Microcirculation and O Systemic Vascular Changes

Dalla฀et฀al฀studies฀in฀2004฀the฀effects฀of฀acute฀and฀chronic฀smoking฀on฀skin฀microvas- cular฀properties฀of฀young฀healthy฀subjects.฀In฀this฀observational฀study,฀using฀a฀totally฀non- invasive฀approach,฀employing฀continuous฀palmar฀microvascular฀low฀laser฀Doppler฀and฀ arterial฀pressure฀measurements,฀a฀total฀of฀20฀healthy฀male฀subjects฀nine฀habitual฀smokers฀ and฀11฀non-smokers;฀aged฀27฀±฀1฀and฀29฀±฀2฀years,฀respectively฀were฀examined฀ [150] .฀ Measures฀were฀obtained฀at฀baseline฀and฀after฀iontophoretic฀administration฀of฀acetylcholine฀ ACh,฀ an฀ endothelium-dependent฀ vasodilator฀ and฀ of฀ sodium฀ nitroprusside฀ NP,฀ an฀ endothelium-independent฀vasodilator.฀The฀study฀showed฀that฀smokers฀showed฀signiicant฀ lower฀baseline฀microvascular฀resistive฀Z0฀and฀oscillatory฀impedance,฀i.e.฀ZC฀properties฀ than฀non-smokers.฀In฀the฀non-smokers฀group,฀ACh฀and฀NP฀iontophoresis฀induced฀a฀signii- cant฀ decrease฀ of฀ both฀ Z0฀ and฀ ZC,฀ before฀ and฀ after฀ smoking฀ one฀ cigarette฀ p฀ ฀ 0.02.฀ Conversely,฀in฀the฀smokers฀group,฀both฀Z0฀and฀ZC฀were฀not฀affected฀by฀ACh฀iontophoresis฀ before฀acute฀smoking,฀while,฀after฀smoking,฀a฀signiicant฀decrease฀of฀both฀Z0฀and฀ZC฀p฀฀ 0.02฀was฀detected฀after฀ACh฀challenge.฀The฀study฀indicates฀that฀smokers฀have฀a฀complex฀ disruption฀of฀peripheral฀microcirculatory฀regulation,฀including฀inappropriate฀resting฀vaso- dilation,฀ impaired฀ endothelium-dependent฀ and฀ independent฀ vasodilation,฀ paradoxical฀ recovery฀of฀endothelium-dependent฀vasodilation฀in฀response฀to฀acute฀smoking฀ [151] . In฀a฀further฀study,฀the฀acute฀effects฀of฀smoking฀on฀microvascular฀function฀in฀healthy฀ smokers฀was฀studied฀using฀measures฀of฀HR,฀blood฀pressure,฀capillary฀recruitment฀during฀ peak฀reactive฀hyperaemia฀and฀endothelium-dependent฀and฀endothelium-independent฀vaso- dilatation฀ of฀ the฀ skin฀ microcirculation฀ with฀ iontophoresis฀ of฀ acetylcholine฀ and฀ sodium฀ nitroprusside฀respectively฀combined฀with฀laser฀Doppler฀luxmetry฀ [151] ฀It฀was฀found฀that฀ in฀comparison฀with฀sham฀smoking,฀acute฀smoking฀caused฀increases฀in฀HR฀smoking,฀9.3฀±฀ 4.1฀beatsmin;฀sham,฀−1.3฀±฀3.0฀beatsmin;฀p฀฀0.001฀and฀systolic฀blood฀pressure฀smok- ing,฀6.3฀±฀8.8฀mmHg;฀sham,฀0.8฀±฀4.4฀mmHg;฀p฀฀0.05.