TABLE I.-Continued.

Study          Population

Data collection
  method

Measure of
atherosclerosis

Results

Distribution by percentage of degree of atherosclerosis by smoking habits standardized
for age (macroscopic study)

Current cigarette smokers

Degree of
atherosclerosis

NWW                               EX-
smoked   < pack   l-2 packs  2+ packs Cigar/ cigarette
regularly per day per day per day pipe smoker

Lif&.ic
(371

894 autopsies of
males 20-79 at
death in Yalta

Interview with
relatives

Visual grading

None or minimal   59.8     45.2      36.6      32.6    36.3    50.9
Slight          24.7     26.9      27.9      21.5    28.4    25.5
Moderate        10.2     16.2      16.0      16.5    21.0    12.6
Advanced        5.3     ii.7      lY.5      23.4     14.3    11.0
Total        100.0    loo.0     loo.0     1OQ.O    1Oil.o    loo.0
Ratio of the extent of atherosclerotic lesions in the average coronary artery between
nonsmokers and smokers

          Total               Compli-
         athero-   Fatty    Fibrous    cated    Calcified   Raised
         sclerosis   streak plaque    lesion     lesion    lesion

Nonsmoker to
heavy smoker

Nonsmoker to
smoker

1.0      1.1      1.0      1.5       0.6      1.0

1.0      1.1      1.1      1.0       0.6      1.0


TABLE l.-Continued.

                        Data collection     Measure of
Study          Population       method      atherosclerosis                           Results

Schettler      Autopsies of 89     Interview with   Visual grading                            Stenosis
et al.       males aged 60-94    relatives
(63)        at death in Tokyo                      Smoking              No            Yes          Total

                                                  No                  6              8           14
                                        Yes, daily              8             67           75
                                                 Total                14             75           89

Rhoads et al.    109 sutop&s of    Interview with   AHA panel      Mean coronary atherosclerosis grade versus selected attributes
(56)         Japanese American  subject
           male8 born 1900-                                              Regression coefficients
         1919 who parti-
         cipated in Honolulu                         Examination variables             Simple         Multiple '
         heart study

                                        Relative weight 1%)                 0.031 J           0.025O
                                        Cigarettes/day                     0.022*           0.024 3
                                      Cholesterol(mg/dl)                  0.011 3           0.0093
                                        Triglycerides(mg/dlI                 o.Oo22            NS'
                                        Glucose(mg/dl)                    0.004 2             NS'
                                            Hematirit 1%~                    o.069z            NS '

                                      `Multiple regreaxon was done by B stepw.ee ehmmatmn procedure begmnmg wth the set
                                     of vanables shown: coefficwnts are for the final step. Multiple correlation (final step1~0.46
                                                 IN- 108l
                                            ~Slgnlficant at on5 level
                                            ~S1gmficant at 0 01 level
                                      `NS. vanable included ,n timt step. deleted an not slgmficant at 0.05 level.



TABLE l.-Continued.

Study          Population

Data collection
  method

Measure of
atherosclerosis

ReSUlti

35-44         X     4.4   a.4    x   32.2   32.1    X   60.3   62.1   2    8    12
45-54         X     5.5   0.4    x   25.1   31.4    x   65.7   70.4   2    25    12

55-64         a.1    47   7.2   31.4   31.1   20.8   60.3   57.4   62.4 11 15    9

' ATL as percent surface fatty streaks (F) plus raised lesions (Rl: FaF=F - (100 - R%E in percentage units
explained in the text; X indicates subgroups having fewer than five members

Holme et al.
(29)

129 autopsies from   Interview with   Visual grading     Correlation coefficient between number of cigarettes and raised lesions in the coronary
16,2CGC males aged  subject                  arteries = ,039, not significant.
4M9 in Oslo
prospective CHD
stwiv

Sternby
(711

60 autopaiea of 703   Interview with   Visual grading    Smoking and stenosis or atherosclerosis in the left anterior descending coronary artery
males in CHD     subject
study in Malmo.                                                           LAD        Coronary
SW&n                             Smoking category      Number       rased lesions     artery stenosis

                                     Non                3            68            33
                                     Ex                 8            52             38
                               Light               18            45            39
                              Heavy              17            54            59


TABLE l.-Continued.

