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WORKSHOP: CARBON SIONOx7DE ANI) CVD short and mild carbon monoxide exposure are explained by an impairment of the oxygen-transport and oxygen-unloading functions not only of hemoglobin- but - also of myoglobin which j~ a high affinity for CO. Furthermore, CO competes at the cellular level with oxygen for the various herne-containing enzymes, the com- petition being more deleterious at-low oxygen tensions. - Friedberg.(13) and Buchner (9) first drew. attention to, the fact_ that acute iiiyocardial infarction without a denionstrable coronary thrombosis was a com- mon finding at autopsy. Baroldi (4), Spain and Bradess (33), and others formulated the concept that myocardial infarction frequently-is triggered by metabolic distur- - bances in a hypoxic myocardium often furnished by an artery with a critically low blood flow. Therefore, under certain circumstances, high carboxy hemoglobio sat- urations in smokers, in connection with the arrhythmia-inducing effect of nicotine, could be deleterious to myocardial function without the occurrence of any throm- s bosis and thereby could contribute to the understanding of the high frequency of sudden unexpected death in heavy cigarette smokers. This increased risk of sudden death in smokers actually disappears overnight. at any rate in a few days, when people stop smoking, indicating that the risk is caused by a functional disturbance and not by a coronary thrombosis. In our opinion, it is most likely that carbon monoxide is the compound primarily respon- sible for this risk, also because severe physical exercise in nonsmokers is known to be associated with risk for heart attacks- - _T ARTERIAL WALL-INJURING EFFECTS OF NICOTINE AND CARBON MONOXIDE Nicotine Several studies have dealt with the effects of nicotine administration upon the development of arterial wall injuries (36). The main results are that nicotine, when administered alone, has no injuring effects on intima but might lead to moderate fibrosis and calcifications in the-media o€arteries (32). This might be explained by an effect via the catecholamines since their administration in animals has a similar effect (23). When nicotine has been administered to hypercholesterolemic or hypertensive animals, no effects or only limited additive effects of nicotine on the arterial wall injuries have been observed (36). It is remarkable that, in general, the daily dose of nicotine in the animal studies has been several times higher per kilogram of body weight than the daily amount of nicotine absorbed by heavy smokers as demonstrated in Table I. By assuming that I mg of nicotine is ab- sorbed in humans for each cigarette smoked, up to 1200 cigarettes should be smoked and inhaled per day by an individual to absorb similar amounts of nicotine as administered to the animals in the mentioned experiments, where no arterial wall- injuring efPects of nicotine were observed. Therefore, since such doses of nicotine are unable to produce atheromatosis in rabbits, it is very unlikely that nicotine is the responsible agent in tobacco smoke for the increased incidence of athero- sclerosis in smokers. - _ Carbon J4ono.ride The pathology of blood vessels in carbon monoxide intoxication was first studied in Germany in 1865 by Klebs (20). Later works [Roseablath (29), Rix (28), _

°jiL- _3--_-._ ASfRUP AND IUELDSEN ~ induced increase in myocardial oxygen consumption, and probably secondary to that (17). In animals with damaged myocardiuin and in humans with coronary heart disease, the response to nicotine administration may not lead to an increase in oxygen consumption or Pn coronary blood flow as in normal animals or humans (27, 36) indicating that patients with coronary heart disease may not be able to respond to the stimulus of tobacco smoke in the same way as normal individuals (12). Further, nicotine administration leads to a decrease in ventricular fibrillation thresholds in animals (5), and to increased arrhythmia in animals with damaged myocardium (3). The acute effects of nicotine are less pronounced in the adapted than in the nonadapted organism. This