฀Also,฀decreases฀in฀absolute฀smok- ing,฀−4.9฀±฀6.9฀per฀mm 2 ;฀sham,฀0.8฀±฀2.1฀per฀mm2;฀p฀=฀0.01฀and฀relative฀smoking,฀−13.8฀±฀ 21.4;฀sham,฀1.9฀±฀6.9;฀p฀=฀0.02฀capillary฀recruitment฀during฀peak฀reactive฀hyperaemia;฀ and฀decreases฀in฀absolute฀[smoking,฀-62.4฀±฀47.7฀perfusion฀units฀PU;฀sham,฀−30.8฀±฀32.6฀ PU;฀p฀=฀0.04]฀and฀relative฀smoking,฀−147฀±฀163;฀sham,฀32฀±฀225;฀p฀=฀0.07฀vasodilata- tion฀caused฀by฀acetylcholine฀were฀demonstrated.฀From฀this฀study฀it฀can฀be฀concluded฀that฀ acute฀ smoking฀ is฀ associated฀ with฀ impaired฀ capillary฀ recruitment฀ during฀ peak฀ reactive฀ hyperaemia฀ and฀ impaired฀ microvascular฀ endothelium-dependent฀ vasodilatation.฀ These฀ indings฀may฀also฀explain฀the฀increased฀blood฀pressure฀and฀decreased฀insulin฀sensitivity฀ that฀have฀been฀observed฀after฀acute฀smoking฀ [151] . Vascular฀response฀and฀O 2 ฀supply฀of฀the฀skin฀and฀deeper฀tissue฀layers฀can฀be฀measured฀ by฀laser฀Doppler฀lowmetry฀and฀by฀determining฀transcutaneous฀partial฀O2฀pressure฀with฀ platinum฀electrodes,฀as฀our฀own฀research฀has฀demonstrated฀ [9] .฀Attention฀was฀drawn฀long฀ ago฀to฀the฀differences฀between฀the฀reactions฀produced฀by฀cigarette฀smoke฀and฀by฀nicotine฀ [152] .฀Reactive฀hyperaemia฀occurring฀after฀1–3฀min฀occlusion฀of฀the฀upper฀arm฀with฀a฀ blood฀pressure฀cuff฀and฀its฀normalisation฀have฀been฀found฀to฀differ฀between฀smokers฀and฀ non-smokers฀ [9,฀153,฀154] ,฀with฀reactive฀hyperaemia฀in฀smokers฀being฀less฀than฀that฀in฀ non-smokers฀see฀Fig.฀ 6.6 :฀the฀reasons฀for฀this฀are฀certainly฀to฀be฀sought฀in฀vasorespon- siveness฀NO฀production฀and฀in฀the฀viscosity฀of฀the฀blood,฀which฀inluences฀its฀low฀prop- erties฀ [9] .฀ The฀ differences฀ in฀ vasoreactivity฀ were฀ still฀ detectable฀ even฀ after฀ a฀ 6-month฀ observation฀period฀Fig.฀ 6.7 ฀ [8] .฀For฀a฀summary฀of฀the฀indings฀on฀this฀topic,฀readers฀are฀ referred฀to฀ [155] .฀Simultaneous฀photoplethysmographic฀recordings฀of฀blood฀low฀at฀differ- ent฀tissue฀sites฀revealed฀a฀considerable฀vasocontrictive฀response฀in฀the฀ingers฀and฀a฀more฀ modest฀response฀in฀the฀toes;฀the฀response฀was฀absent฀in฀the฀forehead฀and฀ear฀recordings฀ [154] .฀The฀magnitude฀of฀the฀vascular฀response฀in฀the฀ingers฀did฀not฀correlate฀with฀the฀ nicotine฀yield฀of฀the฀cigarettes. O 2 ฀supply฀is฀associated฀with฀tissue฀perfusion.฀After฀smoking฀or฀chewing฀nicotine-con- taining฀gum,฀digital฀blood฀low฀was฀reduced,฀and฀this฀effect฀occurred฀earlier฀after฀smoking฀ after฀5฀min฀than฀after฀chewing฀nicotine฀gum฀after฀45฀min฀ [137] .