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i4-7-r `l 1 >t. ~ : o. ,-. 3~s s. V;et of Dro e : =t or queries. ~~~ (~~;cate aU u, ec:"=,s Pc;ential Mechanisms for the Augmentation of Atherosclerosis and s,'^eresclerotic Disease by Cigarette Smo:cing'•z HeNRs" C. >IcGirL. JR.' P.G. .,. t __. -. S.. . 4 Tc,.a 7s"5 - Ci_ ~c-_ -.....-..is c,__ ... .._.c:-o..r..lnthcd.._.;...c. cthe ` .c -_.e e,:emi.e =.-_'.cr ar.d LDL c6olescerot. s::^4::c Iower da rons^u:ers. In the ..irection of s-v:ea _re L_r.ec ar..l^?-.e b-..c: N.vd pressures than --Aers. Ob sene_e eca~.`.;ch_Is.,-_}•___-en:s:.`. ~-c'.crosaits:roAersaseo-tp~red~:~r.srru:ers i:.cr--ed * e; _: .= r.i.c' of _ _ _r._ ...__r_c cor.::ihutes :. IN i F:.O::UCTION Ti-.; p,-..,._ncc of car'-:.a rnor.o\i.ie _n' nicotine in .-a:e:tc smoke. [htir pre .;e i- ::-e hlood oI cic_ ctee sc:o=cd the l.noti, ledee of their nemerous ph.si~'.:_:; a-. bio 5 r:,_; e_ a in ^_..._.. and e\pe:imental animals ha%e led to tt: t,i=_,c:r_d su<cir.on :-_: one er :xh of these s.:b1tar,es ma_~ be the 2Ce'.:s for t.^.e --3:o.laUon ):`et\seerl .Igaretle srP,on1C: and :_-_...._ hz~art dis;ase. Th., °.r7 and agaicst their b:icc responsible for a_, _.... _ the ri,k of :tis d:•e~se ~._s :_en re% ie.ued repeatcdl~- Ci;are::= smoke cor:a:n s r..an } o;`:_r s,bstances that are p^armacolecicalh acti%e. a _enic• mu:scer.ic. or tosi:. It \tould be surprisirg if the efiec[s of as cor^:e\ --s atherosclerosis t% ere due to only one or n:o co-:rorents. or if Ih= effec:s produced by onl} one mechanism. We ill in this re-,:,n to ex2.-,-t ~o.me of the responses to cicaretre smo}.e ,%.;:ich mat" at:ea a;heroceccsis o: ischemic heart disease. ~ ' P-e--~e: :: a \l"oasF~ Lr. C-=.e \:~-,=r_ Cardio._scc'a: Dieeuse. spon-red b~ the FcLr- O:f:cc. Fedcrat Rc,.a%c of Gcrcany. Bcrli,. Oc:::er :S'd. _s .,, Gr:nt HL-1976'_ f:o:n t`e \..ional Heart. C. l!cG.":. L•.. ?: D.. Dc;:r,ncnt of P:,'F.o1::,. Thc Lr.i.cv:~ or Te.=s E:_:n Sccrtc Cc:cr •: F:r.L C:: C-i.c S,n An:onw Tc,_s -S'. ^ ..._.._ w/jVl(vKS , ' ts - , t ~ •'. r. ... , ~_... . u~ . . (.. ~ .r...-.r_ 0 t • '~ Av -X

_ HLNRY C. MCGILL. JR. ATNER3SCLi=r;CS:S CR ATHEROSCLEROTIC D:S=ASE? The status ofo:.. :on.ernin, t` i' :hoct;:e-,t~ of --:!:_:.l.:lcro>1,~ ;in.j the mechanisrn b~ smol;ir.c risk of di•z;:Ie. .;e must r-.:ake a prz:!i:::cai !esions and c'.in::a! di~za-e. be- :ause the me.:f~-::sm.s of a_::on in :;.t tao mav be cu::e different. Atherosz!Z:0 ('Z~:C5 1.^. :~1!.'hood \ll:h ,.._ depOsi::on of Iir:.j `to!esterol ..nd .:s estenl ... :!:e s:aoo:It =,_:!e cells of the ao-i.: int;mL_ In :`:e ,econd and :`:ird de:ades of l:,`e. similar fa::.- strzaks ar}_ar in the coron::rA- arterizs. and la:er t:a_% in the arteries. Ir. N-0:-'^E: pJpulatlOns th~. have hich ov,.-A le~els of ~...~rJSC!eNSI:. some fatt\' :tre,:t.s `t ' a!~^'~~: f ` 1 Si O\1" In:r:: rZ~ i'.Cro~:~. }:ul: er:alon oLs: :uJth mu~: z Lz!:s. .nd fibrosis. La-er, t`ey :_~clcp lesions core of z~t-::el!u'.ar lipid ~-d a :apsu!e of smoo:h :muscle celis and co::r.ec::%"e :issue-a .h~r`c:e is;i: stru_;ure -,nown as the f c: JUs p'.aoue. In subszquznt %ears, fib: o::s plaques ic;-ease in extent ar.d size, and some produce s;enJs:s ot tn.°. lurr.en_ The•." :-:av undzrcovas:;:'.s:izationo he-or- rhaE!e, or u1.zmtion. and :re~;e and other poo ;y unders:ood changes lead to the formation of a ti::o:abus or. :he i:::imal surface. The thrombus rr.a% " be orca::izzd to add to the th:c:ness of t':e t:^-ous p1aqL'e. or it ma., cause suf*`::.ient ischemia of the organ surrl:ed b% t`a: a;.ery to pre,:::_e in.farctior.. T}e ._sultin~ c'.i::ical ss ndrome is su; den dea:h o: r~ ocardial i-farc:ion if the co:,,:far\" artz: x is af- fected: pe:ip.`._ral %ascu!_r disease if the f,:-oral artery is affzctzd: or ce:_bral vascular di~,ease if the vessels are If fi~rous plaques or bosis produce se% ere stet:osis but not ir.farc::on. one of the s~ n': omes baszd on partial is:hzr.:ia rr.ax " appear-angina pectoris or intermittent claujication. This relatior.snia of diszase to :he fibrous p!aqi~e of atheres.l_rosis makes it clear tl:at on e set of f..:.:ors. actir.n o%er mans• % ears. may be responslb'•e S{+bU~d k~~ for the pro_ressio;t of a:`:e:os.lerosis: an~ another se, of condi:ions ma~ ~ „ . ~. precipate the te: m:..al o.ci_si•._ zpisode. usually is t`-o rbosis. Stii'. c•,'te: reClr i taf-'C : di i : ~ h h i i ' con tlons r.::.. r.t ue c_ : e s:aczp:--) t e orpar, to ._: em a, an : e survival of the person a dam.aged h°a.