is demonstrated, for instance, by the fact that differ- ences in blood pressure and in heart rate between smokers and nonsmokers in general are very small, if they exist at all. _ Carbon Monoxide Exposure to carbon monoxide leads to decreased myocardial oxygen tensions. This has been demonstrated in men and dogs by Ayres er a^(2). In 26 human subjects with a mean COHb of 9%u, they found decreases of 5% in arterial Po,, and 20% in venous Poa; increases of 20% in ventilation, 25% in coronary blood flow, 10ry in cardiac output and approximately 50% in alveolar-arterial oxygen differ- ence. The coronary sinus oxygen tension was lowered considerably and the cardiac oxygen consumption was reduced. Correspondingly, it was found in humans that 4 hr exposure to 100 ppm CO (COHb levels of 5-9%) resulted in greater myocardial stress at comparable work. In 7 of 26 persons aged 41 to 60 years, abnormal electrocardiograms were found, and arrhythmia developed in 2 of these. In a younger group of 12 persons aged 25-36 years, no abnormal electrocardiograms were seen (21). These findings are consistent with the degenerative myocardial changes after acute and chronic carbort monoxide exposure described in humans and animals as early as the 19th century, mostly by German workers. Later, thorough and careful studies of prolonged, mi7d carbo~ monoxide intoxication in experimental animals were made by Campbell (9), aad"Christ (10), Ehrich er al. (11), and Lewey and Drabkin (22). The anatomical changes closely resembled those produced by hypoxia and consisted of edema, fatty degeneration of the muscle fibers, multiple small perivascular necroses and hemorrhages. Macroscopic scarification of the heart muscle was also reported. Ultrastructural studies in our laboratory have demonstrated local areas of par- tial or total necrosis of myofibrils and degenerative changes of mitochondria in the myocardium of rabbits and ,Macaca irus monkeys exposed to about 200 ppm CO for not more than 2 weeks (37). Pronounced pathological changes such as severe mitochondrial injury, muscle necroses, and myelin bodies are irreversible and ultimately will lead to formation of fibrotic scar-like tissue. Similar pathological changes have been observed after various forms of hypoxia, included studies in which the oxidation processes were inhibited by eyanide, fluoride, and malonate (35). TTT--- ---'Ibe -pro-nounce_d_mo_rphological changes_seen _in the myocardium after_ a rather. -- _ A.- "CCC 999 nnn--- Z 0 1

r c.r n a . - r arm c oye und oar og.e es srauc cs, -¢mc . i C a T ba SmnPn. 1968. • 32- $chicr<IGein, H.. Londonp V., /pndong, W.. Grvmbach. H...vd(1 RcmGlik. V. Nicurine and ~r/J4~+sC! j A~ Q~ IkMY15K arterimclerosia: An sprmneno! cmniSalion lo Ue influencc of niwrinr on (at mctabolism. Z. . ~ , ASTRUP AND KJELDSEY. ~ 1V. Sann., I- S. M., rlimanns, H., Ideka, S., and Bing. R 1. TM1e eAca of orom m~ooalJC on Ilpld maabolisln of human coronary aneris. AJrrmarlcrmia 22. 193-198 I191r1. . 11 Scb' i N lS H(FA )" ka R W ' d T td ' A h" TF Slre. Chem, Kfin. Brur/rrn. g, 190-196 (1910). - ]1.,Spun,D.M.,andBndees,V,A,Bdalonshipofcerun>ry[hmmbosislocorunaryaihemedsoels ` and ischemie hcan diseue: Necmp+y SmdY co.ering a period of'_S Years. A~rrr. J:.NrA. Sri. ]01-11U (19FA6 H. Smnder, S., Aewp. P., and KXldsen. K. The eRect o( carban monoaid< on cholevnol in Ihe wnic wll oT sbblls. Ardrrwr(rrorlx. 28. J9-361 (1911), 3 5. Suauki, T- VI[rvwcmral ehangea of Lean mmale In cyanide pusuning. Tdm4r J. Ery..tlrJ. 95. T21-:91 u96gf. . )G "The Heallb Con[e9ucnco arSmoking:' U.S. PuSllc Heallh S.rvice. IvN. 37. Thomsen, H. K. Carbon monmide-induced atherosclerorie in Grimama. An electron micro.vopia 4udy on [hc coronary anrris oUlocncn irr.a monkc Arlnroarfnurir 20, ~3-'_a01191~s ~ I/ ~ 33. Yirchnw, R. "Gesammehe Abhandlungrn tur wissen r~fl6chen 6ladhin," Slaatrdruckerd. 2rl ... $L %4 F(.., Fnnklun, Ik56 . 39. Yam. W. P., CTomyak. J.. Schrtnk. H. H., Pany, F. A.. and Saym. R. R Smdlcs In asphyala. ' PoblicHmhh BnIL 211, Wathin8lon, D.C., 1931. ' I .opur~3'rr l

