Coronary Artery Disease and Myocardial Infarction

had฀reduced฀health-related฀quality฀of฀life฀HRQoL฀beneits฀after฀PTCA฀where฀they฀had฀ not฀stopped฀smoking฀after฀the฀procedure฀ [21] . In฀contrast฀to฀nicotine฀carbon฀monoxide฀CO฀is฀partially฀responsible฀for฀the฀development฀ of฀arteriosclerosis฀in฀smokers.฀Additionally,฀other฀toxic฀agents฀included฀in฀cigarette฀smoke฀ have฀a฀pronounced฀impact฀ [22–24] .฀Experimental฀animal฀work฀indicates฀that฀such฀substances฀ include฀formaldehyde,฀nitrosamines,฀acroleine,฀and฀NO x .฀Several฀pathological฀processes฀are฀ involved฀in฀the฀aorta฀of฀fowls฀treated฀with฀carcinogenic฀agents฀ [25] .฀Smooth฀muscle฀cells฀ proliferate฀and฀penetrate฀into฀the฀intima฀of฀larger฀vessels฀ [25–28] .฀3-Methylcholanthrene,฀ benzo-[a]-pyrene฀BP,฀and฀7,12-dimethylbenzaanthracene฀DMBA฀initiate฀comparable฀ intima฀lesions฀in฀the฀aorta฀of฀chickens฀and฀doves฀ [25,฀26,฀29,฀30] .฀Aortic฀tissue฀of฀chicken฀ contains฀the฀subenzyme฀CYP 1A1 ฀which฀activates฀or฀detoxiies฀carcinogenic฀substances฀ [31] ,฀ and฀which฀can฀be฀induced฀by฀polycyclic฀aromatic฀hydrocarbons฀PAH฀ [25,฀27] .฀CYP 1A1 ฀is฀ also฀present฀in฀human฀aortic฀smooth฀muscle฀cells,฀and฀the฀hydroxylation฀of฀BP฀and฀DMBA฀ has฀also฀been฀described฀in฀cultured฀human฀foetal฀smooth฀muscle฀cells฀ [32] .฀Thus,฀it฀seems฀ highly฀likely฀that฀carcinogenic฀agents฀are฀partly฀responsible฀for฀lesions฀at฀the฀vessel฀wall฀and฀ for฀activation฀of฀blood฀platelets฀ [33] . Room temp. 25.5°C 78°F Smoking corn silk cigaret Smoking standard cigaret Intravenous nicotine Blood pressure Pulse 120 110 100 90 80 70 60 120 110 100 90 80 70 60 Beats per min. Control Control Control period period period Temperature mm of Hg saline, intravenous °C 35 34 33 32 31 30 29 95.0 93.2 91.4 89.6 87.8 86.0 84.2 82.4 80.6 78.8 77.0 Toe Finger Time in minutes 28 27 26 25 °F Fig. 6.1 ฀฀฀Effect฀of฀smoking฀two฀corn฀silk฀or฀standard฀cigarettes฀and฀of฀intravenous฀injection฀of฀2฀ mg฀nicotine฀on฀extremity฀skin฀temperature,฀blood฀pressure฀and฀heart฀rate฀HR฀of฀one฀normal฀ person฀ [152] Haematocrit฀is฀a฀decisive฀factor฀for฀the฀prognosis฀of฀CHD฀ [34] :฀the฀association฀between฀ haematocrit฀and฀CHD฀mortality฀was฀assessed฀in฀the฀large-scale฀NHANES฀II฀Mortality฀Study฀ 1976–1992฀in฀8,896฀patients฀aged฀30–75฀years,฀with฀smoking฀status฀as฀one฀of฀the฀covari- ates฀included.฀Women฀with฀haematocrit฀in฀the฀upper฀tertile฀were฀1.3฀times฀CI฀95:฀0.9–1.9฀ more฀likely฀to฀die฀from฀CHD฀than฀were฀women฀with฀haematocrit฀in฀the฀lowest฀tertile.฀Since฀ similar฀associations฀could฀not฀be฀demonstrated฀for฀men,฀this฀must฀be฀a฀multifactorial฀phe- nomenon฀ [34] . Among฀the฀4,000฀or฀more฀toxic฀substances฀absorbed฀during฀smoking,฀carbon฀monoxide฀ CO฀and฀glycoproteins฀play฀a฀particularly฀important฀role฀in฀the฀development฀of฀smoking- related฀arteriosclerotic฀changes฀see฀Sect.