hostaglandins ch Lamnan

Leukotrienes and Essential Grouo UK Ltd 1992

Fatty Acids

(1992) 46, El-86

Review

Cigarette Smoking and Platelet-vessel Wall Interactions R. Lassila and K. E. Laustiola Wihuri Research Institute, Kalliolinnantie 4, SF-00140 Helsinki, Finland (Reprint requests to RL)

measuring elevated excretion of thromboxane A2 (2, 3-dinor) metabolite (TX-M) in urine by gas chromatography-mass spectrometry (9-14). FitzGerald and coworkers have demonstrated the platelet origin of TX-M by a platelet-selective low dose of acetylsalicylic acid (ASA) which blocks the cyclooxygenase enzyme (11). The increased smoking-induced excretion of TX-M could be masked with ASA for the survival time of platelets (7-10 days).

Cigarette smoking is a well-established risk factor for cardiovascular diseases both for chronic atherogenesis and its acute thrombotic complications. Smoking-induced atherosclerotic disease of the arterial wall is most prevalent in the aorta and lower limb arteries and somewhat less in the coronary arteries (1, 2). However, cigarette smoking has been established as a major risk factor for myocardial infarction even in the absence of significant coronary artery disease (3, 4). This implies direct smoking-induced thrombogenic effects. On the basis of current knowledge, cigarette smoking leads to platelet activation via direct effects on platelets and indirect effects on the arterial wall. The three key factors regulating platelet-vessel wall interactions which can lead eventually to thrombus formation are blood (especially platelets), the extent of vascular damage and rheological flow conditions (5, 6). The following is a review of evidence that cigarette smoking affects all these three factors.

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CIGARETTE SMOKING AND PLATELETS

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An acute enhancement of platelet deposition on the subendothelium in flow conditions was reported after the smoking of one cigarette by nonsmoking subjects (7). In a canine experimental model, cigarette smoke or nicotine induced acute flow reductions in a stenosed coronary artery due to thrombus formation (8). Folts, also using this model, reported that smoking-induced thrombus formation can be abolished by phentolamine, suggesting a basic role of adrenaline probably via arz-adrenergic receptors on platelet membranes. These data support the concept of acute platelet activation by smoking. A chronic effect of cigarette smoking on platelet activation has also been shown by a few studies

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There is evidence that the effects of smoking on platelets are directly or indirectly linked to enhanced arterial wall damage induced by the constituents of cigarette smoke. Cigarette smoke extracts have been shown to stimulate prostacyclin (PGI2) synthesis via calcium mobilization and to potentiate stimulatory prostaglandin release by the isolated rat aorta (15). This effect has been shown to be biphasic: stimulatory at low concentrations of cigarette smoke extract and inhibitory at high concentrations. Our in vivo evidence with identical twins discordant for smoking (12), and studies by Nowak et al (11) showed that smokers excreted an elevated amount of prostacyclin (2,3-dinor-6-ketoPGFIJ metabolite (PGI-M), in addition to TX-M (Fig. 1). Enhanced urinary TX-M and PGI-M excretion indicates that platelets have interacted with the vessel wall, as happens in unstable angina and severe atherosclerosis (16, 17). Enhanced PGI-M excretion is in accordance with smoking-induced arterial wall damage due to atherogenesis. It can be speculated that the preserved endothelium would compensate by increasing its prostacyclin production. Indeed, in our twin study the smokers had significantly more signs of atherosclerosis in their carotid arteries compared to the nonsmokers, which has been confirmed in a larger group of smokingdiscordant twins (12, 19). However, it has also been shown that a-adrenoceptor agonists are potent stimulators of endogenous PGI2 synthesis and that o-adrenoceptor antagonists inhibit noradrenalinestimulated PGI;! synthesis (20). Thus, the increased concentrations of noradrenaline seen in smokers could also contribute to the increased PGI-M excretion. This is in accordance with the potentiating effect of cigarette smoke on noradrenaline-induced PG12 synthesis by aortic tissue (15). Both pack-years for assessing the long-term effects and urinary cotinine reflecting acute smoking correlated with the excretion of TX-M, thus favouring both direct and indirect platelet-activating mechanisms (Fig. 2). Additional support for an acute direct enhancement of TXA2 synthesis comes from a study where the metabolite excretion decreased to the nonsmokers’ baseline level within 3 weeks of abstinence. After reinstituting smoking, TX-M excretion increased back to the high level of smokers recorded initially (9, 19). Along with the urinary prostanoid data uniform results have also been obtained by platelet survival studies which show that smoking shortens the lifespan of platelets (21, 22). These studies were also unable to discriminate between a direct effect on platelets or altered platelet function due to smoking-induced endothelial vascular damage. The data on platelet aggregation and platelet-derived products, such as thromboglobulin and platelet factor 4 have been conflicting. This probably reflects

