for smoking cessation and can improve success rates by two to threefold. However, there is still need for improved strategies of smoking cessation to reduce the high socioeconomic impact of smoking. Keywords: ??????????????????????????

smoking cessation,

INTRODUCTION In 1964 the Surgeon General’s first report concluded that smoking was a definite cause of cancer of the respiratory tract and chronic bronchitis [1]. Later reports stated that smoking causes a number of other diseases such as cancer of the bladder, oesophagus, mouth and throat; cardiovascular diseases, and reproductive effects. More than 40 years later, we have now clear evidence that tobacco smoking is the leading preventable cause of death [2]. Physicians across the world are faced every day with the devastating consequences of tobacco smoking. Cigarette smoking is responsible for about one in five deaths every year [3], and on average, smokers die 13 to 14 years earlier than non-smokers [2]. Worldwide, tobacco consumption causes more than 5 million deaths per year and current trends suggest an increase to more than 8 million deaths/year by 2030 [4]. Moreover, cigarette smoking represents a major socioeconomic burden: In the United States, the economic toll related to tobacco amounts to $193 billion, which is evenly split between health care expenditures and costs from lost productivity [3]. Approximately one third of tobacco-related fatalities are attributable to cardiovascular disease, amongst which ischemic heart disease is by far the most common. In fact, smoking triples the risk of dying from heart disease among middle-aged men. Based on these epidemiological evidence, tobacco smoking is nowadays considered a major risk factor for atherosclerosis and coronary heart disease (CHD) and an overwhelming number of studies has sought to eludelete cidate the mechanisms by which smoking contributes to the develparenthesisopment of cardiovascular disease [5]). The detrimental effects of smoking span all stages of cardiovascular disease, ranging from early functional alterations of endothelial and microvascular function to the overt clinical manifestations of CHD (Fig. 1). In this review, we aim at presenting an overview of the current literature linking tobacco smoking to CHD, the effects of smoking on endothelial and microvascular function, the cross-link with other cardiovascular risk factors (arterial hypertension, diabetes mellitus and dyslipidemia), and its role in the development of coronary *Address correspondence to this author at the MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, United Kingdom; Tel: +44 20 8383 3186; E-mail: [email protected]

nicotine replacement,

artery disease (CAD). The effects of smoking are reversible and cessation can lead to a partial or complete normalization of cardiovascular risk through a halt or regression of specific pathophysiological processes. Finally, we outline the therapeutic strategies for smoking cessation and their relative impact in clinical practice. EFFECTS OF SMOKING ON ENDOTHELIUM AND MICROCIRCULATION Endothelial and microvascular dysfunction are present early in the course of cardiovascular disease and, albeit often coexisting with CAD, tend to precede the apparent structural and clinicopathological manifestations by many years (Fig. 1) [6]. Endotheliumdependent vasomotion and microvascular function contribute to different extents to the regulation of myocardial blood flow and have been shown to be independently associated with CHD risk [710]. A large body of evidence shows that tobacco smoking is associated with impaired endothelium-dependent and microvascular vasodilator function therefore contributing to an increased risk of insert "as" CHD in smokers [11-19]. The endothelium regulates vascular tone by releasing either vasodilator substances like nitric oxide (NO), prostacyclin and endothelium-derived hyperpolarizing factor (EDHF) or vasoconstricting agents such thromboxane A2 and endothelin (Fig. 1) [20]. The balance between vasodilating and vasoconstricting factors determines endothelium-dependent vasoreactivity and can be impaired by cardiovascular risk factors such as dyslipidemia, hypertension, diabetes and tobacco smoking. In addition to its detrimental effect on coronary vasoreactivity, dysfunctional endothelium also acts by releasing a number of prothrombotic (von Willebrand factor, tissue factor and plasminogen activating inhibitor factors (PAI-1 and -2)), promoting peroxidation of LDL particles, attracting inflammatory cells and stimulating smooth muscle cell proliferation, thereby promoting atherosclerotic plaque formation and progressive adverse remodelling of the coronary arteries [21]. Tobacco smoke contains more than 4000 different substances and an amount of free radicals that has been shown to reach the number of 1015 units per cigarette puff [5]. Nicotine, the source of tobacco addiction, carbon monoxide and polycyclic aromatic hydrocarbons, components of tobacco tar, have been independently shown to induce endothelial dysfunction [22]. The detrimental ef-

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© 2010 Bentham Science Publishers Ltd.

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Fig. (1). Endothelial damage leads to impaired endothelium-dependent vasodilatation (decrease of eNOS endothelial nitric oxide synthase; PGI2S prostacyclin), and increase of vasoconstriction through increase of ET-1: endothelin and Thromboxane A2. Oxidative damage leads to transmigration of PMN. After entering the subendothelial space the PMN activate into macrophages; activated macrophages cumulate cholesteryl fatty acids esters forming foam cells. Macrophage apoptosis/necrosis form extracellular pools of lipids: NC necrotic core. Smooth muscle cells proliferate and migrate from the media to the intima and produceby matrix producing cells and the fibrous cap (FC). "radical"

