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7/-o-el 61 Reprinted from ANNALS o'F'IiNTEAtNAL MEDICINE'Vol. 74, No. 5 MYy 1971 Printed'in US.A. Heart Rate and Carbon Monoxide Level After Smoking High-, Low-, and' Non-Nicotine Cigarettes A Study in Male Patients with Angina Pectoris , WiLB'ERT S. ARONOW, M.D., F.1#:iC.P., JAMES DENDINGER, B.S.,,andISTANLEY N. kOFfAW, N1.D:, Irvine and Los Angeles, California . Ten cigarette smokers with angina pectoris had bloodd pressure, heart rate, and expired+air carbon monoxide measurements before and after smoking each of five high,, low-, and non-nicotine cigarettes. There was a significant increase in systolic and diastolic blood pressure after smoking each high- and low-nicotine cigarette,,with a sigtlificant'increase in peak systolic and diastolic blood pressure from cigarette 1 to cigarette 5.11here was a significant increase inn heart rate after smoking each high- and low-nicotine cigarette but no i significant' increase in peak heart rate from cigarette 1 to cigarette 5. There was no significant increase in blood pressure or heart rate after smoking a non+nicotine cigarette. There was a significant increase In carbonmonoxideJevel after smoking,each hig11-, low.,, andlnon-nicotine cigarette, with a significant increase in peak carbon monoxide level from cigarette 1 to cigarette 5. S tuoKINt; one high-nicotine cigarette (1) aad, one low-nicotine cigarette (2) caused a significant increase ia systolic blood' pressure, diastolic blood pressure, and heart rate inipatients with angina pectoris caused, by corondry artery disease. Thene was no significant change in systolic or diastolic blood1 pressure or in heart rate after smoking one non-nicotine lettuce leaf cigarette (3). 'This study was pertormed to determine the effects on blood' pressure, heart rate, and' expired-air carbon b- From the Cardiology Seaion. Medical Ser+iae. Long Bearb Veter- am Adnumstracion Hospltal; the Tuberauloafs and ReaQarasorr Diaeans AasociaUon of, Los Anaetes County; and the Udvenit7r of Calitormia Colk;e o!' Jfadlcine; Ir.ins, Calit. monoxide level before and after smoking each of five high-nicotine, low-nicotine, and nonnicotine cigarettes every 30 min. Materials and, Methods Ten men between the ages of 40 and 56 (rneani age, 51')-alli of' whom smoked 20 to 30 cigarettes daily- were subjects. Each subject had, a classical history of ex- ertional angina pectoris. Five subjects had a previously documented myocardial infarction at least 1 year ago; the other five subjects had coronary artery disease docu- mented, by previous coronary angiography, with, 50%, or greater narrowing of the lumen of at least one major vessel. The patients were brought to the laboratory and'famil- iarized with the equipment and the procedure before the study was performed. No patient smoked a cigarette for at least 8 hr before the three consecutive mornings of this study. In a statistically randomized order each, sub- joet smoked on three consecutive mornings either stand- ard nonfilter high-nicotine cigarettes, standard filter low- nicotine cigarettes„ or standard non-nicotine lettuce leaf cigarettes. The high-nicotine cigarette contained 2:0' mg of' nicotine andl 28 mg of' tar;, the 1ow-nicotine cigarettee contained' 0.3' mg of nicodne and 7 mg of tar, and the non-nicotine lettuoe'leaf' cigarette contained 24.7 mg of' tar. The patients did' not know which cigarettes they' were smoking. The patients remained in, the same room under constant, observation during, the entire study period. Heart rate was recorded during each observation pe- riod, with an electrocardiograph using lead II. The same observer recorded blood pressure in the right arm of r each patient in the sitting position during each observa- tion periodi using a mercury sphygnnomanometer. After 20-sec breath holding (4, 5) an expired-air sample was collected in a rubber breathing bag,d'uring each observa- tion period by the same technician and, immediately an- alyzed' for carbon monoxide content, using a Beckman Annals of InUmal Medlnin. 74:697-702. 1971' 697