^.. leg. or br: ir. Sr e:1tlcltC of t`e endpoint-that is, atheros.lzrosis or athero~clerotic disease-is necessar, in order to determir.e-patho_e-:e:i: mechar.ism.s. Atheroscle:osis includes se•::~1 di:iz:e. :'.esions, and it also is necessary to select specific les:on er.dpo:n:s. The abo~ e b: ef account of pa:hogenesis omas the controversy concerning the of the :izrJus p!aque. So...: evidence suggests that fibrous plaques arise by a process inJer.::dent of fatty s:reaks, and that thz ~ anatomic association of the vao lesions is coincidental. TherzfJ-e, in exarr:nir., the relationship of a suspected etiolo_ic agent to clinically signifizant atherosc.:rosis. the deposition of lipid i.,: e is not suMi_ier,t_ Hov~ever. i: is necessarv to Shoa a rel~:i~~a~ tip of the a__t:: to lesions -%%ith at Itast some of ti-:-e ,:haracte:istics of the fibrous plaque, since t`tis is the earliest lzsion that unques- ! tionably is linked to clinical disease. Specificity also must extend to the aaer:_1 seement in.-ot•ed and the organ affected. For exar .ple, ci~ re;te smoking aprzars to affect sz.zcti%el} the coro ~ N T __"tJ!'J. u ~ N ab C!1 a

\\~)tiF>Ilt~l': (.\E:I:uN \a0"O\It)L ." l) ( \ 1) rtan_• a.._::;s. the a!~.'.o; :ir.:a :+orta. and the ar:erie> of the Io\\cr extremities. S:C.'_:C~ :.. ::n:.:,:a t':;..tels. t`:erefore. should focus on t`:e5e >e~m~na in contr:v~I to tl e :`, .-:.z ::.~r;2 or the cerebral \~essels. E\z- :.`a s;:<p ected causative :•cent had no effect on :::herocencsis. but some- l:o'• to I~:o:::i osls. It C7 2.'tt contr:."u:Z sl_ ..:L:antl\' to a:herosclerotic di=za:_ ia a :.•ith a hich a\er. _ level c,` _ d.-: nced a:hero~clerosis. FLr_:.`.='. _.. ;h.: t s:he r.:e:abolic e,`5:ier..\ ..~f a:issue or inzrea ses the \io'i.*,,-... oi Il:e ]l;!ar1 contrlc:.te to :11ZrJ~:Iz:J::. .!Isease. Ia IJrmula::n_ :!te q'.:zs;lon :ncrea se sutistanll:aly tFe i~ li\' of Z::o':s to Zlucl"':::Z the n:ech;::asC'_ i\ \\hlch ci_:'.reite sm01:- 1:1_ :he ^~1: o: a:ilzrosclero:!,: disease. =T;.,_C.~: :'C .V::E\T; . RISK FF.CiORS. AND I\T=.R\'EN!NG V:,Pi;,BLES ..::o"\ n r:s; factors for atneros.:_rotic dae_-- ~_ (h,. pcrcholes:ero!cmia, sr^o;incand di~~~,es) •\er_ z~.~~' ~hed on the basis of tF Ir __: ~:._.:J1 \\ith a:l':--rosciero:ic d:se._r.° pr-l,-.:.:ral!\ Coronar\' hea rt di5easc". Tr._\ assOcia.ed \\ith more evensl\'e ..::d _e,-erz atherosc!erosis (5,9). Ris: s::ch as h\rer:holesterole;..ia and h_, Fc.__..:iorn almost ce^ainly are due :o ~ co-::r.a:io;- of znviro;lr:e,::al and pe; e:ic :~.to; s. and :he particular ,:.a\- be d;_Ff;frznt for each H\r :,:holesterolemia and h\re.._..::o^ rrs\ :e c~ .siderzd "r:sFonses" of t':e i::~i\-idual to }as zn\~iron- r:ec:. `:._:_ :esro szs i:, turn ma\ acze'.er::.e aa:e-e=e::-f-~is and ir..rease the risk of p:ecipita:e disease. S,-,:h ma\ be considered \a-iab:es in the chain of :"._a;ioa f:.m e:io!o_eic acent to and :::e\ ma\ . ieI ± some c!t:es as :o :h e _ _ ~ re po-_._._ fo; titem. S_~U~.. L!P:D AND LIPCrRC-EIV CCNCE"NTRAT!OtiS Si-::c choesterol concentr--:ion is the most co::,istent and most frequent ris'." for corona- hfart dise_~sz. and since i: ._ \::,?,l\ E~l:e\ed to be an l:'":,-0.7 _': .... . e.^.'.r'z \,...._Cle in the ^a::1:(-er:esls or_.:.erJcclZNslsf it is reason- c~ Z:o for ZitZzi~ J: :lZ=:Zlte sr::ok1.^.c O:: :..e :_:,...m. ctilo:es:e:ol concentra- tio .m......_::isrn. C:_ca-_...e s;..ol:inc --_eo uas estsbl:shed as an risk Iazto: In that its e:IcCt \\as not LJ\' :Ite mtions in the o:her ..~k fa:.to:s. i^cI~ in~ h\pzrch.les:eroler::ia. In of the more recent e\-i,:e-ce su_~estin_ thst lo\\-dens::\~ lipoprotei^ 1 LDL or 2-lipoprotein) is a:`te:._ ._.c trat hi_h-densitv lipopro:ein tHDL or C_- -l:roFroteini is protective, it a?so :s r.e_essarv to lool for alter-a:ions in the l:r:,rrotein pat:ern as \\ell as cha:~=e; :.. :o:al serum cholesterol concer.::-ation. \z;-:,-rous stuJies have investi- ~_'zc .