fect of smoking on the endothelium is primarily caused by a dose dependent pro-oxidative effect of the components present both in tar and gas phase smoke [5]. Both phases contain a relevant quantity of free radicals: reactive oxygen species (ROS) and radicals of organic nature, which can form the highly reactive hydroxyperoxide (OH•) radical (Fig. 2) [23]. Peroxynitrite (ONOO• ), a highly reactive radical with strong cytotoxic activity, forms from the reaction of NO with the superoxide anion (O2•–) (which directly originates from tobacco smoke), thereby contributing directly to a reduced bioavailability of NO [24]. Experimental observations in humans

show that even smoking a single cigarette temporarily increases oxidative stress which can be quantified by significant reductions in serum antioxidant levels (ascorbic acid, methionine, cysteine, and uric acid), and in turn decreases concentrations if nitrite and nitrate, indices of NO concentration [25]. Nicotine itself also contributes to increased oxidative stress in smokers [26, 27] and can cause endothelial dysfunction, although to a lesser extent than smoking a cigarette with the same nicotine content [28]. Moreover, nicotine has been demonstrated to increase both superoxide and peroxynitrite concentrations [28, 29], and in-

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Nicotine Addiction and Coronary Artery Disease: Impact of Cessation Interventions

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insert ")" Fig. (2). The fraction of polinuclear quinones and semiquinones escaping the cigarette filter can solubilize in the lung-lining fluid and lead to the formation of O2.- (superoxide anion radical) by redox cycling. ROS (Reactive Oxygen Species O2.- ; H2O2 hydrogen peroxide, .OH hydroxyl radical; ) and RNS (Reactive Nitrogen Species NO. nitric oxide; ONOO- peroxynitrite) are generated endogenously. When the concentration of nitric oxide rises to micromolar concentrations it can compete with superoxide dismutase due to its rapid rate constant. Peroxynitrite is particularly toxic due to its remarkable stability as an anion.

terferes with ATP-sensitive potassium channels in vascular smooth muscle cells, thus contributing to a reduced vasodilatory response via an alternative NO-independent mechanism [26]. Nicotine, at the same plasmatic concentration present in smokers’ plasma affects the expression of a variety of genes, thereby increasing mRNA levels of eNOS, angiotensin-I converting enzyme, tissue-type plasminogen activator (t-PA), PAI-1, vWF, and vascular cell adhesion molecule-1 (VCAM-1) [30, 31]. These proteins play pivotal roles in the regulation of vascular tone and thrombogenicity and their altered expression by nicotine may tip this balance in favour of reduced vasorelaxivity and a prothrombogenic environment. A recent in vitro study in which monolayers of human umbilical vein endothelial cells (HUVECs) were incubated with serum from smokers and nonsmokers found that impaired endotheliumdependent vasodilatation in smokers correlated well with reduced levels of basal and stimulated NO production, and increased levels but lower activity of endothelial NOS from HUVECs [12]. Similarly, in a rat model cigarette smoke caused reduced endotheliumdependent vasodilatation and promoted vascular inflammation by increasing vascular mRNA expression of pro-inflammatory cytokines like IL-1, IL-6 and TNF- and inducible NO synthase (iNOS) as well as the activation of NF-B [32]. Vasomotor function was normalized after administration of the inhibitor of NAD(P)H oxidase apocynin, and cytokine levels and NF-B returned to baseline after apocynin or catalase indicating that ROS released from cigarette smoke play an important role in the pathogenesis of endothelial dysfunction. Further evidence is found in an in vitro study, in which human coronary artery endothelial cells (HCAECs) were incubated with serum from 10 nonsmokers and 15 smokers with or without the addition of either superoxide dismutase (SOD), SOD plus catalase, or tetrahydrobiopterin. HCAECs incubated with smokers’ serum showed significantly lower NO production, and endothelial NO synthase (eNOS) activity, but higher eNOS expression than nonsmokers. The addition of SOD, SOD plus catalase, or tetrahydrobiopterin to smokers’ sera significantly increased NO levels and eNOS activity [33]. Ex vivo, the detrimental effects of smoking on endothelial function and NO biosynthetic pathways appear to be independent of smoking frequency. In an in vitro study

using confluent monolayers of HUVECs, sera from light smokers (1 pack/week) induced similar levels of basal and stimulated-NO production, eNOS protein, and eNOS activity, despite higher serum concentrations of cotinine (the principal metabolite of nicotine) in heavy smokers [34]. Smoking has a negative impact on both the large epicardial arteries and the microcirculation. In humans, studies with highresolution ultrasound have shown increased wall thickness of the brachial artery [35] (a finding which is independently correlated with the presence of CAD [36], and reduced flow-mediated dilation [11-13, 35] in habitual smokers compared to healthy non-smokers. A direct observation of the inhibition of NO-mediated vasodilatation was confirmed by the blunting of the vasodilator response induced by intracoronary infusion of acetylcholine in smokers [14, 15]. In a large study involving 881 patients, intracoronary Doppler ultrasound flow measurements demonstrated significantly lower acetylcholine-induced hyperaemia in smokers compared to nonsmokers (50% vs. 81%) [37]. The coronary flow reserve (CFR) in the left anterior descending artery declined significantly from 2.8±0.56 to 2.31±0.51 after smoking light cigarettes (measured by nicotine and tar content in the cigarette), and, similarly, from 2.8±0.56 to 2.21±0.45 after smoking regular cigarettes [38]. Positron emission tomography (PET) using or 15O-labelled water or 13N-NH3 is the gold standard for noninvasive assessment of myocardial perfusion and microcirculatory function [39]. In contrast to intracoronary Doppler techniques which measure coronary flow velocity, PET has the ability to measure myocardial perfusion in mL\min\g of myocardium. In the absence of coronary stenoses, PET perfusion provides a reliable assessment of microcirculatory function [6]. In a recent investigation using 13N-NH3 and PET, Campisi et al. showed that cold pressor test (CPT)-induced myocardial blood flow increase was blunted in smokers (15%) compared to non-smokers (34%) [40], and could be normalized with the administration of the natural substrate of NOS L-arginine [41]. Kaufmann and colleagues demonstrated that CFR measured with 15O-labelled water was reduced by 21% in smokers compared to controls. CFR was normalized in smokers after intravenous ad-