Table 1. Mean ExplredAlr Carbon Monoxide Level Befbre and Atter Smoking Eachi of Fve High-,, law+, andi Non-Nicotine Cig; arettes' t Measurement Average Expired-Air Carbon Monoxide Level . Period High-Nicotine Low-Nicotine Non-Nicotine Base 14.6 t 7:6' 13.6 t 6.3' 13.2 t 9.1 IA 1'9:4t8:0 18.9t6:3' 18.2t9:0 IB 18:0~7:0 17.3 6.0 0 1. 16.6 9.1 2A 214 7.1 1 22.6 6.6 6 21.2t 818 2B 21.9~6.'41 19.9t6.2 19.6,± 8:5'. 3A 27:2t8:1 25:4t6:2 24.3 t 9:0 3B 24.8 t 7:0 23.4 ~ 6:3' 22.6 ± 8.6 4A 29:3't8:2 28,2~7:0 28.0t9:0 4B 27.2 t 7:5' 26.1 t 6:2 25.9 ± 8;1. $A 32:8t 8.1 31.7 ± 7.7 31.8t9:4' . • Ia p,pm = 1 so. Base - baseiine; IA - immediately after smoking dprette 1; 1B - immediately before smoking maarette 2; 2A - isa, mediately after,srnoi:iaa,cigarette 2; 2B - immedlaaely'before srnokiat' dgarette 3; 3A - iisunediately' after smoking cigarette 3; 38 - lmmed, lately before smoking ci{arette 4; 4A - immediatelr ' after smokinf dgarette 4;, 4B - immediately before amokici' cigarette S; JA = thr mediately after smoking daarette s. IR-215' nondispersive, infrared, carbon monoxide ana- lyzer (4, 5)'. At &AM each morning the blood pressure and heartt rate of each patient were recorded in the sitting position, and then an expired'-air sample for carbon monoxide contentt was obtained. At' 8:05 AM, 8:35 AM, 9:05' AM, 9r3S AM, and L0:05 AHt each patient smoked one ciga- rette in the sitting position at his normal pace, inhaiing the smoke. Immediately after smoking each cigarette and 1 min before smoking the next cigarette, the blood pres- sure and heart rate were recordedi in the sitting position,, and then an expilI sample for carbon monoxide content was collected and immediately analyzed. An analysis of variance tests for factorial design was used to analyze the data (6). Results Table 1 shows the mean expired-air carbon mon- Us. •-• Hig~ nicotlna icigarettK o--m loanicotineciWanat o-.u No,nicotine ciq4r.ttes. ® 7A In ' 3A MNauranal irrlads oxide level in parts per million i- 1 standard, devia tion for the 10 patients before and immediately after smoking, each of the 5 high-, low-, and non-nicotine cigarettes. An analysis of variance test showed' a sig- nificant increase in mean carbon monoxide leveli after smoking,each cigarette (P < 0:01)and a significant increase in peak mean carbon monoxide level from cigarette 1 to cigarette 5(P' < 0.01). 'There was no significant difference between the high.-nicotine,, low- nicotine, and non-nicotine cigarettes. Figure 1 illustrates the mean expired-air carbon monoxide level in parts per million for the 10 patients before and immedlately, after smoking each of' the 5 high-, low-, and nonnicotine cigarettes: 'hable 2 indicates the mean heart rate in beats per minute ± l standard' deviation for the 10' patients be- fore and, immediately after smoking each ofl the S high-, low-, andi non-nicotine cigarettes. An analysis of variance test showed a significant increase in mean heart rate after smoking each of, the high-nicotine and low-nicotine cigarettes (P' < 0.01) but not after smoking,the non*nicotine cigarettes. There was no sig- nificant increase in peak mean heart rate after smok- ing the first high-nicotine or the first low-nicotine cig- arette. There was a significantly higher mean heart rate after smoking a high-nicotine cigarette compared with a low-nicotine or a non4-nicotine cigarette (P < 0:01')- There was a significantly higher mean heart rate after smoking & low.nicotine cigarette compared with a non-nicotine cigarette (P <' 0.01). Figure 2 illustrates the mean heart rate in beats per. minute for the 10 patients before andlimffiediately af- ter smoking each of the 51 high*, low-, and non-nico- tine cigarettes. _, 