฀By฀contrast,฀no฀changes฀ in฀tcpO 2 ฀were฀measured฀either฀after฀smoking฀or฀after฀nicotine฀ [156,฀157] .฀These฀indings฀ stand฀in฀contrast฀to฀our฀own฀long-term฀results฀from฀the฀NiveS฀Study฀Fig.฀ 6.8 ฀where฀a฀ change฀in฀tcpO 2 ฀could฀still฀be฀detected฀even฀after฀6฀months’฀smoking฀cessation,฀in฀compari- son฀with฀smokers฀ [8] .฀Investigation฀of฀tcpO 2 ฀in฀smoking฀and฀non-smoking฀mothers฀has฀ revealed฀a฀less฀pronounced฀hyperaemic฀reaction฀in฀smoking฀mothers฀than฀in฀non-smoking฀ mothers฀see฀ Chap.฀8 .฀When฀an฀invasive฀method฀was฀used฀to฀measure฀O 2 ,฀a฀reduction฀in฀O 2 ฀ supply฀lasting฀for฀30–50฀min฀was฀detected฀after฀a฀single฀cigarette฀had฀been฀smoked฀ [158] .฀ In฀overall฀terms,฀according฀to฀the฀results฀of฀the฀6-month฀NiveS฀Study฀ [9] ,฀the฀inhaled฀com- bustion฀products฀of฀tobacco฀have฀greater฀signiicance฀for฀the฀pathogenesis฀than฀nicotine.฀ While฀nicotine฀does฀possess฀vasoconstrictor฀properties฀of฀its฀own,฀these฀are฀not฀responsible฀ for฀ the฀ hypoxaemic฀ reactions,฀ as฀ also฀ conirmed฀ by฀ clinical฀ trials฀ in฀ angina฀ patients฀ 18 16 14 12 10 8 6 4 2 1 2 3 4 5 6 7 8 Time [min] Arbitrary units Fig. 6.6 ฀฀฀Post-ischaemic฀ reactive฀hyperaemia฀on฀the฀ skin,฀measured฀by฀laser฀ Doppler฀lowmetry฀in฀16฀ smokers฀before฀straight฀line฀ and฀after฀dashed฀line฀ smoking.฀The฀vertical฀bars฀ indicate฀±฀standard฀error฀of฀ the฀mean฀ [210] –2 2 6 10 14 18 22 26 13 12 11 10 9 8 7 Reactive Capillary Flow t -pmax [sec] Relapsers 70 Smokers 30 Abstainers 50 Weeks Fig. 6.7 ฀฀฀Changes฀in฀maximal฀ rate฀of฀increase฀t-p max ฀in฀s฀in฀ intracapillary฀low฀of฀red฀cells฀ after฀3฀min฀of฀forearm฀ ischaemia.฀Ex-smokers,฀ relapsers฀and฀smokers฀over฀ the฀26-week฀study฀period.฀ The฀vertical฀bars฀indicate฀the฀ standard฀deviations฀at฀each฀ measuring฀time฀ [9] see฀ Table฀ 6.3 ฀ [55] .฀ Ultimately,฀ the฀ facial฀ colouring฀ of฀ a฀ person฀ who฀ has฀ smoked฀ for฀ decades฀speaks฀for฀itself฀ [159] . Blood฀low฀defects฀were฀recorded฀by฀ 82 rubidium฀emission฀tomography฀in฀8฀out฀of฀13฀ patients฀with฀CHD฀undergoing฀bicycle฀ergometer฀exercise;฀in฀6฀of฀these฀8฀patients฀the฀ blood฀low฀defects฀were฀also฀recorded฀at฀the฀same฀sites฀when฀a฀single฀cigarette฀was฀smoked.฀ A฀causal฀relationship฀with฀smoking฀may฀be฀assumed,฀with฀reduced฀O 2 ฀availability฀ [95,฀ 103] ,฀increased฀platelet฀aggregation฀together฀with฀raised฀plasma฀ibrinogen฀concentrations฀ [5,฀109,฀160] ,฀reduced฀NO฀and฀EDRF฀ [49,฀50,฀113] ฀and฀increased฀blood฀CO฀levels฀ [161,฀ 162] ฀contributing฀to฀myocardial฀ischaemia.