ministration of Vitamin C, which lends further support to the hypothesis that the pro-oxidative effect of smoking is a major cause for impairments in coronary hemodynamics [19]. Similarly, using PET, Schindler and co-workers highlighted the heterogeneous response of endothelium-dependent vasodilatation to acute and long term administration of vitamin C [42]. At baseline, myocardial perfusion during CPT revealed a markedly blunted increase of peak myocardial blood flow (MBF) in hypertensive and hypercholesterolemic patients as well as chronic smokers, compared with the control group. Smokers showed a marked and sustained improvement of peak MBF both after acute and chronic administration of vitamin C, hypertensive patients improved MBF only on the long term, whereas no change was detectable in hypercholesterolemic patients. MBF responses to both endothelium-dependent and independent mechanisms are improved by antioxidants in smokers. Furthermore, vitamin C has an inhibitory effect on platelet aggregation associated with an improvement of arterial vasomotion suggesting that the beneficial effects of vitamin C may also impact on uncoupled and dysfunctional eNOS in the platelets of chronic smokers. SMOKING AND ATHEROSCLEROSIS: THE COMBINED EFFECT OF SMOKING AND OTHER CV RISK FACTORS The endothelial dysfunction caused by tobacco smoking can, in itself, induce and aggravate at different stages the atherosclerotic process that over time will result in formation of an atherosclerotic plaque and vessel remodelling (Fig. 1). There is general agreement in studies employing various imaging techniques about the close association of smoking with atherosclerosis in several arterial beds [43-50]. Smoking is an independent predictor for the evolution of new coronary lesions [46], and on the other hand, smoking cessation slows the pace of progression of atherosclerotic lesions compared to chronic smokers [50]. During plaque formation, low density lipoprotein (LDL) particles accumulate within the intimal layer of the vascular wall. Circulating free radicals originating from tobacco smoking can oxidize LDL forming oxLDL, which is more toxic to the endothelium and microcirculation than native LDL [24, 51]. Bioactive phospholipids released from dysfunctional endothelium up-regulate the expression of intracellular adhesion molecule (ICAM-1), VCAM-1 and endothelial cell-leukocyte adhesion molecule (ELAM-1) facilitating entry of inflammatory-immune cells into the vessel wall intima [52]. Furthermore, nicotine causes macrophage activation and enhances the production of proinflammatory cytokines through activation of NF-B [53]. Smoking concurs with other major cardiovascular risk factors such as diabetes, hypertension and dyslipidemia to induce and accelerate the development of coronary atherosclerosis [54, 55]. Acting in a vicious cycle, smoking predisposes to the development of the other cardiovascular risk factors. Cigarette smoking is associated with an increased risk of type 2 diabetes in both genders, with a relative risk ranging from 1.4 to almost 2 in heavy smokers (more than 25 cigarettes per day) compared to non-smokers [56]. In patients with type 1 diabetes, larger insulin doses are needed to achieve similar glucose control in smokers compared to nonsmokers [57], and smoking was shown to be more common in patients with higher HbA1c levels in insulin dependent diabetics [58]. In non-diabetic individuals tobacco consumption is correlated with HbA1c levels indicating a deleterious effect on glucose metabolism in apparently healthy subjects [56]. PET studies using the glucose analogue 18F-fluorodeoxyglucose (FDG) have demonstrated that under standardized metabolic conditions with hyperinsulinemic euglycemic clamping myocardial glucose uptake was 40% lower in non-diabetic smokers compared to non-smokers [59]. Patients with type 1 and type 2 diabetes are particularly susceptible to the adverse effects of tobacco. In large diabetic cohorts, smoking was significantly associated with an increased risk of CAD, stroke, and pe-

