Carboxyhemoglobin Caused by Smoking Nonnicotine Cigarettes: Effects in

Angina Pectoris
WILBERT S. ARONOW and STANLEY N. ROKAW
Circulation. 1971;44:782-788
doi: 10.1161/01.CIR.44.5.782
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX
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Carboxyhemoglobin Caused by Smoking

Nonnicotine Cigarettes
Effects in Angina Pectoris
By WILBERT S. ARONOW, M.D.,

AND

STANLEY N. ROKAW, M.D.

SUMMARY
The effects of increased carboxyhemoglobin levels caused by smoking nonnicotine
cigarettes upon exercise-induced angina were investigated in 10 patients. The mean
carboxyhemoglobin level after smoking eight nonnicotine cigarettes, one every 30
minutes, rose from 1.58 to 7.79%. Smoking significantly decreased the mean exercise
time 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, and
product of systolic blood pressure times heart rate after exercise-induced angina after
smoking compared to the nonsmoking state. Smoking nonnicotine cigarettes increased
the carboxyhemoglobin level, decreasing the rate of oxygen deliverability to the
myocardium, with angina developing sooner, following less cardiac work.

Additional Indexing Words:

Nicotine
Coronary heart disease

Exercise

S MOKING one high-nicotine' or one lownicotine2 cigarette caused patients with

angina pectoris due to coronary heart disease
to have a significant decrease in exercise
performance before the onset of angina.
Smoking one nonnicotine lettuce-leaf cigarette3 did not cause any significant change in
exercise performance in these patients before
the onset of angina.
Smoking high-nicotine, low-nicotine, or nonnicotine lettuce-leaf cigarettes caused a significant similar increase in carboxyhemoglobin
levels in normal subjects4 and in patients with
angina pectoris due to coronary heart disease.5
The presence of increased carboxyhemoglobin
probably reduces the amount of oxygen

deliverable to the myocardium. Therefore, this

study was performed to determine whether
patients with angina pectoris would have any
significant difference in exercise performance
after serial smoking of nonnicotine lettuceleaf cigarettes, compared to the nonsmoking
state.

Materials and Methods

Ten men, all of whom had smoked at least 20
cigarettes daily for at least 19 years, were
subjects. Each subject had a classical history of
exertional angina pectoris. Five patients had a
previously documented transmural myocardial
infarction, at least 2 years old. The other five
subjects had coronary artery disease documented
by previous coronary angiography, with 50% or
greater narrowing of the lumen of at least one
major vessel.
The subjects were familiarized with the
equipment and the procedure and had practiced
exercising on the bicycle ergometer before the
study was begun. The studies were performed on
four consecutive mornings. Smoking was performed on two mornings. The order of the two
smoking and the two nonsmoking mornings was
randomized. Smoking was not permitted for at
least 12 hours prior to the onset of the study each
morning and was not permitted during the study

From the Cardiology Section, Medical Service,

Long Beach Veterans Administration Hospital, the
Tuberculosis and Respiratory Disease Association of
Los 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 for
publication July 9, 1971.

782

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CARBOXYHEMOGLOBIN FROM SMOKING

783

Table 1
Age and Spirometric Observations for Each Patient
Pt.

Age

1.
2.
3.
4.
6.

7.
8.
9.
10.

Predicted
FVC6

Observed
FVC

Observed FVC X 100 Observed Observed FEV

FEV 1.0 a, Observed FVC
Predicted FVC

(yr)

(cc)

(cc)

(%)

(cc)

(%)