Study          Population

Data collection
  method

Measure of
atherosclerosis

Results

Sorlie et al.
( 70)

139 autopsies of    Interview with   Visual grading     Association of atherosclerosis in coronary arteries with antemortem characteristics:
9,824 Puerto Rican  sub@                 simple correlation coefficients (Puerto Rico heart health program)
males aged 35-79 m
a prospective study                                                       Correlation coefficients

Characteristics
measured at exam 1

Total
(139)

Rural
(36)

Urban
( 103)

Systolic blood pressure
Diastolic blood pressure
Serum cholesterol
Age, exam 1
Relative weight
Physical activity
Blood glucose
Hematocrit
Education level
Income
Cigarettes smoked
Calories (24.hour recall)
Starch (24.hour recall)
Alcohol (24.hour recall)
Total fata (24.hour recall)
Triglycerides (fasting)
Ventricular rate
Vital capacity

0.22          0.07       0.30
0.26          0.09       0.30
0.42          0.59       0.38
0.01          0.32      4.08
0.21         JJ.15       0.25
-0.18          0.06      -0.22
0.20         4.04       0.21
0.14          0.36       0.12
0.14         a.40       0.24
0.16         4 17       0.16
4.16         xl.05      xl.22
a.14         a.43      407
-0.17         -0.29      -0.09
a.10         -9.10      a.13
-0.04         xl.53       0.03
0.23          0.49       0.19
0.13          0.20       0.08
-0.19         a.13      4.16


lesions were not identical, the findings from both of these large
studies of autopsied men in the United States were remarkably
similar. Both studies reported more extensive coronary atherosclero-
sis among the cigarette smokers than among the nonsmokers, and
for the major comparisons, with only rare exceptions, there was an
orderly progression of least extensive lesions in nonsmokers, inter-
mediate extent of lesions in light or moderate smokers, and most
extensive lesions in heavy smokers.

In the New Orleans study (741, lesions were measured not only by
visual evaluation, but also by optical electronic scanning of radio-
graphic images of the flattened arteries. The measurements of
lesions from radiographs-relative mean coronary wall thickness
and percentage of the coronary artery intima involved with calcifica-
tion-were consistently greater for the heavy smokers than for the
nonsmokers. A variety of statistical analyses on smoking measures
and atherosclerotic lesions were performed to determine the signifi-
cance of the various differences and trends. These analyses con-
firmed that the major differences between the heavy smokers and
the nonsmokers in extent of raised atherosclerotic lesions (the sum of
fibrous plaques, complicated lesions, and calcified lesions) were
significant. A one-way multivariate analysis of nine atherosclerotic
variables clearly indicated that there were statistically significant
differences among the three categories of smokers (heavy, light to
moderate, and nonsmokers) for mean coronary wall thickness, raised
lesions in the coronary arteries, percentage of cases positive for
fibrous plaques, percentage of cases positive for complicated lesions,
and percentage of cases positive for calcified lesions, with lower
values in nonsmokers and higher values in the heavy smokers.

Pate1 et al. (53) evaluated this same data on smoking and
atherosclerotic lesions to examine further the interrelationships
with measures of obesity. The confounding effects of diseases such as
hypertension and diabetes mellitus were controlled by excluding
such cases from the analysis. The confounding effects of age and
measures of smoking habits on the association between atherosclero-
sis and obesity were controlled by multivariate regression analysis.
This analysis disclosed an inverse relationship between smoking
habits and obesity. There was also a weak positive association-
when age and smoking were controlled for-between measures of
obesity and mean coronary wall thickness and raised lesions in the
coronary arteries among whites, but not among blacks. In the black
men, again with age and smoking controlled in the analysis, a weak
association between fatty streaks in the coronary arteries and
obesity was found. This analysis confirmed the previously reported
relationships between smoking habits and atherosclerosis, as mea-
sured by mean coronary wall thickness, coronary calcifications, and
raised lesions in the coronary arteries.

