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`da§~ - JOSEPH T. DOYLE able as to the premorbid characteristics of Ihe patient and do not delineate the natural history of the disease. . - Theaxistence oflarge international differences in mortality rates from coronary heart disease as well as in the extent of atherosclerosis at autopsy compels the conclusion that potentially identifiable differences in lifesty9e may account for varying susceptibility to this disorder (32, 45). If this is true, then amclioration, if not outright prevention, may be feasible. Intense interest has been directed to- ward this question over the past 25 years. Age, sez, race, heredity, somatotype, .Jbesity, physical activity, glucose intolerance, thyroid function, estrogenic activ- ity, blood lipid levels, polycythemia, coagulation factors, diet. mineralization of water, trace element poisoning, urbanization, occupation, personality type, life stresses, usage of tobacco, alcohol, and eofTee have all at one time or another been implicated with various degrees of plausibility as etiologically important-in atherogenesis. The validation of such hypotheses is difficult. Accordingly, it has been necessary to establish prospective studies of carefully selected and defined populations in an effort to detect etiologically significant precursors of cardiovas- cular degeneration (48). Logistical and economic constraints limit the number of individuals who can be maintained under surveillance over a realistic period of time. For this reason it has been necessary in the United States to consolidate the findings of several such studies into the so-called Pooling Project in order to accumulate a number of coronary events large enough to correlate reliably with precursor traits (35). In this and other studies carried out in areas µ-here coronary heart disease is highly prevaient, hypercholesterolemia- arterial hypertension. and heavy cigarette smoking have proved consistently to be the most potent risk factors, particularly in men approaching middle aee- Each factor increases risk about equally, but in combination their effects are compounded rather than simply additive, indicatine synergism (Ib, 24, 35. 36) (Fig. I). The impact of these risk factors diminishes nith increasing age and the predictive accuracy is less for recurrent myocardial infarction (10, 47). Relatively little information on ssomen has been collected but, allo.vin_g-for age, the risk profile appears to be identical. The role of cholesterol in atherogenesis was once asserted by Leary to fulfill Koch's postulates (26). Molecular biologists_.vouid now hardly aeree to so simplis- tic a view. Nevertheless. epidemiological evidence does suggest that in the human a serum cholesterol level concentration above some critical level is the sine qua non of atherosclerosis. Below a serum total cholesterol level of perhaps 150 mgidl, atherosclerotic disease is rare while above this level the frequency of coronary heart disease increases continuously as serum cholesterol rises (23, 27, 40). The K•eieht of circumstantial evidence implicates the amount of dietary.fat as the primary determinant of the serum cholesterol level (21). Familial hypercholes- terolemia manifested by precocious coronary heart disease secondary to acceler- ated atherosclerosis is fortunately rare while the heterozygous form is estimated to occur in 2 of every 1-000 persons in the general population and in about 59c of patients with myocardial infarction (8, 34). It is believed that serum lipids perco- late continuously in losc concentration through the intact arterial endoihelium (50). Hyperlipidemia Ferse may increase endothelial permeability (31. 39). In any event, once in the subendothelial space, lo"-density lipoproteins (LDL) and very I I

