Arteriosclerotic and Inflammatory Vascular Reactions

The฀vessels฀gradually฀become฀“denuded”฀of฀endothelial฀cells,฀which฀in฀turn฀disappear฀in฀the฀ lowing฀blood฀ [173] .฀The฀collagen฀of฀the฀subendothelial฀matrix฀supports฀platelet฀adhesion฀ and฀ aggregation,฀ resulting฀ in฀ the฀ increased฀ production฀ of฀ platelet-derived฀ growth฀ factor฀ PDGF฀which฀acts฀as฀a฀mitogen฀for฀the฀vascular฀muscle฀cells,฀the฀true฀starting฀point฀for฀arte- riosclerotic฀changes฀ [163] .฀Having฀undergone฀these฀changes,฀the฀vascular฀cells฀take฀up฀oxo- LDL฀ molecules฀ in฀ large฀ numbers,฀ and฀ this฀ leads฀ in฀ turn฀ to฀ the฀ release฀ of฀ inlammatory฀ cytokines฀with฀the฀likelihood฀of฀cell฀death. An฀insertiondeletion฀ID฀polymorphism฀of฀the฀ACE฀gene฀has฀been฀associated฀with฀ increased฀risk฀for฀acute฀myocardial฀infarction,฀cardiomyopathy,฀cardiac฀hypertrophy฀ and฀carotid฀thickening.฀The฀DD฀genotype฀in฀particular฀should฀be฀considered฀as฀a฀risk฀ factor฀for฀early฀arteriosclerosis,฀even฀controlling฀other฀potential฀confounding฀factors฀ such฀as฀smoking฀ [174,฀175] . Smoking฀is฀the฀most฀powerful฀risk฀factor฀for฀the฀development฀of฀atherosclerosis,฀even฀ ahead฀of฀hypertension,฀diabetes฀mellitus,฀and฀male฀gender.฀Pack-years฀smoked฀correlate฀ with฀the฀extent฀of฀arteriosclerotic฀changes฀in฀the฀common฀carotid฀artery฀ [176] .฀The฀risk฀ of฀having฀severe฀atherosclerosis฀for฀a฀person฀who฀has฀smoked฀for฀40฀years฀is฀increased฀ 3.5-fold฀compared฀with฀that฀for฀someone฀who฀has฀never฀smoked.

6.3 Blood Coagulation and Fibrinolysis

Critical฀events฀myocardial฀infarction,฀stroke฀due฀to฀arteriosclerotic฀changes฀are฀triggered฀ by฀unstable฀arteriosclerotic฀plaques:฀acutely฀formed฀thrombi฀occlude฀vessels฀of฀varying฀ calibre.฀Smokers฀have฀a฀shortened฀platelet฀survival฀half-life฀ [177] ,฀a฀situation฀in฀which฀ thromboxane฀A 2 ฀synthesis฀is฀increased฀ [178] . Smokers฀live฀permanently฀at฀risk฀because฀their฀platelets฀react฀very฀much฀more฀rapidly฀ to฀form฀aggregates฀than฀those฀of฀non-smokers. • ฀ Activation฀of฀the฀blood฀coagulation฀system฀thrombosis฀is฀important฀for฀the฀occur- rence฀of฀acute฀and฀chronic฀coronary฀events,฀and฀in฀this฀context฀the฀effect฀of฀smoking฀on฀ platelets฀has฀been฀studied฀most฀extensively:฀smoking฀two฀cigarettes฀increases฀platelet฀ activation฀100-fold฀ [41] . • ฀ Smoking฀increases฀the฀production฀of฀PDGF,฀a฀key฀factor฀in฀the฀atherogenic฀growth฀of฀ vascular฀cells฀ [14] . • ฀ Smoking฀but฀not฀nicotine฀stimulates฀pro-aggregatory฀prostanoids,฀thromboxane฀B 2 ฀ and฀A 2 ,฀prostaglandin฀F 1 a ,฀platelet฀factor฀4฀and฀b-thromboglobulin฀ [178,฀179] . • ฀ Plasma฀fibrinogen฀levels฀ [35,฀129,฀179] ฀and฀factor฀VII฀activity฀ [35] ฀are฀elevated฀in฀ smokers,฀and฀the฀increase฀in฀the฀fibrinogen฀level฀depends฀on฀the฀number฀of฀cigarettes฀ smoked฀ [129] .฀Raised฀fibrinogen฀is฀a฀risk฀factor฀for฀venous฀bypass฀graft฀patency฀and฀for฀ restenosis฀after฀PTCA฀ [180,฀181] .฀Normalisation฀after฀smoking฀cessation฀takes฀a฀few฀ months฀ [8] ,฀if฀not฀several฀years฀ [35] .฀The฀RIVAGE฀Study฀has฀clearly฀shown฀that฀the฀ plasma฀fibrinogen฀level฀is฀the฀only฀independent฀variable฀associated฀with฀increased฀risk฀ for฀a฀cardiovascular฀event฀ [182] . Although฀some฀studies฀have฀found฀the฀ibrinolytic฀activity฀of฀the฀blood฀to฀be฀unaltered฀ [129] ,฀the฀data฀summarised฀in฀Table฀ 6.2 ฀point฀to฀a฀reduction฀in฀such฀activity.฀Nicotine฀itself฀ induces฀substance฀P-mediated฀release฀of฀tissue฀plasminogen฀activator฀t-PA฀without฀any฀ effect฀on฀endothelium-dependent฀or฀-independent฀vasodilatation฀ [183] .฀One฀recently฀pub- lished฀study฀points฀to฀reduced฀ibrinolytic฀potential฀in฀the฀myocardium฀of฀smokers.฀An฀ inverse฀correlation฀was฀found฀between฀plaque฀burden฀in฀the฀left฀anterior฀descending฀coro- nary฀artery฀and฀the฀release฀of฀t-PA฀r฀=฀−0.61;฀p฀=฀0.003.฀Cigarette฀smoking฀is฀associated฀ with฀considerably฀impaired฀coronary฀release฀of฀active฀t-PA฀ [184] .฀After฀smoking฀cessation฀ ibrinogen฀levels฀fall฀by฀about฀5฀within฀5฀years฀ [160] .฀Fibrinogen฀should฀also฀be฀regarded฀ as฀important฀irstly฀as฀a฀haemorheological฀factor฀because฀blood฀viscosity฀rises฀when฀ibrin- ogen฀levels฀increase฀ [8] ,฀and฀secondly฀as฀a฀mediator฀of฀inlammation฀because฀leucocyte฀ adhesion฀to฀activated฀endothelium฀and฀cytokine฀release฀IL-8฀and฀MCP-1฀are฀increased฀at฀ a฀time฀ [185] ฀when฀plaque฀formation฀is฀still฀not฀at฀all฀important฀ [186] .฀Consequently,฀even฀ before฀ plaque฀ formation฀ occurs,฀ the฀ correlation฀ between฀ ibrinogen฀ concentration฀ and฀ carotid฀wall฀thickness฀seems฀to฀be฀plausible฀ [187] .