WORKSHOP: CARBON MONOXIDE AND CvD I -. the blind technique. It is, however, an open question as to whether it is correct to perform morphological evaluations of randomized biopsies in a disease in which ': the lesions appear focally. Thtmost satisfactory approach. of course. would be to perform a quantitative evaluation of the morphological changes in the whole aorta, but such a procedure is so time-consuming that it is hardly realistic. Another important question is the-nature of the edematous-intimal changes observed in our studies as well as in a number of other studies in humans (14).. The.possibility that they are artifacts cannot be excluded, although great care has been taken to use optimal methods of fixation and preparation (19). EFFECTS OF NICOTINE AND CARBON MONOXIDE ON UPID METABOLISM Nicotine The effect of nicotine on lipid synthesis in isolated arteries has been studied by various groups with contradictory results (32). Tne latest study by Sarma and co-workers (30) using perfusion technique on human coronary arteries a few hours after death did not show any effect on lipid synthesis of nicotine addition to the . perfusion fluid. Nicotine administration and cigarette smoking lead to an increase in free fatty acids in serum as first observed by Kershbaum er al. (16). There is no change in serum concentrations of triglycerides, cholesterol, and phospholipids (32, 36). Rabbits given 1.14 mg of nicotine per kilogram of body weight twice daily for 20 months did not show changes of lipids in heart and aorta. Otherwise, no reports have appeared on any significant influence of nicotine on lipid metabolism. Carbon Mono.cide It has been known for many years that acute exposure of animals and men to hypoxia by bleeding, hemolysis, or low atmospheric pressure leads to hyper- lipemia. It was first noted by Boggs and Morris (6) in 1909 and later was studied by various authors. The hyperlipemia involves most of the plasma lipids, the concen- tration of which may increase considerably during the first I or 2 weeks before returning to normal values. Increased synthesis may be a cause of the hypoxic increase in plasma lipids, but no definite proof has been given. Carbon monoxide exposure also leads to hyperlipemia as shown first by Astrup er al. (I) and by Kjeldsen (18). This was demonstrated in rabbits fed a usual diet with or without the addition of cholesterol and exposed to COHb levels between 15 and 259'c. We have seen this effect of carbon monoxide exposure in all our later experiments with cholesterol-fed rabbits. The carbon monoxide (COHb 16 to I8%)-induced elevation of serum cholesterol has usually led to 15 to 20% higher levels for the first 2 to 3 weeks in comparison with the groups not exposed to carbon monoxide, after which the levels have been approximately the same in the two groups. There is no doubt that this carbon monoxide-induced increase of serum choles- terol in cholesterol-fed animals is responsible for the increased cholesterol ac- cumulation in aortas of the exposed animals in comparison with nonexposed control animals. This can be demonstrated by keeping the serum cholesterol con- centrations at the same level in two groups of animals. respectively exposed or nonexposed to carbon monoxide, by individual cholesterol feeding. In this case, _ I

. . ItEVEtVTIVE A1 otanE 8, 000-000 (1979) jrCxr Model Studies Linking Carbon Monoxide and/or Nicotine to Arteriosclerosis and Cardiovascular Disease' This set af ,r,l'Q!s s:Sc;a all cri ;•'r ,arts Or GUefIG$. F~J4 vi Qr Or .7!II "i~js~ indicate all corlrec~Qns on this set, " POUL ASTRUP AND KNUD KJELDSEN Drparrmenr o/Qinicaf Chrmit/rv. Rigs6ospitatet, Univertir,r Hnrpiml. 