WORKSHOP: CARBON AtONOX1DI AND-CVD 39. Schv.artz. C.1.. Ehrhart. L. A., and Gcrrity. R. G. Athcroma: A rcview. J/mP..yfrd. 13. IB-32 119771- 40. Scott. R. F.. Lee. K. T.. Kim. D_ N.. Morrison. E. S.. and Goodale. F. Fattv acids of serum and adipose tissue in sia groups eating narural diets containing from 7 to 40 percent fat. Amrr. J. Cfin. Ali/r. 14. 280-290 (1964). 41. Sneps. S. G.. and Kirkpatrick. K. A. Hypcrtension. .Vncn Clin. Prnc 50. 709-7'_0 (075). 1•. Slander, 5.. Aurup. P.. and Kjeldsen, K. The eRact of carbon monoxide on chalcslerul in the aonic uall of rabbits. AJrrrnerfrrasis 28. 357-367 (1977). 43. Strong. 1. P.. and Richards. M. L. Cigarette smoking and atheroscfcrosis in autopsied men. Alhr•nsrlrn•sis 23. 451-i70 (1976). 44. Thomscn. H. K. Carbon mono.idc-induced achcrosclcrosis in primates: An ckclrommicrn•cnpic stud_c on the coronary arterics of?lurnra /ras monkcys. Ancerrn(lrr.nl• 20, 1J3-'_-0119731. 45. World Health Organization. Vflal statistics and causes oCJealh. "Nt'ortd Hcallh Slaliaics An- nual." Vol. 1. 1977. 46. N'ald. N.• Houard, S.. Smith. P- G-. and Kjcldsen. K. Association bctuecn athcrosclcrolic diseases and carbot)haemoglobin 1e.ds in tobacco smokers. Brir. S1rd- J. I, 761 -765 11973). 47. N'einbtau. E.. Shapiro. S.. Frank. C.. and Sagrr, R. V. Prognosis of men after first m7ocardal infarction: Mortality and first rccuncnce in relation to scleacd paramctcrs. Arvrr. J. Puh. Hralrh 58. 13'_9-1347 (1968). 48. Wcinstein. B. J.. Epstein. F. H.. and 71te y%orking Subcommiuec on Criteria and Methods. Committee on Epidemiological Sludies. Amer. Heart Assoc. Csrrularinn 30, 643-653 11966). 49. kisslcr. R. N'., Vesselioovitch, D.. and Ge¢. G. 5. Abnormahlics of the arterial and its metabolism in atherogenesis. Progr. Cordior. Dis. 18, 341 -369 (1976). 50. K'olinsks'. H. A ncwlook at atherosclerosis. Cardin.. blyd 1, 41 -54 (19761.

JOSEPH T. DOYLE until 1954 that the massive prospective study of middle-age tsfiite American men by Hammond and Hom under the aegis of the American Cancer Society showed that this excess of deaths is due largely to coronary heart disease (18). Four years later their second report overuhelmingly confirmed these initial observations (19). Furthermore, there was persuasive evidence that cessation of cigarette smoking uas associated with a reduction in the risk not only of lung cancer but also of coronary heart disease. A few years later these observations Here strongly sup-- ported by the prospective experience reported jointly by the Albany and Fram- ingham studies ( t5) and subsequendy by the Pooling Project (Fig. 2). The combina- tion of heavy cigarette smoking Scith h,vpercholesterolemia and arterial hyperten- sion aucmenls the risk of coronary heart disease far more than the sum of the contribution of the individual risk factors(-0). Autopsy evidence demonstrates that heavy cigarette smoking is associated with far more severe atherosclerosis in hyperlipidemic populations (4, 43). On the other hand, heavy cigarette smoking in populations in which serum cholesterol concentrations are low and atherosclero- sis rare, has little influence on the risk of coronary hean disease (16, 23, 43). How- cigarette smoking exerts its vasculotoxic effect remains undetermined despite intensive investigation. The present consensus is that-carbon monoxide, gener- ated in substantial volumes by smoldering tobacco, is most likely the injurious agent. Carbon monoxide has an enormously greater affinity for hemoglobin than does oxygen and• at the lo«oxcgen tensions preeailing in the capillaries• hinders- the release of oxygen from hemoglobin (7). Moreover, the half-life of car- boxyhemoglobin in healthy resting adults is at least 4 hr (25). Carboxyhemoglobin concentrations of 5-155r, commonly are encountered in ciearette smokers and can exert a powerful hypoxiating effect (20. 