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' I i v a ClIn Vol. 299 No. 1 PASSIVE SMOKING AIVD ANGI:tiA - AROIUO14! 21 EFFECT OF PASSIVE' SMOKING ON ANGINA PE'CTORI':S Abstract The effect of passive smoking on exercise- induced anginal in a well ventilated and in an unven- tilated'roo'm was evaluated in 10 patients with angina. Patients exposed to 15 cigarettes smoked within two hours in a weli' ventilated room or an unventilated room increased their resting heart rate, systolic and diastolic blood pressure, and venous ear'boxy,herna globin and'' decreased their heart rate and systolic blood pressure atangin'a. Patients ex'posed to passive smoking in an unventilated room had a larger in- P ASSIVE smoking is the breathing of smoke-con- taining air composed of mainstream smoke ex- haled by smokers and of' sidestream smoke,, which leaves the burning end o:f the tobacco product during puffl intermissions; The amount of smoke produced~ the depth of inhalation on the part of the smoker, the ventilation available for the removal or dispersion of the smoke, the nearness of the nonsmoker to the smoker and the duration of the exposure to the p'ol- lutants in tobacco smoke influence the passive smok- er's' absorption of the atmospheric pollutants causedl by smoking.' I'n patients with angina pectoris anginal pain develops sooner after exercise when they have smoked high-nicotine cigarettes," low-nicotine cigarettes' or non-n'icotine cigarettes.! The effect of passive smoking on duration of exercise untill angina pectoris also needcd! to be investigatedi Therefore, I performed a randomized study evaluating the effect of passive smoking in ai ventiilated room and in an unventilated room on duration of exercise until the onset of angina pectoris. The data from this'.studyaree reported below: MATERIALS AND METHO'DS'. Ten men, with a meanage of 34.3f8:1 years (fl S:D!); who had. classic stable exertional angina pectoris and angiographic evidencee of severe coronary-artery disease with >75 per cent narrowing of at least one major coronary vessel, were subjects. Eight subjects were ex-smokers. Two subjFcts smoked two to four cigarettes daili/ but did non smoke for at least 16 hours before the study or during the study on each of the three study mornings: After careful explanation of the risks: involved, written informed consent was: obtained' from all 10 men with angina pectoris who participatedlin this study. The subjects understood the experimental design. Care was takenAur- ing the informed-consent discussion not to introduce psychologic factors related to the risk of passive smoking. The 10 subjects were familiarized with the eqpipment and the procedures and practiced exercising upright on,a Collins' constant- load bicycle ergometer before the study began. The study was perr, formed on three consecutive mornings: From the Cardiovascular SectionMedical Service, Long Beach Veterans Administration, FBosprtal, and the University of California College of Medi¢ine;,Irvine (address.roprintreqVeststo: Dr. Aronow at the.Cardiovas- cular Section, Veterans Administration t9ospital„Long Beach, CA 90822); 'Warren E: Collins, Inc., Braintree, MA, crease in restingi heart rate, systolic and diastbl- i¢ blood' pressure, and venous carbo,xyhemogl!obin and a greater reduction inheart rate and systolic: bloodl pressure at angina. The du'ration of, exercisee until angina was decreased 22 per cent after passive smoking in a well ventilated roo'm (P<0.001), and!de- creased 38 per cent after passive smoking in an unventilated room, (P'<0:001). Passive: smoking, ag- gravates angina pectoriis. (Ni Engl J Med 299:2y-24', 1'978) On three,successive study, mornings, at 8 o'clock;,with the subject in the fasting state, venous blood was drawn and analiyzed,for car- boxyhemttglobin,and hemoglbbin levelswith a 182 Co-Oximeter.t Then„ Leads 2 and V, were simultaneously, recorded with an elec- trocardiograph with the patient sitting on the bicycle ergometer. The resting heart rate was : obtained from this