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ripheral vascular disease. Compared to non-smoking diabetics, smoking of 15 to 34 cigarettes per day increases overall mortality by 64%, and smoking more than 34 cigarettes per day by 119% in women [60]. Obesity and dyslipidemia are also closely related to smoking habits. In the short term, nicotine increases energy expenditure and reduces appetite, which may explain why smokers tend to have lower body weight. Conversely, chain smokers tend to have greater body mass indices than light smokers or nonsmokers [61], which can be reversed to normal if long-term abstinence is achieved [62, 63]. Smokers have significantly higher serum triglyceride levels, lower high-density lipoprotein (HDL) cholesterol, a higher proportion of atherogenic small dense LDL particles than control subjects. A meta-analysis combining 56 published reports found a dose effect between the number of cigarettes smoked and the changes in lipoprotein profile. Progressive increases in total cholesterol (0, +0.8, +4.3 and +4.5%), triglycerides (0, +10.7, +11.5 and +18.0%), very low density lipoprotein (VLDL) (0, +7.2, +44.4, and +39.0%), and LDL (0, 1.1, 1.4 and +11.0%) and a progressive decrease in HDL (0, 4.6, 6.3, 8.9%) were observed as smoking frequency increased from none to heavy [64]. One mechanism identified as responsible for increased triglyceride levels is reduced lipoprotein lipase (LPL) activity which is decreased in skeletal muscle of smokers. LPL is regulated by insulin, and smoking-induced insulin resistance can lead to reduced LPL activity thus worsening circulating triglyceride levels. Arterial hypertension is also closely related to smoking habits. Nicotine can act as an indirect sympathomimetic agent by facilitating the local release of vasoactive catecholamines [65] manifested by the acute blood pressure rise seen after smoking a cigarette [66]. Nicotine-induced cardiovascular effects are mainly due to stimulation of sympathetic neurotransmission, as nicotine stimulates catecholamine release by an activation of nicotine acetylcholine receptors localized on peripheral postganglionic sympathetic nerve endings and the adrenal medulla. The nicotinic acetylcholine receptor is a ligand-gated cation channel with a pentameric structure and a central pore with a cation gate, which is essential for ion selectivity and permeability. Binding of nicotine to its extracellular binding site results in the influx of sodium and calcium ions. The resulting depolarization of the sympathetic nerve ending stimulates calcium influx through voltage-dependent N-type calcium channels, which triggers the nicotine-evoked exocytotic catecholamine release [67]. Excitatory nicotinic receptors are located on peripheral chemoreceptors both in the carotid arteries and the aorta, and their activation increases blood pressure and heart rate [66]. The radial augmentation index of aortic pressure wave reflection and central blood pressure are higher in habitual smokers compared to non-smokers or former smokers, although brachial systolic pressure may be similar among these groups [68]. Notwithstanding the harmful effects of smoking, the increase of blood pressure observed with acute cigarette smoking may not be sustained over time. Surprisingly, in a large cohort of 8170 healthy male employees at a steel manufacturing company, smoking cessation itself resulted in increasing systemic blood pressure, and even hypertension through an unknown mechanism [69]. SMOKING AND CORONARY PLAQUE STABILITY Tobacco smoking not only promotes the development of atherosclerosis, but also induces plaque destabilization such as plaque rupture or erosion, conditions capable of triggering acute coronary events [70]. Rupture-prone plaques have been linked to a number of morphologic (thin fibrous cap, large lipid-rich necrotic core) and functional (intrinsic thrombogenicity, intraplaque inflammation) plaque features [71, 72]. Intraplaque inflammation plays an important role in the progression and destabilization of coronary plaques [73] and inflammatory infiltrates rich in macrophages and lymphocytes are found


in the majority of ruptured plaque leading to cardiac death [74]. Long-term cigarette smoking induces a systemic inflammatory response shown by a dose-dependent increase in total white blood cell counts, driven mainly by a rise in polymorphonuclear cells (PMN) [55, 75]. Smoking induces the expression of high concentrations of L-selectin on the membranes of PMNs’, a protein that initiates adherence of PMN to the endothelium [55]. Smokers also have higher levels of circulating inflammatory markers such as Creactive protein (CRP), IL-6, TNF-, soluble-intercellular adhesion molecule-1 (sICAM-1), and fibrinogen than non-smokers [76-79]. The population-based Prevention of Renal and Vascular Endstage Disease (PREVEND) study, a 6-year follow-up study, has clearly established the link between systemic inflammatory markers and cardiovascular risk by demonstrating that increased levels of highly sensitive CRP were associated with high-risk angiographic features and progression of plaque during follow-up [80]. Activated mast cells are abundant in human atherosclerotic plaques and contribute to the immune-mediated plaque destabilization. Mast cells have been identified in the shoulder regions of coronary plaques at sites of plaque erosion, rupture or haemorrhage [81]. Mast cells can secrete serine proteases, like chymase and tryptase, which activate caspase-8 and caspase-9, two key effector molucules in the apoptosis cascade. Cigarette smoking induces overproduction of chymase and tryptase, and chymase in particular promotes apoptosis of vascular smooth muscle cells and increases the levels of inflammatory markers [82-84]. The central role of monocytes in the pathogenesis of atherosclerotic lesions is highlighted by a 7-year follow up study, in which the monocyte count was an independent predictor, along with systolic BP and total cholesterol, of novel plaque formation [85]. For every increase in one standard deviation in monocyte count, the risk of developing plaques increased by 18%. Cigarette smoking is associated with a 70% to 90% increase in adherence of human monocytes to endothelial cells, which is a fundamental step initiating the migration of blood-borne monocytes into the vascular intima and subsequent differentiation into lipid-laden macrophages [86]. Smoking affects several components involved in blood coagulation by providing an environment favourable to platelet aggregation and reduced fibrinolysis. The reduced NO-bioavailability in smokers leads to changes in the tissue factor (TF) and TF pathway inhibitor-1 (TFPI-1) pathways that consequently induce an increase in thrombogenicity [87]. In smokers’ plasma tissue-plasminogen activator (t-PA) antigen and activity are reduced [88]. HUVECs treated with smokers’ serum show a lower basal and substance P-stimulated t-PA production and a lower t-PA/PAI-1 ratio compared to controls. TFPI-1 levels and substance P-stimulated NO production are also significantly reduced in smokers [87]. Platelets are affected by smoking and exhibit increased stimulated and spontaneous aggregation [89, 90]. Additionally, smoking reduces bioavailability of platelet-derived NO and decreases the sensitivity of platelets to endogenous NO, in turn promoting activation and aggregation. Sudden cardiac death (SCD) is responsible for more than half of CAD-related deaths and is considered the most devastating consequence of acute coronary events. An 8-year follow-up study has shown a higher likelihood of SCD in smokers suffering acute myocardial infarction or stable angina compared to non-smokers [91]. In 370 smokers 30 (8.1%) experienced SCD whereas the SCD incidence was 4.6% in patients who had quit smoking and nonsmokers. On multivariate analysis, current smoking increased the SCD risk by 147%. THE BENEFITS OF SMOKING CESSATION Cessation of smoking is the most important intervention for reducing cardiovascular (CV) mortality and morbidity in smokers. A number of studies have shown that smoking cessation reduces the risk of subsequent mortality and cardiac events among CHD patients by up to 50%. In a systematic review including 12,603 smok-