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the limited sensitivity and specificity of these assays in measuring platelet activation (23). In our platelet aggregation studies the responses at rest were similar in nonsmokers and smokers (24). After submaximal exercise smokers’ platelets responded less than nonsmokers’ platelets, especially to adrenaline, and secretion of serotonin and TXB2 were subsequently diminished. Accordingly, their capacity to produce TXB2 after spontaneous clotting was diminished. The exhausted responses of platelets in vitro could be a reflection of in vivo activation (19). Despite the increased excretion of prostacyclin platelets were not desensitized to it. The responses to prostacyclin in terms of platelet aggregation and production of cyclic AMP were not altered in smokers (25). Smokers have elevated fibrinogen levels in plasma (26). Prospective studies have shown a direct association between plasma fibrinogen concentration and the incidence of ischemic heart disease (27). Fibrinogen contributes significantly to blood viscosity together with hematocrit, and fibrinogen is also an important ligand for platelet to platelet in-

Cigarette Smoking and Platelet-vessel

teraction. Therefore, smokers can be speculated to possess a more thrombogenic background in their plasma than nonsmokers. On the other hand, the elevated plasma fibrinogen concentration can also be secondary to vascular damage as an acute-phase reactant (28). Altogether both acute and long-term cigarette smoking induces platelet activation which can be detected by increased prostanoid excretion. Enhanced platelet-vessel wall interaction by smoking seems also to depend on secondary vascular wall damage contributed by the constituents of cigarette smoke itself, as is discussed next.

CIGARETTE WALL

SMOKING AND THE ARTERIAL

Intimal accumulation of extracellular cholesterol is one of the very early events of atherosclerosis. There is in vitro evidence that cigarette smoke exposes low density lipoprotein (LDL) to enhanced metabolism by macrophages via increasing the negative charge and peroxidative modification (29, 30). In animal models, cigarette smoking causes endothelial damage in the form of subendothelial edema and blebing on the luminal surface (31, 32). The permeablility of the arterial wall to fibrinogen is increased by inhaled cigarette smoke and carbon monoxide (33). Scanning electron microscopy of the surface ultrastructure of human uterine arteries and umbilical arteries and veins is also suggestive of decreased integrity of the arterial endothelium (34, 35). High circulating levels of endothelial cells in venous blood have also been reported (36). In autopsies, fibrous thickening of coronary arteries and intramyocardial small arteries are frequently seen in smokers (37). The atherosclerotic changes in coronaries tend to affect mostly the distal vessels (38). A biochemical composition of coronary endartectomy and aortic biopsy samples obtained during coronary artery bypass grafting (CABG) demonstrated that smokers had a significantly higher content of collagen in both specimens and a higher content of cholesterol in the aorta than nonsmokers (39). In addition, Oberai et al have reported that in chronic smokers coronary and renal arterioles are thickened due to increased collagen content and smooth muscle cell hyperplasia (40). In autopsy studies, aorta and peripheral arteries are shown to be strongly affected by atherosclerosis in smokers (1, 2). The great proportional increase in lesions in the abdominal aorta is consistent with the well known predisposition of smokers to aneurysms of the abdominal aorta and to peripheral vascular disease (41). In our own studies with duplexDoppler smoking co-twins had significantly more signs of atherosclerosis in their carotid arteries

Wall Interactions

83

compared to nonsmokers even in the absence of the traditional atherosclerosis-prone alterations in lipoproteins (12, 18). The increase in lesions in the coronary arteries does not seem sufficient to account for the 2-fold or greater increase in risk of coronary heart disease among heavy smokers. This fact underscores the importance of thrombogenic mechanisms in the pathogenesis of smoking-induced cardiovascular disease. Smoking, however, is strongly correlated with atherosclerosis in the abdominal aorta and peripheral lower limb arteries. One needs to appreciate and direct studies at the connection between smoking and the predilection sites of atherogenesis before the mechanisms behind the atherosclerosis related to smoking can be understood.