49

4,080
4,260
3,780
4,100
4,500
4,240
4,180
4,220
4,380
4,400

4,030
4,450
3,480
3,780
4,200
3,890
3,840
4,030
4,120
4,150

99
104
92
92
93
92
92
95
94
94

3,180
3,800
2,990
2,950
3,160
3,000
3,260
3,430
3,380
3,570

79

56
57
49
50
a6
53
50
52
41

Abbreviations: FVC = forced vital capacity; FEVI.o

periods except by protocol. The subjects remained

in the same area during the study periods and
were carefully observed to make sure they did not
smoke outside the protocol.
At 8:00 a.m. each morning, the resting blood
pressure was recorded with a mercury sphygmomanometer and the resting heart rate with an
electrocardiograph with the patient sitting upright on a bicycle ergometer. Then, venous blood
was drawn and analyzed immediately for carboxyhemoglobin and hemoglobin levels with a 182
Co-Oximeter.* All determinations were made in
duplicate.
If the morning was a smoking morning, the
subject smoked eight nonnicotine lettuce-leaf
cigarettes, one every 30 minutes, at his normal
pace, inhaling the smoke. The last cigarette was
smoked while the subject was sitting on the
bicycle ergometer. The blood pressure and heart
rate were measured immediately after the last
cigarette was smoked. The subject then performed
upright exercise at a load of 60 watts until he
experienced and reported the onset of angina
pectoris. Immediately after the onset of angina,
the blood pressure and heart rate were again
measured.
If the morning was a nonsmoking morning, the
blood pressure and heart rate were measured at
8:00 a.m. as above. Then, venous blood was
drawn and analyzed immediately for carboxyhemoglobin and hemoglobin levels as above. On
the first nonsmoking morning, at 9:00 a.m., a
measurement of the 1-sec forced expiratory
volume (FEV10 see) and the forced vital capacity
(FVC) was obtained in each patient by a Model

*Manufactured by

Instrumentation

Inc.

.o ce

X 100

85
86
78
75
77
85
85
82
86

= forced expiratory volume.o(

170 Wedge Spirometer.t At 11:35 a.m., the

blood pressure and heart rate were measured.
Then, venous blood was drawn and analyzed
immediately for carboxyhemoglobin and hemoglobin levels. At 11:40 a.m., the patient
performed upright exercise on the bicycle ergometer at a load of 60 watts until he experienced and
reported the onset of angina pectoris. Immediately after the onset of angina, the blood pressure
and heart rate were again measured.
Electrocardiograms, using lead II, were obtained at rest, immediately before exercise, and
immediately after the onset of angina pectoris on
the smoking and nonsmoking mornings.
Results

Table 1 shows the age and the spirometric

observations for each subject. The patients
(all male) were between the ages of 41 and
56 years, with a mean age of 51.3 years. The
observed FEVy.0osec/observed FVC ranged
from 75 to 86% in our patients, indicating the
absence of significant airway obstruction at
the time of study. Similarly, the normal FVC
values suggest that no significant restrictive
disease (pulmonary congestion, fibrosis, etc.)
was present at the time of study.
Table 2 reveals the blood pressure and heart
rate measurements at rest, immediately before
exercise, and immediately after the onset of
angina; the carboxyhemoglobin measurements
at rest and immediately before exercise; and
the exercise time before the development of

Laboratory,
tManufactured by Med-Science Electronics, Inc.

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784

ARONOW, ROKAW

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

Pt.

S or NS
S

2.

3.

4.

5.

6.

7.

8.

9.

10.

(1)

NS
NS
S
NS

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

(2)

Blood
pressure
(mm Hg)

Resting state
Heart
rate

160/98
162/100
138/98
156/92
136/80
128/76
132/80
126/76
104/64
102/66
104/64

100/62
124/86

132/96
130/94
134/96
134/100
130/96

130/94
138/96
104/68
104/68

102/66
100/66

124/76
116/74
114/72
114/72

144/80
148/82
140/78

136/76
132/92
136/88
136/86

(beats/min)
82
74
72
72
72
76
84
72
72
72
84
60

96
98
94
94
84

78
68
86
76
74
72
74
78
67
74
84
86
90
86
74
72
82
80

138/90
116/70
112/70

84
84

114/68

84
86

114/72

80

COHb
level

()