฀ 6.4 ,฀and฀the฀severity฀of฀the฀changes฀produced฀is฀ inluenced฀by฀the฀cigarette฀dose฀and฀smoking฀duration฀ [35,฀36] . Smoking฀disturbs฀the฀O 2 ฀supplyconsumption฀ratio฀up฀to฀15฀of฀haemoglobin฀is฀no฀ longer฀available฀for฀O 2 ฀transport,฀causing฀heart฀rate฀HR฀and฀blood฀pressure฀to฀increase฀ slightly฀see฀Fig.฀ 6.1 ฀ [35,฀37] .฀The฀nicotine฀absorbed฀with฀every฀cigarette฀puff฀50–150฀mg฀ may฀possibly฀not฀be฀entirely฀responsible฀for฀these฀changes,฀even฀though฀the฀alkaloid฀does฀ produce฀measurable฀increments฀in฀plasma฀concentrations฀of฀adrenaline฀and฀noradrenaline฀ [38] .฀These฀increases฀are฀very฀much฀smaller฀in฀habitual฀smokers฀than฀in฀occasional฀smokers.฀ Also,฀while฀the฀occurrence฀of฀cardiac฀arrhythmias฀after฀smoking฀may฀be฀attributable฀to฀the฀ effect฀of฀nicotine฀ [39] ,฀this฀phenomenon฀is฀due฀more฀to฀the฀inhalation฀of฀other฀toxic฀฀substances฀ CO,฀formation฀of฀CO-haemoglobin฀ [16] . Years฀of฀habitual฀cigarette฀smoking฀lead฀to฀coronary฀constriction฀and฀lower฀coronary฀ reserve฀on฀effort฀ [40] .฀In฀habitual฀smokers฀simultaneously฀suffering฀from฀CHD,฀cigarette฀ smoking฀ lowers฀ the฀ angina฀ threshold.฀ Just฀ 5฀ min฀ after฀ smoking฀ one฀ cigarette,฀ coronary฀ blood฀low฀is฀reduced฀7฀and฀coronary฀resistance฀is฀increased฀21,฀accompanied฀by฀a฀ simultaneous฀rise฀in฀the฀rate-pressure฀product฀ [41] .฀These฀changes฀are฀caused฀by฀coronary฀ vessel฀constriction฀and฀by฀the฀very฀rapid฀onset฀of฀myocardial฀hypoxia.฀In฀angina฀patients,฀ regardless฀of฀the฀number฀of฀cigarettes฀smoked,฀cigarette฀smoking฀produces฀narrowing฀of฀ the฀coronary฀artery฀lumen฀detectable฀on฀angiography฀ [42,฀43] ,฀and฀this฀effect฀is฀particularly฀ severe฀in฀patients฀with฀vasospastic฀angina฀ [44] . Results฀conirm฀the฀minimal฀“harmfulness”฀of฀nicotine฀on฀the฀circulation฀Fig.฀ 6.2 ฀ [45] .฀ This฀study฀compared฀cardiovascular฀risk฀factors฀in฀smokers,฀non-smokers฀and฀users฀of฀snuff฀ and฀chewing฀tobacco฀smokeless฀tobacco.฀Smokeless฀tobacco฀consumption฀over฀a฀period฀ of฀years฀does฀not฀produce฀a฀signiicant฀increase฀in฀risk฀factors฀for฀the฀development฀of฀CHD฀ or฀in฀the฀atherogenic฀index฀Fig.฀ 6.2 ฀ [45] .฀These฀data฀also฀point฀to฀the฀harmful฀effects฀of฀the฀ combustion฀products฀of฀tobacco฀smoke฀in฀the฀development฀of฀cardiovascular฀disease. In฀the฀Trial฀on฀Reversing฀Endothelial฀Dysfunction฀TREND฀Study฀54฀patients฀smok- ers฀and฀non-smokers฀each฀underwent฀quantitative฀coronary฀angiography฀at฀baseline฀and฀ again฀after฀6-month฀follow-up฀to฀measure฀coronary฀artery฀diameter฀responses฀to฀acetyl- choline฀ [46,฀47] .฀Impairment฀of฀endothelium-dependent฀vasodilatation฀by฀chronic฀smok- ing฀is฀clearly฀caused฀by฀tobacco฀smoke฀and฀not฀by฀nicotine฀ [48–51] .