ers with established CHD (i.e. either previous myocardial infarction or stable angina), smoking cessation reduced total mortality by 36% and the risk of myocardial infarction by 32% [92], which is highly comparable with risk reductions achieved with other secondary preventive therapies such as statins, aspirin, beta-blockers or ACEinhibitors. Some findings suggest that the risk of myocardial infarction (MI) among smokers declines soon after smoking cessation and normalizes within three to-five years [93,94] whereas others have suggested a longer time interval of 10-14 years [95, 96]. Other studies have found that the increased risk in cardiovascular mortality persists for up to 20 years following smoking cessation [97]. Nonetheless, the earlier smoking cessation occurs, the larger the increases gained in terms of life expectancy. Smokers who stop before middle age have a similar life expectancy as those who have never smoked [98]. Smoking cessation has been shown to be particularly beneficial in high-risk cardiac patients. In the 6547 diabetic women included in the Nurses’ Health Study, the CHD risk was greatly increased in light and heavy smokers by 66% and 168%, respectively [60]. However, CHD risk approached the levels seen in non-smoking diabetics, if women had quit smoking, underlining the importance of smoking cessation in the coexistence of insulin resistance. In the Study Of Left Ventricular Dysfunction (SOLVD) Prevention and Intervention trial [99], which included patients with left ventricular systolic dysfunction, smoking cessation for more than 2 years reduced the risk of death, hospitalisation due to heart failure and MI to the same levels than non-smokers. Overall, mortality decreased by 21% and 32% for ex-smokers of 2 years and >2 years duration, respectively, which is comparable with proven drug treatments recommended in patients with left ventricular dysfunction. Smoking cessation has been shown to play an important role in high risk patients with frequent ventricular ectopic activity and left ventricular dysfunction after acute myocardial infarction [100]. In a subset of patients who did not undergo revascularisation or thrombolysis, smoking cessation greatly reduced the incidence of arrhythmic death and was associated with a statistically significant benefit in survival. Furthermore, smoking cessation significantly improves outcome after a percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG). Patients who continue to smoke after PCI have a 44% higher risk of all-cause death than those who quit smoking [101]. Similarly after CABG, smoking cessation reduces mortality by 68% compared to continuing smokers [102]. The estimated absolute benefit of survival for the quitters increased from 3% at five years to 14% at 15 years. Besides mortality, smoking cessation also reduces the rates of MI and repeat revascularisation procedures after PCI or CABG [101, 102]. In a previous section we have described the synergistic effects of smoking on cardiovascular risk factors and the various mechanisms by which it contributes to the acceleration of atherosclerosis. Many of these mechanisms can be reversed or improved by smoking cessation. The following section outlines the beneficial effects of smoking cessation on cardiovascular risk factors and the mechanisms by which smoking cessation can slow or halt the progression of atherosclerotic disease and prevent cardiovascular events. Cessation of smoking decreases oxidative stress and thereby reduces the susceptibility of LDL to oxidation [103]. Refraining from smoking for only a few days has been shown to effectively reduce oxidative stress measured by serum und urinary levels of isoprostanes (particularly 8-epi-prostaglandin F2) which are closely associated with the formation of oxLDL [104]. Isoprostane levels continue to decrease thereafter and reach a steady state after approximately 4 weeks after smoking cessation. (8-epi- PGF2). Similarly, intracellular oxidative stress, measured by intraplatelet redox status, is rapidly reversed within two weeks of smoking cessation, and returns two baseline values if smoking is resumed [105].