__..e dat`e past '_5 years. Tne evide ncz is confli.ting and a clear ::o: vet avail~b'.e. but a succ.-stive tr;~::d has de.e!oped. Go.`-.=- r: c!. (2u) \\ ~!: e,he firs: to inves:i-ale tr.e co-zer.tz-atio^s of serum lipids and ._r;r; in smJi:zrs and not1s: Ioe;ers. TCe\ r_r:ornl~d uliracentrifupal =ral\ses on 310 men and 91 •:o~:en f:o.m 20 to 59 \ears of a_e. In r,.r..._... ~ \o-_-- ..._.n ar.d mon,en. the to:al serum choleste:ol concentration .;as, on the hi_che-:n sr:okz: s tl:an no:amo=:er s. Also. most ca:ecories of the I:p.p ~~ro:z':ts aere hig'er in ---s,..o~: 'ers .}:arn t:~,r. s:no;ers. Results \\ere a.:._.. _... :~.. I

liI_NRl' C. MCGILL. JR. ~rt \'arf:~b!z in the older men. None of the differences \tas i:ant. Kanonen rt ei l. (_9) compared >crum cho lestzrOl cUncer.tr~tions oi :60 !~r.^.o;zrs :h those of 165 n.n~mokern in FMl~nd. Overall. ~.erum cho!estL-roi %%as ahout'_3 _.il hi_her sr::Aers than in no=.okers. and the diffzrence \%as rz'.a:ed to the :ount smo;ed. Ti:! dif;erence \t::s less in oldzr men. Da.\bzr rr t:i. 4131. rep;Jrt- _ earl)' findincs f:o:n the Fra,;,. ,::h_m Stud) de~,c.^:bed slicht1} -_her ser.:nt '.es:erol ]e\ e!s ar or.e smokers. Blackburn r: cl. (;)fot:nd sli_ ::1\ : i_! er serum J!z:stZrol 1:\eiS in U.S_ smokers :!ia t'. tn U.S. noCsmJl:ers. bJt t}e a: L- s of :o 9 mEi'dl %• z: enot s:'nifcant. °-LiYoprotein cholesterol levels Finnish .\o:;:ers% the differer.:e \cas 2reater (26 m_ dl) and just as :\ oc.n ct rr'. 1=9i nad found. Thomas (6?) found sli_chtl)' hi-h:_- se. ~:n cho!es- rol con:z:a^:ions i.^n smokers than in r.onsmo;ers amonc 621 rc~-.'.::--1 stt:c:er.ts_ _~eson and Jess.p (1) found no d:fference ~et\\een smokers and ::c-smol:ers nong e1,J:r1\' r.:ea 6~~ \ears and Bronte-S:e\\ar. (S) studied c:pa:e::e smok- z and other risk factors in thre: mcial groups of Cap:to\.n. Hea\-\' ci_arette co;ers 25-39 \ ears old had }:ic:;er serum cro'.es*.zrol levels ,0nsr::o;;ers. it in the 40 to 4_-vear-old ero::r s the trend was reversed. Ho\~ e•. er. ,he choles- rol in ,3-lipop:o:ein \%as consis:er.:lv higher in s:-toners. an.: c::o?estzrol in -lipoprotein uas consis•entl)' lo\\er i-t smokers at all aces and in a:: rac:a'. groups. Konttir.en (=01 suuied 314 \ our._ Finnish sold:ers 18-25 years o?.::. i nere \\ ere o differences betv een smokers and nonsmokers in serur: c'.:o!esterol. -lipoprotein cho'.esterol, orP-lipopr..~:ein cholzsteroL McDonald -: .:l. (="-) foand o relationship bet\%een smoking habits and seru:n cholesterol .:on.:e:a .~_tion in 76 men in militan' service after adjusting for regression on age and ponderal ;dex. Hi2_ins and Kie!sbers ('_"t found no differences in serum c::o!es:ero! levels et\\een smol:ers and nonsmokers in Tecumseh. Michigan. Andrus er c1. f'_) found no co:'re'.a:ion between smohinL, and zi:he- :ota1 serum holesterol con.zr.'r,•ton or y3-!Ipo^rotein cor.cer.tration in a co--t:::::rity stud\ in alifornia. Amocc ?.G00 health.- men. ages 39 to 59 \ ears. Jenkins ~: ci. t= 6) found mean serum cho:_-,erol le\el of 2 17 m~'dl ir, nor.:mo}:ers \zrsL- in heavv mol:ers (P < 0.001). The P'c.-lipop:o:ein ratio also \\'as higher in smokers than in onsmokers. . Pozner and BiP.i:::oria (52) fou; d the total ser;:m cholesterol con:en:ration 24 nc,'dl hiE!her in `i heav\• smoi;ers than in '_0 nonsmokers (P < 0.0~). f3- and )re-j3-lipoproteins also «'ere significantly higher in heavy sr.:ok-ers than in tonsmokers. but there was no difference in a-lipoprotein. -Ml s::~jects \\ere : oung, heal:h\- \'olunteers. 19 to :0 }'ears old. HoWe1l (='_) found no differences in total serum cholesterol or 3-lipoprotzin oncentraT.tor:s ::moac 1.483 m;-n. 40-54 \e: rs ol.j. re!ated to sr::oea::^. Pl.^.ch'.rlc.' 51), in a stuiv of 7,133 men examined in routine hz!alth found a rend of in.:zasei serum choles:erol concentration related to s;r.okin_ •.\.ithin ace :roups, but th;~ di`.`zrznces \%ere not statisticallv sicnificant. Sch\:a.z er cl. (56) :ompared smokers ..i'.h nonsmokers in 7.972 Parisan male ci\'il se:%ar.ts. «Ten :djusted for diff~fren.es in body build, the serum cholesterol co::czntra:ions of -mJl:ers %k ere h:^her than those of nonsmokers. and the differences. thou2h sli_ht, V L , 5laoold b e : 1"aris~Clw~ ~' _n>N