฀One฀study฀involving฀ angiographic฀assessments฀over฀a฀2-year฀period฀demonstrated฀progression฀of฀coronary฀ath- erosclerosis฀and฀the฀development฀of฀numerous฀new฀coronary฀lesions฀in฀smokers฀ [52] .฀The฀ reduced฀vascular฀response฀e.g.฀measured฀at฀the฀brachial฀artery฀is฀reversible฀after฀smoking฀ cessation฀ [48] ,฀and฀a฀correlation฀has฀been฀found฀between฀the฀CO฀content฀of฀expired฀air฀ [53] ฀ and฀the฀ischaemia฀threshold฀ [54] .฀If฀this฀response฀also฀applies฀for฀the฀coronary฀arteries,฀it฀ probably฀explains฀the฀lower฀incidence฀of฀reinfarction฀among฀men฀who฀stopped฀smoking฀ after฀a฀irst฀myocardial฀infarction฀compared฀with฀those฀who฀continued฀to฀smoke฀ [55] . Cigarette฀smoking฀appreciably฀increases฀the฀risk฀of฀myocardial฀infarction.฀In฀the฀multi- centre฀GISSI-2฀Trial฀ [56] ฀risk฀factors฀were฀determined฀in฀916฀patients฀with฀acute฀myocar- dial฀infarction:฀by฀comparison฀with฀lifelong฀non-smokers,฀the฀relative฀risk฀RR฀was฀1.3฀ for฀ ex-smokers,฀ 2.0฀ for฀ current฀ smokers฀ of฀ less฀ than฀ 15฀ cigarettesday,฀ 3.1฀ for฀ current฀ smokers฀of฀15–24฀cigarettesday,฀and฀4.9฀for฀current฀smokers฀of฀more฀than฀25฀cigarettes day.฀The฀duration฀of฀smoking฀was฀less฀important฀than฀the฀age฀of฀the฀smoker:฀below฀the฀age฀ of฀45฀years,฀smokers฀of฀25฀or฀more฀cigarettesday฀had฀a฀33-fold฀higher฀risk฀compared฀with฀ non-smokers,฀ whereas฀ older฀ smokers฀ had฀ smaller฀ risks฀ 45–54฀ years:฀ 7.5-fold;฀ 55–64฀ years:฀4.4-fold;฀65฀years:฀2.5-fold฀ [56] .฀In฀Italy฀about฀50฀of฀all฀acute฀myocardial฀infarc- tions฀could฀be฀directly฀attributable฀to฀smoking. According฀to฀the฀Rochester฀CHD฀Project,฀a฀study฀conducted฀in฀40–59-year-old฀women,฀ cigarette฀smoking฀increases฀the฀risk฀for฀CHD฀or฀sudden฀cardiac฀death.฀The฀odds฀ratio฀for฀ the฀association฀between฀steroidal฀oestrogen฀use฀in฀non-smokers฀and฀CHD฀was฀0.6฀and฀rose฀ to฀5.1฀in฀smokers,฀with฀64฀of฀all฀cases฀of฀myocardial฀infarction฀and฀sudden฀cardiac฀death฀ occurring฀ in฀ smokers฀ [57,฀ 58] .฀ A฀ cardiac฀ catheterisation฀ study฀ in฀ 8,705฀ smokers฀ also฀ revealed฀an฀association฀between฀the฀location฀of฀coronary฀sclerosis฀and฀smoking฀behaviour:฀ stenoses฀occurred฀more฀commonly฀in฀the฀right฀coronary฀artery฀than฀in฀the฀left฀circumlex฀ artery฀or฀left฀anterior฀descending฀artery฀ [59] . According฀to฀one฀case-control฀study฀in฀555฀women฀below฀the฀age฀of฀50฀years,฀the฀risk฀of฀ myocardial฀infarction฀increased฀with฀the฀number฀of฀cigarettes฀smoked,฀regardless฀of฀whether฀ other฀ predisposing฀ factors฀ total฀ cholesterol,฀ HDL,฀ oral฀ contraceptive฀ use,฀ hypertension,฀ diabetes฀mellitus฀were฀present฀ [60] .฀The฀risk฀to฀women฀is฀underscored฀by฀a฀further฀study,฀ according฀to฀which฀the฀risk฀of฀myocardial฀infarction฀was฀increased฀2.47-fold฀in฀smokers฀of฀ just฀1–5฀cigarettes฀daily฀ [61] .