38, 46). Experimentally, the continuous inhalation of low concentrations of carbon monoxide damaees arterial en- dothelium and increases permeability to lipids (3• 1'_. 42• 44). The threshold to ventricular fibrillation is lowered in the experimental animal by the inhalation of carbon monoxide (14). Furthermore, the positive chronotropic and inotropic 200 O 175 _. : c- iobJ. 1• < 150 U Z 0 125 V Z_ 100 ~ 0 75 < 0 Z 5O' ~ ,~ n L 5 . r..~w ..V 1V b.......a Frn. 2. First major coronary event Fy smoking panern (Pco 51. This craph is based on the same dala displa}ed in Fig. I. The risk of a Grst coronary e.ent increases progressively with the number of cigareues smoked daily. -0Y"yrij~- r ~:~ -..+-...--f.+u~,...>• .o... ...~......< ».,» ..-.-,. ~._ _

w'ORKSHOP: CARBON.MONOXIDE AND CVD 200 175 [50 125 100 75 H I-n M Q V rMr....,..a. ! Ournlde of Risk of First Coronary Event Fto. I. Multivarialc logistic Idiaslolic blood pressurc, scrum lolal cholcsterol. smoking habill by quintile of estimaled risk IPooI 51. This graph is based on observalions on 8.422 men in fve major studies included in the Pooling Ploject (5) and covers 77,011 person-years experienec. during which 658 major coronarp' ecents occurred. The endpoints were fatal and nonfatal m)ocardial infarction and sudden death occurring uithin 3 hr. The frequency of major coronary events is strikinglr increased by a combination of hyperchotesterolamia: arterial hypertension, and heavy cigarette smoAing y low-density lipoproteins (VLDL) cholesterol above some threshold level initiate a complex series of events of which the most important is a(lorid proliferation of primitive smooth muscle cells that may evolve into fibrous and lipid-rich _ atheromatous plaques (d9): These plaques characteristically are situated at points of nceoloeical stress where the endothelium is repeatedly damaeed and even - sheared off. As a consequence. the subintimal area is exposed more or less di- rectly not only to the serum lipids but aiso to platelets mobilized both by hyper- lipidemia and by the effect of endothelial injury. Platelets aggregated to injured ' and denuded segments of the arterial wall secrete substances schich powerfully excite the proliferation of the primitive smooth muscle cells (37). The cycle of endothelial damage and repair is a universal phenomenon. In the absence of hyperlipidemia this process is self-limited and is uncomplicated save by the occa- sional development of fibrous plaques that do not impede blood Slow. In the presence of hyperlipidemia_ however, this process is accelerated. aggravated, and is a cause of the complicated atheroma which encroaches on the arterial lumen and unpredictably is liable-to rupture or intemal hemorrhage with disastrous is- chemic consequences. Arterial hypertension accelerates and aggravates atherosclerosis by increasing the rate of percolation of lipids through the endothelium (50). Permeability is further increased by the stretching effect of elevated blood pressure on the arterial wall which opens intercellular spaces (50). In populations in which hyperlipidemia is common, arterial hypertension is associated with an increased risk of coronary heart disease- The striking association, now generally conceded to be causal, benveen cigarette smoking and cancer of the lung for some time overshadowed the even more dramatic excess of deaths from all causes in cigarette smokers. It was not ' - --------------- ---- ._..-- ---