Before exercise
Blood
Heart
COHb
pressure
rate
level
(mm Hg)
(beats/min) (%)

1.3
0.5
0.8

0.,5
0.7
0.4
0.8
0.5

3.0
2.9
3.1

1.7
2.0
1.6
0.9
1.7
1.2
1.4

0.7
0.6
1.3
0.8
1.0
0.6
2.0
0.8
0.6
0.3
2.0
1.0
2.5
1.7
3.3
3.0
3.9
3.3
2.0
0.8
1.2

0.5

162/96
158/98
156/98
158/90
138/80
130/76
126/76
130/76
106/66

104/68
102/64
106/68
128/88
138/98
138/98
138/100
138/98
126/94

132/94
136/98
104/68
104/66
104/66

106/68
122/74

118/72
114/72
112/74
142/78
150/80

142/80
138/78
138/94
134/86
132/82
132/86
110/66
114/72
116/70
112/70

84
74
72
72

68
84
80
80

68
76
76
66
88
92
88
88
82
74
72
88
74

76
76
72
82
65
74
82
82
90
88
76
78
80
78
80

78
76
88
84

9.3
0.3
0.6
6.1
0.6
6.6
6.4
0.2
2.0
9.5
8.9

1.3
6.9
0.9
0.6
5.8
6.2
0.7
0.1
5.5
1.0
8.3
9.6
0.2

6.7
0.2
0.2
5.4
1.6
9.8

After exercise
Blood
Heart
Exercise
pressure
rate
time
(mm Hg)
(beats/min)
(see)

184/106
186/102
184/102
170/90
156/88
146/82
148/82
170/80
138/74
128/78
124/74
134/78
148/98
160/104
158/100
150/104

164/102
178/100
180/102
174/108
138/76
130/78
126/80
140/76
146/82
152/78
150/80
140/84
170/88
162/88

12.2
1.1
2.8
9.7
9.6
2.6
7.3
0.a

160/88
174/84

0.7
5.9

148/78
136/78

154/98

144/96
142/90
160/92
142/72
142/78

106
116
116
112
112
104
100
120
120
116
116
120
136
138
138
125
130
132
130
125
110
104
100

42
72
69
47
135
94
92
156
73
66
70
79
130
138
156
140
193
260
254
197
61
62
38

114
125
130
130
116
108
104
100
108
108
106
104
112
106
116
116
104

65

84
92
111

68
56
49
42
72
54
40
42
70
102
108
114
72

*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

mornings. All the hemoglobin values were
within normal limits.
Table 3 indicates the mean carboxyhemo-

globin levels 1 SD at rest and immediately

before exercise on the two smoking and two
nonsmoking mornings. An analysis of variance
tests was performed.7 The carboxyhemoglobin
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CARBOXYHEMOGLOBIN FROM SMOKING

78.55

Table 3
1 Standard Deviation at Rest and before Exercise

Mean Carboxyhemoglobin Levels +

the Two Smoking and Two Nonsmoking

on

Days

Day 1

Mean carboxyhemoglobini
level at rest (%)
Mean carboxyhemoglobiin
level before exercise (%)