electrocardiogram. The resting blood pressure was then measured with a mercury, sphygmomanometer. Eaeh, subjpct then exercised upright on the bicycle ergometer with a progressive,work load until the onset of angina pectoris;,and the duration of exercise was recorded with a stopwatch The,patient was monitored by telemetry with Leads 2 and :Vs throughout exer. cise: Aneleetrocardiogram with Leads 2land V, simultaneously,was recorded at the onset of angina pectoris. The heart rate was ob- tained from this electrocardiogram. The blood pressure was recorded at~ the onset of anginal pectoris, with the:patient continu- ing to exercise until the blood'pressure was obtained.. In a room 3.51 meters (11115 ft) long, 3.20:meters (11D.5 ft) wide and 2.74 meters,(9.0 ft) high, near the research exercise laboratory, the subject then sat with three asymptomatic volunteers for two hours. The patient and,asympeomatic volunteers talked, read news- papers or magazines or listened to music. On one morningi the asymptomatic volunteers did not smoke. On a second morning, each of the asymptomatic volunteers smoked five cigarettes, his or her owm . brand;, during the two hours. The room, was well ven- tilated, with a ventilation rate ofl 11.4 volumetric air changes per hour: On a third morning, each of the asymptomatic volun. teers smoked five cigarettes,,his:or herown brand, during the two hours, with the room unventilated! The order of exposure of the patients with angina pectoris to no smoking, smoking, in a well ventilated room or smoking in an unventilated roomiwas random- ii:ed. After exposure to no smoking for two hours,,exposure to passive smoking for two hours in a,well~ ventilated room, andlexpmsure to passive smoking for two hours in an unventilated room, the patient sat on, the bicy,cle ergometerand had,an electrocardiogram with Leads 2 and VS simultaneously recorded. The heart rate was measured from this electrocardiogram. Then, the blood pressure was recordedl withia mercury sphy,gmomanometer. Venous blood was next drawn and analyzed for carboxyhemoglobini and hemoglobin levels.. Subsequently, the patient exercised upright on the bicycle ergometer until the onset of anginaipectoris, and the:duration of ex- ereise was recorded with a stopwateh. An electrocardiogram with Leads 2'and V, was simultaneously recorded at the onset of angina pectoris: The heart rate:was obtained from this electrocardlogram. The blood pressure was recorded at the onset of:angina pectoris,, with the patient continuing,to exercise until the blood pressure was obtained. The physician who performed the exercise tests knew whether the patients were exposed to no smoking; smoking in a well ventilated room or smoking in an unventilated room. Tlnstrumentation Laboratory, Inc., Lexington, MA. Ili i r sK" . I I

) r 22 THE,IVE1'N~ENGLA1DjI,O[UR'NA'L.OE ufEDIICINE~ July~6, 1978 In the asymptomatic volunteer smokers venous bloodlwas drawn and analyzed for carboxyhemoglobin before and after smoking of five cigarettes each,dUring'tM1Vo hours. The same smoking volunteers were present for the successive study mornings. Written informed consent was obtained from these volunteers. The data were analyzed with Student's t-test for correlated' means, R EsuZrs Table 11 indicates the duration of exercise in secondss until the onset of angina pectoris for each~patient and the mean exercise duration f 1 S.D. in the three con* trol periods, after exposure to no' smoking, after ex- posure to smokingin a well ventilated room~and after exposure to smoking in an unventilated room. Table 1 also presents the statistical analysis of the differences shown. Table 2 shows the resting mean heart ratie;, systolic and diastolic blloodipressure,,product of systolic blood' pressure X heart rate/100, and venous carboxyhemo- g'lobin f 1 S.D. in the three control periods, after ex- posure to no smoking; after exposure to'smoking in a well ventilated room and after exposure to smoking in an unventilated room. Table 2 also presents the statistical