฀The฀risk฀was฀increased฀74.6-fold฀in฀women฀who฀were฀heavy฀ smokers฀ ³40฀ cigarettes฀ daily;฀ oral฀ contraceptive฀ use฀ did฀ not฀ entail฀ any฀ increased฀ risk,฀ whereas฀there฀were฀additive฀risks฀with฀hypertension฀and฀diabetes฀mellitus฀ [61] . In฀ one฀ study฀ in฀ 5,572฀ patients฀ at฀ risk฀ compared฀ with฀ 6,268฀ controls,฀ the฀ coronary฀ risk฀fell฀from฀3.5฀to฀1.5฀for฀men฀and฀from฀4.8฀to฀1.6฀for฀women฀who฀had฀quit฀smoking฀for฀ 25 p = 0.28 p = 0.14 p 0.0001 p 0.0001 Framingham CHD Risk index Atherogenic index 20 15 10 5 25 20 15 10 5 Fig. 6.2 ฀฀฀Box฀plots฀showing฀the฀10th,฀25th,฀50th,฀75th฀and฀90th฀percentiles฀of฀the฀indices฀for฀cardiovas- cular฀risk฀factors฀Framingham฀CHD฀Risk฀Index฀and฀Atherogenic฀Index.฀ANOVA฀and฀Fisher’s฀test฀ for฀the฀comparison฀of฀different฀tobacco฀users฀smokeless฀tobacco฀users:฀cross-hatched฀boxes;฀smokers:฀ stippled฀boxes฀with฀non-smokers฀white฀boxes฀were฀statistically฀signiicant฀p฀฀0.05฀ [45] 1–3฀years฀ [62] .฀After฀4–6฀years฀of฀smoking฀cessation,฀the฀risk฀was฀comparable฀with฀that฀of฀ never-smokers฀ [62] .฀Also,฀compared฀with฀non-smokers,฀the฀irst฀myocardial฀infarction฀has฀ been฀shown฀to฀occur฀13.8฀years฀earlier฀in฀male฀smokers฀and฀3.6฀years฀earlier฀in฀female฀ smokers฀ [63] . The฀data฀presented฀in฀the฀literature฀indicate฀that฀nicotine฀itself฀exerts฀no฀appreciable฀ deleterious฀effects฀on฀myocardial฀perfusion฀or฀in฀terms฀of฀increasing฀risk฀factors฀for฀CHD฀ [55] .฀While฀nicotine฀administration฀to฀rats฀during฀the฀post-infarction฀period฀does฀lead฀to฀ delayed฀regression฀of฀left-ventricular฀changes฀ [64] ,฀it฀would฀be฀premature฀to฀draw฀far- reaching฀conclusions฀from฀these฀indings.

6.2 Systemic Vascular Changes

Cigarette฀smoking฀is฀associated฀with฀a฀sevenfold฀increase฀in฀the฀risk฀for฀PAOD฀ [65,฀66] ,฀ whereas฀the฀risk฀for฀CHD฀is฀merely฀doubled฀ [67,฀68] .฀The฀vascular฀changes฀caused฀by฀ smoking฀differ,฀depending฀on฀location:฀for฀example,฀heavy฀smoking฀produces฀more฀severe฀ damage฀in฀the฀vessels฀of฀the฀leg฀than฀in฀the฀coronary฀vessels฀ [69,฀70] . No฀ reliable฀ epidemiological฀ studies฀ have฀ been฀ performed฀ concerning฀ the฀ develop- ment฀of฀hypertension฀in฀cigarette฀smokers.฀On฀average,฀in฀fact,฀lower฀blood฀pressure฀ values฀are฀measured฀in฀smokers฀than฀in฀non-smokers,฀and฀blood฀pressure฀in฀ex-smokers฀ is฀comparable฀with฀that฀in฀non-smokers฀ [13,฀71] ,฀apart฀from฀nocturnal฀diastolic฀measure- ments฀which฀are฀elevated฀compared฀with฀those฀of฀non-smokers฀ [72] .฀In฀habitual฀smokers,฀ smoking฀a฀single฀cigarette฀produces฀increases฀in฀blood฀pressure฀6,฀HR฀14฀and฀ cardiac฀index฀16,฀whereas฀stroke฀volume฀and฀total฀peripheral฀resistance฀are฀not฀sig- niicantly฀altered.฀After฀wrist฀occlusion,฀only฀muscle฀blood฀low฀and฀not฀skin฀blood฀low฀ is฀increased฀ [73] .