\\Ui<1>HUP: C:\RfiU\ .`.:ONOXIDC .\'•t) C\'1) _1% .cere st::istically -~~i-_ni'lc:,nt. Jenkins ct (::. t3-1 re<<'r.c.l that 9 'r m.ire hea\•)• smokers had serum cho:es:erol lc.el.s or ere::ter :han 260 m_ dl than did r.onsrao;ers t'_4, vs 15 c). The'_.31S su`':_::s on \.hi.h ;^is comparison \+as based aFFare.^.t:\' \lzre the sa.:,e group pre\described by Jenkins c'1 [fl. 1`6). Da'es ct ul. (1') an--.l%zed multiphas:,: reslth e\z:rr.i; ation results from the Kaiszr-P:rTanen;e 'Mie2ical Care Pre_-am on \.`ite pursons and 9.81'_ black pe.-ons 15--9 \ ears of age. Whi:e .,.:ae sr :o:ers had siQnifi.an:ly higher ser•::1 cholzst_rol'.z\els than nonsmo:ers. The saTe :-zr.d \':as true for \%Jmen but the U`=fzrence \kas less. Amon_e b'.::ck- men and \'•o:::en, the diffz:er.cz \~as re\zrszd in direcllon. nJ nsmokers ha\ine :1:e hi=*-,e- s_rum cho!e•terol !e\els. Ar.,on_^_ \Ah:te male .:-:,•;e:s. there \kas :_ p, -i:Pvz between numbers of clea-et:_~ smoked e:e\atloa in serur-: c1:Jles;erJl. D::;erences %lerz ereater at \ ot:-.=Zr aces th::nones. ~ . Biliimo7.a et rll. (6) fou:,i that 23 tr.ale heav\ s.-no;e:s h~.l a mean serum choles- terol conc;fntr3tion 2S rnc -1l hicher th~n tl:-t of 2 - r::~l;~ nonsmokers (P < 0.0ni). There x\as no differz:..z bet\\een fern~!e i:ea\.• smokers and female nonsrnokzrs. ~f !e licht smokers did not differ from r.ons::'lokers but their mean s=r.lm c.`.o':zsterol cJr:ce:ar::tion was 16 mc 11 create: t:an that of nonsmJl;ers. In a la'zr ana':s sis of Fralnin2ham d:::a. Gordon cr cl. (?3) acain found no d1;'erzr._z bet'.\ee;: s: ::::_rs and noas:; o;ers in serL'r:i :!:Jizsierol cor:czn'.r:-tlons, and no ciLn-es. ei:;:e: short or ior._ te:nn. in subjzcts \'.^o quit smoking_ Hjer,:.a^n er cIL 12-91 found a positiVe a~~o.:ia:ior. be:\°.een ciparettes smoked per da\ a.^.~l ~Zrum c!loies:2rJl concetltra:lJn a: all aces f:J:T. 20 to 49 \e~rs in 16.i-)~ heal:h\- O~lo rnen. cholesterol le\el.s %:ere lov.zr i n ex-ci~arettz smokers 5 }ears .~:.er quitting in p:esznt ciea-zt:e smokers. - Nforz rzcer.tlv. the disco\-erv that :~t densit\ lip~~r-J:zin 1HDL1 cholesterol is in\erse!y associated «i:h risk of hzart di~z::se focused :::tzntion on factors -ffectin~ this !:p.protein ("). ;z\:r; of the o:.:er s.udies rz\ie\\ed above hie:e,J ;:: reduced :a-iip.pro,zin fthe e:ec::ep^Jrz:i,: z~~:\alent of HDL) in smok- ers. bu: tr:e rest:'.ts e:a:er \\zre no: or their b:Jloclcal s1c- nili_accz «as not apr-ec:ated. _ - The:e \kas no association bet\kezr. HDL and amon- ".S15 men and uoc:;zn ;9-S'_ .esrs of age in the Fr:.-1i-,g-:lam St.:dti t'_), nor in approximately 450 mzn and women ('5). Irn contrast to the~e negative rzsul:s Hulley et cl. (3) found. ar:Jr._ -,01 men in a mL!:ip!e risk Ez:t0r intervention program, a ne^ati\e and statis:ica::y siL-nifizar,t r..u::l\anate re_rzssion coefficient bet\\een chance in serum tlt:occanate level (used as a measure of smokine) and chan2e in plas^ia HDL cho!zs:ero1. Goldbourt aad Medalie (221) found in 10.000 Isrdeli civil servants 40-65 \ears oface an inverse association bet\%een ciearette smokine and aQe-2~1;usted HDL chJlesterol, \%hiz~h \._as approxirr:2:ely 2.5 madl higher in no;:smc;en than in those .•ho smJked '21 cicarette~ per da} or more. er al. (1S) examined the b;f;v~eea ciQarette smo'%inQ and HDL cholesterol l.e\zl in the off~pri.-- of the Framin2ham su~jects. Ci~are::e smo;in_ .'.as associated \ti:h an avera^z di te-ence of about 4 m_ dl less in r..ern and 6 r.lc'd! lzss in \\ omen. Wcer. ':eavv alcohJ: u~er s\%ere elimi.n.ated. an in-vzr,;e association co~!d be dzmor.s:rat_d ~et\%zen nur:-ihzr of cicarettes smoked P