CIGARETTE SMOKING AND HEMODYNAMICS There is normally an outward movement of material from the lumen of arteries across the wall to adventitial lymphatics. The medial layer in thick-walled vessels may hinder this and thereby favour accumulation in the intima (42). Thus, the tone of the smooth muscle in arteries could regulate the efflux of substances from the intima. Cigarette smoking acutely increases heart rate and arterial blood pressure (43). These changes during acute smoking have been shown to increase arterial wall stiffness and reduce flow pulsatility. In coronaries, cigarette smoking causes important vasomotor influences. In patients with overt coronary artery disease smoking decreases coronary sinus blood flow and increases coronary vascular resistance independently of changes in heart rate (44). A reduced vasodilatory capacity has also been shown in the human hand, suggestive of general microcirculatory abnormality (45). One potent mechanism of smoking-induced peripheral vasoconstriction could be enhancement of sustained a-adrenergic stimulation. Winniford found that the administration of phentolamine, an a-adrenergic blocker, during smoking abolished the vasoconstrictor effects, while propranolol, a nonselective beta blocker, increased these effects (46). Smoking, by increasing catecholamines, enhances cu-adrenergic stimulation without /3-adrenergic compensation. In our laboratory, we have data that suggest that smoking reduces the number of b-adrenergic receptors on lymphocytes in a reversible manner (47, 48). This finding is in accordance with the diminished capacity of nonselective beta blockers to reduce blood pressure or adrenergic cardiac stimulation (49, 50). We have also reported renin-angiotensin

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Prostaglandins Leukotrienes

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Fig. 3 The unifying hypothesis based upon the presented findings of the thrombogenic and vasoactive effects of cigarette smoking and peripheral atherosclerosis.

activation in smokers in accordance with enhanced vasoconstrictive reactivity, increased sympathetic tone and possibility of decreased perfusion pressure of the kidneys due to atherosclerosis (51). The different susceptibility of different vascular beds to smoking-induced atherosclerosis could at least partly originate from the altered adrenergic regulation and its effects on blood flow and tone of arteries. As discussed earlier, local blood flow dynamics has an important influence on plateletvessel wall interaction and therefore the thrombotic complications of atherosclerosis. Further research should clarify what role smoking plays in secretion of the new endothelial regulators of vasotonicity, such as endothelin and endothelium-derived relaxing factor (EDRF). In conclusion, the increased cardiovascular risk associated with smoking is reversible, which emphazises the role of thrombogenic and vasoactive factors as mediators for smoking-induced cardiovascular events. The specific features of catecholamine responses to chronic smoking, desensitization of l32-adrenergic mechanisms and activation of the renin-angiotensin system suggest an increased vulnerability of peripheral conduit and resistance arteries to atherosclerosis and platelet-vessel wall interaction (Fig. 3). The multiple regulatory connections between the adrenergic system and prostaglandin metabolism in response to smoking reveal the vast potential of cir-

culatory homeostasis. Therefore, it is reasonable to speculate that smoker’s compensatory efforts might be exhausted at the moment they would really be in demand - during an acute circulatory disturbance due to arterial thrombosis. References 1. Stemby N H. Atherosclerosis, smoking and other risk factors. pp 67-70 in (Gotto, Jr. A M, Smith L C, Allen B, eds). Atherosclerosis V. Springer Verlag, New York, 1980 2. A report of the Surgeon General. The health consequences of smoking: cardiovascular disease. US Department of Health and Human Services, Rockville, MD, 1983 3. Lindsay, Jr. J, Pichard A D. Acute myocardial infarction with normal coronary arteries. Am J Cardiol54: 902-904, 1984 4. Pecora M J, Roubin C S, Cobbs W, Ellis S G, Weintraud W I, King III S B. Presentation and late outcome of myocardial infarction in the absence of angiographically significant coronary artery disease. Am J Cardiol 62: 363-367, 1988 5. Turitto V T. Blood viscosity, mass transport and thrombogenesis. pp 139-177, in Progress in Hemostasis and Thrombosis, Grune & Stratton, New York, 1982 6. Baumgartner H R, Sakariassen K S. Factors controlling thrombus formation on arterial lesions. Ann NY Acad Sci 454: 162-177, 1985 7. Pittilo R M, Clarke J M F, Harris D, Mackie I J, Rowles P M, Machin S J, Woolf N. Cigarette smoking and platelet adhesion. Br J Haematol 58: 627-632,1984 8. Folts J D, Bonebrake F C. The effects of cigarette smoke and nicotine on platelet thrombus formation