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As outlined above, endothelial integrity and function is closely linked to oxidative stress. Smoking cessation rapidly improves endothelial-dependent vasomotor function dilation in ex-smokers. Venous vasomotor function is also under control from the endothelium (similar to arterial tone), and can be measured directly and in vivo by measuring changes in diameter of the dorsal hand veins. In smokers, maximal venodilation induced by bradykinin, an endothelium-dependent venodilator, was lower than in nonsmokers, but was restored to normal within 24 hours of smoking cessation [106]. Studies with PET have also shown that reduced arterial endothelium-dependent vasodilation can be reversed by smoking cessation to a magnitude comparable with nonsmokers [107]. In this study, endothelial dysfunction improved significantly at 1 month and this effect was preserved at 6 months of smoking cessation. Cessation of smoking results in an increase in HDL, whereas other lipids and lipoproteins remain unchanged [108]. Studies examining the effects of smoking cessation on HDL metabolism show that increases in HDL levels can occur in a matter of a few weeks and they remain normal for as long as smoking cessation continues [109, 110]. Higher levels of HDL are thought to be anti-atherogenic as it promotes “reverse cholesterol transport” from peripheral cells to the liver. Systemic inflammatory activity is reduced as shown by a reduction in circulating inflammatory markers (TNF-, soluble TNF receptors, soluble VCAM-1, CRP, and IL-6) after short term smoking cessation [79, 79, 111]. After a short period of smoking cessation fibrinogen levels decrease, and can be found in levels comparable to those of nonsmokers [112, 113]. Similarly, platelet aggregability is reduced thereby reducing the risk for acute thrombotic events [105]. Additionally, intraplatelet oxidative stress is decreased resulting in an improved bioactivity of platelet-derived NO which acts via a negative feedback mechanism to inhibit platelet aggregation. Smoking cessation rapidly improves not only the systemic oxidative stress but also the imbalance of intracellular redox state, resulting in improvements of bioactivity of PDNO and platelet aggregability in long-term smokers [105]. STRATEGIES FOR SMOKING CESSATION Of all components of tobacco smoke, nicotine is the most addictive substance, which is responsible for about 1.2 billion smokers worldwide [114]. The pharmacological and behavioural processes that determine nicotine addiction are similar to those of illicit drugs such as heroine and cocaine, and therefore require powerful strategies to achieve permanent abstinence. In the United States, more than 70% of smokers intend to quit smoking every year and 45% make and attempt, however less than 5% in the general population succeed in the long term [115]. Nevertheless, heartening progress has been made in tobacco control in the last 40 years. This progress is based on advances and achievements of scientists, clinicians, the public health community, health care organizations, insurers, and smokers who have successfully quit. As a consequence, in the United States, the prevalence of smokers has declined from approximately 44% in the 1960s to less than 21% today [116]. Available treatments for smoking cessation are targeted towards dealing with the physical addiction to nicotine, the psychological dependence on the effects of smoking, and the behavioural aspects of tobacco. They can be subdivided into nonpharmacological (counselling) and pharmacological (nicotine replacement therapy (NRT), non-nicotine compounds) treatments. Nonpharmacological Treatments In a general population, unaided smoking cessation attempts are notoriously unsuccessful and cessation rates are generally lower than 10% which corresponds to the cessation rates seen in the placebo arms of randomized interventional trials. Healthcare providers are in the unique position to enhance these cessation rates significantly through their interaction with the patient. Their role ranges

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from identifying tobacco dependence, assessing individual risks of smoking, personalized patient education, motivation and encouragement, to providing effective pharmacological treatment if willingness for smoking cessation is present. However, a disinclination of physicians to intervene seems to prevail across many countries and results in smoking being the most prevalent, most lethal, but most neglected addictive condition, despite effective and readily available interventions [117]. Therefore, the 2008 U.S. Public Health Service Clinical Practice Guidelines on treating tobacco use and dependence have urged clinicians to provide evidence-based counselling to all smokers and make pharmacotherapies readily available if not contraindicated [116]. Patient counselling consists of personalized motivation and education on the beneficial health effects of smoking cessation. Important components of counselling programs include problem solving and coping skills training, which consists of developing methods and coping skills on how to deal with high-risk situation for tobacco use, and providing social support as part of treatment. A recent systematic review of 33 randomized or quasi-randomized studies comparing counselling interventions to standard care revealed that “high-intensity counselling” (i.e. counselling that began during hospitalisation and included supportive contacts for more than 1 month after discharge) increased the odds of smoking cessation at 6 to 12 months (odds ratio 1.65, 95% CI, 1.44–1.90) [118]. However, no benefit was found for counselling programs with less than 1 month post discharge contact, emphasizing the importance of replace "two-threesustained psychological support for smoking cessation.

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Pharmacological Treatments three-fold" Nicotine Replacement Therapy (NRT) Pharmacotherapies for smoking cessation can increase abstinence rates by about two-three-fold [116]. NRT is available in different preparations and variable application routes and is considered a first-line treatment of nicotine addiction [119]. It is used to mainreplaces "This" by tain the effects of nicotine while reducing the addiction potential through "These" decreases in amount and speed of nicotine delivery, and may also act via desensitization of nicotinic receptors, resulting in reduced reinforcement from cigarette smoking [120]. In the Cochrane meta-analysis which included 111 randomized trials with over 40'000 participants, NRT resulted in a 58% higher abstinence rate compared to placebo at 6 months or more (Table 1) [121]. This effects was largely independent of the duration of therapy, the intensity of additional support provided, the setting in which the NRT was offered (community setting, smoking clinic, primary care, or hospital), and the type of NRT product used. In high-dependency smokers, however, nicotine gum containing 4mg of nicotine appears to be more effective than 2mg. Four randomized trials documented an 85% higher chance of smoking cessation with 4mg nicotine compared to 2mg, whereas there was no significant difference between both doses in low-dependency smokers [121]. Bupropion An alternative first-line treatment for nicotine addiction is the aminoketone antidepressant bupropion. Bupropion adresses directly the neurochemistry of nicotine addiction by blocking the reuptake of dopamine and norepinephrine and therefore increasing their concentrations in the synaptic cleft. Additionally, it has been shown to function as a non-competitive antagonist of the nicotinic acetylcholine receptor [122]. It may therefore work be blocking nicotine effects, relieving withdrawal [123] or reducing depressed mood [124]. The usual course of treatment is 7 to 9 weeks [125] and the quit attempt is generally initiated a week after starting pharmacotherapy. In a systematic review of the literature including 36 randomized trials with over 11,000 subjects, sustained release bupropion increased the odds of long term cessation by 69% compared to placebo (Table 1) [126]. If trials were grouped according to length of follow-up, 6-month cessation rates were 81% higher, and 12-month cessation rates 64% higher in the bupropion group.