9 BfnlCJpmstvj, DK-2f00 Cn rnha en /. Drmmark Received November 19, 1978 The cardiovascular effects of anima/! xposure to carbon monoxide and/or nicoline arx 0' surveyed. The myocardial effects are produced by carbon monoxide as well as nicotine and lead to decreased myocardial oxygen tensions with compensatory increases in coronary blood flow. There is an increased tendency to arhythmia. Carbon monoxide exposure Icads to degenerative changes and partial necrosis of myofibrits, similar to the changes observed after hypoxia. After nicotine exposure. moderatn fibrosis and calcification may be seen in arterial media, a!though no injuring effects on intima have been observed. The effects of carbon monoxide exposure on ar,erial intima have_been feF 3luated, and previoos findings of arterial intimal changas have rwt been confirmed. It is concluded that tobacco smokers' enhanced risk of heart infarct is caused by the myocardial effects of nicotine and carbon tswnoxide. The structural changes in the arteriat media probably are caused primarily by nicotine, and secondarily by carbon monoxide. The compounds responsible for the en- - hanced intimat changes in the smokers are not identifed with certainty, but may be related to carbon monoxide induced changes in cholesterol metabolism. The components of tobacco smoke responsible for the association between smoking and cardiovascular diseases have not been identified with certainty. The research so far has been focused mainly on nicotine and carbon monoxide, but other components, such as hydrogen cyanide, carbonyl sulfide, and trace ele- ments, particularly cadmium, might be of pathogenetic significance. When evaluating the animal models linking carbon monoxide and/or rticotine to cardiovascular diseases, it is appropriate to distinguish between effects on the myocardium and effects on the arterial walls as the effects of smoking deal partly with a direct effect on the heart leading to an increased risk for sudden death, probably caused by oxygen lack, and partly with an effect on the arterial walls leading to an enhancement of the atherosclerotic process. EFFECTS OF NICOTINE AND CARBON MONOXIDE ON THE HEART Nicofine - - The cardiac effects of nicotine administration in normal subjects and in animals include increases in heart rate, cardiac output, blood pressure, and coronary ~ blood flow. The increase in coronary blood flow is proportional to_ the nicotine- T--- -- - - _ ~ 'Presented at a Workshop on Carbon Monoxide and Cardiovascvlar Disease, sponsored by the American Health Foundation and the Federal Health Office. Federal Republic of Germany. Berlin- .Oetober 10-12. 1978. 0091- 7 435r%008 3-0000502.000 CueyrVx ~, I9+v by Audea,.c Pe3f. Ine. An.pl„ ef rep,nE,eeiun u,.r fonn re~,v.d. l-~r- r r'i l I I ~

ASTRUP AND KJELDSEY to difference in the aortic concentration of cholesterol could be demonstrated 34). Further, by using a special double-isotope technique, we were unable to lemonstrate any effect of CO exposure on the aortic in vivo uptake of cholesterol n hypercholesterolemic rabbits. However, there might be a slight increase of :holesterol uptake in the aortic arch of normocholesterolemic rabbits-due to CO exposure (34). The coronaries were not investigated. Sarma er al. (30) found that tuman coronary arteries, by perfusion with blood having a COHb concentration lf l5%, increased the cholesterol uptake in comparison with coronary arteries +erfused with nbmal blood, while the lipid synthesis in the arterial wall did not .hange. - Many investigators have found somewhat higher serum cholesterol levels in mokers, usually about 10 to 15 mg%, in comparison with nonsmokers (31), which nay be explained by raised COHb levels. This increase in serum cholesterol :oncentrations in smokers in comparison with nonsmokers-undoubtedly will en- iance the accumulation of cholesterol in the smokers' arteries. No quantitative tudies have been carried out for evaluating the relation between increased serum holesterol and enhanced atherosclerosis in smokers in comparison with tonsmokers. However, the enhanced atherosclerosis in smokers might be ex- -lained, at least to some extent, by the CO effect on the serum lipid values or on he lipid metabolism in the vessel walls. CONCLUSIONS The myt5cardial effects of smoking are produced by carbon monoxide as well as ticotine and are associated with the availability of oxygen, as determined by the -xygen capacity of blood and of tnyocardial tissue, by the oxygen affinity of emoglobin and of myoglobin, and by changes in oxygen consumption. Animal exposure of carbon monoxide alone leads to microscopic myocardial :sions, the severity depending