Day 2

Smoking

Nonsmoking

Smoking

Nonsmoking

1.66

1.54

1.49

1.2(0

0.87
8.03

0.97
1.06

1.26
7.54

0.86
0.76

1.44

0.83

2.3.5

0.76

level after smoking compared to the baseline

level was significantly increased (F 206.7,
P<0.01).
Table 4 reveals the mean exercise performance + 1 SD from the onset of exercise until
the onset of angina pectoris on the two
smoking and two nonsmoking mornings. An
analysis of variance tests was performed.7
There was a significant decrease in exercise
performance after smoking compared to the
nonsmoking state (F 22.4, P < 0.01). There
was no significant difference in exercise
performance on the second smoking day
compared to the first smoking day. There was
a significant improvement in exercise performance on the second nonsmoking day compared to the first nonsmoking day (F 6.89,
P<0.05).
Figure 1 reveals the mean exercise time in
seconds until the onset of angina pectoris in
the smoking and in the nonsmoking states for
each individual patient.
Table 5 indicates the mean systolic and
diastolic blood pressure, heart rate, and
product of systolic blood pressure times heart
rate + 1 SD at rest, immediately before exercise, and immediately after the onset of
angina pectoris on the two smoking and two
nonsmoking mornings. An analysis of variance
tests was performed.7
There was no significant difference in either
the mean systolic and diastolic blood pressures, heart rate, or product of systolic blood
pressure times heart rate at rest and immediately before exercise, in the smoking compared to the nonsmoking state.
There was significantly less increase in the

systolic blood pressure immediately after the

onset of angina in the smoking compared to
the nonsmoking state (F 42.3, P < 0.01).
There was significantly more increase in the
diastolic blood pressure immediately after the
onset of angina in the smoking compared to
the nonsmoking state (F 7.6, P < 0.05).
280-

250 -

22O CD
-cc

:E

190-

I-

Nonsmoking state

&

Smoking state

I-

160-

C-,

LAJ

X)

130 -

100-

70 An

I
I

1I

3
4 5
6
7
NUMBER OF PATIENTS

1O

Figure 1
Mean exercise time until the onset of angina pectoris
(sec) in the smoking and nonsmoking states for each
individual patient.

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ARONOW, ROKAW

7(86
Table 4

Mlean Exercise Performance +1 Standard Deviationi until Onset of Angina on the Two

Smnoking and Two Nonsm?oking Days

Day 1

Mean exercise

Day 2

Smoking

Nonsmoking

Smoking

Nonsmoking

86.2

104.9

80.8

114.6

47.3

62.6

.51.1

60.1

performance (sec)

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

At rest
BP in mm Hg
HR in beats/min
SBP X HR

Before exercise
BP in mm Hg
HR in beats/min

SBP X HR

Day 2

Smoking

Nonsmoking

Smoking

Nonsmoking

127.6/81.0

127.2/82.0

127.0/80.2

124.6/79.6

18.1 12.0
81.8

18.4/13.1

17.6/11.9

18.0/13.2

77.5

82.8

75.6

7.3
10,494

8.9
9,887

6.7
10,516

9.5
9,458

2,040

1,977

1,635

1,944

128.2/79.8

128.2/82.0

126.2/80.0

126.8/80.8

19.1/11.9

17.5/12.8
75.1

18.3/12.6

82.0

81.2

16.0/12.2
76.8

4.7
10,572

7.8
9,674

5.8
10,260

7.2
9,760

2,041

1,930

1,715

1,620

Immediately after exercise

BP in mm Hg
HR in beats/min

SBP X HR

Abbreviations: BP
times heart rate.

149.4/88.2

157.4/88.6

147.0/87.8

159.8/87.2

16.7/11.6
113.7

16.5/11.7
119.0

17.0/10.9

17.0/10.7
120.4

12.3
16,992

10.8
18,759

16,248

9.4
19,237

2,649

2,821

2,787

2,a1O

110.2
10.0

blood pressure; HR == heart rate; SBP X HR

There was significantly less increase in the

heart rate immediately after the onset of
angina in the smoking compared to the
nonsmoking state (F 52.8, P < 0.01).
There was significantly less increase in the
product of systolic blood pressure times heart

systolic blood pressure

rate immediately after the onset of angina in

the smoking compared to the nonsmoking
state (F 86.3, P < 0.01).
No ischemic S-T-segment depression was
precipitated after smoking the nonnicotine
cigarettes in any of the 10 patients. The
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CARBOXYHEMOGLOBIN FROM SMOKING