31


Since their first report in X65, Auerbach and his associates have
investigated the relationship of cigarette smoking to microscopic
findings in the coronary arteries (4). This study indicated that lesions
were most extensive in cigarette smokers and confirmed earlier
studies by Auerbach et al. (6) and Strong and Richards (74). The
microscopic portion of the Auerbach et al. study (4) showed that
fibrous thickening, atheroma, and calcifications of the coronary
arteries all increased with increasing number of cigarettes smoked
per day. They also found that the fibrous thickening of arteries
increased in relation to the number of cigarettes smoked per day as
the size of the artery decreased; i.e., it was least in the coronary
arteries and greatest in the myocardial arteries.
Lifsic (37) reported on the relationship of cigarette smoking to
coronary atherosclerotic lesions based on the Yalta sample from the
World Health Organization (87) autopsy study of five cities in
Europe. Information on cigarette smoking was obtained by means of
interviews with the subjects' near relatives. The prevalence and
extent of atherosclerotic lesions were evaluated in autopsies of 865
men, aged 20 to 79 years, out of the 1,220 deaths occurring in Yalta
residents of this age and sex group during the period of study. There
was a positive association of smoking with the extent of coronary
calcification; however, the author explained this association as being
related to coexisting alcohol consumption and stated that smoking
alone tended to be negatively associated with coronary calcification.
The following paragraph from Lifiic's discussion provides additional,
information from this report.

There was little significant difference between smokers and nonsmok-
ers in the prevalence and extent of atherosclerotic lesions in the
coronary arteries. Thus, of the total of 210 comparisons of different
indices of the prevalence and extent of atherosclerotic lesions between
subgroups X and W, significant differences positively correlated with
smoking were found in only 20. The tendency toward a positive
correlation of coronary atherosclerosis with smoking was found mainly
in subjects up to the age of 50, but after 60 the opposite tendency
prevailed. These age peculiarities agreed with data from other studies
showing that differences in the degree of atherosclerosis between
smokers and nonsmokers. . . are more distinct below age 60.
The author also mentioned a positive association between smoking
and coronary calcification in "strenuous workers." A note added in
proof to LifGic's article states, "Additional study of this material by
individually matched case-control analyses revealed a marked trend
toward a positive association between smoking and atherosclerotic
raised lesions in the coronary arteries" (82). Thus, while the author's
abstract does not indicate an important relationship of smoking and
coronary atherosclerosis, there are findings in the study that do

32


indicate significant relationships between smoking and coronary
atherosclerosis, especially in the younger subjects.

A subsequent study by Vikhert et al. (83) on material from five
cities in the U.S.S.R. evaluated the effect of nutritional status and
tobacco smoking on atherosclerotic changes in the coronary arteries
as measured by a visual planimetric method. This material was also
utilized for a WHO-sponsored epidemiological study of atherosclero-
sis (87). The vessels examined were from 430 men 40 to 69 years of
age. The major analyses concerning tobacco smoking were made
from 313 male heavy smokers and 82 nonsmokers. The investigators
studied both manual workers and white-collar workers and found
that tobacco smoking in combination with overnourishment had a
much more positive effect on the development of coronary athero-
sclerosis in white-collar workers than in the manual workers.