fii %nY C. \I( (~t! 1., JR. ir.d HDL in h,::h T_n ::cd \~or..~... Former sho.ked :o .'.iffcre..:zs in HDL c}o:__. :ol. .-;rniZer::us ~•t u1. (3) su ey ed apr roxi...a:el: -•-0 .% or.:ea in Leiden for riNk ",c;ors for coronary heart d:=ease. Bo:h o nI co:,trncc;, i\e use and ci_ :rette ~.;.oK in2 \te:_ ..<so=.ated •.%iilt lo•.:er HDL c'.:oi__...rol le\zIs _ - :o = mg'dl. There Aas r.o i:e a=t:on beht een oni contra.er :Kz..se and it::: ;i-:. RZ\'iz\\ of ttz s~ot'e Stu'.':os su'_gzsts :Ga: -_arZtte of:en cau-ZS a li_It* to r o _:a:e zle.ation of total szru^ c`c'._sterol The early ..:rponed by i_:z: observa::o-s \:::h largz r.i.... _rs of su:_ _.__ T.`._ a\ail::hili:, of __.:er r.iz:hc2_ of z!nalysis fo- :_:im HDL su=.`. :-_ :he precir i;a:iJn me:hod, hi\ _ made feas;blz K_er sun eys f.,~: :cis cha. __._..-.,_. The a\ er::ge .:::,'ereczes . _:11cZ.^, s ;7o.-~e:: : -.' : onsr':o'.•:.:s :"1 HDL chJ0=._:c: concer:i:atlens up to about = r::: 11 a rc.' s: ?AI. hut th.'. \'ar::.l...:\" in ihls Ili:t:o:Z::i chMs;Zrol is Lrally rr.:.:h s^aIler than A= for LDL c..:.~1osteroL. ~.... .i:;:orzn:.zs of this .-_nitude are associatzd a:..h differecces in risk of coror._-.- heart disease. A cozsistent dei7zssion in HDL 2...,np \ou^_ ...:?:hJod (tha, is..:o^: `out 30to40 \za:5 of ageI co:1l~ l:,f::.,'.i..'.e s1_ niflCant:: :r:e r:o_ress:Jit of _2'.:o5clerowls if current h'.pJ:.._:eS ?.}`ou: :Go -.-.:''theroge..... f1.^.=.tlon of HDI..L we correct. Thc- ofFJ`1:': Z•.`:ZwS of s:':;i,_ on LDfL a-d HDL also e\plaln the ..^.consls:.nt o=:ervctlons on :::at serum ..'.o:_::Zrol JoC:..'....a.:o't. An effect on bJ:h frc.io: s in oYposite c:-e=.Ons woW .__.. :o no char.: in .-_ cor.cen:r:aion of total szrt:-: cho;est_ro'.. S:-=e c`ances in LDL are usua".- ..._=h _recter :han chanees in HDL. t;:e net z:._=- som..eti:::_s is an e'.e\Ztio: in :o;al chole.~,tzrol .oncer.tra:io :. The relat'oa:-:i of HDL to __._.._ smo;i-p :..so is confounded ~'J\ln 3SSOJ::::.:"' of :!g3rZ:._ smoking \1l'.1: :..=J::o1 usage. \\h1=.h in by the \cZll ,. tun is asso:ia:ed ukh ele\•a:lon in HDL \t: _: t::e alcohol is relati\el\ lo\k. In con.lusio:-t. it appears'.:M\- that ciga:e::o _r.:oking rr.:.\ ._=t atheroeenesis by intluenci::; the conceet r-::on of serum HDL. This rela:ions`:p does not offer an explanation for an effect of '_: e;te s:r.J;i: _ on the term:::_l occlusi\ e episode nor on the Iikzl:hood of =_- .:A after t::_\-c=ardi::1 or ~_._..... infarction. The componen: of cl°rette si*..o:e :esponsif-le :o: tris zffect a-1 its mechanism of action are no: I:no"n, but t::: pheaomenon F.o\ i2es an in:e.;..e.aa:e endpoint that would be mu,n easier to inves::_cate than the u::i:-:ate effects on a:herosclerosis or on atherosc:oro:ic disease. hTOCRIT. -=t.,0GL0o: \. :,N D ERY-: ;=QCY-1 E S Observations on smokers and nonsmokers are remar;:ahl_ consistent .\ iih re- gard to er. th:o=\ :es. he^.a:oc:::. and hemiJ_:oh:n. Eisen iaa I:_-:mond (14) "ere the first to T2io.^, hi:ghzr \'aIL't= for these va':iC::S in smokz:S :t:: in ni7n~, moi:ers, and suc_ =.ed rossib.e re:_aJ :ship tet\le_.. .;es: fir.d:-_s a.d :he przdisposi- i:on to thro-:;oSls. Cu'r:ouAt, :t:ol" o}'Se:\ e~ a S1: =nllar cila '_ .Y:er smoking only 51\ Wan::ZS aS u e'll as a chronic Zii-Z:i in ;i=_::ual SmonZ'`1. Si^seOuentll', \1lth only one e.c_yiJn. e\er.- re_ o: of a sim:Iar comparison 1'_. 6. =6. 32. 34, 37, 57) , Q., has d~5cazo.~j a Sl: lllar eiZ\ a:IJn of t!1oS_ \ ai~os in s.^.1~~:o'S a s comparzd ~~~) A nonsmo=:ers_ The one e\cer ::Jn is Blacl:cn::r: cl. (7). MJs: st: 'ies sho\k differ- ences in the .._.....:ocrit of 0o:.. 0.5 to i_0"`:. One stud. i:-i. al:i=h examined a i

l\iJkK•Ifut': C \I:ltcr,~ \ttt~tt\:tlt. t~lt ( \tt .mall 1t1r:: _: of terv heavt •tmAer> tkith a r..,:t:] ;•1ooJ CO !ctc! of 1 1.V~. found 1 dt.fCf~^.~ ... .~f^a?J:fll of -.4f. Some htCll as 6Jl. The of Set'eral o: :h,.e rei J's i o;.., out t':at =-:reite smo}:ir.~~ should be =e-,:.'ered as a c:_use of po!vc.the:r.ia cz.`ore extensite l:zmr,to'c_ c .-\. _ ations are ,.,.:..z d out- Increas2-' has as a tr.i ~~~r risk f:.z:,,r for coronar}. heart disea-_. :h:° m::rkzd ......~se seen in so.^.^e ~,mehers cuntribute to the pre_... - c: a Ihrom. .._ .-• :h ° p:2s..,_C cf sct e: e cor o.~ _:':erosclcrosis. ~=UCCCY -1 ES I-!oa2ll ~`_ L' 2\z2ss of 25 in he E'.C:.. oi~r.:ol,ers. The 1 • T.e::n !:u:oc}-2 cc ,.: in _, `;~x ~. s. - _n s 12 0 ce.:2s o- -J-z dail}•) tt as 7.56S Fer c:-- ....., a- com,Yared45.y50 in 605 n..~-_.-o;zrs.o;zrs. Co:r: ~. .:1_ ( 101 found a SI'lllaC or.'