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PATIENTS WITH ANGINA PECTORIS develop ar.ginal pain sooner after, exercise follmwin3cigarette srnokine for at leasL two reasons: 1) nicotine increases the mvocardial oxygen demand'j's and 2) car- box:.nerno2lobini decreases oxygen delivery to the r.tyocardium!'"` Srnokin, high-nicotine cigarettes'•' z°tzravates exercise-induced angina pectoris more tharn smoking low-nicotine cigarettas.? Smoking low- nicotine ciearettesz aggravates exercise-induced angiita pectoris more than smoking non}nicotine c:Yarertcs: Tobacco fmokie contains more than 4000 known c:.r.:oounds.1° In addition to carbon monoxide and' ble for a small decrease in exercise performance until angina. nicotine, tobacco smoke cont'ains' oxides of nitrogen, It-vdrogen eyanide and carbon disulfide that may play a role ini asgravating cardiovascular dlisease:'"'" T,~serefore. I ii:vestigrted the effect of smoking five ,•,:nan-nicotint: ciparettes and of breathing enough car- bon monoxide to produce a carbon:cyhemoglbbin level similar to that after srnoking on the duration ofexer- cise until! the onset of angina pectoris. The data, from this study are reported below. „ _ _ i . -,tl~- AQ111it Effect of Non-nicotine Ciga~rettes anid Carbon Monoxide on Angina WILBERT S. AROtVIp'w„ M.D. SUMMARY The effect of smoking five non-nicotine cigarettes andl of breathing carbon monoxide on exercise-induced angina was evaluated in 12 patients withi angina: Smoking increased venous ear- boxyhemoglobin from, 1.71to 5J5176, decreased exercise duration until angina 45%, increased ischemic S'F- segmentdepression at angina fromil.33to 1S2 mm, andldecreased systolicblood pressure times heart rate at angina. Breathing earbonimonoxide increased venous carbox}'hemoglobin from I173 to5.379e, decreased exer- cise duration until angina 35fio, inereased ischemic ST-segment depression at angina from 1.31 to 1.50 mm+ and decreased systolic bloodlpressure times heart rate at angina. Greater decreases in exercise duration until angina and in systolic blood pressure times heartrate at angina (p < 0.00111) wereobsersed aftersmoking; than after breathing carbon monoxide. Tobacco components other than nicotine or carbonimonoaide are responsi- Materials and Methods Twelve men, mean age 52.1 ± 5.1 years (± slD), all of whom smoked'one package of cigarettes daily, were subjects. Each, subject had classic stable exertional angina pectoris and angiographic evidence of coro- nary artery disease with > 75% narrowing of at least one major coronary vessel. After careful explanationi of the risks iitt•olved, wri'tten informed consent was ob- tained from ail'1 12 men. The 12 subjects were familiarized with the equip- ment andi the procedures and practiced' exercising uip- right on a Collins (Warren E. Collins, Inc:, Braintree, Massachusetts) constant-Ioad bicycle ergometer From the Cardiovascutar Sectlon, Long Bcach Veterans Ad- ntinistration Ntw:dical Ccnter and the University of California„Ir- rine. Address for aurrespondence: 1Vilbert S. Aronou•, M :D., Chicf. Cartlitu•a,wculur Sc4tioni Veterans Administration \tedical Cunter: Lan_ Hcath. Cairornia 90822. Rei :1'pril 26. 1979: revision it.repted Jul) 27; 1979. Cirtiulution i6l. No. 2. 19AU. 262 before the study began. The study was performed on two consecutive mornings. Smoking was not per- mitted for at least 12 hours before the study each morning and was not permitted during the study periods except by protocol. The subjects remained in the same area dluring the study periods andi were carefully observed' to ensure adherence to the protocol. On two successive study niornings, at 8 o'clock, with the subject in the fasting state, venous blood was drawn and analyzed for carboxyhemoglobin and 'hemoglobin levels with a 282 Co-Oximeter ('Irn- strumentation Laboratory , Inc., Lexington„ Massa* chusetts). Then„ leads 2 and V, were simultaneously recorded with an electrocardiograph with the patient sitting