3e 4A m 1oos0s29Q31 Figure 1. There was a significant ' increase in mean expired-air carbon monoxide level after smoking eacA, of the high-, low-, and noanicotine cigarettes, as wellias in peak meani carbon monoxide level' from cig+ arette 1 to, cigarette 5. Base = baseline; 1A = immediately after smoking cigarette 1; 1!B = immed- lately before smoking cigarette 2; 2JA' = immediately' after smoking cigarette 2: 2BI = immediately be- fore smoking cigarette 3, 3A' _ Immediately after smoking cigarettr 3: 38 = immediately before smok+ Ing cigarette 4; 4A = immediately after smoking cigarette 4: 4B = Immediately before smoking, ciga- rette 5: 5A = immediately after smoking cigarette 5. SA 0 t' MayI971 • AnnI lnternrl Medicine •Volume 74 -NumberS 698

- High nicotine cigarettes a-3'Low nicotine cigarettes No nicotine cigarettes INean heart rate for 100 patients in beats per minute. 0.0! : V; T Base --r lA 1B' 2A 21B' 3W. ~-~ 3'B __V4A 4181 -,- 5A Measurement Periods r Rgure~2: There was a significant increase in.mean heart,rate after smoking each oft thei high-nicotine and, Iow-nicotine: cigarettes but not' after smoking the non-nicotine cigarettes. There was no significant increase in peak mean heart rate from cigarette 1 to cigarette 5. For explanation ofimeasurement periods,,see Figure 1 legend. Table 3 1 shows the mean, systolic blood pressure : in millimeters of inercury, ±1' standard deviation for the 10 patients before and immediately, after smoking each of the 5 high-, low-, and'' non-nicotine cigarettes. An analysis of variance test showed a significant rise in! mean systolic blood pressure after smoking each of~ the high-nicotine and low-nicotine cigarettes (P <' 0.01) but not after smoking the non-nicotine ciga rettcs. There was a significant increase in~ peak mean systolic blood' pressure after smoking, high-nicotine and Iow-tticotine : cigarettes from cigarette 1 taciga- rette 5 (P < 0:011), The mean systolic bloodipressure was significantly higher after a high-nicotine ciga- rette compared with a low-niaotine, or a non-nicotinee cigarette: (P < 0.01). There was a significantly higher mean systolic blood pressure after smoking & low- nicotine cigarette compared with a non-nicotine ciga- rette (P < 0.01). Figure I illustrates the mean sys- Tablei2. Mean Heart Rate Beforrand Aftar Smoking Eaeh of Flve. High-• Loww and Non.Nicotine Cigarettes Measurement Average Heart Rate+ Period High-Nicotine : Low-Nicotine Non-Nicotine Beae 7ll0It11.0 72:4t11.1 72:2t9:1, 1A 86.8 t 9.2 81.0 t 9.4 74.9 t 9:3' IB 79.1' t 12.0 75.7' t 10.5 70.5 ~ 8:3 2A . 87.2 10.5 5 8'Z.0t10.0 8 71.7 8.8 2B $0.6 11.4 4 76:3t12:0 70.9 7.6 6' 3A 87:8 t 9:5 83.6 t 10.6 73:8 t8.5 . 36 ` 80.0 11.0 0 76.6t11.1 70.6't7:6 4A 87.6 t 11.3 83.0 t 9.8 73.4 y 7:4. 4B 820 t 11.2 77.6 t 10.1 70.T t, 8.1 SA, 89.4 11.2 2 83.2t 9.9 728t7:9 • In bean/mis ± I so. For ezpiaaatlon ot measutement' puiods;, srr Table Ii tolic blood pressure in millimeters of mercury for the 10 patients, before and'immediately after smoking, each of the S high-, low-, and non-n'tcotine cigarettes. Table 4 indicates the!meam diastolic blood pressure in millimeters of mercury ± 1 standard deviation for the 10 patients before and!iizlmediately after smoking each of the 5 high-, low-, and: non-nicotine cigarettes. An analysis of variance test showed a,significant rise in mean diastolic blood pressure : after, smoking each of the high+nicotine an& low-nicotiae cigarettes (P < 0.01) but' not after smoking the non-nicotine ciga- rettes. There was a significant increase in. peak mean diastolic blood pressure after smoking high-nicotine and low-nicotine cigarettes from cigarette 1 to ciga- rette 5 (P < 0:0!1i). There was a sigmificantly, higher mean~ diastolic blood' pressure after, smoking a: high- nicotine cigarette compared with a low-nicotine or a non-nicotine: cigarette: (P < 0.01)as well! as after, Tabie 3. Mean Systolic Blood Pressure Before and,AYter Smoking Each of' Fve High., 4ow-,, snd! Non-Nicr4tine Cigarettes Measurement Average: Systolic Blood Pressure' Period High-Nicotine Low-Nicotine Non-Nicotine Base 121.4 20.5 5 121.0 20.4 4 7 121.4 21.7 IA 135:0t1'9:9 128.0 21.2 2 1224~22.3 1B 128!4 y 19.8 123.8 t 20.6 120.6 ~ 21.7 2A 137:2t20.0 129.2 21.1 1 121.0 21.0 0 2B 130.4 t 1!9:1 125:8 +; 20.1 121.4 t 21.5 3A 138!6i1'9:9 130.2 21.7 7 123.0 21.5 5 3H 13Z6t20:0 126:8t20.5 121.2t20.7. 