Prospective epidemiologic studies of cardiovascular disease with
autopsy followup provide additional information concerning the
relationship of smoking to atherosclerotic lesions in the artery wall.
The epidemiological studies in Oslo, Puerto Rico, and Honolulu are
characterized by careful documentation of selected major risk
factors, including cigarette smoking habits during life, and by
standardized evaluation of atherosclerotic lesions at autopsy (29, 56,
70). Each of these three studies reported findings on the relationship
of CHD risk factors to atherosclerotic lesions in more than 100
autopsies of deceased men who had been part of larger cohorts that
had been examined and followed during life. In addition, a smaller
study from Malmo, Sweden, had some of the same features as these
larger studies (71). The Oslo, Malmo, and Puerto Rico studies used
identical methods for grading the extent of atherosclerotic lesions.
These prospective epidemiologic studies with autopsy followup are in
general agreement concerning the relationship of serum cholesterol
levels and blood pressure to the extent of atherosclerotic lesions in
the coronary vasculature. The findings concerning the relationship
of cigarette smoking to the extent of coronary atherosclerosis are not
uniform. The Honolulu study (56) showed a significant relationship
between smoking habits and extent of coronary atherosclerosis. The
Oslo study (29) did not show a significant relationship between
cigarette smoking and coronary atherosclerosis. The Puerto Rico
study (70) also did not show a significant relationship between
smoking and the extent of coronary athersclerosis. A somewhat
similar study from Japan by Hatano and Matsuzaki (26) indicated a
significant relationship between cigarette smoking and coronary
artery stenosis. Thus, there is some inconsistency concerning the
association between cigarette smoking habits and coronary athero-
sclerosis in the prospective epidemiologic studies with autopsy
followup.

33


In considering this entire body of evidence, however, the prepon-
derance of evidence suggests that cigarette smoking has an effect on
the development of atherosclerotic lesions in the coronary artery
wall in the U.S. population, and that its effect is not limited to those
events immediately surrounding the occlusive episode.

Small Arteries in the Myocardium

Table 2 reviews those studies that. have examined the relationship
between cigarette smoking and lesions of the arterioles within the
myocardium. Auerbach et al. (7) found a relationship between
smoking habits and thickening of the walls of the arterioles and
small arteries of the myocardium. Auerbach et al. (4) also performed
a microscopic study of coronary artery lesions in autopsied men in
relation to previous smoking histories. In the microscopic portion of
this study, fibrous thickening, atheroma, and calcification increased
with an increased number of cigarettes smoked per day. Moderate to
advanced hyaline thickening of the arterioles in the myocardium
was strongly related to smoking. It was found in 98.6 percent of the
autopsied subjects with a two pack per day smoking habit and not
found in the group of subjects who never smoked regularly. Naeye
and Truong (51) reported essentially similar alterations in the
intramyocardial arteries, which developed more rapidly in cigarette
smokers than in nonsmokers.

The Aorta

Those studies that provide autopsy and other evidence for the
relationship between cigarette smoking and atherosclerosis of the
aorta are summarized in Table 3.

Wilens and Plair (85) found significantly more severe sclerosis of
the aorta in cigarette smokers than in nonsmokers. Sackett and
Winkelstein (61) reported that elderly cigarette smokers had signifi-
cantly higher rates of aortic calcification, detected on chest X-ray,
than did nonsmokers. Sackett et al (601, in an autopsy study, found a
significant relationship between the use of cigarettes and the
severity of aortic atherosclerosis. An interim report by Strong et al.
(75) concluded that atherosclerotic involvement of aortas was
greatest in heavy smokers and least in nonsmokers among autopsied
men in New Orleans.

Most of these studies, reviewed in the 1971 Report of the Surgeon
General The Health Consequences of Smoking (801, indicate that
differences between heavy cigarette smokers and nonsmokers are
particularly great in young individuals, and that heavy smokers
have increased surface involvement with fibrous plaques or more
advanced atherosclerotic lesions.

Since the 1971 review, a study of smoking and atherosclerosis in
deceased men in New Orleans has been completed. Several reports

34


TABLE 2.-Autopsy studies of atherosclerosis involving small arteries in the myocardium

Study   Population

Measure of
atherosclerosis

ReSUlta

Auerbach
et al
(7,

1,164 males   Records and    Biopsy of      Grade of thickness of walls of arterioles'
autopsied    family       myocardium
at VA                                                      Number of men          Percentage of men

                                                    Grade Grade Grade        Grade Grade Grade
                          Age       Smoking     Total    0     1    2. 3   Total     0     1    2. 3
                                                          -