_t`out 1.700 r2r cu l::Tl .:~ :.'so a rz'_.:Jnship of he IZu:oct te :o ::'.!:alattoa. a as an l:;:rZaS2 tC n2utfJr':1-s. 1% ,m,phocytes. 4r:d moaozt:__. T:•e increase ••tas not re!~t~d :o thz pres2n:e of :hronic bron- chitis. Frie.::-,:an r: <..'. I 17) ex::-l:r.e ::`:e reia::on of leu.:oct ?2 co::::: to smokinc h_~hits in o••_. ciultip`:a_. L2u.oc. _ counts tvere i,_:eased in of all r.es. and there ttas a dose-r2~po::-_ rel::tionship. Or.l} a sTa:- r=.. of tlle eletc, as a::r::...ac'.e to chroni b:o-.hitis. Using d---:a from ..... _=_ so .ce. F~ ~..._.. er c!. t 16i !a:er co;-:par2d .__;o_%te counts of 464 pe: 5J::~ 2~. 2 2)21i.~ a f`: S: .^.:t t'.:::: :!:J-2 of matched controls. I=._ !e..cozyt :.^.. of !6.S ...: -::rs before :!:e m} o:ard_: _:e;_ ..._ soc._.ed.. i: ':his e\ er:. C _rLtI2 sAlol:- aas asso_.~-ed •.t.:'t th212~ce __:o~.....r.:: ~cco:....2d for .-o-thirds of the rzlatio:: of :'e co::nt to Th.e lzuc..t ;e count tt as no: :el =:ed to risk , of mtocarc:s+ + ...._--_:iorr in r.o^_-:;t:ers. ~..z=.::.,»-:-r-`-= ~.. .._... ..=. _. T.e ` e coc}'te co -: aso arp_are,a. :o possess acd:;i, r.at p:edictit•e ro.ter ir.derecde: ? of smo:ir._-:iat is. s.^•:oll-ers ttith hi_l:er c_un?s had a ~:2a:2r ris: ;,: -_, c rdial irfzrc::?n. d:ff2rer.tial c,'::-:s tt ere not 2\ ai!able. Nelman ar.d R~e-stein (26t a-' B:!li:noria P: ci. 16I cor,firmed an increased !et oc\ te .o::r:: i-: s:rlok-ers. Fisch and F: ee~- ~ l( l5)sna!t zed factors u hi:e Flo,.)d cell count in 14.961 he '.:~ } t~-e l. and also f; _nd he i:-,:reased leuco.yte co,,:.., in smokers. :1.?:hou_^h oi.:.l co-: ~_z2pa\'Z 12r2 1'._.~. oP.l%- a effect on lZuz:.?:.l ;z count in nonsmokers. ;2-_:coc.:osis «as muc c-__,er in v.f:o both s:: oled and used oral cont.-a:.2p,:i'._s. Thus, there epfez:ed :o be ...n i^.: rction :e.'.teen ;.iparettz smokinc and o=-1 Ls_. This o^--. ~:io l ma} be •e:e ant~to the ,;:e,.'isposi.^:O:: f0- -t o;.ardial a-::o-_ t°..-en v.1:o bo:`l ~r.:3le _--nd use o:-l zoc?r:.•zzi:. _:- The ,! >Z.srIS1.4 >Z.s t'.ho 4J ::o: Smol:Z 1S much sr-.:a'er. None of the i-~e-z::_ators rzpo:;. .- :he 2!zt a:ed v. h::e-ceil co::^? has :u^^ested the ross;.'.e link bet.-eea :he !eucoc%te cot_:.,. ..r.d the in- creased risk of:o-o::arv heart d:sev__ and a:herosc!erosis in smokers. / jo ~ l~UP~`IC'4 r r_S ~ 6~ Z ~~~SJP rfJ pi A " ~~S r~'~ ~r• CG ~ `T~l . J I I ~! 1

lt1=*%Rl' C. s7CG:t.L. JR. We th.:t this ir.;er.cl::tion,,hip further, p:irticuLarly in of the Fossi: i!i:% ihat anllCenlc su~,t:,nczs in tob.:cco smoke may play a role in i:s a:herocer.ic e:-.tcts (see beto%% l. - OLIS^ 1 ' ,E ...E T:,E , _ , . _ C:.P~CHYDP. Se.e-a1 :•es:i_a:ors }:ave ctud:ed ihe Hood •_lucose in smokers as com- pared jd'::,,ns;no;ers. Tvo s:udies l%. 1'_1 found the fastinp h!ood _lucose of s^ol.ersio :-e sliz--a;l- I::bout ~ r^, .', :..att that of r.o^s;nokzrs. Hipcins and a 10 d1 differeace. it v:as not statisticalk• sicnific: nt. Recder L nd Ro:h 1:_ 1 fo :.^d no increase in fastinL- blood c!ucose in h::bitual ~TOI Zr~ ~:._. :hev s:r.o,zd t.,.o cicarz::zs _~.. in a simil::r experi:,~ent. Sandber_ ~'r 01. 0: i,::d t: d a r.se a`:er smo}:in-. / . \ h Sza.^.to (41)! `: L(-'d i!.~ fc~ill~ blood of 26 h~Za.~% smokers aftera abst;ilt~' ~Py~`~ ('t 6ST01~~ Jral i- from for 24 hr ::nd acaln a::L-;- S:^.to'K1~7^ t\t0 clcarettes. The ',--loo:j t- GC Q ( ) S plucose !e ;l rz.:+ainzd :he sa:~~ e~e after s:-:o'-.. _:n 12 subje.:ts, and rose b~ from 8 MOs~ed to'_'_ r.:a d'. in ;^. rer a...ir.~ !4 _ He did no: zo:-.pare the presmoking le,~ els ssith those of nons^:J;ers. Latzr. Sza:::o iF11 found that 4 of 5 smo'tl-ers had F.sperins::':;.e,aia du: a ~; :ose tole:_-._e :est, and that insulin levels during a plucose te:e:e _: test decrea~zd after cz!___.:.~.n of srnoi::n^. Diab_:zs :r.~-!litus is c!eari•% rzcoenize:: a_ -~tron, contri~_-u;or to the se\-erit\• of ::therosclero_is and as a factor for a.-erJS.!erotic disease. There is no clear consensus co',: rec_r`:'nc s:: eiher ele~'a:e~ t-:Jod elucose contributes to the car- dio~as:~; - co^:-_"i,a*.io-.s of JiaEetes. G:_zo~2 becomes at:ached to hemoclobin after it is s% r.:hesized. and ,he presen ce o= excess glucose in plasma and body fluids mav l;.