Cigarette Smoking and Platelet-vessel in stenosed dog coronary arteries: inhibition with phentolamine. Circulation 65: 465-469, 1982 9. Murrav J J. Nowak J. Oates J A. FitzGerald G A. Platelet function during smoking ‘and withdrawal. Clin Res 33: 350A, 1985 10. Fischer J, Bemutz C, Meier H, Weber P C. Formation of prostacyclin, and thromboxane in man as measured by the main urinary metabohtes. Biochim Biophys Acta 876: 194198,-1986 11. Nowak J, Murray J J, Oates J A, FitzGerald G A. Biochemical evidence of a chronic abnormality in platelet and vascular function in healthy individuals who smoke cigarettes. Circulation 76: 6-14, 1987 12. Lassila R, Seyberth H W, Haapanen A, Schweer H W, Koskenvuo M, Laustiola K E. Vasoactive and atherogenic effects of cigarette smoking - a study of monozygotic twins discordant for smoking. Br Med J 297: 955-957, 1988 13. Barrow S E, Ward P S, Sleightholm M A, Ritter J M, Dollery CT. Cigarette smoking: profile of thromboxane - and prostacyclin-derived products in urine. Biochim Biophys Acta 993: 121-127, 1989 14. Wennmalm A. Smoking induced alteration in thromboxane biosynthesis: a population study. Presented at the Winter Prostaglandin Conference. Keystone, CO, 1988 15. Jeremy J Y, Mikhailidis D P. Vascular and platelet eicosanoids, smoking and atherosclerosis. p 135-146, in Tobacco Smoking and Atherosclerosis (Diana J N ed), Plenum Press, NY, 1990 16. FitzGerald G A, Smith B, Pedersen A K, Brash A R. Increased prostacyclin biosynthesis in patients with severe atherosclerosis and platelet activation. N Engl J Med 310: 1065-1068, 1984 17. Fitzgerald D J, Roy L, Catella F, FitzGerald G A. Platelet activation in unstable coronary disease. N Engl J Med 315: 983-989, 1986 18. Haapanen A, Koskenvuo M, Kaprio J, Kesiniemi Y A, Heikkill K. Carotid atherosclerosis in identical twins discordant for cigarette smoking. Circulation 80: 10-16, 1989 19. Murray J J, Nowak J, Oates J A, FitzGerald G A. Platelet-vessel wall interactions in individuals who smoke cigarettes. pp 189-198, in Tobacco Smoking and Atherosclerosis (Diana J N ed), Plenum Press, NY, 1990 20. Jeremy J Y, Mikhailidis D P, Dandona P. Adrenergic modulation of vascular prostacyclin svnthesis. Eur J Pharmacol 114: 133-140. 1985 21. Mustard J F, Murphy E A. Effects of smoking on blood coagulation and platelet survival in man. Br Med J 1: 846-849, 1963 22. Fuster V. Chesebro J H. Frve R I. Elveback L R. Platelet survival and the’developmknt of coronary artery disease in the young adult: effects of cigarette smoking, strong family history and medical therapy. Circulation 63: 546-551, 1981 23. Hirsh J. Hyperreactive platelets and complications of coronary artery disease. Editorial. N Engl J Med 316: 1543-1544,1987 24. Lassila R, Laustiola K E. Physical exercise provokes platelet desensitization in men who smoke cigarettes - involvement of sympathoadrenergic mechanisms - a study of monozygotic twin pairs discordant for cigarette smoking. Thromb Res 51: 145-155,1988 and 25. Lassila R. The platelet aiadrenoceptor prostacyclin sensitivity are not altered by cigarette smoking - a study of monozygotic twin pairs discordant for smoking. Thromb Res 54: 339-348, 1989 26. Meade T, Imeson J, Sterling Y. Effects of changes in smoking and other characteristics on clotting factors and the risk of ischaemic heart disease. Lancet 2: 986988.1987 27. Cook N S, Ubben D. Fibrinogen as a major risk factor in cardiovascular disease. TiPS 11: 444451, 1990.