฀Cigarette฀smoking฀leads฀to฀disturbances฀of฀left-ventricular฀diastolic฀ function฀regardless฀of฀whether฀coronary฀sclerotic฀changes฀are฀present฀or฀not฀ [74–76] .฀ Administration฀of฀nicotine฀in฀a฀transdermal฀patch฀produced฀a฀minimal฀increase฀in฀dia- stolic฀blood฀pressure฀in฀normotensive฀but฀not฀in฀hypertensive฀smokers฀2–4฀h฀post-dose.฀ Simultaneously฀measured฀thromboxane฀B 2 ฀levels฀were฀increased฀in฀response฀to฀nicotine฀ in฀non-smokers฀but฀not฀in฀normotensive฀or฀hypertensive฀smokers฀where฀thromboxane฀B 2 ฀ was฀already฀elevated฀ [77] . Smokers฀with฀hypertension฀are฀less฀likely฀to฀be฀aware฀of฀their฀high฀blood฀pressure฀or฀฀ to฀ be฀ treated฀ than฀ non-smokers฀ ex-smokers฀ with฀ hypertension฀ OR฀ 1.25;฀ 1.06–1.47;฀฀ p฀=฀0.009฀ [78] . In฀one฀study,฀1,016฀professional฀athletes฀using฀smokeless฀tobacco฀were฀compared฀with฀ a฀control฀group฀without฀tobacco฀consumption฀in฀terms฀of฀cardiovascular฀risk฀factors.฀Over฀ a฀1-year฀period฀there฀were฀no฀changes฀in฀systolic฀blood฀pressure,฀HR฀and฀total฀or฀HDL฀ cholesterol฀in฀the฀tobacco฀users฀or฀in฀the฀controls.฀Only฀diastolic฀blood฀pressure฀correlated฀ with฀the฀plasma฀nicotine฀level.฀Overall,฀the฀inluence฀of฀smokeless฀tobacco฀on฀cardiovas- cular฀risk฀factors฀was฀classiied฀as฀minimal฀ [79] .฀According฀to฀one฀Danish฀study,฀blood฀ pressure฀is฀slightly฀lower฀in฀smokers฀than฀in฀non-smokers,฀indicating฀that฀the฀“white฀coat”฀ effect฀during฀ambulatory฀blood฀pressure฀measurements฀was฀less฀pronounced฀in฀smokers฀ than฀in฀non-smokers฀ [80] . Kidney฀disease฀is฀associated฀with฀an฀increased฀risk฀for฀the฀development฀of฀cardiovascular฀ disease฀and฀end-stage฀renal฀disease;฀however,฀risk฀factors฀for฀kidney฀disease฀have฀not฀been฀ well฀studied฀and฀smoking฀is฀a฀candidate฀factor฀ [81] .฀Fox฀et฀al.฀identiied฀predictors฀of฀the฀ development฀of฀new-onset฀kidney฀disease฀in฀2004.฀A฀community-based,฀longitudinal฀cohort฀ study฀of฀2,585฀participants฀who฀attended฀both฀a฀baseline฀examination฀in฀1978–1982฀and฀a฀ follow-up฀examination฀in฀1998–2001,฀and฀who฀were฀free฀of฀kidney฀disease฀at฀baseline.฀The฀ researchers฀showed฀that฀after฀a฀mean฀follow-up฀of฀18.5฀years,฀244฀participants฀9.4฀had฀ developed฀kidney฀disease.฀In฀multivariable฀models,฀baseline฀age฀odds฀ratio฀[OR],฀2.36฀per฀ 10-year฀increment;฀95฀conidence฀interval฀[CI],฀2.00–2.78,฀GFR฀฀90฀mLmin฀per฀1.73฀m 2 :฀ OR,฀3.01;฀95฀CI,฀1.98–4.58;฀90–119฀mLmin฀per฀1.73฀m 2 :฀OR,฀1.84;฀95฀CI,฀1.16–2.93,฀ body฀mass฀index฀OR,฀1.23฀per฀1฀SD;฀95฀CI,฀1.08–1.41,฀diabetes฀OR,฀2.60;฀95฀CI,฀ 1.44–4.70,฀and฀smoking฀OR,฀1.42;฀95฀CI,฀1.06–1.91฀were฀related฀to฀the฀development฀of฀ kidney฀disease฀ [81] . In฀the฀cerebral฀vessels฀smoking฀causes฀acute฀vasodilatation฀and฀increased฀blood฀low฀in฀ the฀grey฀matter฀+15.7.