(45

None
Cigar-pipe
ctte3 1-19
Ctte 2&39
ctte 40+

45-59

None
Cigar-pipe
ctte l-19
ctte 2cL39
Ctte 40+

60-69

None
Cigar-pipe
ctte 1-19
ctte 2&39
ctte 40+

70+

None
Cigar-pipe
ctte 1-19
ctte 20-39
ctte 40+

22     2
4     -
50     1
a5     4
29     -

15      1
13     -
33     -
99     -
50

56     4
35
92
193
67     -

32     2
40
30     -

46     -
9     -

19      1    loo.0
1      3    100.0
31     18    lc0.0
35     46    100.0
10     19    loo.0

12     2    loo.0
8     5    lc0.0
17     16    loo.0
35     64    loo.0
11     39    1Oc.o

36     16    loo.0
22     13    loo.0
44     4.3    100.0
58    135    1WJ.O
21     66    loo.0

18     12    100.0
19     21    loo.0
12     18    1lx.o
12     34    100.0
3     6    loo.0

9.1     66.4   4.5
     25.0* 75.0'
2.0    62.0   36.0
4.7    41.2   54.1
-     34.5   65.5

6.7    80.0   13.3
     61.5   38.5
-     51.5   48.5
-     35.4   64.6
     22.0   78.0

7.1    64.3   26.6
-     629   37.1
     47.0   52.2
-     30.1   69.9
-     24.1   75.9

6.3    56.2   37.5
     47.5   52.5
-     40.0   60.0
-     26.1   73.9
-     33.3'  66.71

`In the right ventrmdar wall of 1,020 men by age and smoking habits
`Percentage8 baeed on less than 10 cases
`Ctte indicates cigarettes.


TABLE 2.-Continued.

Study   Population

Smoking data
  BO"TlX

Measure of
atherosclerosis

ResUlts

Auerbach
et al.
(4

1,056 males
autopsied
at VA

Relatives
and records

Microscopic
examination

Distribution by percentage of degree of fibrous thickening of myocardial arteries, subepicardial arteries.
and hyaline thickening of myocardial arterioles (microscopic myocardial study), by smoking habit
standardized by age

Current cigarette smokers

Demee of

findings

Never
smoked

                                Ex
~1 pack   1-2 packs   z+packB   Cigar/   cigarette

regularly   per day   per day   per day    pipe    smokers -

Myocardial arteries
None or minimal
slight
Moderate
Advanced
  Total

S&epicardial arteries
None or minimal
Slight
Moderate
Advanced
  Total

97.3      24.1
2.7      62.2
+16      12.3
-       1.4
100.0     loo.0

74.7      17.5       2.4       1.4
24.9      56.8      35.1      32.7
0.4      19.0      28.8      23.8
-       6.7      33.7      42.1
loo.0     100.0     100.0     100.0

2.9       1.1      22.0     32.0
37.1      29.6      70.6     63.2
39.0      45.0       6.7      4.2
21.0      24.3       0.7      0.6
loo.0     100.0     100.0     1rKl.o

21.5     26.2
64.8     60.5
9.9      11.6
3.8      1.7
loo.0     loo.0

Myocardial arterioles
None or minimal
Slight
Moderate
Advanced
  Total

92.0       2.1      -       -       -       3.2
8.0      28.7       2.2       1.4      39.6     40.8
-       20.8       9.6       7.9      19.6      19.1
-       40.4      68.2      90.7      40.8     36.9
100.0     100.0     loo.0     loo.0     loo.0     100.0


TABLE 3.-Autopsy studies of atherosclerosis involving the aorta

Study

      Smoking data    Measure of
Population     source     atherosclerosis                              Results

Wilens and
Plair
WI

989
consecutive
necropsea
at NY VA
hospital

Patient chart  Visual grading   Percent of subjects by smoking status and atherosclerosis

                 Severity of        Non-                             Pipe/
                    sclerosis         smoker     Heavy      Moderate     Light     cigar    Other

                    Number           161        199        288        152       70      119
                    Percent above average   9.9       25.1        26.4       19.1       10      10.9
                    Percent average      60.2       61.3        62.5       63.2       60      63.0
                    Percent below average  29.6       13.6        11.1       17.6       30      26.1