(~ ~ - rul~ir~ Ct ~~2cT~cxaJ . . , - s set of ;,,T,~:. : racvcnrtsc .reotctwr 6, (100-[q0 (1979) , _ tlll queneS, ktlt i0' o: f,~~~~ qfe a1l correcfi~rs r,= ~ ~ A V U ~~ HAR g 1979 - th's set. t40h&t.a, de'rk2aLe~n.aJ Risk Factors in Arterioscierosis and Cardiovascular Disease with Special Emphasis on Cigarette Smoking' JOSEPH T. DOYLE Deparvnrnr of .SfedirinG Diruimr ofCnrdinlogc, Alhnn..tfrdirnl C,rllegr, A/hutn^Ke.r Tnrl, lldClS, and rhe Cnrdincasndnr Hrnlrh Crntrr of rhe Nn,' Pod $rnte Depnrr.rrrnr nf Henhh. Aibnm-.-Neor Porr. 12?68 Izrge international differences in mortality from the atherothrombotic diuases, notably coronaq heart disease. suggest that differences in encironment and lifestyle may be impor- tant. Cholesterol is the lipid characteristically found in the atheromalous plaque. Serum cholesterol concentration is invariably higher in populations with high rates of coronary I:ean disease than in populations where the prevalence is los.. The serum cholesterol level is probably determined by the amount of far habimallc consumed and only infrequently by genetic factors. Arterial hypertension and heavy ciearnte smoking powerfully increase the risk of coronary heart disease in the presence of hvpercholesterolemia. The mechanism r.hereby cicarette smoking aggravates and accelerates atheropoi<sis is unknown, but carbon monoside and mobilization of catecholamines are probably implicated. The prevalence of the atherothrombotic diseases and of their ischemic complications can. in theory. be re- dusd by' controlling hypercholesterolemia and hypertension and eliminating cigarette smok- inc. ' - Cardiovascular diseases are the leading causes of death in most of the technologically advanced countries of the western hemisphere accountinc, for example. for more than half of all deaths annually in the United States (45). Of these diseases• by far the most common are the ischemic complications of ar- teriosclerosis or. more precisely, atherosclerosis and notably coronary heart dis- ease f'_). Since the etiology and pathogenesis of atherosclerosis are incompletely knossnw the prevention of this disorder is empirical and unsatisfactory. The stud3' of atherosclerosis is singularly difficult. No model of atherosclerosis - in the experimental animal exactly replicates the human disease in all its mor- pholocical and clinical details. Investigation of atherosclerosis in human subjects is frustrated by inability to diagnose the disease in its preischemic phases except by invasive techniques of strictly limited applicability. The antemortem diagnosis of atherosclerosis in humans is still inferential and depends on the recognition of its ischemic complications in the head, the heart. and the legs, by which time it is usually far advanced. Diagnostic certitude is high in the recognition of coronary heart disease and of severe peripheral vascular disease, but much lower in atherothrombotic cerebrovascular disease. The uncquivocal diagnosis of athero- sclerosis rests ultimately, of course, on tissue examination. Painstaking clinical descriptions of the ischemic syndromes that compel the patient to seek attention have been enormously helpful to the medical practitioner, but are wholly unreli- i ' Presented at a yJLOrkshop on Carbon Monoxide and Cardiovascular Disease. sponsored by the American Health Foundation and th^Federal Republic of Gemtany, Berlin, October 10-12, 19188 rn~ o i ~ --- - ~ 0091-7435179t030000.00502.00'0 Cor.tr.n~ t, tvA br A<,u.m.c s+r,,. tnr. A!I nrhn of r.prrNuuion in.nr rorm rruned. ^ / i -A