Wall Interactions

28. Meade T W. The epidemiology of hemostatic and other variables in coronary artery disease. pp 37-60, Thrombosis and Haemostasis 1987 (Verstraete M, Vermylen J, Lijnen R, Amout J, eds), Leuwen, International Society on Thrombosis and Haemostasis and Leuwen University Press, 1987 29 Yokode M, Kita T, Arai H, Kawai C, Narumiya S, Fujiwara M. Cholesteryl ester accumulation in macrophages incubated with low density lipoprotein pretreated with cigarette smoke extract. Proc Nat1 Acad Sci USA 85-2344-2348, 1988 30 Harats D. Ben-Naim M. Dabach Y. Hollander G. Stein 0, Stein Y. Cigarette smoking renders LDL susceptible to peroxidative modification and enhanced metabolism by macrophages. Atherosclerosis 79: 245-252, 1989 31 Pittilo R M, Mackie I J, Rowles P M, Machin S J, Woolf N. Effects of cigarette smoking on the ultrastructure of rat thoracic aorta and its ability to produce prostacyclin. Thromb Haemostas 48: 173-176.1982 32 Zimmerman M, McGeachie J. The effects of nicotine on aortic endothelium, a quantitative ultrastructural study. Atherosclerosis 63: 33-41, 1987 33. Allen D R. Browse N L. Rutt D L. Butler L. Fletcher C. The effect of cigarette smoke, nicotine, and carbon monoxide on the permeability of the arterial wall. J Vast Surg 7: 139-152, 1988 34. Asmussen I, Kjeldsen K. Intimal ultrastructure of human umbilical arteries. Circulation Res 36: 579-589,1975 35. Bylock A, Bondjers G, Jansson I, Hansson H-A. Surface ultrastructure of human arteries with special reference to the effects of smoking. Acta Pathol Microbial Stand 87: 201-209, 1979 36. Davis J W, Shelton L, Eigenberg D A, Hignite C E, Watanabe IS. Effects of tobacco and nontobacco cigarette smoking on endothelium and platelets. Clin Pharmacol Ther 37: 529-533, 1985 37. Auerbach 0, Carter H W, Gartinkel L, Hammond E C. Cigarette smoking and coronary artery disease. A macroscopic and microscopic study. Chest 70: 697-705, 1976 38. Sugrue D D, Thompson G R, Oakley C M, Trayner I M, Steiner R E. Contrasting patterns of coronary atherosclerosis in normocholestrolaemic smokers and patients with familial hypercholesterolaemia. Br Med J 283: 1358-1360. 1981 39. Ribeiro P, Walesby R, Edmonson S, Jadhav A V, Travner I. Oaklev C M. Thomoson G R. Collaeen conient of atherosclerotic artehes is higher in smokers than in nonsmokers. Lancet 2: 1070-1073, 1983 40. Oberai B, Adams C W, High 0 B. Myocardial and renal arteriolar thickening in cigarette smokers. Atherosclerosis 52: 185-190, 1984 41. McGill H C, Jr. Smoking and the pathogenesis of atherosclerosis. pp 9-16, in Tobacco Smoking and Atherosclerosis (Diana J N ed), Plenum Press, NY, 1990 42. Caro C G. Cigarette smoking causes acute changes in arterial wall mechanics and the pattern of arterial blood flow in healthy subjects: possible insights into mechanisms of atherogenesis. pp 273-280, in Tobacco Smoking and Atherosclerosis (Diana J N ed), Plenum Press, NY, 1990 43. Cryer P E, Haymond M W, Santiago J V, Shad S D. Norepinephrine and epinephrine release and adrenergic mediation of smoking-associated hemodynamic and metabolic events. N Engl J Med 295: 573-577.1976 44. Klein L W. Editorial comment. Cigarette smoking, atherosclerosis and the coronary hemodynamic response: a unifying hypothesis. J Am Co11 Cardiol 4: 972-974, 1984

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45. Richardson D R. Effects of habitual tobacco smoking on reactive hyperemia in the human hand. Arch Env Health 40: 114-119, 1985 46. Winniford M D, Wheelan K R, Kremers M S, Ugolini V, von den Berg Jr., E, Niggeman E H, Jansen D E, Hillis L D. Smoking-induced coronary vasoconstriction in patients with atherosclerotic coronary artery disease: evidence for adrenergically mediated alterations in coronary artery tone. Circulation 73: 662-667, 1986 47. Laustiola K E, Lassila R, Kaprio J, Koskenvuo M. Decreased beta-adrenergic receptor density and catecholamine response in male cigarette smokers a study of monozygotic twin pairs discordant for smoking. Circula& 78: 1234-1240, 1988 48. Laustiola K E. Kotamiki M. Lassila R. Kallioniemi O-P, Mannine; V. Cigarette’ smoking alters

sympathoadrenal regulation by decreasing the density of &adrenoceptors. A study of monitored smoking cessation. J Cardiovasc Pharmacol 17: 923:928,199l 49. Sir Dollerv C. Brennan P J. The Medical Research Council Hipehension Trial: the smoking patient. Am Heart J 115: 276-281, 1988 50. Penny W J, Mir M A. Cardiorespiratory response to exercise before and after acute beta-adrenoceptor blockade in nonsmokers and chronic smokers. Int J Cardiol 11: 293-304, 1986 51. Laustiola K E, Lassila R, Nurmi A-K. Enhanced activation of the renin-angiotensin-aldosterone system in chronic smokers - a study of monozygotic twin pairs discordant for smoking. Clin Pharmacol Ther 44: 426-430, 1988