Circulation 1971 ARONOW 782 8

WILBERT S. ARONOW and STANLEY N. ROKAWAngina Pectoris

Carboxyhemoglobin Caused by Smoking Nonnicotine Cigarettes: Effects in

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright 1971 American Heart Association, Inc. All rights reserved.

75231is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TXCirculation

doi: 10.1161/01.CIR.44.5.7821971;44:782-788Circulation.

http://circ.ahajournals.org/content/44/5/782located on the World Wide Web at:

The online version of this article, along with updated information and services, is

http://circ.ahajournals.org//subscriptions/is online at: Circulation Information about subscribing to Subscriptions:

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

document. Permissions and Rights Question and Answer of the Web page under Services. Further information about this process is available in thewhich permission is being requested is located, click Request Permissions in the middle columnClearance Center, not the Editorial Office. Once the online version of the published article for

can be obtained via RightsLink, a service of the CopyrightCirculationoriginally published in Requests for permissions to reproduce figures, tables, or portions of articlesPermissions:

by guest on May 11, 2014http://circ.ahajournals.org/Downloaded from by guest on May 11, 2014http://circ.ahajournals.org/Downloaded from

Carboxyhemoglobin Caused by SmokingNonnicotine CigarettesEffects in Angina Pectoris

By WILBERT S. ARONOW, M.D., AND STANLEY N. ROKAW, M.D.

SUMMARYThe effects of increased carboxyhemoglobin levels caused by smoking nonnicotine

cigarettes upon exercise-induced angina were investigated in 10 patients. The meancarboxyhemoglobin level after smoking eight nonnicotine cigarettes, one every 30minutes, rose from 1.58 to 7.79%. Smoking significantly decreased the mean exercisetime from the onset of exercise until the onset of angina from 109.8 to 83.5 seconds.There was significantly less of an increase in systolic blood pressure, heart rate, andproduct of systolic blood pressure times heart rate after exercise-induced angina aftersmoking compared to the nonsmoking state. Smoking nonnicotine cigarettes increasedthe carboxyhemoglobin level, decreasing the rate of oxygen deliverability to themyocardium, with angina developing sooner, following less cardiac work.

Additional Indexing Words:Nicotine Coronary heart disease Exercise

S MOKING one high-nicotine' or one low-nicotine2 cigarette caused patients with

angina pectoris due to coronary heart diseaseto have a significant decrease in exerciseperformance before the onset of angina.Smoking one nonnicotine lettuce-leaf ciga-rette3 did not cause any significant change inexercise performance in these patients beforethe onset of angina.Smoking high-nicotine, low-nicotine, or non-

nicotine lettuce-leaf cigarettes caused a signifi-cant similar increase in carboxyhemoglobinlevels in normal subjects4 and in patients withangina pectoris due to coronary heart disease.5The presence of increased carboxyhemoglobinprobably reduces the amount of oxygen

From the Cardiology Section, Medical Service,Long Beach Veterans Administration Hospital, theTuberculosis and Respiratory Disease Association ofLos Angeles County, and the University of California,Irvine and Los Angeles.

Address for reprints: Wilbert S. Aronow, M. D.,Cardiology Section, Veterans Administration Hospital,Long Beach, California 90801.

Received April 23, 1971; revision accepted forpublication July 9, 1971.

782

deliverable to the myocardium. Therefore, thisstudy was performed to determine whetherpatients with angina pectoris would have anysignificant difference in exercise performanceafter serial smoking of nonnicotine lettuce-leaf cigarettes, compared to the nonsmokingstate.

Materials and MethodsTen men, all of whom had smoked at least 20

cigarettes daily for at least 19 years, weresubjects. Each subject had a classical history ofexertional angina pectoris. Five patients had apreviously documented transmural myocardialinfarction, at least 2 years old. The other fivesubjects had coronary artery disease documentedby previous coronary angiography, with 50% orgreater narrowing of the lumen of at least onemajor vessel.The subjects were familiarized with the

equipment and the procedure and had practicedexercising on the bicycle ergometer before thestudy was begun. The studies were performed onfour consecutive mornings. Smoking was per-formed on two mornings. The order of the twosmoking and the two nonsmoking mornings wasrandomized. Smoking was not permitted for atleast 12 hours prior to the onset of the study eachmorning and was not permitted during the study