f f19691 33. hfialrnen. U, Turpeinen. o_ Kanonen. nl. L. flosui R_ and Paa.dalnen. f. EReo nf AE IOg UO 615-616 119 61. 29. Ie¢n. P. The eRCa of C!a+ma cFe'oero: lo.erir.p diu in ma!e mprrv6urs of m.ocardral onfarc- n. 4cre SIeJ. SrmrJ. Sr.P~"/. Mb. 5-9' II9ed1. 30. I<uinc P. H. An.cu¢ eRcu orn_e.rene.mokine on pla:elcl fuoction-. A possLlr link ber.een . moking and arncnal thromFOSn Cvnd.urn 38, 619-6]3 H9731 )I. McCullach,K.G.RCSnedconcep:rnrartrragrnesis.C/nr!nlECl...Qoarr.a3,'D-1f6r19161. 31. RIeLrIL H. C.. L_ Ed The gcocrapkc parh0logy of arhermrlerosie. Leb. lnseae. I8. a65--0<b yeie: /OSEPHT.DOYLE . ~ I). Danoo, 5. and Pea . M L. Rearntion or roromry 6cee disease and other c mpllc-alions of I arhemsdcro+is hy moGrLed dlcs. Amrr. J. ArJ. 46. 151-i6] 1196a1. I' N. DeBur.o.A.Rarcrjca,C.81_BVghead,4.C_Grucne.C.H..Smu,iD_andHarrer.W.V. ER¢n of cvbon m°noelde inlea6en on •enlncular fmrplation. Arrh £n•.ron. Health 31. C-a6119i61. \ 15. Dorle. 1. T.. Da. 6er, T. R. Kanecl. N'. B_ Heslin, A. 5.. and Kahn, H. A. Cigareue smoking - n New, and c nary heart dlx c Cum ncd o.peneaccof Ihc A!CanS' nd Fnmingham smS,n. M1^ /ey) Enef J~)feC. 266, 996-g01 1196'/. 16. Oordon. T.. Gardz-D+Imleri, 4. R. Ka-an. A Kannel. `A'. B_ and SchJRman. 1. DiTerenco In onap hean 6sease in FraminFan. Honolulu aod Pueno Ricn./. CM1eoeir Du. 1>, 329-1u (1974, IT. Gordon. T.. KanncL W. 9.. aod HcGcc. D- Dealh and cto a;ks onaf¢r FisinF uV I eiFar oLlnpA repert fron the Fnminpham Slud5l^re , I}J£-Ita9119%al. I I8. Hammend.E - C..andHom.D.ThC:e!ariomhipbcrweanAumansaolinFh.aClsanddrvlhran. Afollo.-upsmd>ofIBT.)60man./1LLi155.1311i-1J:81195a1. 19. Ham:uor.d. E. C_and Hurn. D. Sc'.eLmc anddeu!r nrer. Repon on fanl-four monrhs offollou- ~and L. L~Z7-r fG~CS bv Cc.aSH.. uPofIg1J93mrn.I-T°talmonili0_JA11A 16G, 11)9-IIT-fl9'81, 20-In:er-SOdesCoomi.uonforHeanDiseaanResources.Prrmar.'prnemionofrhearACrmclonne dheases. Cirrubrbn a2 A!5-A95119T01. re•'ISCd Aynl 192` ~Lyti ~ I: - 31. Kahn, A. Rurlcdee. R 8.. DaHS. G. L.. Ahes, 1. A_ Gznmu. G. E.. Thnmron. C. A. znd ! Nalbce. N. D. Carboobemoe . ...... s rn Ihr mnwpnWm St. Lnuis popu!.rron .brF. I £n. irma. l1rr.IrA 92. I D-U91I9 <L 22. KanneLN R.Eprdemroleroleudiesonsmo4mgincoeFdardperipheral.'a.cudrduna.e,r ~ "5mc4ng and HeaIIF. I Mot.fsing he RiA for he Smu:u-- rE. N)ndcr. D. HoRmann, and 0 9. G°i. Eds.l. pV-=S7-',{ DHFN PabLcr.lan Po.61H1'61_^_I. 19Y}. _ 1_l. Kcps. A_ Ed. "-Corooar. Haan IS..eax In Se.en Coumries." Cp- 11-1'1I. AHA Nunngnph:9. ~ 19-0 'a. KeSS. A Coronan sean disra,r The Flohal pinure. ArLrrarJe.nrh :2 N9- 19' ( 19)5i. - '-1. Urdn.- S. A, TTC eRca. of crnrr.rz saoG, on roral boh Furdrn a.,d r.crr,ion r.¢e of carl W n °rlde l. Orrnp. Iled. 15.'31- 13s 11973) -6. LrannT TheFencslsufa~.Carrr5.oe•is.A•rA.Pnrbo/.)Lr0i_ea/1W!1. 27 - Lec K. t_ n aC Gcognp"Jc pm.w,c!ogl of m.ocardral mfarcdon. AnrrrA l. CnrJrol. 13, 30-a0 f1WJ! I 28. LeM1e.:¢. R. 1. EdlmnalSmo6nFI mleholamrnes, and the hean. M1^Enp/. l. JIeJ 295. /C4) e6oln erd-Im. ring die n m on a!:h fro m eorocar y hean dn me and oncer cauaes. A r.dse Iear cllnic.al vial in men and anmen. Lnnrer 2, 835-838 O9"pr. N. N°lulor A. G. The generic M1.PerL;ldemias.?n6rP/, l. Ifrd. 24e, 8R-8D I IY61. 35. TTe Pou!Ing Projr.r Rnoah G:oup. RCViomnry of hlnod prenwe. smokmg hablll relau•e .einSl and elrtrocarGi°FnpLC aCnornaf.ies to incideece of major comr.arT c.rnnFnal ¢pnn of he Poulmg Rojrnr l. CFrreir Dir/)1. ^_01-306 f 14'31. 36 . Reid. D. D. Halr.dmn, P.1. 5_ McCanncs. P.. R°se. G_ lanc:r. R. 1.. and Kccn, 11. Snolmp aed orbcr nsl facron for cerosar. M1eart-disease in Briush ci•r] sename Lrr.rer 2, 9)9-9YI 119-61 37 . Ross. R.. and Hadrr. L. H~per1!pi_<mia and alhero+tlerosis.5dr,rre 113, 109a"1100119161. 38. Rusve9. V. A. H Blood earbos; hamoFlobm changes durng tobacco smokmy Pa.rrper:J 6/eJ L a9,6B:-6g1119]T. ft't