on the bicycle ergometer. The resting'heart rate was obtained from this ECG. The resting blood pressure was then ' measured with, a mercury sphygmomanometer. Each subject then, exercised upright on the bicycle ergometer with a progressive work loadt' until the onset of anginal discomfort, andthe durationofexer- cise was recorded' with a stopwatch. The work load was increased' 25 watts every 3 minutes. The initial work Ibad' was chosen so that angina pectoris would develop 180-360 5econds after exercise in the control periods. The patient was monitored by telemetry with leads 2 and VS throughout exercise. An ECG with leads 2 and V, was simultaneously recorded at the onset of angina pectoris. The heart rate was obtained from this ECG. The blood pressure was recorded, at, the onset of angina pectoris, with the patient con- tinuing to exercise until the blood pressure was recorded. Within 2 hours on the first morning, the subject' smoiked five non-nicotine Mint Bidis cigarettes purchased from a tobsccoshop in Los Angeles. These cigurcttes were made from Indian herbnlf leaves. Immediately aftcr smoking the fifth cigarette, the patient sat on the bicycle cr-omcter and an ECG with leads 2 and V, was simultaneously recorded. The heart rate was measured from this ECG. Then, the blood pressure was recorded with a mercury sphye- monnant7meter. Next, venous blood was drawn and 1005052926

. was obtained. _ TOBACCp~COMPONENTS AND ANGINA/A'ronow nrlyied for carboxyhemoglobin and hemoglobinm levels. ~ Then, the patient exercised upright on the bicycle ergometer until' the onset of angina pectoris, and the duration of'exercise was recorded with a stopwatch. An ECG with leads 2 and V, was simultaneously recorded at the onset of' angina pectoris. The heart, rate was recorded& from, this ECG. The blood pressure was recorded at the onset of angina pectoris„with the patient continuing to exercise until the blood pressure was obtained. On the second morning„ the subject breathed 1100, ppm of carbon monoxide untol the rise in venous car- boxyhemoglobin level' was identical to that after he had smoked five non-nicotine cigarettes. The patient C them sat on the bicycle ergometer andl an ECIG with leads 2 and V, was simultaneously recorded. The heart rate was measured from this ECG. The blood pressure was next recorded with a mercury sphygmoman- ometer. ometer. The- patient then exercised upright on the bicycle ergometer untilf the onset of angina pectoris, and the duration, of exercise was recorded with a stopwatch. An ECG with leads 2 and V, was simultaneously recorded at the onset, of angina pectoris. The heart rate was obtained from this ECG. The blood pressure was recorded at the onset of angina pectoris, with the ctient continuing to exercise until, the blood pressure '~a THe ECGs were coded and analyzed! in a, blind manner afiter the study was completed. The data were analyzed using the t test fior correlated means. . Results ,~,'_;Table 1 tndicatcs the duration of exercise until'the ~ onset of angina pectoris for each patient and the mean exercise duration in the two control periods, after smokirAg five non-nicotine cigarettes and' after breathing carbon!monoxide. Table I also presents the statistical analy,sis of the differences shown. Table 11 shows a reduction in mean exercise duration until angina pectoris after smoking non-nicotine cigarettes and after breathing carbon monoxide (p < 0.001). The decrease in mean exercise duration until angina was grcater after smoking non-nicotine cigarettes than after breathing carbon monoxide (p < 0.001). Table 2 shows the resting mean heart rate„systolic and diastolic blood pressure, product of systolic blood pressure times heart rate/'100, and venous car= boxyhemoglobin level in the two control' periods, afterr smoking five non-nicotine cigarettes and after , brerthing,carbon monoxide. Table 2 also presents the statisticall analysis of the differences shown. Table 2 indicates no change in mean resting,heart rate„systohc -_ or diastolic bl'ood pressure or resting product of i systlolic blood pressure times heart rate/1100' after `'snooking non-nicotine cigarettes or after breathing carbon monoxide. Table 2 also shows equivalent, im cre•rses in mean venous carboxyhemoglobin level after smoking non-nicotine cigarettes and after breathing carbon monoxide (p <' 0.001), 263. TaBur. 