Circulation, Volume XLIV, November 1971

by guest on May 11, 2014http://circ.ahajournals.org/Downloaded from

CARBOXYHEMOGLOBIN FROM SMOKING

Table 1Age and Spirometric Observations for Each Patient

Predicted Observed Observed FVC X 100 Observed Observed FEV .o ce X 100Pt. Age FVC6 FVC Predicted FVC FEV 1.0 a, Observed FVC

(yr) (cc) (cc) (%) (cc) (%)1. 49 4,080 4,030 99 3,180 792. 56 4,260 4,450 104 3,800 853. 57 3,780 3,480 92 2,990 864. 49 4,100 3,780 92 2,950 78

50 4,500 4,200 93 3,160 756. a6 4,240 3,890 92 3,000 777. 53 4,180 3,840 92 3,260 858. 50 4,220 4,030 95 3,430 859. 52 4,380 4,120 94 3,380 82

10. 41 4,400 4,150 94 3,570 86

Abbreviations: FVC = forced vital capacity; FEVI.o = forced expiratory volume.o(

periods except by protocol. The subjects remainedin the same area during the study periods andwere carefully observed to make sure they did notsmoke outside the protocol.

At 8:00 a.m. each morning, the resting bloodpressure was recorded with a mercury sphygmo-manometer and the resting heart rate with anelectrocardiograph with the patient sitting up-right on a bicycle ergometer. Then, venous bloodwas drawn and analyzed immediately for carboxy-hemoglobin and hemoglobin levels with a 182Co-Oximeter.* All determinations were made induplicate.

If the morning was a smoking morning, thesubject smoked eight nonnicotine lettuce-leafcigarettes, one every 30 minutes, at his normalpace, inhaling the smoke. The last cigarette wassmoked while the subject was sitting on thebicycle ergometer. The blood pressure and heartrate were measured immediately after the lastcigarette was smoked. The subject then performedupright exercise at a load of 60 watts until heexperienced and reported the onset of anginapectoris. Immediately after the onset of angina,the blood pressure and heart rate were againmeasured.

If the morning was a nonsmoking morning, theblood pressure and heart rate were measured at8:00 a.m. as above. Then, venous blood wasdrawn and analyzed immediately for carboxy-hemoglobin and hemoglobin levels as above. Onthe first nonsmoking morning, at 9:00 a.m., ameasurement of the 1-sec forced expiratoryvolume (FEV10 see) and the forced vital capacity(FVC) was obtained in each patient by a Model

170 Wedge Spirometer.t At 11:35 a.m., theblood pressure and heart rate were measured.Then, venous blood was drawn and analyzedimmediately for carboxyhemoglobin and hemo-globin levels. At 11:40 a.m., the patientperformed upright exercise on the bicycle ergome-ter at a load of 60 watts until he experienced andreported the onset of angina pectoris. Immediate-ly after the onset of angina, the blood pressureand heart rate were again measured.

Electrocardiograms, using lead II, were ob-tained at rest, immediately before exercise, andimmediately after the onset of angina pectoris onthe smoking and nonsmoking mornings.

ResultsTable 1 shows the age and the spirometric

observations for each subject. The patients(all male) were between the ages of 41 and56 years, with a mean age of 51.3 years. Theobserved FEVy.0osec/observed FVC rangedfrom 75 to 86% in our patients, indicating theabsence of significant airway obstruction atthe time of study. Similarly, the normal FVCvalues suggest that no significant restrictivedisease (pulmonary congestion, fibrosis, etc.)was present at the time of study.

Table 2 reveals the blood pressure and heartrate measurements at rest, immediately beforeexercise, and immediately after the onset ofangina; the carboxyhemoglobin measurementsat rest and immediately before exercise; andthe exercise time before the development of

tManufactured by Med-Science Electronics, Inc.*Manufactured by Instrumentation Laboratory,

Inc.Circulation, Volume XLIV, November 1971

783


784 ARONOW, ROKAW

Table 2Blood Pressure and Heart Rate at Rest, before Exercise, and after Exercise, Carboxyhemoglobin Level atRest and before Exercise, and Exercise Performance until Onset of Angina in Smoking and NonsmokingStates*

Resting state Before exercise After exerciseBlood Heart COHb Blood Heart COHb Blood Heart Exercise

pressure rate level pressure rate level pressure rate timePt. S or NS (mm Hg) (beats/min) () (mm Hg) (beats/min) (%) (mm Hg) (beats/min) (see)