฀In฀63฀patients฀non-smokers฀with฀stable฀angina฀ and฀with฀proven฀70฀stenosis฀for฀at฀least฀one฀coronary฀artery,฀ergometer฀exercise฀pro- duced฀ST-segment฀depression฀after฀exposure฀to฀2฀or฀4฀carbon฀monoxide฀see฀Fig.฀ 6.9 .฀ Simultaneously,฀the฀time฀to฀onset฀of฀angina,฀time฀to฀ST-segment฀depression฀as฀well฀as฀ exercise฀time฀were฀recorded฀as฀endpoints฀Fig.฀ 6.9 ฀ [162] .฀The฀effects฀were฀very฀much฀ more฀pronounced฀after฀exposure฀to฀4฀CO฀than฀to฀2฀CO.฀Smokers฀with฀CO-Hb฀levels฀ 5฀should฀give฀up฀smoking฀because฀of฀the฀danger฀associated฀with฀the฀consequences฀of฀ existing฀ischaemic฀heart฀disease. 60 50 40 30 TcpO2 [mm Hg] −2 2 6 10 14 18 22 26 Week Abstainers 51 Relapsers 72 Smokers 33 Fig. 6.8 ฀฀฀Changes฀in฀transcutaneous฀partial฀oxygen฀pressure฀base฀value฀mean฀±฀standard฀deviation;฀ 95฀CI฀between฀baseline฀and฀26฀weeks.฀฀p฀฀0.001฀between฀baseline฀and฀the฀various฀time฀ points฀in฀abstainers฀and฀relapsers.฀Signiicance฀p฀=฀0.0339฀to฀p฀฀0.001฀also฀between฀smokers฀vs.฀ abstainers฀or฀relapsers฀at฀all฀time฀points฀ [9] Controls฀฀ n฀=฀36 14฀mg฀nicotine฀ patch฀n฀=฀36 21฀mg฀nicotine฀ patch฀n฀=฀36 p-value Perfusion฀defect฀฀LV –฀Total 17.5฀±฀10.6 12.6฀±฀10.1 11.8฀±฀9.9 0.001 –฀Ischaemia 10.1฀±฀8.5 ฀ 7.2฀±฀6.7 ฀ 6.7฀±฀6.3 ฀ 0.036 CO฀ppm 23.3฀±฀10.5 13.8฀±฀9.6 12.4฀±฀8.8 0.001 Nicotine฀ngml 15.8฀±฀8.3 24.2฀±฀12.0 30.4฀±฀10.8 0.001 Cotinine฀ngml ฀฀290฀±฀137 ฀฀338฀±฀186 ฀฀422฀±฀224 0.002 Cigarette฀consumption฀ daily ฀฀฀ 31฀±฀11 ฀฀฀ 11฀±฀10 ฀฀฀ ฀ 8฀±฀7 0.001 Table 6.3 ฀฀฀Effect฀of฀nicotine฀patches฀on฀perfusion฀in฀the฀damaged฀myocardium฀of฀patients฀with฀ CAD฀ [55] Measurements฀by฀201Tl-SPECT฀3฀and฀6฀days฀after฀daily฀application฀of฀a฀nicotine฀patch

6.2.4 Arteriosclerotic and Inflammatory Vascular Reactions

Disturbed฀NO฀production฀and฀prostacyclin฀synthesis฀are฀just฀one฀aspect฀of฀the฀vascular฀ changes฀initiated฀by฀smoking.฀In฀addition,฀the฀increased฀adhesion฀and฀migration฀of฀mono- cytes฀into฀the฀subendothelial฀space฀are฀important,฀and฀these฀phenomena฀are฀intensiied฀by฀ cytokines฀and฀LDL฀oxidation฀ [163] .฀Leucocytes฀come฀into฀contact฀with฀the฀endothelium฀ where฀ they฀ deposit฀ proteins฀ and฀ glycoproteins฀ on฀ to฀ endothelial฀ cells฀ and฀ monocytes฀ Fig.฀ 6.6 .