1. Duration of'Ezcrcfae Unhif Angina in the Control Periodtr, After Smoking, and After Breathing Carbon.tlonoside Durat6on of exercise (see) Carbon !uf ter Pt Smoking; After control xmoking, monoxide csrbon control monoxide. 1 289 155' 281 177 2 203 117 186 123' 3' 359 1'87 372 238'. 4 243 134' 254' 165 s 232 135 ~ 219 153 8 210 119 225 148 7 251 145 264 18m 8 246' 121 237 144 9 224 1'36' 212 152' 10 239 124 250• 147 11 220 118 209 138 12 211 107 226 141 Mean 243.9 133 .2"t ' 244.6 139.01 + sn + 43.0 ~ 21.6 + 47.9 ~ 29.4 •p < 0.001 after smoking compared' with respective eoatzol' and after carbon monoxide compared with riespectixe oontzoL fip < 0.001 after smoking minus respective control com- pared with after carbon monwode minus respective eonumL Table 3' indicates the mean heart rate, systolic and diastolic blood pressure, product of systolic blood pressure times heart rate/100 and the amount of exercise-induced ST-segment depression at the onsez of angina pectoris in the two control' periods, aP.=r smoking five non-nicotine cigarettes and aftrr breathing carbon monoxide. Table 3'alsb presents the' statistical analysis of the differences shown. All 12 pa- TASZE 2. Restvaq Mean Huut Rate, Systolic and DiastoIie. Blood Pressure, Product oJ Systolic Blood Pravure X Heart Rate/100, and Venous Carbozyiurmoglobin in the Conitrol Periods, After Smol,-ing, and ditv Brcathinq Carbon Monosidr, ~ Carbon After Smoking After mono!cide cartton Meaetuement control smoking control monoxide Heart rate 68.0 69.6 67.4, 67.9 (beats/min) +5.3; -5:4 -3.6 -3:7 SBP ,122.1 1'23.8 121.2' 1'^_1.4 (mm Hg) +7.1 -6.3 w- 52 -4:7 DBP 79.2 80.1 78.3 78.4 (mm Hg) •+4.9 -4.3 ' +3.9 -3.8 ' Heart ntie X 83.1 50.2 81.7 82.5 SBP/100 -816 -8.9 -6'.0 i5.4 Ckrboxy- hemoglobin 1.711 5.35' 1.73 3.3Y• (%)1 -0.16 +0.16 -k0.14, -0.19 Valiies are mean - sn. •p < 0.001, aftersmoking;compared mit;hire.cUcetave control and after carbon monoxide compared with re+rcetive contzol. Abbrevintions: SSP' - systolic blood pressure;; DBP - diaatolic blood pressure.

non-nicotine cigarettes and! after breath'ing, carbon monoxide. The reditction in mean heart rate at the onset of angina was greater after smoking non- nicotine cigarettes than, after breathing carbon monoxide:(p < 0i001'): The decrease inimean systolic blood pressure at the onset of angina was greater after smoking nomnicotine cigarettes than after breathing carbon monoxide (p < 0.005). The reduction in mean product of heart rate times systolic blood pressure/' 100 at the onset of'angina was greater aftersmoking non-nicotine cigarettes'than after breathing carbon monoxide (p <0.00I). Similar increases in the mean amount of exercise-inducedi ischemic ST-segmenrt depression at the onset of' angina, occurred after breathing carbon monoxide and after smoking non- nicotine cigarettes. Dis[ussion The data from this study show that smoking five non.nieottnC: ctgarettes caused ai rise in venous car- ~ boxyhentoglobin from IL7i1 to 5.35% an& a 45% ~ i decrease in exercise duration until angina pectoris. A'fter, breathing sufficient carbon monoxide to raise ~ ~ _ ..,,..y.rr..•.~:~ :., ~ ....,.. ...,.. - . . ,, .. . . _. 264 CIiRCULATI©N Vot. 6l(. No 2; Fi:xttcAav 1980 ' .. Twata 3. .tleoa Xeart Raty Syuol"u and Diaato(fe Btbod Prtawt; Prodod I of Sy"io . Bldod Pr•etar¢e XArart Rare/ 100, ond. E:eroi,e-indrtnd' STrepntentDeprrition at Oiud . of Anyiaa in, the Control' Perior4, Aykr Smo+kiraq, , and Ayrtr Brtothinp, Carbon aYonosfdt b'feasurement Heart rate (~tata/min) SBP - "' y:-... . (tttm HC) . DBP i~ (ttun Hg) Hesrt rate X - SBP/100 ST-se3tmnt depression , (xm) Smoking oonttoli After smoking t.'arbon' monmide tontrol efter. tarbon monoxide 129:1 10.i.4•,1' 129.3 110.4• r8.'9 _6.0 +4.9 .83 155.2 1a8.6-,5' 154.9. 