S (1)NS (1)NS (2)S (2)

2. NS (1)S (1)S (2)

NS (2)3. NS (1)

S (1)S (2)

NS (2)4. S (1)

NS (1)NS (2)S (2)

5. S(1)NS (1)NS (2)S (2)

6. NS (1)S (1)S (2)

NS (2)7. S(1)

NS (1)NS (2)S (2)

8. NS (1)S (1)S (2)

NS (2)9. NS (1)

S (1)S (2)

NS (2)10. S(1)

NS (1)NS (2)S (2)

160/98 82 1.3 162/96 84 9.3 184/106162/100 74 0.5 158/98 74 0.3 186/102138/98 72 0.8 156/98 72 0.6 184/102156/92 72 0.,5 158/90 72 6.1 170/90136/80 72 0.7 138/80 68 0.6 156/88128/76 76 0.4 130/76 84 6.6 146/82132/80 84 0.8 126/76 80 6.4 148/82126/76 72 0.5 130/76 80 0.2 170/80104/64 72 3.0 106/66 68 2.0 138/74102/66 72 2.9 104/68 76 9.5 128/78104/64 84 3.1 102/64 76 8.9 124/74100/62 60 1.7 106/68 66 1.3 134/78124/86 96 2.0 128/88 88 6.9 148/98132/96 98 1.6 138/98 92 0.9 160/104130/94 94 0.9 138/98 88 0.6 158/100134/96 94 1.7 138/100 88 5.8 150/104134/100 84 1.2 138/98 82 6.2 164/102130/96 78 1.4 126/94 74 0.7 178/100130/94 68 0.7 132/94 72 0.1 180/102138/96 86 0.6 136/98 88 5.5 174/108104/68 76 1.3 104/68 74 1.0 138/76104/68 74 0.8 104/66 76 8.3 130/78102/66 72 1.0 104/66 76 9.6 126/80100/66 74 0.6 106/68 72 0.2 140/76124/76 78 2.0 122/74 82 6.7 146/82116/74 67 0.8 118/72 65 0.2 152/78114/72 74 0.6 114/72 74 0.2 150/80114/72 84 0.3 112/74 82 5.4 140/84144/80 86 2.0 142/78 82 1.6 170/88148/82 90 1.0 150/80 90 9.8 162/88140/78 86 2.5 142/80 88 12.2 160/88136/76 74 1.7 138/78 76 1.1 174/84132/92 72 3.3 138/94 78 2.8 154/98136/88 82 3.0 134/86 80 9.7 144/96136/86 80 3.9 132/82 78 9.6 142/90138/90 84 3.3 132/86 80 2.6 160/92116/70 84 2.0 110/66 78 7.3 142/72112/70 80 0.8 114/72 76 0.a 142/78114/68 84 1.2 116/70 88 0.7 148/78114/72 86 0.5 112/70 84 5.9 136/78

106116116112112104100120120116116120136138138125130132130125110104100

114125130130116108104100108108106104112106116116104

4272694713594921567366707913013815614019326025419761623865

8492111

68564942725440427010210811472

*Each observation period is numerically delineated in parentheses in the order in which it was performed.Abbreviations: S = smoking state; NS = nonsmoking state; COHb = carboxyhemoglobin.

angina on all of the smoking and nonsmoking globin levels 1 SD at rest and immediatelymornings. All the hemoglobin values were before exercise on the two smoking and twowithin normal limits. nonsmoking mornings. An analysis of variance

Table 3 indicates the mean carboxyhemo- tests was performed.7 The carboxyhemoglobinCirculation, Volume XLIV, November 1971



Table 3Mean Carboxyhemoglobin Levels + 1 Standard Deviation at Rest and before Exerciseon the Two Smoking and Two Nonsmoking Days

Day 1 Day 2Smoking Nonsmoking Smoking Nonsmoking

Mean carboxyhemoglobini 1.66 1.54 1.49 1.2(0level at rest (%)

0.87 0.97 1.26 0.86Mean carboxyhemoglobiin 8.03 1.06 7.54 0.76level before exercise (%)

1.44 0.83 2.3.5 0.76

level after smoking compared to the baselinelevel was significantly increased (F 206.7,P