analysis of the differences shown. Table 3' indicates the mean heart rate, systolic and diastolic blbod pressure, product of systolic blood pressure X heart rate/'100 and amount, of exercise- induced ST-segment depression at the onset of angina pectoris ± 1 S.D. in the three control periods; after ex- posure to no smoking, after exposure to smoking in a well ventGla'ted room and after exposure to smo'ki'ngini an unventilated room. Table 3 also presents the sta- tistical analysis of the differences shown. The mean venous carboxyhernoglobin in' the vol~ unteer smokers rose from 5:87f0;90 per centi before to 9:75 f 1.05' per cent after smoking in the well ven- tilarted room (P<0.00'1). The mean venous carboxy- hemoglobini in the vollunteer smokers rose from 5.92f0.95'per cent before smoking in the unventilated room to 9.83f 1.19 per cent after smoking in the un- ventilated room (P<0.001)I Premature ventricular beats were not recorded inn the electrocardiogrami before exercise or after exercise iniany patient during the three control periods or after exposure to no smoking or to passive s'moking', in a well ventilated room. After exposure to passive smokin'g,in an unventilated roo'm„oneof1i0pa~tien'ts(110percenti)', had three premature ventricular bearts per minute recorded inithe electrocardiogram before exercise;,and three of 10 partients (30 per cent) had premature ventricular beats recorded in the electrocardiogram after exercise. One patient had seven premature ven- tricular beats immediately after exercise,, with pre- matureventricular beats lasting,for five minutes; one patient had 110 premature ventricular beats per minute immediately after exercise;, with premature ventricular beats lastfing, for eight minuties„ and one patient had 12' premature ventricular beats' per minute immediately after exercise, with premature ventricular beats lasting for 14 minutes. Table 1. Duration of'Exercise until A'ngina in the Control Periods* and afrter, Exposure to No Smoking, Smoking,in a,Well Wentilatedi Room and Smoking in an Unventilated Room. C.kSE DURRTION IOF E%ERCISE'.($EC) No. EKPOSi:ItE.TO. NO SMOKING, EXPOSURE TO'. NO SMOKING EKPOSURE SMOKING I TO'. EXPOSt:RETO SMOKINGIN N' E'.KPOSURETOi EKPOSURETO. SMOKING rN' SMOKING IN I -CONTROL WELL. WELL UNVENTILATED'UNVEYTItaTED. VENTIWTE ROOM - CONTRO D. VENTILATED ROOM L ROOM - CONTROL ROOM I 193 217 191 149 202 1'27' 2' 206 214 203 169 189' 130 3' 188 197 18'1 14'5' 192 128 4 375 412 400 306 387 230' 5 204 199 2111 170 196 ' 132. 6 28'7, 310 304 243 312 198 lV 7, 22t' 216' 213' 158 232 135 ~~. 8 216 223 207' 155 209 124 11` °~ 9 195' 208 186. 144 200 129 r ~ 10 2311 224 227 172 218 12'5'. Mean 1 231.6 241.9 232:3 18'1.1t 233.7' lIk5:8t# Vl rf~ f 1 f SiD t57.9 t67,8' t68;4 ±52.4 t6418 t36.9 V J. •Contro4 values were'measurcd.on each of the thrce.dagsAxfore.ezposure or non-caposwretosmok'e.e tP<0.001 for exposure', to . smoking in well ventilated roomm minus . respective control ass compared too exposure to no smok!ing mi.nus respeetive eontro4 orr for' exposura : toamok'.ing in unvcntilated room minus.respectivexontrol as.compared.to eaposureYono.smoking.minusrespeetive control.. ;P<01001 for caposure to'smoking.o in unven~tilated room minus Tespeetive control as compared to lexposurcrlo smoking.in well ventilated room minus respectivrcontroll

Vol. 299 No:, I PASSIVE SNfOIcING AND ANGINA - ARONOW F 23 Table2: Resting Mean Heart Rate, Systolic and Diastolic Blbod Pressure, Product of Systolic Blood Pressure X Heart Ratie/1100 and Venous Carboxyhemoglobin in the Control Periods and afterExposure to No Smoking, Smoking in a Well Ventilated Room and Smoking in anlUnvenrtilatedlRoom (±1 S!D:), I MEASUREMENT' EXPOSURE.TD. No SMaKINo. - CONTROL EXPOSURE.TO. Nb 6>AOKrvG EXPOSURETO. $MQIKINGtN WELL VENTILATED. ROOM H CONTROL EXPOSL'.RETO $MOKINGIN WELfl. VENTIUA?ED'. ROOM EXPOSURE TO $MOKING.IN UNVENTIUATED. ROOM- CONTROL EXPOS.URE'TO SMOK7NG'itY UNVENTILATED RDOMI Heart,rate 72.4 7016 72.1 77:2 72:9 80.5 (beats/min) ±7.7 t'7:1 ±7.3 ±6.8t ±7.8 :17.5t$ SiBP (mm H8): 122.8 122.0 122.6 127.5 123:2 130 :7 ±4.9 t4:5 t5.6 t5.9t t4;4 f4.6t§', DBP(mm Hg')' 79.2 78.6 79.4 82.9: 79.8 85.4 t' 2.5 t' 2.5 t' 3.3 t3.lt t2:0 t1.8t§ Heart,rate 89.0 86:2 88.4 98.5' 89:8 105.2 X SBP/I00 t11.0 t'9:6 ±10.3 t10.1t ±10.2 t10:2tj Carboxyhemo- 1.29 1.26 1.25 1.77 1.30 2.28 globin (%) ±0.22 ±0.18 t0:20 t0.16f ±0.18 t0:15t¢ •SBPdenotas.systolic blood.pressure R.DBPdiastolie blbod.pressured iP<01001forexposure tosmo:.king in w.ell.ventilatedroom minus reapective control as compared to.exposuretono.smoking minwrespeciive control or for exposure to smoking inunvemilatediroom minus'.respective controlas,compared to exposure.to no'sm~oking minus.respective controli ;PC0AOlforsxposuretosmokingln~unventilatedroomminus',respectivecontrol.ascompareditoexposureto.smoki ng',inwell'ventilated. roomminusrespeetive'sontrol. ¢P<0.0037orexposurcrtosmokinginunventilatedroomminusrespective..control.ascompareditoexposureto.smo king;inwell'ventilated room minus'respecCivecontrol. DiISGU5SION. The data from this' study clearly demonstrate that under the conditions of' this experiment, passive smoking, eavses anginail pain' to develop' sooner after exercis'e.The duratiio'n of'~ exercise until angina pec- toris is also decreased' more after passive smoking in an unventila''ted'I room than after passive stmok'in,, in a ventilatedl room. Smoking high-nicotinez•s6' or low-nicotine'-5i cilga~ rettes~causes am increase in resting, heart rate andl inn systolic and d'tastol'ic', b'lood pressure in pa'tients with angina pectoris, increasing their myocardiall oxygen dernandl This increase in heart rate and in blood pres- sure does not occur after smoking of non-nicotine cigarettes",S or after breathing of carbon monoxide.6`g The increase in heart rate and systolic and diastolic binod'pressure at rest in ourpatients~with angina pec- toris after exposure to passive s'moking' was presum- ably due to albsorption of' nicotine. Russell and Feyerabend''showed that after norrnall exposure to tobacco smoke, nicotine was present in urine collected during the early aftiernoon' in 26 of 27' nonsmokers ('96 per cent). The mean'urinary nicotine level of these 27 nonsmokers was 10.7' ng per milliliter. Russell and Feyerabendg' allso had 112' nonsmokers. Table 3. Mean HeaffRate;,Systolic and Diastolic Blood Pressure;,ProductoflSystblic Blood Pressure x Heart Rate/100, and Exercise-Induced ST-Segment Depression atOnset',of,Angina inithe ControllPeriods and after Exposure,to No Smoking, Smoking in a Well Ventilated Room and Smoking ini an'Unventilated Room (±1 S.D.). ME'ASI:REMENT- EXPOst:RETO. NoSMOKING - CONTROL Fi'XPOSURETO NO.SMOKING. EXPOSURE'TO SMOKING~IN WELL. VENTI'LATED. RooM - CONTROL ElPOSURETO SMOKING IN' WELL. VENTIUATED. ROOM EXPOSURETO'. $MOKINQ': 1.4 UNVENTILATED ROOM - CONTROL EXPOSURETO. SMOK1NG ~IN U.NVENTILLATED RDOM Heart,rate 128'.7 129.7' 128.9 122.8~ 128.4 119:9; (beats/min) t5.6' 35.6' ±4.4 t4.7t t5.3 t5:ot$ S!BP(mm Hg) 156:4 157,T 156.11 150 4' 155 6 147 4 t7.6 ±7.4 ±7.2 . t7.8i . ±6.9 . f7.8t# DIB~P(~mm Hg)~ 80.12~~ 79.8' 81.0 81i5 81.3 81.8 ±3.3 ±2.9 ±2.2 t3.4 f3.11 t2.2 Heart rate 201.4 203.9 201.2 184.7' 1919.8 ! 176,7 x'SBP/100. t14.7 14.0 .0' t11.8 t 12! 3t t 11.9 311 9+$ ST-segment de- 1.38 1.35' 1.33 1.40 1.33 1.45 pression (mm) t0:24 t0:24' t0:21 t0:241 ±0.26 t0.26 'S'BPdanotes'systolic blood pressure drDBP'diastolie blood pressure. •P<0.001 forr exposuree too smkingin well ventilated room minusrespectfves control as's compared to exposure to no smoking minus respectivee control' or forexposure to.smoking'.im unventilated room minuss respective control ascom~paredi.to ex~posure.to no smoking mi~nusrespective'.control., jP<'0.001 for exposure to.smoking',in unventilated Iroom minus respective control as comp,ared to exposure',to smoking in well ventilated room minus respective control. L tw*