1K8.0• r 10.2 .10.8' -9.7 r i10.4' 81.7 82.8' 81.0. 81.8 .4.2 +4.0 +3.8. .4.4. 200.4 ISt.9•,1 200-s 163.r +1a4 -13.4 +1'5.8 -17.4 . 2.33 1.324 1.31. 1.50( -0.19 -0:31 -024. ~ 0.38 Valoea.us mew~.-so. •p <'0.001 atteramokiag eompared with respective control a.mrl aftesea.-bon.monoaide compared mith~reepeetive,oonttoL tp < 0.00U alter emoking'minus reypeetive 6ontrol' aom- pRd with after carbon atonoride mintt.i respective eontroL , :~, . <8.003atter amoking'nsinus respeativeoontrolI com- pated with atter earbon monoxide minus repeotive mntroL iy. <0.02i after smolting:compared with respective contml' aad aiter'urbon monoxide camparsd with respective aontrnL Ebbreviatiena: SBP - aystatic blood ptemure;, 1DBP' ~ &atcoue blood pressure. „ . . - teau developed at least 1.0'mm of exercise-induced is:iiernic ST-segment depression at'the onset of angina pertoris during the four study periods. Table 3 indicates a reduction in mean heart rate (p <'0:00I).systolicbloodpressure',(p<0:001)„product oC heart rate times systolic blood' pressure/ 100 (p <' ••, - 0.001) and exercise-induced ST-segment dep,ression i(p < 0.02.5) at the onsgt'of angina pectoris after smoking the venous carboxyhemoglobin level from i 1.73 to-~_~ 5.37%. the exercise duration until angina'; decreased =' 35°5. Th'erefore, the dataishow th'arcarbon monoxide ` is:the major eomponenc in non-nicotine cigarettes re-"_'•' ' sponsibic for the decrease in exercise: duration until r." angina pectoris. The'greater deerease,iniexercisedura `4-= tion until angina pectoris after smoking the non-.±'-" nicotine cigarettes than after breathing carbon ~ monoxide (p <'01001') is a(tributable to components of' ` tobacco smoke other than nicotine or carbon monox- V ide. +:r.'r Smoking non-nicotine cigarettes'did not affect the resting product of systolic blood pressure times heart rate and, therefore, did not increase the myocardial .:r•Y-'• oxygen demand. This observation is consistent with~4 previous data.'- e- ta The product of systolic blood pressure,times heart :'+a rate at the onset ofangina'is a good index of myoear- ~: dial oxygen delivery.!a•" I found a reduction in - product of'systolie blood!pressure times heart rate at the onset of angina after smoking, non*nicotine ., cigarettes and after, breathing carbon monoxide, find, .: . ings consistent with previous data'- `-'° The greater --i reduction in product of systolic:blood pressure times heart rate at angina after smok'ing', non-nicotine -, cigarettes than after, breathing oarbon monoxide (p <; 0.001) is attributable to components of tobaceosmoke other than nicotine'oncarbon monoxide. The data also show' that carbon monoxide is the major component in non-nicotine cigarettes responsible for the decrease in product of systolic blood pressure'times heart rate at angina~and; therefore, probable decrease in oxygen supply to the myocardium . More ischemic ST-segment depression iat the onset ,~ of angina occurred after smoking non-nicotine ,, cigarettes and after'breathing carbon monoxide than in the control periods. The increases'in isehemic ST- segment depression at exercise,indUced angina pee- .: toris after smoking non-nicotine cigarettes and after breathing carbon monoxidrwere similar (p "NS). Finally, although this study shows that tobacco eomponents other'than nicotine or carbon monoxide cause a small decrease in exereise performance until angina pectoris'add a small'.probable decreasein oxy- genisupply to the myocardium, this study does not ' clnrify which components of tobacco smoke are responsible. Further studies must be performed to in- vestigate the effects of concentrations of oxides' of' nitrogen, hydrogen'i cyanide, carbon disut5de, andl - other components inhaled in tobacco smoke on the cardiovascular system. Acknowledgment 1'.am iinde:bocd Ito Clifford Roueae.e.,Kdthi Murdocl-.,and Hklen Mithonond fnr tcchniaat assiuance andto Mary Ellen Dunnhak for secret'adall asskunct. " Reftrenttt'. 1. AronoWwS. Kapfan MA.:Jacbb,D•.Tobacco,, e prcripitating, faunniniancina tmctoria.,Ann Inoern RIed69: 519;.196a'. 2. .4ronrrN•S. Sl-annon AJ: Thretfcct ofd6w.nicodne eiprettet on anrina ta•etoris. Ann Intern Bted2lk 599: 1969 '