4A 140:2±21.0 131.6 y21.6 121.8 t 20.0 4B 134:5 t 20.5 128:6 t, 20.8 121.6 t 21.4 5A 141.4'± 22.6 132:6~21.6 1226~21.6 • In mm Ht = I so. For e:ptanation of', measurement periodl. ter Table 1. Aronow at al. •'Heart Rat., Co RerN. and ISmokint! 699 80. 0 ~ 75: 0 -

in, mmHg biood'pressure for 10 patients 130.0 142.0 140.0 ~ 133. 0 ~ Mean systolic I '- High nicotine cigarettes tT--a' Low nicotine cigarettes" oN..o No nicotine cigarettes r i % `` / .% IV / i .d i ..0, ~ .N.. ...M... 1/ Nw, ••~•~Ny ~ .• .NMM 01.• ..... .M . ••0.......uw....O.u.....a...«O ~.u.N.... --I Bbse T 1A i t 18 2A ' 28 3J1 Measurement Periods Figure 3., There was a signiflcant increase In mean systolic blood pressure after smoking, each of'the high-nicotine and /ow nicotine eig• arettesbut not after smoking,the non-nicotine cigarettes. There was also a significant increase in peak mean systolic: blood pressure from cigarette l to cigaretta1 5 after smoking ,the high-nicotine and and low-nicotine cigarettes. For explanation of'measurement peri- ods, see Figure I legend. cipitated! in 2 of, 10 patients (20% ) after smoking the high-nicotine cigarettes, in 1 of 10 patients (10% )i after smoking the low-nicotine cigarettes, and: in none of the patients (0% ) after smoking the non-nicotinee cigarettes. No ischemic ST=segment depression was precipitated after smoking hig.li-nicotine, Iow-nicotine, or non-nicotine cigarettes in any of the 10 patients. Discussion Riehder and Roth (7) found that nonnal subjects who smoked:ini successioni two thirds of' each of'two Table 4. Mean miastolic Blood Pressure Before and After Smokln`. Each of Five High-, Low-, and Non,Nlcotine Cigarettes Measurement' Average Diastolic Blood Pressure!' Period H'igh-Nicotine Low-Nicotine Non-Nicotine Base 79!6' ± 9.7' 80!0 t 9.0 ~ 80.8' ±,10:3 .IA 87:4!±8.6I 84.1 t,9.0 81.0t110.2' 1B' 83.0 t 8.7' 81,6' t 8.8 80r'4' ~ 10.5 2A 88.2 t 8.1 84.2' t 9.0 80.16' t 10.0 26 84.6' t 8.7' 82.2' t 8.4 80.16 t 1118, ' 3A 89A t 7.7' 84.8 t 8.8 81.2' t 10.4 3B 83;1~+9.0 82'8t8.7 79!8t110.3 4A 89:8 t 8.91 8&0 t 8.9 80A', t 9.01 4S 86:6 ~9:8' 84:0 t 8.3 80.161 t 9.6 3A 91.2 9.21 ' 86:2t8.3 7 81.0 10.7 • to mm H¢ = 1 so:, For explamuon of ineasnrement perunds, sue Tabie 11 filtered cigarettes had, during smoking, an increase in mean systolic bloodl pressure of 21' mm Hg; an in- crease in meani systolic blood pressure of 16 mm Hg, and an increase in mean heart' rate of 23 beats/min. tYronow;, Kaplan, and Jacob (1) previouslly found that patients with angina pectoris caused by coronary artery disease had after smoking one standard non- filter high-nicotine cigarette an increase in mean sys- tolic blood pressure of 16' mm Hg, an increase in mean diastolic bloodl pressure of 9 m¢n Hg, and an in- crease in mean heart rate of 17 beatsJmin: After smoking one low-nicotine cigarette their patients had an increase in mean systolic blood pressure of 8 maa Hg, an increase in mean diastolic blood pressure of 4 mm Hg, and: an increase: in mean heart rate of' 9 beats/min (2). After smoking one non-nicotine ciga- rette their patients had' no significant increase in mean systolic blood pressure„mean diastolic blood pressure, or mean hearti rate (3),. - Our results iitdicatedi a: significant increase in mean heart rate after smoking each of the five high«nicotine and five.low-rlicozine cigarettes but not after smoking the non-nicotine cigarettes. These