฀This฀increase฀in฀blood฀low฀was฀detected฀without฀any฀change฀in฀O 2 ฀ metabolism฀and,฀following฀consumption฀of฀a฀single฀cigarette,฀was฀most฀pronounced฀in฀ non-smokers,฀ less฀ pronounced฀ in฀ ex-smokers฀ and฀ least฀ pronounced฀ in฀ smokers฀ [82] .฀ Cerebral฀blood฀low฀was฀measured฀by฀ 133 Xe฀inhalation฀in฀a฀population฀of฀192฀volunteers,฀ including฀84฀patients฀with฀risk฀factors฀for฀stroke.฀The฀study฀population฀included฀75฀habit- ual฀smokers฀0.5–3.5฀packs฀per฀day฀for฀25฀years.฀Grey฀matter฀blood฀low฀was฀clearly฀more฀ impaired฀in฀the฀smokers฀than฀in฀the฀non-smokers฀ [83] ,฀and฀the฀arteriosclerotic฀vascular฀ changes฀also฀appear฀to฀be฀the฀decisive฀factor฀in฀terms฀of฀a฀subsequent฀stroke.฀The฀incidence฀ of฀stroke฀in฀relation฀to฀cigarette฀smoking฀was฀investigated฀over฀an฀8-year฀period฀in฀a฀cohort฀ study฀of฀118,539฀women฀between฀the฀ages฀of฀30฀and฀55฀and฀free฀from฀CHD,฀stroke฀and฀ cancer.฀In฀the฀274฀patients฀with฀stroke,฀compared฀with฀women฀who฀had฀never฀smoked,฀ those฀who฀smoked฀1–14฀cigarettesday฀had฀a฀relative฀stroke฀risk฀of฀2.2,฀whereas฀those฀who฀ smoked฀25฀or฀more฀cigarettesday฀had฀a฀relative฀risk฀of฀3.7.฀The฀71฀observed฀cases฀of฀suba- rachnoid฀haemorrhage฀mainly฀included฀smokers,฀whose฀relative฀risk฀for฀such฀an฀event฀was฀ 9.8,฀as฀compared฀with฀women฀who฀had฀never฀smoked฀ [84] .฀These฀data฀support฀the฀associa- tion฀between฀cigarette฀smoking฀and฀stroke฀among฀young฀and฀middle-aged฀women. According฀to฀newer฀research,฀a฀correlation฀exists฀between฀increased฀serum฀thiocyanate฀ levels฀and฀stroke฀risk,฀as฀shown฀by฀investigations฀in฀67฀stroke฀patients฀OR฀3.00;฀1.06– 8.48;฀p฀฀0.05,฀prompting฀the฀recommendation฀that฀serum฀thiocyanate฀levels฀should฀be฀ measured฀as฀an฀indicator฀of฀smoking฀status฀in฀stroke฀patients฀ [85] . Aortic฀ aneurysms฀ occurring฀ predominantly฀ in฀ the฀ abdominal฀ region฀ are฀ a฀ common฀ cause฀of฀death฀among฀elderly฀men฀ [86] .฀In฀one฀study฀in฀73,451฀veterans฀aged฀50–79฀years,฀ most฀of฀whom฀were฀smokers,฀vascular฀changes฀were฀detected฀by฀ultrasound฀screening.฀A฀ larger฀proportion฀of฀abdominal฀aortic฀aneurysms฀AAA฀n฀=฀1,917;฀3.6฀were฀£3฀cm฀in฀ diameter,฀and฀only฀613฀aneurysms฀1.2฀were฀4-cm฀or฀larger.฀The฀respective฀odds฀ratios฀ for฀smoking฀were฀4.45฀CI:฀3.27–6.05฀and฀5.07฀CI:฀4.24–7.31,฀whereas฀a฀raised฀choles- terol฀ level฀ yielded฀ odds฀ ratios฀ of฀ only฀ 1.29฀ 1.06–1.58฀ and฀ 1.54฀ CI:฀ 1.31–1.80.฀ The฀ excess฀prevalence฀associated฀with฀smoking฀accounted฀for฀75฀of฀all฀AAA฀of฀4฀cm฀or฀ larger฀in฀diameter฀in฀the฀total฀population฀of฀126,196฀persons฀studied฀by฀this฀research฀group฀ [87] .฀One฀noteworthy฀and฀as฀yet฀unanswered฀question฀is฀why฀patients฀with฀diabetes฀mel- litus฀have฀aortic฀aneurysms฀more฀rarely฀OR฀=฀0.50;฀CI:฀0.39–0.65฀and฀0.54;฀CI:฀0.44–0.65฀