Table 1. Common Pharmacological Therapies of Smoking Cessation

Drug

Mechanism of Action

NRT (nicotine Replaces nicotine in topatch, gum, bacco, desensitization of inhaler, nasal nicotine receptors spray, lozenge, microtab)

Number of RCT’s*

Number of Pooled OR (95% CI) Patients for Nicotine AbstiEvaluated* nence*

111

43,040

1.58 (1.50-1.66) [121]

Most Common side Effects

Precautions

Local irritation (skin, Cardiac disease, unstable coromouth, throat, nasal munary syndromes, peptic ulcer cosa), dyspepsia (oral prepadisease, hypertension, pregrations) nancy or lactation, hyperthyroidism, phaeochromocytoma, type 1 diabetes mellitus

Bupropion

Dopamine and norepinephrine reuptake inhibitor, non-competitive antagonist of nicotinic acetylcholine receptors

36

11,140

1.69 (1.53-1.85) [126]

Varenicline

Partial agonist of the 42 subtype of the nicotinic acetylcholine receptor

6

2,582

2.33 (1.95-2.80) [135] Nausea, vomiting, insomnia, abnormal dreams, headaches, flatulence

Renal impairment, pregnancy, unstable psychiatric disease, operation of heavy machinery

Nortryptiline

Norepinephrine and serotonine reuptake inhibitor

6

975

2.03 (1.48-2.78) [126]

Dry mouth, sedation, blurred vision, urinary retention, light headedness, cardiac arrhythmia

Cardiovascular disease, pregnancy, MAO inhibitors, operation of heavy machinery

Clonidine

2-adrenergic receptor agonist

6

776

1.63 (1.22-2.18) [142]

Dry mouth, sedation, dizziness, postural hypotension, constipation

Pregnancy

Dry mouth, insomnia, nausea

Seizure disorder, bulimia or anorexia nervosa, concomitant or recent use of MAO inhibitors

*Only trials included comparing the active drug as single pharmacotherapy to placebo Abbreviations: NRT, nicotine replacement therapy; MAO, monoamine-oxidase; RCT, randomized controlled trial; OR; odds ratio; CI, confidence interval

However, there is insufficient evidence to suggest that adding bupropion to NRT may improve cessation rates. Although bupropion may alleviate some subclinical symptoms of depression, its main mechanism of action on nicotine addiction is probably independent of its antidepressive effect [127], and subgroup analyses have failed to show any interaction of bupropion efficacy with a history of clinical depression [124]. Treatment with bupropion carries a risk of approximately 1 seizure per 1000 patients, which is increased in patients with a history of alcohol withdrawal, anorexia or head trauma. Varenicline In 2006, the U.S. Food and Drug Administration (FDA) approved varenicline for the treatment of nicotine addiction. Varenicline is a partial agonist of the 42 subtype of the nicotinic acetylcholine receptor [128], which is located in the ventral tegmental area of the brain and is believed to play a central role in the dependence-producing properties of nicotine [129]. The central 42 receptor activates dopaminergic neurons projecting to the nucleus accumbens, the site responsible for positive reinforcement, and is saturated by very low concentrations of nicotine [130] (Fig. 3). Varenicline acts by providing relief from tobacco withdrawal and nicotine craving by its agonist action and by blocking the reinforcing effects of continuing nicotine use through its antagonist action. Since its introduction, a number of phase II and III clinical trial has demonstrated its value for treating nicotine addiction [131-134]. A systematic review pooling six studies with 2,582 patients showed 133% higher rates of smoking cessation at 6 months with vareni-

cline compared to placebo (Table 1) [135]. Three trials also performed a direct comparison of varenicline with bupropion and the pooled analysis revealed superiority for varenicline with an odds ratio of 1.52 (95% CI, 1.22-1.88) at 12 months. Finally, one single open-label study has compared varenicline to NRT showing a modest benefit for varenicline (odds ratio, 1.31 (95% CI, 1.01-1.71) at 12 months [136]. In 2008 the FDA issued a warning section in the prescribing information about serious neuropsychiatric symptoms of varenicline, prompted by increased appearance of changes in behaviour, agitation, depressed mood and suicidal ideation, with or without attempted and completed suicide [137]. Although these neuropsychiatric side effects are rare, they should be carefully monitored in patients taking varenicline. Nortriptyline Nortriptyline, a tricyclic antidepressant which inhibits the presynaptic uptake of norepinephrine and serotonin, is considered a second-line agent for smoking cessation. Like bupropion, the effects of nortriptyline on nicotine addiction are thought to be independent of its antidepressive action, based on published trials showing comparable efficacy in smokers with or without depression [126]. A pooled analyses of six published randomized trials with 975 subjects comparing nortriptyline to placebo demonstrated 103% higher rates of smoking cessation with nortriptyline [126] (Table 1). However, no additional benefit of nortriptyline was noted if added to NRT (relative cessation rate, 1.29, 95% CI, 0.97-1.72). In three trials that directly compared nortriptyline with bupropion,


Gaemperli et al.