results also showed no significant increase in peak mean heart rate after smoking the first high-lnicotine: or, low-nicotine ciga- rette. Our data; alsa showed a si_nificant increase in mean systolic blood pressure: and in mean diastolic bloodi pressure after smoking each of the five high-nicotine and five low-nicotine cigarettes bu!Cnot after smoking the non-nicotine cigarettes. The peak mean systolic blood pressure and peak mean diastolic blood'presstlre were also significantly increased from. cigarette 1 to \1 - 700 Nliy 1'971 •/Annals of Intarnal Medicine • Volume 74 • Numbar 1 smoking, a Iowrnicotine cigarette: compared with a non-nicotine cigarette (P < 0.01). Figure 4 illustrates the meatl, diastolic blood pres- suredn millimeters of'mercury for the 10 patients be- fore and immediately after smoking each of the S' high-, low-, and non-nicotine cigarettes. Occasional premature ventricular systoles were pre- 10050052901051

Measurement Periods - Fguoe 4. There,was a significant increase in mean diastolic blood pressure after smoking',each of the high•nicotlnrand low-nicotine cig- arettes but not'after smoking,the,non-nicotine cigarettes. There was also a significant increase, in peak mean diastolic bloodl pressuree from cigarette 1 to cigarette 5 after smoking',the high-nicotine and low-nicotine cigarettes. For explanation of ineasurement, periods, see Figure 11 legend. ' Mean diastolic. 9Z0-q ~ 90.0-I «--• High nicotine cigarettes a--a Low' nicotine cigarettes a-10 No nicotine cigarettes blood pres's'ure' '~ for 10 patients ~ im mm Hq 85„0 ~ ,' cigarette 5 after smoking the high-nicotine and low- nicotine cigarettes. The increase in heart rate and blood, pressure caused by smoking high-nicotine and Iow-nicotime cigarettes is based on the : known increase ini catechol- amine discharge from the adrenai medulla and from chromaffin tissue in the heart that occurs during', smoking (8-10). Nicotine also acts on chemorecep-. tors in the carotid andi aortic bodies, refleziy, causing, acceleration of the heart rate and an increa5e in blood pressure (11). In addition, low concentrations of' nicotine can stimulate sympathetic ganglion, cells: Our data also indica2ed' a significant increase in mean expired-air carbon monoxide level after smok- ing each high+nicotine, low-nicotine, and non-nicotine cigarette, with a significant increase in peak mean carbon monoxide level from1 cigarette 1' t,o cigoLrette-5. There was no significant difference in mean carbon monoxide level after smoking high-nicotine, low-nico- tine, and non-nicotine cigarettes, as has also recently been found by Cohen and associates (12). Carboxyhemoglobin determinations may be ap- prpximated from expired-air carbon monoxide levels (4, 5)1. The equation, Carboxyhemoglobin % =-0.5 + 0.2 (carbon! monoxide in' ppm), may be used~ for estimating carboxyhemoglobin levels (4),. Using this equation, it can be calculated from our data that the mean carboxyhemoglobin concentratiotr ia our paL tients was 7.105 after smoking the fift;h high-nicotine' cigarette, 6.8% after smoking the fifth, low-nicotine cigarette, and 6,95'o after smoking the fifth non-nico- tine cigarette. The levels of carboxyhemogl,obin (as approximated from expired-air carbon monoxide levels) producet, by repetitive cigarette smoking in our study did not have any significant effect on the systolic or diastolic blood pressure or on the heart rate. The principal noxious eBects of carbon monoxide inhalation on the organism are'caused by the recognized interference of this gas with oxygen delivery, related to competition for hemoglobin transport'capacity' and inhibition of oxyhemoglobin dissociation in the presence of car- boxyhemogIobin (13-16). Current research also indi- cates other significant effects of carbon~ monoxidc in- haiation on the organism' (17)-for example, inter- ference with central nervous system functioning, at