., I . ' R'ORRSHOP: CARBON AfOA'OXIDL-AND CVD myocardial effects of catecholamines mobilized by nicotine inhaled simulla- neousl)• with carbon monoxide may furthcr jeopardize the ischemic heart (11, 23). Finally, the mobilized catecholamines may recruit platelets and significantly en- hance their stickiness, thus increasing the potential for endothelial damage and for obstructing thrombus formation on ulcerated atheromatous plaques (30). - Although the documentation is less complete than for coronary heart disease, cigarette smoking increases the risk of atherothrombotic brain infarclion and of intermittent ciaudication (22). The association of heavy cigarelle smoking uith many of the coronary risk factors enumerated earlier augments the hazard of sudden death and heart attack, althoueh the supporting evidence is statistically less solid. . The lo+cerine of risk of coronary heart disease by cessation of smoking-is most encoura_ine (5• 17, 19). The benefits of antihypertensice treatment are less con- vincine but demonstrable (6. -0I). It is scarcely surprising that acute, relatively short term studies of the effects of lov~ering serum lipids have not yielded striking results as it is difficult to envisage the rapid involution of.a complex obstrucling atheroma that may have evolved over many years. (13. 29, 33).-Evidence that platelet antiagereeants appear to protect against sudden death and stroke is gratifying in the light of current notions of their role in atherothrombotic disease (I, 9). There is increasinghope that rational and effective measures are becoming available to mitigate and perhaps ultimately to prevent the ravages of the athero- sclerotic diseases. - REFERENCES l. . An:uran< Reinfarcfion Trial Research Group. Su!finpyrazone in the pre.ention of cardiac death ~ f1 NGw ` after m}omrdial infarttion: The antnnne reinfarction trial. A^EnpL J. srrd. 298. 289-295 /P.tW / I9781. 2. '-Arteriosclerosis: Reperts by NHLI Tack For<e on Aneriosclerosis: • Vols. 1 and Il. DHEH' PubL - \o. INIHt 7_-1?7119717. - - 3. Asirup. P.• }yeldsen. 1., and Kanstrup• J. Enhancing influence of carbon monoride on the de- selopment of atheromatosis in cho!esterot-fed rabbits. J. Arhrrnsri'r.. Rrs. 7•?d3-35-0 f 19671. _ 4. Auerbach. O.. Hxmmond. E. C.. and Garfinid. L. Smoking in relation to atherosclerocis of the / /!. S Qw~S eornoarr aneries..\A~:eL J. 11cd. 273. -5-77911965L e W N. 5. Batl. K., and 7urner. R. SmoAinc and the heart: The basis for action. J,nrrr 2. 823-8'61197<I. 6. Berglund. G.. Rdhelmsen. L.. Sannerstcdt. R., Hansson, L.- Anderrsson. 0., Sivensson. R.. • \i'edel. H., and N_ikytnnd. 1. Coronarc heart-disease after vcztmem of hypenension. Jsnrrr I, 1-5 119781. 7. Bioloeical effects of cigaretle smoking on total body burden and e%cretion rates of carbon mono: ide. !. Ocrur- .I frd. 15, '_31-'_ a5 (1973). - 8. Brown, Af- S-. and Go!dstein• J. L. Famlial hppcrcholesterolemia' A genetic defect in the lo.- d i ii / w A• at _ u~ [~C ens ty poprotein reccptor.J. •Sfrd. 294, 1386-1390 119i61. e t 9. The Canadian Cooperatise Stud7 Group- A randomized trial of aspirin and sulfinpyrazonc in ' threatened stroke. J. Afrd. 299, 53-59 (1978). 10. Coronaq' Drue Project Research Group. Factors influencing lone-term prognosis after reco.cry i from myocardial infarction: Three-lear fmdings of the Coronar.' Lhug Project.l. Chror,lc Di,. 27,'_67-285 /19711: - ' • 11. Cccer, P. E-. Hacmond. ht. N -- Santiago. 1. V.. and Shah- S. D. Korepinephrine and epinephrinc reiease and adrenergicc media;ion or smoking: Associatcd hcmodynamic and metabolic c.cnu- A^En¢L J. 3rrd. 295, 573-5ir (19761. 12. Dacies. R. F.-Topping. D. L. and Turncr. D.-xt. The eRen of intermittent carbon mono.ide ' enposure on experimcntal atherosctcrosis in the rabbit. Arhrrosdrroais 2<, 527-536 (1976). I I . I _- . - I m , J _--__ - - _ - N - ~ ` IPA IP A N N