24, TIIIE NEWENG,L A1VD JOURNAL OF' NfEDICINE July 6, 1978' ./ sit for an average of 78'minutes among,smokers in an REFERENCES unventilate& smoke'-filledl room with dirnensions' of 4'.57 by 3.66 by 2:441 meters (115 by 12 by 8' ft). The smoke was produced by smoking or burning, of 80 cigarettes and two cigars andl caused a rmean carbon rnonoxidc level of 38' ppm in the room air. Urine specimens collected', 15 minutes after the nonsmokers had left the smoke-filled room revealed a mean urinary nicotine llevell of 80: ng per millilit~er: J S'moking high-nicotine,5'~6 low-nicotine5 or non- nicotine cigaretltes",' causes ani increased carboxyhe- moglobirl level, which reduces the amount of oxygen availab'le to the myocardium. Numerous studies havee documented the har'rnful effects of carbon menoxide' in patients with coronary heart disease:",1a-1a The decrease in product of systolic blood' pressure times heart rate at the onset of'angina pectoris after passive _ smoking ini the study reported above indicates a probable decrease in oxygen delivery to the myocar- diium, A number of investigations have shown the ex- posure of passive smokers to carbon monoxide', 1ev- els"-'a that may cause adverse effects in patients with coronary heart disease. The dhta from this'study also indicate that passive sInoking causes an increase in carboxyhernoglbbin - more after passive smoking in arl; unventilated room'than after passive smoking in a ventilated room. Piemartture ventricular beats occurred after exercise in three of 10 patients exposed, to'passive smoking in an unventilated room. The increase in sudden deatlh from coronary heart disease in cigarette snnokers" may be related to ]owering', of the thresholdl f'or ven- tricular fibrillation by nicotine2D3' or carbon monox- idez2•z7' during an episode of myocardial i'schemia, Finally, in addition to carbonimonoxidc and nico- tine, other components ofl tobacco smoke, including oxides of nitrogen and hydrogen cyanidc and possiblyy psychologic factiors, may have contributed to the decrease in exercise performance observed in these patients with hearti disease after passive smoking through effectsi on the cardiovascular or respiratory systems. For example, do the oxidcs of nitrogen in- haled i'n, tobacco, smoke interfere with myocardial ox- ygen delivery? This possibility needs to be in- vestigated.. I am indebted taCllffordlRousseve and!Yaul_T'roop for technical assistance. 1'. Public exposure to air pollhtion, from tobacco smoke, The Health Consequenoes of Smoking: A report of the: Surgeon General: 1972. (DHEW Publication Na [HBMI] 72-7516). Washington, DC, Govern- ment Printing Office, 1972, pp 117-135 2. Aronow WS, Kaplan h'fA,Jacob D: Tobacco: a precipitating factonin angina pectonis: Ann Intern Med 69:529-536;,1968 3'. Aronow WS, Swanson AJ: The effect ofl low-nicotine cigarettes on angina pectoris: Ann Intern Med 71k599-601, 1969 41 Aronow WS, Rokaw SN: Carboxyhemoglobinicaused by smok'ing nont nicotine cigarettes: effects in angina pectoris. Circulation 44:782-788; 1971 5: Aronow WS, Dendinger J, Rokaw SN: Heartirate,and carbon monox- ide level after smoking high ,,low., and lnon-nicotine cigarettes: a study in male patients with,angina pectoris. Ann Intern Med 74:697-702;,1971 6: Aronow WS, Cassidy 1, VangrowJS, et aL Effect of cigarette smoking, andibreathing carbon monoxide on1 cardiovascular hemodynamics in anginal patients. Circulation 50:340-347;,1974 7. Aronow WS, HllrrisCN, Isbell MW, etali Effect of freeway travel on angina pectoris. Ann Intern Med 77i6'69-676, 1972 8. 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Archilniern Med 123`.707-742; 1969 21. Bell@t S; Deguzman NT, Kostis JB, et al: The effect of inhalation oficigaretle.smokeon ventricularfibrillationdhreshold ininormal dogs and dogs with acute myocardial infarction:, Am Heart, J 83:67-76; 1972' 22. DeBias DA, Banerjee CM, Birkhead NC, et' a]: Effects of carbon monoxide: ihh'alationon ventricularfibrillation:,Areh EnvironiHealth 3 G:42-46, 1976 23:.. Aronow WS, Stemmer EA„ Woodl B;, et al: Carbon monoxide and ventricularfibrillationrthreshold in dogs with acute myocardial injury. Am Hearr195754-756, 1978