-a,-' to avcosn ia::on of other Fr o:eins also and concei%ablv aucment athzroze;t:_is. Be%ond :ais point, ho~~eser. the relationship of elevated blood clucose to :::herozene:is is ~reculati~e. BODY '::ElGHT AND 3! OOD PRESSURE Obesit\. ce::era!is• is recc=ized as 2n rish factor for a,heroscierosis :hrouch i:s associ::;ion «a : diabe;es a::: i:-, c..ension. In of the immediate efffects of r.:coan e on b'.ood }rzssure an;: hea- --e. it is reasonac'z to examine the z 0 ~ isual blood przssure of smo:ers as cor-Ya-ednonsmo';ers. lJ~l W/ f Kar.on,n (39) found tha: Finnish sr::ol:e.-s hal slighily lo\~er blood pressures and ~ere ,.ear.zr than nonsmokers. Dav.~er et cl. (13) found no association of :itherbloo.i rressu:e o; re'at_se ~teich: t~i: : c:_areite smOt::n_ in the Framin2nam popu.atioa. Thor,:--s :. o_ ound h: :z!r heart rates but slightly lo%~er dia- stolic blood precseres in smokers than in : J::smokers. Blackburn er al. (7) found higher heart ra:es and lov.e: blood przssures a:non2 smol:ers than nonsmol, ers and a te::len;.y for smokers to be 1~-a-:!r than nonsmokers. Bronte-Ste.k art ;8) found no si~nit:.2nt d:_"erzr,ces betx%ze n b'.oo3 pressure or obesitv irr smokers ;n,4 non J~ers c,` Car et; u n. althouch i.`.e b'ood p; essures of smokers tended to re slic^:l~ lov.zr. Petzrs (:G) found no .:i: e,ences in bod%- between smol:- =rs and cr.::r.:okers ar.:onc Harvard Smokers in the Tecurnseh popula- tion s~ ei;!:ed lzss. thin ner. had lo.. er diastolic blood pressures. and had 'aster I::_-- ra:es than ~i.ad r.oasmo;ers t?-l. T:,- %kei,ht diffe:zn:.es remained after :djustir.c for drinlar.c habits. ~ ~G7Jf; jr~ 1w 1-11 'X /Akx~ (a: ~ C~1.tcA') ~

\\[)} Ii'. I P: C.\I:It()% \t[I\U\I11L \I-t) l % I) R~n.! 1541 sur\c~c3 rr.~:n in ~ir,:i!:Ir.~::~,^:::i. n, in E:n_!::r,3 ar.,i t.`.. U.S. SmoF.inf! \.: s a_ s. ;iated \\ith :.)th lo\•er :o..'\ - ei_ht :Ind lo~+cr b!oo ± p::;cures: but \\;ten ?`:e ::ood pressures \tizr. f.,r ~.~ei_ht. :hzre \'•2s li::!c if any InJeFzn.'.o:::::sroziation of smokine \\ith io••\Cr blood pressure. cr [r!. (36. 37) f~~u }d that smokers in the Wzs:z:n Colisborati,e Gro::p S:u {. .__^zd less and ha d:o«zr dias:oli,: blood p.ressures t`~~n did nonsr::ol,_rs. ('_) found th_a' r.r.deral indices. skir.fe!d *•hi.knzsses. and bo:h dtastolic b!o.j F:essures .\zre :n I:: _ Ci:. C::lifornia. bu*. most of the corrclatioa \•.erc not ..:- 1:_. .. 5~;.\~ ~ Z[ r ul. 1:61 a._o f..~un d th:,t smokers :.S-2 P::- <an male ci\ il _dr \ i_~ z.':'^1o\ ees. In a.. _ral\sis of cha _cs in the Fr,rn. _h::m popu:...:o;: re::...d to c,u`.... _ ,m,L:i-:. Gordon ct al. (_=, found that men ,ained \.ei=!:: cui:tinc. hu: t!:ere \% ere )-1\- trivial changes i: c':-oo3 pressure in both dirz,:::.,ns. H;er:-a ;n ct nl. (29) found that smokers in Oslo 5::d lok.e: bodv \kei_h:s t; a-:: Cid -c-; :::o'rlers. and bod\ •°.ei_ht in.:reaszd after qui:,ir,c smol"In,. They did r.o: c:e__..r_ blo.d pressure_ G.'...:our'. and \led_~li: ('_1). in 10.C:0 ls.aeli male s. s.T.oLers \\ zi^*- e i:zss. had trinnzr s}:infolds. ar.2 had lo\k er sk ~~:o'.i: a-a blood pressu:es. $~~,j o n thZ com'L-in-.~, ;t\ a:e n c e trom t:.zse o}'sz:\ a:'o::~: ~t::dles, it C~..~ t...~•. on tht! a\z;___. -:_arz:te smoke:s cre Iea..e.. ;a\ e lo'•tZr blood -_!- s,;:_s_ a-d ; a\e faster hea- rz:es than do nonsnekers_ The :.n.?_rc\ for e\s-::o';- ers :~.1 __:n \\c.'i_°_ht in.~..lz2:;_ i!:al the \lelcfa lillfZrL-::cZ is ::0i a :.or~':ituilo:::a hr.L-. tu: is ---etiect of smoli-_. It is not clear \k iiether t}:~e iov• e- ::, od Fressurz is .:..Lto !:s:~bod\fat, or \\~e:^e: it is due to an indzr:r.se-: e::ect of smol:ir._. T:e.: are manv studi=s oi ti z acute effects of s .^..Jl:inz and of ni on pressure, hear-, tate. catechol3mines, anc'd se-u:n free fatty acids 'for exi:_ (11. 28)). This topic is too complex to Ln.?z-r._;~ to re-, iz\% here. is \\ell r_co_nized that these acL:e effects include an i,:crccs~ in b:..,od pressure. 1: is no: ossib:_. \cith avai:a_... i-f,-=tion. to rela:e the o; __r% e,. ..cu:. effects to t.`.= zr :h. o:se:-ed chronic efiec:s :hroueh biolo._i:a1 r..z.har::s:::s. Whater rez-=r.iscs. sinc.: the .._- z:_zt of habitual smo:i^~ is to redu;.f both an,! "::otl p:essure, it sz-_...