TOBACCO COi41PONENTS AVD A~4CilNAlAronosv 3. Aronow WS; Dendin er J Rok-w SN: Heart rate and carbon g . monoxide level after smoking high-, low.,, and non-nicotine i eigarettes: a study in male patients with angina pectoris. Ann lhtern Aled 74: 697; 1971 i. Aronow WS. Cassidy J. Vangrow IS. March H. Kern 1C, Goldsmith JR. Khemka M. Pagano J, ViN,tor M: Effect of cigarette smoking, and breathing atrbon, monoxide on car, diovascular hemodynamics in anginal patients. Circulation 50: 340. 1974 S. Aronow WS1,Cassidy Jc Effect of'smok'ing man'huana versus aa high*nicotine cigarette on angina peetoris. Clin Pharmacol Ther 17: 549, 1975' 6., Ayres SM, Mueller HS; Gregory JJ, Giannelli S. Jr. Penny JL•. Systemic and myocardial hemodynamic responses to relatively small concentrations of carboxyhemoglobin (CO H B), Arch Ett- viron Health 18: 699, 1969 7. Ayra'SM, Giannelli S'Jr: Mueller HS: EfTieetof'low concen- trations of carbon monoxide: myocardial and systemic responses to carboxyhemoglobin. Ann NY Aad Scii 11A4:Z68; 1970 g. Aronow WS,, Rokaw SN: Carbozyhemoglobin caused by smoking non,nicotine cig;ncttes: effecu in,angina pectoris: Cir- culatioc 44: 782, 1971 9. .#ronow WS. Harris CN, Isbell MW. Rokaw SY; Imparato B: Eftect of freeway travel onangina pectoris. Ann Intern Mcd 77c 699. 1'972, 10. Anderson EW, Andclman RJ, Strauch JMi Fortuin NJ, Knelson JH:,Effect'of low•-level carbon monoxide exposure,on onset andiduration oGangina peetoris: a study in•ten patients with ischemic,heart'disease. Ann Intern Med'79: 46. 1973 11. Aronow WS„Isbell MV1'; Carbon monoxide effect on exercise- induced angina pectoris. Ann Intern Med 79: 392. 1973' 12. Aronow WS. Swanson AJ: Non+nicotini¢ed cigarettes and angina pectoris. Ann, lhtern Med 70: 1227, 1969 13, Constituents of Tobacco Smokc, Smoking and Health: A' report of the Surgeon Gcneralf 1979. Pteprint. Washington, DC. Government Printing,Offiice. 1979; pp 33-70. 14, McMillan GC: Evidence for components other than carbon monoxide and nicotine as etiologial factors in cardiovascular disease. In Proceedin¢s of the Third World Conference on Smoking and Health. New York, June 2-5. 1'975': Volume 1. Modifying the Risk for, the Smoker, edited by Wy,nder EL, Hoffmann D, Gori GB. US'Department of Health, Education,. and Welfare, Public Healthi Service. National Institutes of Healthl National Cancer Institute, DHE1V Publication No (NIH) 76-122!1', 1976. pp 363-367 15. Aronow WS: Introduction to smoking andlcardiovasculardis- eased ln Proceedings of theThird WorJdiConference on Smok- ing andlHealth, New York. June 2-5, 1975. Voluma l. Modify- ing the Risk for the Smoker, cdited'by Wynder E1., Hoffmann D, Gori' GB. US Department of! Health. Edttcation, and Welfare. Public Health Service„National Institutes of Health4 National Cancer Institute, DHEW Publication No (TtIIH); 76- 122'I, 1976, pp 231-236 - 16. Aronow WS: Efrect of, passive smoking on angina pectoris. Ni Engl J' Med 299: 21, 1978 17. Redwood DR. Rosing, DR, Goldstein i RE. Beiser GD. Epstein SE: Importance of the designi of an exercise protocol in the evaluatiomof I+atientaK ith angina pectoris. Circulation •L3:b18. 1971 18. Amsterdam E4., Hughes Jh. Demaria AN. Zelis R. !slason DT: Indirect assessment of myocardial oxygen consur..;,tjot: in the-e*•aluation off mechanisms and therapy of angina p=oris. Am I Cardiol 33: 737. 1974 19. Gobel' FL Nordstrom LA. Nelson RR: Jorgensen CR. Wang Y: The rate-pressure product as an index of myocartEal oxsc.a consumption during eser.:sa in patients with angina ;=oris: Circulation 57: 5;9, 1978