ARONOW, ROKAW

Table 4Mlean Exercise Performance +1 Standard Deviationi until Onset of Angina on the TwoSmnoking and Two Nonsm?oking Days


Mean exercise 86.2 104.9 80.8 114.6performance (sec)

47.3 62.6 .51.1 60.1

Table 5Mean Systolic and Diastolic Blood Pressure, Heart Rate, and Product of Systolic BloodPressure and Heart Rate + 1 Standard Deviation at Rest, before Exercise, and afterExercise on the Two Smoking and Two Nonsmoking Days


At restBP in mm Hg 127.6/81.0 127.2/82.0 127.0/80.2 124.6/79.6

18.1 12.0 18.4/13.1 17.6/11.9 18.0/13.2HR in beats/min 81.8 77.5 82.8 75.6

7.3 8.9 6.7 9.5SBP X HR 10,494 9,887 10,516 9,458

2,040 1,977 1,635 1,944Before exerciseBP in mm Hg 128.2/79.8 128.2/82.0 126.2/80.0 126.8/80.8

19.1/11.9 17.5/12.8 18.3/12.6 16.0/12.2HR in beats/min 82.0 75.1 81.2 76.8

4.7 7.8 5.8 7.2SBP X HR 10,572 9,674 10,260 9,760

2,041 1,930 1,715 1,620Immediately after exerciseBP in mm Hg 149.4/88.2 157.4/88.6 147.0/87.8 159.8/87.2

16.7/11.6 16.5/11.7 17.0/10.9 17.0/10.7HR in beats/min 113.7 119.0 110.2 120.4

12.3 10.8 10.0 9.4SBP X HR 16,992 18,759 16,248 19,237

2,649 2,821 2,787 2,a1O

Abbreviations: BP = blood pressure; HR =times heart rate.

There was significantly less increase in theheart rate immediately after the onset ofangina in the smoking compared to thenonsmoking state (F 52.8, P < 0.01).There was significantly less increase in the

product of systolic blood pressure times heart

= heart rate; SBP X HR = systolic blood pressure

rate immediately after the onset of angina inthe smoking compared to the nonsmokingstate (F 86.3, P < 0.01).No ischemic S-T-segment depression was

precipitated after smoking the nonnicotinecigarettes in any of the 10 patients. The

Circulation, Volume XLIV, November 1971

7(86



electrocardiographic changes from preexer-cise to onset of angina did not differsignificantly in the smoking compared to thenonsmoking state.

DiscussionThe results of the present study and of our

previous ones3 5 indicate that smoking non-nicotine lettuce-leaf cigarettes does not signifi-cantly affect the resting systolic or diastolicblood pressure or the resting heart rate. Thereis, however, a significant increase in thecarboxyhemoglobin level.Smoking high-nicotine, low-nicotine, or non-

nicotine cigarettes adversely affected the meanA-wave ratio in the apexcardiogram in patientswith coronary heart disease.8 This adverseeffect on the apexcardiogram was most markedafter smoking high-nicotine cigarettes andleast marked after smoking nonnicotine ciga-rettes.8

Chevalier and associates" have reported thatnonsmokers who inhaled carbon monoxide toraise their carboxyhemoglobin level to therange seen in a control group of smokersdeveloped an increased oxygen debt withexercise. Ayres and associates10 have reportedthat carbon monoxide decreases myocardialoxygen tension by three mechanisms: (1)decreased oxygen extraction, (2) decreasedcapillary oxygen tension because of theleftward shift of the oxyhemoglobin dissocia-tion curve, and (3) increased ventricular workand oxygen demand due to stimulation of theadrenergic system. These investigators'0 havealso shown that elevated levels of carboxy-hemoglobin cause an increase in coronaryblood flow to prevent a decrease in coronarysinus and myocardial oxygen tension.

Patients with coronary heart disease havean increased myocardial demand for oxygenwhen they exercise. When their myocardialoxygen demand exceeds their myocardialoxygen supply, angina pectoris develops. Thepresence of carboxyhemoglobin caused bysmoking or other inhalation sources makes lessoxygen deliverable to the myocardium. Thesignificant decrease in exercise performance tothe development of angina pectoris afterCirculation, Volume XLIV, November 1971

smoking the nonnicotine cigarettes comparedto the nonsmoking state is probably related tothis disturbance in oxygen transport.There are theoretical grounds for concern

that other inhaled gaseous pollutants, such asoxides of nitrogen, may also act to impair thehemoglobin-oxygen transport and deliverysystem. Further investigation of these mecha-nisms is clearly indicated.