= arFarent that si.okl :g not exert an efffz: on ....or on a:hZro~:ie.'o:l:: dlsz.7se Ihrol:c'til o: ~S1:\ or elz\'ation 1.^. E: Jd i::z. i-i_!_..'OSTA T IC SYS TJ _E'." In 1955. Murphy and Mustard (47) re\iev.ed tho.ou__!:1\ ihe relations':ip of to coarulation az:. :r.e.,tbosis. The% coacluded :ha: the e. idence On i:: pJrtant pote:a:al eitect of s:no;cinc! u-as sc_ct.. and that \kha: \%as \\as inzon sis:er.: a::,J. in man}• i nstances. co::.aztin_. In !zenzral. no or, the procoag::'_..:s had been dzmor<si:a:ed_ Se.eral s5norm.~'.i:i_s ia F'=:;!'f:s and platelet fun.:ions had been detected in smo;=rs. princip-alh a de- in platelet st:r.ival tirne and an increased rate of F::::L-',et turno\zr (,5i. S.:*-eCuznt to ihe 19c5 review. only a fe,.\ rzFo: ts h--\z::<<eare[i on this t.•;'i.:. Se\.:~] have confirmed an effect of smol;in~~ on p::::e:et fu::ctions: in_-e~~zd ad!:==1\enZss (46). and inzrzaszd tzndenc, for 119. -2`• 4 1). In I

, :.a 1I!.\Kl C. N:C CIl L. Jh. •lth coronary artery Sti2lC i•f i:l. /_C) fVu~ .j no Ir1 ('!:::i!2t urn i.-al time bet..2en smJ.lcrn. and non-~--ok2rs. Ocston ct al. (49) four..' :`::!t chronic srn.l;in_ led to an :- C2n concer.tratione but 5:'to:l.^.g dl J; -no:. Jar.zon aa2 \1,•SJn t 1`) fo::'..! hronic smoking %%as associ~:2d %kith increa~e I ac:i-,i:% of c'.~~..?. The possibility thia strokln^_ Increas2s t'.-:e p: edlsp os:tlon :O :'rJmoJS'S ._ .... Jr;2nt in accountir._ for :he cic.2rette 2ff2ct on hc .asse• if it exists. it cou d zxp?~in the ir..^_'i te 2i:2ct o; d:~.as2 i~_: o:!t i t st r:in_c and stoc okine Ci :e:..r sr^~~i;i-_c r: )' of :hrJClbosls as t. e!! `•s ;.o:;tributc: to t F: oge~'S'.oil FersJn :2:'.seS to S*^: ':2. I'._ may 2\D2r 2..J2 a r~~ ~2 !:C2 in Ihe :o i'.:oris. and II-i~!:2bv 2\r2r::t1Je the rc;:d decline 1'1 ri- l; of sease observed in se~2r1 2pidemiolo=ical stLdies. The ir.creased clerosis, hou2v2r. do_s co: r.cress and :..=--, :s :o prJu::,e ---I of ::sease for several L zars. also as obS2rved in 2-:~'.er.^.IJ?o:!Ic s:e::ies. U`E: SvJ, E ~ ~ There have been no :I:Jro~~--tl SiudleS O: ft2 e.i2:.IS Of J1_cr2ii2 S.:.JI:IC C' :..c mmune ss stem inh:Jr:a::s- T.`.e !euco.:%t.;si; o'-sert ed 1': SC?Jk2.'s G:::v r2.i_ ed n part, a manifestatioa of an inmu;te d:_~`rder. Hold I:eas*. (30! l\'ailable information .'.fi.'.:.I S.:.IS of on 1,:.:::i:::C)IO=1C21 :ur.;::Ja. .-ulmonary alveolar of hur..--n ~--:okers s^o%%-:. r,u: :;_r of :bnormalities. Sev2 vl s:u':es of mice exrosed to ::oderate doses of s:noke have sho.% n an 3~:::=? s:.,-tlu''atlon of T-i'_. ,:.pho:.vi2 fo?:J••-• c.: ?2pression upon lor._tr ex,-os;:re. Becker and his as:oZi_:es (4. 5-) h-~ve a )rotein in tobacco ar."' tJ,_ccJ S.^.tol<e tha: 1S hi~:`tlv a:::i_eniz in ^ian. Tris stance also activated Fac:or .l"II (Ha_ee ::a-t factor). .~, hich is iavois ed ir b J:h icute inflammation and : :rom~osis. Thc obser.ed and su:} e::e,i effects of s^:oke inh-~l::tion on .ions is an importan: rot_...,al r::echar.isc: b; \;.h:_h ci_ ....~ _r:ol:i^_ ;nent atherocenesis. Ir:mu-e-cor*:plex dise---e =:kedi•: ~ p 2n:s a:hero:e-_s:s in rabbits (44) and babo.ns t=l). Er.dotr,..v ._u ~ and ir.c,__seJ ..hich frequently occur in EJth ir.f~amma:io;--nd thro-:bosis. are featured in current h)po:?:eszs of the p°_tf ~`'_~^2S!S of 'z c S in sensitivitv to an; ,..,, ,:._te..als could for ..._ --eat \ari_-..:o- .- r_- sponse to cigarette srao::cp. T' ..ese pos_;i~_'2 - ~-~ . ,:,ecn::nts:~a ' ~_~_:%2 rore ~ :n searchins, for th2 m2~? _:~ms of c!L-::reI:2 s:,^.ola.^.g 2:f2ztS On .a-r(::o% disease, since present 2e iden.e is hiQhlv su_gesti%e but far fro t co !usi~ 2. O i HER EFFECTS Cigaret:e smokers ap_ ear to de\ elop incre-se2 actl% It\.' of t`:e ;..i.ed fu-;:icn ox\genases in li%2r m:crJ_J ;tes as do pe: so::s exposed to o:Ge: e 1v1rJ: -=r.:'_1 con,aminants (9). Thev s!to•x• for exampie, rr.ore rapid d__:a'_tion of F`:e::~z t-.in ,9) and more rapid c:s «ea-ance of sali\ ar, a::tip~ rine (2-=). .a possill-?e s2con.'~ ~ conseq::ence of this re=por.se is more rap : i~. .abo;i> r of siero:d hor.-n.`-es in ~ r ol:ers. - _ I ~~