on the-degree of exposure. The clinical symptoms re, first of all, decreased exercise tolerance with ECG changes, in particular +hen obliterations of coronary arteries already exist. It is likely that the high risk of heart infarct and sudden unexpected death in mokers is caused primarily by the raised COHb combined with the arrhyth- nogenic effects of nicotine: - The structural changes in the arterial media of smokers seem to be caused trimarily by nicotine and, only secondarily, by carbon monoxide. The compound esponsible for the enhancement of atheroscleroticintirnac changes in smokers has tot been identified with certainty. The effect of raised COHb levels on cholesterol .ietabolism may be of significance. REFERENCES I. Astrup, P., Kjeldsan. K., and Wanstrup. J. Enhancfng influence of cartron monoxide on the development of atheromatosis in cholesterol-fed rabbits. J. A+heroicle.. Res. 7. 343-354 / (I967). - - 2Ayres, S. M:, Gianelli. S., and ~luener. H. Myocardial and systemic responses to car- boxyhemozlobin-Ann. N.Y..icnd. Sci. 174,'-bg-?93 (197o). 3. ]dalau. T. Ohtake, S., Cummings. J. R. er al. Ventricular extrasystoles induced by epinephrine. - nieotine, ethanol, and vasopressin in dogs with myocardial lesions. Torrcof. AppL Plmrrnncol. I5.189-?05(1969)._____.__-.__ rI_ '.opyri9hr

_. . , I ASTBUP AND K1ELD5EN "'(,:a TABLE I Avau.s or Nmon.e Uam rw Eaeea1.u.I.c Srvoma i. Reean ' Cotrespond.ntto eipreuer Nkalne - perday AtAeroyeuk AvtLon' per k8'day in a rmokcr effeet '(1)FUhcr.E.R-.RaEUCin.R.,Wholcy.~.H..andNclson.R.ArrhkPorhnl.96.:98-30a(IYDI/ _ RISc6svc2cin.H..LaaGA v.,LRppQpr%W..rraLLAfn.CAr.v.8,190-196(19m)~.()IGms¢o- OMd w Y.. Anpuen. G.. L<Ilau ch.l.. Jacoiffi. B.: and Bearumont. J: L. J. Arhnordee Rrs. 5.-I91-305 (t96]l: ql ScmL R. A., Henson. D. E., Lesak, A.. Turner, R. J.. Millkova. B-S.. and Hu.. G- M. Amer.l. Poeho/. )0, 209-233 p9ZJ1. (- - Perri (16)j focused on the brain vessels where edema of the v<tcel wall, perivascu- . lar edema, and small hemorrhages were described as typical lesions. In 1934, American investigators (39) performed a series of acule and chronic CO intoxica- I [ions in various animals. In these studies pesechial bleedings. swellings of the - I eapillaryendothelium,andperivascularedemaueretypicalfindings.Considerable species differences were noled; dogs developed the most serious lesions, while lats appeared more resistant. - About 10 years ago, we in our laboratory started morphological investigations , on the effect of carbon monoxide in arter9es of rabbits. We found areas with edematous swelling of the endothelium. formation of subendothelial blistcrs, and . subendothelial edema. The arterial surface showed a markedly uneven and swob I len structure. We related these structural Lndings to the physiological enhancc ment of vaseular permeability caused by carbon monoxide exposure. After expo- I sure of humans to carbon monoxide (20 to 25ry COHb for 3 hr. the disappearance i rate of O1I-labeled albumin increased considerably (about 507c) (?4), and in dogs the lymph flow and the protein flux io the thoracic duct increased (25). The concept that focal, arterial edema can be an aarly phase in atherogenesis was first - ~ suggested by Virchow in 1856 (3g), and again was introduced early in this century by German pathologists (Bredt (7) a.o.). Altered endothelial permeability due to ~ fDjury has been supposed to precede the intimal edema. - , Recently, other workers failed to demonstrate morphological arterial chanees after CO exposure (b various animal species. In consequence of this inconsistency rl C/ we therefore decided o repeat our tarlier experiments on a large number of i rabbits at vadous Cxposure levels, including lethal leve(s: To omit subjective (/$ i bias, a blind technique was adopted. Biopsies were taken at random in the same i locations in the aorta as earlier and the specimens were evaluated by two indepen- dent investigators. With this technique, we Cailed to confirm our earlier results (15). I 77x reason for these discrepancies between our earlier and recent results is not I clear, but some possibilities can be memioned: The number of animals in the I oti~inal series may have been too small, or the studies were nut performed with r I aPyr3'nr N})uJ G-eNdoH w IOr ~ N ~ o ~