6.3.1 Genetic Factors

Interactions฀appear฀to฀exist฀between฀smoking฀and฀genotype.฀Apolipoprotein฀polymorphism฀ and฀the฀cholesteryl฀ester฀transfer฀protein฀gene฀display฀interactions฀ [39,฀188,฀189] .฀In฀indi- viduals฀with฀speciic฀genotypes฀smoking฀produces฀an฀increase฀in฀LDL฀cholesterol฀and฀a฀ reduction฀in฀HDL฀cholesterol,฀with฀both฀processes฀occurring฀as฀a฀part฀of฀a฀proatherogenic฀ effect.฀Likewise,฀there฀are฀smokers฀in฀whom฀plasma฀ibrinogen฀levels฀are฀clearly฀increased฀ [190,฀191] .฀Smokers฀with฀a฀rare฀variant฀of฀the฀NOS฀gene฀ecNOS4a฀are฀found฀in฀increased฀ numbers฀among฀patients฀with฀severely฀stenosed฀coronary฀arteries฀veriied฀by฀angiography฀ [192] .฀These฀indings฀appear฀to฀indicate฀the฀potential฀for฀considerable฀interactions฀between฀ smoking฀and฀genetic฀factors.

6.3.2 Nicotine and Ischaemic Heart Disease

The฀indings฀presented฀suggest฀that฀nicotine฀itself฀is฀of฀only฀secondary฀importance฀as฀a฀ harmful฀agent฀in฀the฀context฀of฀CHD.฀Instead,฀the฀inhaled฀combustion฀products฀of฀tobacco฀ smoke฀should฀be฀viewed฀as฀the฀culprits฀in฀this฀respect.฀Nicotine฀replacement฀therapy฀as฀ opposed฀to฀cigarette฀smoking฀produces฀no฀harmful฀cardiac฀effects฀ [55,฀193] .฀When฀nico- tine฀is฀administered฀therapeutically฀after฀smoking฀cessation,฀toxic฀substances฀are฀no฀longer฀ inhaled฀ [194] .฀According฀to฀existing฀data,฀nicotine฀replacement฀therapy฀should฀be฀imple- mented฀with฀caution฀in฀patients฀with฀cardiac฀arrhythmias,฀CHD฀and฀recently฀completed฀ stroke฀ [126,฀195–197] ,฀and฀further฀investigations฀would฀appear฀useful฀to฀establish฀the฀con- traindications.฀The฀consequences฀of฀a฀smoking-induced฀increase฀in฀CO-haemoglobin฀are฀ similar฀to฀those฀of฀chronic฀CO฀poisoning฀ [198] ,฀and฀may฀lead฀to฀an฀increased฀incidence฀of฀ cardiovascular฀complications.