electrocardiographic changes from preexercise to onset of angina did not differ

significantly in the smoking compared to the
nonsmoking state.
Discussion

The results of the present study and of our

previous ones3 5 indicate that smoking nonnicotine lettuce-leaf cigarettes does not significantly affect the resting systolic or diastolic
blood pressure or the resting heart rate. There
is, however, a significant increase in the
carboxyhemoglobin level.
Smoking high-nicotine, low-nicotine, or nonnicotine cigarettes adversely affected the mean
A-wave ratio in the apexcardiogram in patients
with coronary heart disease.8 This adverse
effect on the apexcardiogram was most marked
after smoking high-nicotine cigarettes and
least marked after smoking nonnicotine cigarettes.8
Chevalier and associates" have reported that
nonsmokers who inhaled carbon monoxide to
raise their carboxyhemoglobin level to the
range seen in a control group of smokers
developed an increased oxygen debt with
exercise. Ayres and associates10 have reported
that carbon monoxide decreases myocardial
oxygen tension by three mechanisms: (1)
decreased oxygen extraction, (2) decreased
capillary oxygen tension because of the
leftward shift of the oxyhemoglobin dissociation curve, and (3) increased ventricular work
and oxygen demand due to stimulation of the
adrenergic system. These investigators'0 have
also shown that elevated levels of carboxyhemoglobin cause an increase in coronary
blood flow to prevent a decrease in coronary
sinus and myocardial oxygen tension.
Patients with coronary heart disease have
an increased myocardial demand for oxygen
when they exercise. When their myocardial
oxygen demand exceeds their myocardial
oxygen supply, angina pectoris develops. The
presence of carboxyhemoglobin caused by
smoking or other inhalation sources makes less
oxygen deliverable to the myocardium. The
significant decrease in exercise performance to
the development of angina pectoris after

787

smoking the nonnicotine cigarettes compared

to the nonsmoking state is probably related to
this disturbance in oxygen transport.
There are theoretical grounds for concern
that other inhaled gaseous pollutants, such as
oxides of nitrogen, may also act to impair the
hemoglobin-oxygen transport and delivery
system. Further investigation of these mechanisms is clearly indicated.
Sarnoff and coworkers1l have found the
primary hemodynamic determinant of myocardial oxygen consumption to be the total
tension developed by the myocardium (heart
rate times the area under the systolic portion
of the aortic pressure curve). The present
study shows that the product of systolic blood
pressure times heart rate after exercise-induced angina was significantly less after
smoking the nonnicotine cigarettes than in
the nonsmoking state. This suggests strongly
that less myocardial work can be performed
before the onset of angina in the presence of
elevated carboxyhemoglobin levels, related to
lessened oxygen available for the myocardium.
Smoking high-nicotine' 5or low-nicotine2' 5
cigarettes causes an increase in systolic blood
pressure and in heart rate, thereby increasing
the myocardial oxygen demand, but this is not
found after smoking of nonnicotine cigarettes.'3 However, smoking high-nicotine, lownicotine, or nonnicotine cigarettes does cause
elevated carboxyhemoglobin levels,4= decreasing the amount of oxygen available to the
myocardium. Therefore, patients with historic
angina pectoris develop pain sooner after
exercise following smoking either high-nicotine cigarettes,' low-nicotine cigarettes,2 or
nonnicotine cigarettes, in relation to at least
two factors: increased myocardial oxygen
demand in the presence of nicotine, and
impaired oxygen delivery, whether or not
nicotine is present.
'

Acknowledgment
The 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, Assistant
Chief, Western Research Support Center, for their
suggestions in the design of this study and for
biostatistical analysis of the data, and to John

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ARONOW, ROKAW

788
Schneider and Leonard Blackman for technical
assistance.

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2. ARONOW WS, SWANSON AJ: The effect of lownicotine cigarettes on angina pectoris. Ann
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JR: Carbon monoxide uptake in cigarette

smoking. Arch Environ Health 22: 55, 1971
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