tit ~ uYi WORKSHOP: CARBON MONOXIDE AND CVD ( 4. Baroldi. G. Lack of corl elanon betwecn coronary thrombosis and myocardial infarcilon or sudden " -eoronary" heart deanh..Lnr. N.Y. Arad. SrL 156, SOd-525 (1969). 5. Bellet, S.. Fleischmann. D., Roman, L.. er a1. The effect of cigarette smoke inhalation on the - ventricutar fibrillarion-threshold. Cirrulminn. 42 (suppl. 3). 135 (19701. _ - 6. Boggs, T, R., and A(orris, R. S. Experimental lipemia in rabbits. l. £spt. ,1fed, It, 553--560 (1909). 7. Bredt, H. Changes in the initial oedema, in "Atherosclerosis. Pathology. Physiology, Acriology. Diagnosis and Qinicaf_Managemenl",(F. G, Schetiler and 0. S. Boyd. Eds.) p. 6. Elsevier. _ Amsterdlm/New Yoric; 1969, S. Buchner, F. "Die Koronarinsuf7ziens," p. 88. StcinkopR. DarmstadA(939. - 9. Campbell. 1. A. Tissue oxygen tension and carbon monoxide poisoning.l. Phesi~d. tl.wdun) 68. 91-96 (1929119301. ' ' 10. Christ, C, Expenmente(le Kohlenoxygenvergiflung, HWmuskelnekroscn und E)cktrokardio- gramm. Beirr. Path, Anar. 94, 111-125(1935). - 11. Ehrich, W, E, Bdlet. S., and Lewey, F. H. Cardiac changes from CO poisoning. Amrr. J, ,tfed. - Scr. 208, 511-52J (1944). 12. Frankl, W. S., Winters,-W. L.. and So(otT. L. A. The effects on the cardiac output at rest and during exercise in patients with healed myocardial infareNon. Circulation. 31,42 -44 ((9651. I3. Friedberg. C. K., and Horn, H. Acute myocardial infarction nor due to coronary artery o<clusfon. JA.NA 112, 1765-1T9 (1939). - 14. Haust. M. D. Early permeability changes in human atherosclerotic lesions. Prng. Biochrnr. Phnr- macol. 14, 203-'_07 11977), - IS. Hugod. C., Hawkins. L. H„ Kjelds<n. K., Thomsen, H. K., and Astrup. P. Effect o( carbon monoxide exposure on a6rtie and coronary intimal morphology in the rabbit. Atheroseleroair 30, 333-342 (I978), )6. Kenhbaum, A.. Ballel. S. Dickstein. E. R. et at. Elhct of cigarette smoking and nicotine on serum free fatty acids. Circ. Rei. 9, 631-638 (1961). 17. Kien, G. A., and Sherrod, T. R. Action of nicotine and smoking on coronary circulation and myocardial oxygen utilization. Ann. N.Y. Acnd. Sei. 90, 161-173 (1960) . 18. Kjeldsen, K. "Smoking and Atherosclerosis:" Thesis, p. 145, Munksgaard. Copenhagen- 1969. 19. Kjddsen. K., and Thomsen,.H- K. Recommended preparation method for SEM in the rabbit aorta, Prag. Biochrm. Plmrmocol. 14, 189-191 (1977). 20. Klebs. P. Ueber die Wirkung des Kohknoxyds auf dem Thierischen Organisms. Virchow.r Arch. Pa:hol. Annr. 32, 450 (1865), -- - 21. Knelson, J. H. United States air quality critena and ambient standards for carbon monoxide. VDl Btr_ 180, 99-101 (1972). - 22, Lewey, F. H., and Drabkin, D. L. Experimental chronic carbon monoxide poisoning of dogs. Amer. J. Afed. Sci. 208, 502-510 (19441. 23. Lorenzen, I Alterations in acid mucopoigsaccharide and collagen of rabbit aorta related to age of epinephrine-thryoxine induced anerioscierotic lesions. Acla. Endacrin. (Coprnhagen) 39, 615-626 (1962). 24. Pxrving, H.-H. The effect of hypoxia and carbon monoxide exposure on plasma volume and eapillary permeability to albumin. Scnnd l. Cfin. Lab. Invest. 30, 49-56 (1972). 25. Parving. H.-H.. Olilsson. K., Buchardt-Hansen. H. 1.. and Rorth. M. Effect of earbon monoxide exposure on capillary permeability to albumin and a.-macrogiobulln. Scand. J. Clin. Lab. Invelt 29, 381-388 (1972). 26. Petri, E. lJber Hirngefess-2crreissungen bei Leuchegasvergiftung. Zb7. ARg. Pnrh. Parhnl. Anar. 40. 385-387 (1927). ~ - 27. Regan, T. 1., Hellems. H.. and Bing, R. J. Effect of cigarette smoking on coronary circulat{on and eardiac work in patients with arteriosclerotic coronary disease. Ann. N.Y. Acad. Sci, 90, Ig6-189 (1960). 28. Rix. E. Experimentelle Untersuchungen zur Frage der (.euchrgas-vergiflung Yirchows Arch. Path. Anar. 283, 801-8f6 (1932). 29. Rosenblath, P. L3ber einen Fall von Leuchtgasvergiftung mit scheinbarer Verkalkung der PaI- - lidumgefasse. Deur_Z. ,h'enenhtilk. 84, 276_28_6 (1925). _1- ~ 0 ',r N'frL,.- /