฀The฀adhesion฀of฀the฀cells฀is฀facilitated฀by฀adhesion฀proteins฀intercellular฀adhe- sion฀molecule:฀ICAM-1฀and฀vascular฀cell฀adhesion฀molecule:฀VCAM-1฀and฀by฀integrins,฀ and฀NO฀plays฀an฀important฀regulatory฀role฀in฀adhesion฀ [164] . A฀study฀conducted฀in฀2004฀evaluated฀the฀effects฀of฀cigarette฀smoking฀on฀the฀plasma฀ concentrations฀of฀VCAM-1฀in฀patients฀with฀CAD.฀The฀soluble฀VCAM-1฀level฀was฀quanti- ied฀in฀smoking฀CHD฀patients฀in฀comparison฀to฀those฀from฀patients฀with฀CAD฀alone.฀It฀was฀ found฀that฀soluble฀VCAM-1฀levels฀were฀signiicantly฀higher฀in฀smokers฀than฀in฀non-smok- ers฀32.1279฀±฀21.6421฀vs.฀9.4570฀±฀7.8138฀ngmL,฀p฀฀0.01฀ [165] . Anti-adhesive฀properties฀become฀lost฀as฀a฀result฀of฀smoking.฀Ibuprofen฀has฀been฀shown฀ to฀reduce฀the฀adhesion฀of฀monocytes฀to฀TNFa-stimulated฀human฀umbilical฀vein฀endothe- lial฀cells,฀accompanied฀by฀reduced฀radical฀generation฀ [166] .฀It฀has฀been฀demonstrated฀in฀ human฀umbilical฀vein฀endothelial฀cells฀that฀smoke฀condensate฀causes฀a฀very฀rapid฀rise฀in฀ the฀expression฀of฀both฀adhesion฀proteins฀on฀the฀surface฀of฀cultured฀cells฀ [167] .฀Ascorbic฀ acid฀is฀reported฀to฀counteract฀the฀increased฀adhesiveness฀of฀monocytes฀in฀smokers฀ [168] .฀ On฀the฀biochemical฀level,฀it฀has฀also฀been฀shown฀that฀Nicotine฀could฀augment฀adhesion฀ molecule฀expression฀in฀human฀endothelial฀cells฀through฀macrophages฀secreting฀the฀immu- nomediators฀TNF-a,฀IL-1b฀ [169] . Smoking฀also฀alters฀the฀haemodynamic฀forces฀at฀the฀blood-endothelium฀interface฀ [170,฀ 171] ;฀likewise฀the฀concentration฀of฀adhesion฀molecules฀on฀the฀endothelial฀surface฀is฀regulated฀ by฀haemodynamic฀forces฀ [172] .฀In฀addition,฀the฀concentration฀of฀the฀monocyte฀adhesion฀ protein฀MCP-1฀together฀with฀VCAM-1฀is฀increased฀by฀the฀shear฀forces฀in฀smokers,฀and฀this฀ is฀important฀for฀the฀adhesion฀of฀monocytes฀and฀macrophages฀to฀the฀endothelium฀Fig.฀ 6.6 .฀ −2 −4 −6 −8 −10 −12 −14 P .02 P = .05 P = .004 P = NS P .0001 P .0001 Time to ST-seg- ment depression Time to Angina Exercise duration 2 COHb 4 COHb Percent change of room air to CO Fig. 6.9 ฀฀฀Consequences฀of฀ CO฀exposure฀in฀patients฀ with฀coronary฀artery฀disease฀ CAD.฀Exercise฀time,฀time฀ to฀onset฀of฀angina฀and฀time฀ to฀ST-segment฀depression฀ were฀reduced฀overall฀after฀ changing฀from฀room฀air฀to฀ air฀with฀an฀increased฀CO฀ content,฀resulting฀in฀COHb฀ values฀of฀2฀and฀4฀ respectively฀ [162] 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] .