Fig. (3). Brain positron emission tomography (PET) with the 18 F-labeled ligand of the central 42 nicotinic acetylcholine receptor 2-[18F]fluoro-3-(2(S)azetidinylmethoxy)-pyridine (2-F-A-85380) at baseline (top row) and 3 hours after smoking five different cigarette doses (bottom row, cigarette doses listed) showing a dose-dependent displacement of 2-F-A-85380 by nicotine. Smoking 0.3 cigarettes (the equivalent of 3 puffs) results in more than 50% receptor occupancy. The far right column shows a magnetic resonance image (MRI) for anatomical co-localization and a PET image of nondisplaceable radioactivity distribution (calculated). Reprinted from Ref. 130 with permission of the American Medical Association Copyright © 2006 All rights reserved.

none showed any significant difference between both agents [138140], and although the pooled analysis slightly favoured bupropion, the odds ratio for smoking cessation was non-significant (1.30; 95% CI 0.93-1.82) [126]. Clonidine Clonidine was traditionally marketed as a central acting antihypertensive drug, which has been found to reduce drug and alcohol withdrawal symptoms. It acts as a selective 2-adrenergic receptor agonist which exerts an inhibitory effect on noradrenergic neuron activity and firing in the locus coeruleus thereby alleviating nicotine withdrawal symptoms such as tobacco craving, anxiety, restlessness, tension and irritability [141]. The Cochrane systematic review of six published randomized trials with 776 patients reports a 63% higher rate of smoking cessation with clonidine compared to replace "remains" placebo [142]. However, the high frequency of side effects (up to "remain" 90% in randomized trials) (Table 1) is aby common deterrent to its use for the treatment of nicotine addiction, and make this drug unsuitable as first-line pharmacotherapy. Alternative Agents, Future Directions Although available pharmacotherapies can improve smoking cessation rates significantly, the overall success rates remains fairly low at approximately 20%, leaving enough room for the development of new effective treatments. A number of other agents has been proposed to treat nicotine addiction, such as the tricyclic antidepressants doxepin and imipramine, the monoamine oxidase inhibitors moclobemide and selegiline, the selective serotonine reuptake inhibitors fluoxetine, paroxetine and sertraline, the atypical antidepressants tryptophan and venlafaxine, and the extract of hypericum perforatum (St. John's wort) [126]. However, to date no significant benefit has been reported for any of these agents in randomized trials. Other agents are currently under preclinical or clinical evaluation, amongst which some are noteworthy because of their novel mechanisms of action.

An interesting new agent is the nicotine vaccine, which stimulates the immune system to develop anti-nicotine antibodies, which prevent nicotine from exerting its dependence-generating potential in the central nervous system [143]. Interacting rather with the addictive substance in the blood than with a receptor in the brain, the nicotine vaccine has the important advantage of being free of side effects due to central interaction. A phase II study with the conjugated nicotine vaccine AMNic-rEPA (NicVAX) has shown a good safety and tolerability profile and, albeit not powered as a cessation trial, has yielded higher cessation rates with the highest vaccine dose at 200 μg [144]. To date, three compounds are considered as possible candidates for a nicotine vaccine, and at least two of them are headed towards phase III clinical trials [145, 146]. Another promising agent for the treatment of nicotine addiction is the selective cannabinoid CB1 receptor rimonabant, which is marketed in some European countries to treat the metabolic syndrome. Rimonabant reduces drug-seeking behaviour and tobacco craving by blocking nicotine-induced dopamine release in the the shell of the nucleus accumbens and the bed nucleus of the stria terminalis, which have been implicated in brain reward functions and the reinforcement actions of addictive drugs [147]. A pooled analysis of the STRATUS trials including more than 3,000 subjects showed a 50% increased cessation rate with 20mg of rimonabant compared to placebo at 1 year [148]. CONCLUSION Exposure to tobacco smoke, either active or passive exposure [149-151], produces considerable burden of disease, and its mitigation offers the benefit of improving life expectancy. Light smokers have only a small risk reduction compared with heavy smokers, indicating a flattening exposure-response function. Smoking cessation can reverse pathological mechanisms which contribute to atherosclerotic disease at different stages of disease progression and slow the formation, progression and destabilization of atherosclerotic plaques in the coronary arteries leading to a re-


duction of cardiovascular morbidity and mortality. Smoking ban policy has proven to be enforceable, with ready compliance, and overwhelming public support dispelling the belief that public places should represent bastions of smoking and socialization. ACKNOWLEDGEMENTS O.G. was financially supported by an European Society of Cardiology (ESC) research grant.

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