Sarnoff and coworkers1l have found theprimary hemodynamic determinant of myo-cardial oxygen consumption to be the totaltension developed by the myocardium (heartrate times the area under the systolic portionof the aortic pressure curve). The presentstudy shows that the product of systolic bloodpressure times heart rate after exercise-in-duced angina was significantly less aftersmoking the nonnicotine cigarettes than inthe nonsmoking state. This suggests stronglythat less myocardial work can be performedbefore the onset of angina in the presence ofelevated carboxyhemoglobin levels, related tolessened oxygen available for the myocardium.Smoking high-nicotine' 5or low-nicotine2' 5

cigarettes causes an increase in systolic bloodpressure and in heart rate, thereby increasingthe myocardial oxygen demand, but this is notfound after smoking of nonnicotine ciga-rettes.'3 ' However, smoking high-nicotine, low-nicotine, or nonnicotine cigarettes does causeelevated carboxyhemoglobin levels,4= de-creasing the amount of oxygen available to themyocardium. Therefore, patients with historicangina pectoris develop pain sooner afterexercise following smoking either high-nico-tine cigarettes,' low-nicotine cigarettes,2 ornonnicotine cigarettes, in relation to at leasttwo factors: increased myocardial oxygendemand in the presence of nicotine, andimpaired oxygen delivery, whether or notnicotine is present.

AcknowledgmentThe authors wish to express their appreciation to

Donald C. Butler, Ph.D., Biostatistical Consultant,Emiko J. Nakamura, M.S., Statistician, Edward F.Gocka, Ph.D., Chief, and Fred J. Weibell, AssistantChief, Western Research Support Center, for theirsuggestions in the design of this study and forbiostatistical analysis of the data, and to John

787


ARONOW, ROKAW

Schneider and Leonard Blackman for technicalassistance.

References1. ARONOW WS, KAPLAN MA, JACOB D: Tobacco:

A precipitating factor in angina pectoris. AnnIntern Med 69: 529, 1968

2. ARONOW WS, SWANSON AJ: The effect of low-nicotine cigarettes on angina pectoris. AnnIntern Med 71: 599, 1969

3. ARONOW WS, SWANSON AJ: Non-nicotinizedcigarettes and angina pectoris. Ann Intern Med70: 1227, 1969

4. COHEN SI, PERKINS NM, URY HK, GOLDSMITHJR: Carbon monoxide uptake in cigarettesmoking. Arch Environ Health 22: 55, 1971

5. ARONOW WS, DENDINGER J, ROKAW SN: Heartrate and carbon monoxide level after smokinghigh-, low-, and non-nicotine cigarettes. Astudy in male patients with angina pectoris.Ann Intern Med 74: 697, 1971

6. BOREN HG, KORY RC, SYNER JC: The VeteransAdministration-Army cooperative study of pul-

monary function. II. The lung volume and itssubdivisions in normal men. Amer J Med 41:96, 1966

7. WINER BJ: Statistical Principles in Experi-mental Design. New York, McGraw-Hill BookCo., 1962

8. ARONOW WS: The effect of smoking cigarettes onthe apexcardiogram in coronary heart disease.Dis Chest 59: 365, 1971

9. CHEVALIER RB, KRUMHOLZ RA, Ross JC:Reaction of nonsmokers to carbon monoxideinhalation. Cardiopulmonary responses at restand during exercise. JAMA 198: 1061, 1966

10. AYRES SM, GIANNELLI S JR, MUELLER HS:Effects of low concentrations of carbonmonoxide. Myocardial and systemic responsesto carboxyhemoglobin. Ann NY Acad Sci 174:268, 1970

11. SARNOFF SJ, BRAUNWALD E, WELCH GH JR,CASE RB, STAINSBY WN, MACRUZ R: Hemody-namic determinants of oxygen consumption ofthe heart with special reference to the Tension-Time Index. Amer J Physiol 192: 148, 1958

Circulaxion, Volume XLIV, November 1971

788


Circulation 1971 ARONOW 782 8

Documents

Transcript of Circulation 1971 ARONOW 782 8