low level concentrations (18 ),, and facilitation of ex- pernmental athetosclerosis (19, 20)'. The effects of increased carbon monoxide levels produced by smolcing,cigarettt~s need to be further in- vestigated. We are currently investigating the effec2ss of increased' carboxy'hemoglobin levels prodiaced by smoking many non-nicotine cigarettes on exercise performance in patients with angina pectoris caused by coronary artery disease. AC1:NOWLEDGMEIY'1'St The authors express their appreaa- tionito Donald C. Butler, Ph.D.. Biostatistictl Consultant;,Western Research Support Center, and to Emiko J. Nalcamura, M!S. Statistician;, Western Research Support Center, Sepulveda„ Calif., for biostatistical consultation and biostatistical analysis of' the data. Received 23 November 1'970; revision accepted 22 December, 1970. Aronow.t at. • H.art Rate. CO Levei. and'Srnoklng7~01 Y . ~. . -- . ~ . i N % - le ~ % .y/ Id Q' ,f~....... N.o....... .,,1µ..IQN.M.......... 0 NM.MN...N...•i0 .NN WO M. ....Oa.ua...... +N' - W'~'o~ - O"' + i i I r 0.0 Base 1A 18 2A 28 3A 38' 4A 4!B - 5A

r geqnests, for reprints should be addressed to W'tbert 3. Arononow, M1D, Cardiology Section, Veterans Administration I$ospital, Long Beacb, Caiif. 90801 References LA'aoNOw' WS, KAPLAN MA, JACOw D:! Tobacco: aprecip- itating factor im angina pectoris. Ann Intern Med 69:529-536, 1968 2 AaoNow WS„ Sw,t'NsoN AJ: Ime effect, of low-nicotine cig- arettes on angina pectoris. Ann Intern Med 71 r599-601, 1969 3. A'aoNow' WS, SwANsoN Al: Z;lon-nicotiniaedl cigarettes and angina,pectoris. Ann Intern Myd 70:1=7, 1'96'9' 4. RtNaota A, GoLOSIKt1nt JR, HeLwto HL, et al: Estimating recent carbon monoxide exposures. Arch Enviran i Health (Chkago), 5:308-318, 1962 S. JIDNES, RH,. EL'L'ICOTT. MF, CADIGAN JB, et'. alt Thee relation• ship between alveolar and blood, carbon, monoxide con- centrations during breathholding: simple estimation of' COH''B saturation. I Lab'Cl&e Med 5'1:553-564; 1958 6. WINaE BJ: Statlsrical'Principles in Esparimental'Desigrt. New York, McGraw,HiB Book Co., Inc-, 1962 7. Raxnme K, Ro rN GM: Effect of smoking on the fasting bloodisugar and pressor aatines. Circulation 20:224-228, 1959 8. W.rrs DTi The effect of nicotine and smoking on' the seaetion of epinephrine: Ann NY Acad Sci',90:7480„ 1960 9. KEASxas'UAI A, KHORSANDIAN R, CAPLAN RF, et al: The role of catecholamines in the free, fatty acid response to cigarette smoking. Circulation 28:5Z-57, 1963' . 10. BtIItN JH: Action of nicotine on the heart. Ann NY Acad Sc1 90:70-73, 1960. 11. Cotsaoe 7H Ja: The pharmacological' actions of nicotine. Ibid :, , pp. 48-51. 12. CoxeN SI, PeaxtNs NM, UaY HK, et al: Carbon monoxide uptake in cigarette smoking. Arch Environ Health (Chica`o)- 22:55-60, 11971 13., GoLDSUCtrtt', JR: Carbon monoxide and coronary heart disease. Ann Intern Med 71:199-201, 1969 1'4., AYxes SM, MUet LEr HS, GaeeoaY J1, et al: Systemic and, myocardial hemodynanlic responses to' relatively small con- centrations of carboxyhemoglobin (COHiB'). Arch Environ Health (Chicaga) 18:699-709, 1969 IS. BraxsTlNOL M, CoLa P, HAwoczNa L: Variations, in oxy4 haemoglbbin dissociation with age, smoking, and Buerger's disease. Brdf 1 Surg 54,:615.619, 1967' 16. Asrttur P: Carbon monoxide and peripheral' arterial disease. Scand I ClLI Lab Invesr19(suppl 99'):193-197„1967 17. GoLnsmumt JR; LANDAw SA: Carbon monoxide and human . health. Science 1162:135II=1359, 1968' 1'8- BE;tan RRy WERrtte7at GA: Behavioral impairment associated with' small doses of' carbon monoxide. Aimer l Pftblic, Health 57:2012-2022, 1967 19. Arro<uP P:, Effects of hypoxia and ot'carbon monoxide ex- posures on experimental atherosclerosis. Ann Intern Med 71:426-427, 1969 20. WnExFAr AF: Is atherosclerosis a disorder of intrnmito. chondrial respiration? Ann lntrrn Med 73:125-i26, 1970 702 May 1971 •/IJnnals of Internal Medlcin• •' Volumr 74 • Number6