Strong and
Richards
(74)

1,320       Interview    Visual grading   Mean percent of intimal surface of abdominal aorta involved with raised lesions
autopsies    with relatives
of males                                        Average number of cigarettes smoked per day
aged 25-64
at death                     Age and race             0                   l-24             25+

White males
25-34
35.44
4554
5.%64

Black males
2534
3M4
4&54
55J34

1                    7               7
14                    33               44
33                    52               56
46                    63               71

4                    7               9
6                    20               28
14                    37               45
26                    51               56


g TABLE $-Continued.

Study

      Smoking data    Measure of
Population     source     atherosclerosis                               Results

Sackett and 590
Winkelstein   white male
(61)        admissions
         to Powell
         Park Mem-
         orial In-
         stitute in
         1955

Patient     Chest X-ray   The relationship between smoking and calcification of the thoracic aorta
questionnaire   for calcification
         in thoracic aorta                  Nonsmokers            Smokers

                                         Percent with         Percent with   Probability
                 Age group         Number   calcification   Number   calcification     value 1    Totals

                    50-59              61       13       131        11         0.4      192
                    60-69              90       16       124        26         0.2      214
                    70 and over         116       37        63        54         0.02     164

                      Totals           267       25       323        26         -      590

                 Age-adjusted percent    -        22       -        30         -      -

                  `Chi-square of independence, twotcded.

The relationship between amount smoked and calcification of the thoracic aorta

Age group

m-59
60-69
70 and over

Totals

  Nonsmokers      Light smokers     Heavy smokers

     Percent with       Percent with       Percent with
Number calcification Number calcification Number calcification Totals

61       13      104       9      27      22      192
90      16      107      24       17      35      214
116      37      63      56       5      40      164

267      26      274      29      49      27      590

Age-adjusted percent -       22 -       29 -       32 -


TABLE S.-Continued.

Study

      Smoking data    Measure of
Population     Bource     atherosclerosis                               Results

Sackett
et al.
(60)

1,019      Standardized   Visual grading  Mean ag?+adjusted atherosclerosis ridits versus gr aded use of cigarettes and alcohol
consecutive   interview with on a numerical
autopsies of  patient on    scale                     Alcohol                      Cigarettes
white      admiwion

       patienta                    &/day                None             1 :! pack         1'2 pack+

                                      None                  ,351                  ,466             ,498
                                      0.5-1.5                 ,424                  ,570             .56l3
                                 1.6+                  ,426                 ,526             ,589

Strong et al.  Autopies    Interview    Visual grading  Mean percentage of intimal surface of aorta involved with raised lesions by age, race, and average rate
(75)        of 741      with relativea  and optical    of cigarette smoking in the last 10 years of life
         males 20-64          Bcanning

year8 at
death

Cigarettes pe r day

Age and race

White males
3-4
4654
55-64

Black males
35-44
45-54
55-64

0                  l-24             25+

16                   35              49
29                   52              54
48                   66              70

3                   22              24
12                   38              50
21                   50              49


$   TABLE 3 -4`ontinued.

Study

       Smoking data    Measure of
Population     source     atherosclerosts                              Results

Litsrc
(37)

865
autopsies

Relatives
and records

Visual gradmg  Prevalence of atherosclerotic lesions in the abdominal aorta in different subgroups (percentage)

of males
aged 2&79
at death in
Yalta

Smokrng
group

Never
Lrght
Heavy

Fatty
streak

96.5
92.8
90.7

Fibrous
plaque

96.0
96.5
97.5

Complicated
lesion

  43.0
  53.4
  60.9

Calcified
lesion

25.0
42.3
57.3

Extent of atherosclerotic lesions (percentage of surface) in the abdominal aorta

Smoking        Fatty
group           streak

Never           7.0
Light            6.1
Heavy           5.8

Fibrous
plaque

28.1
31.6
26.5

Complicated
lesion

  2.0
  5.1
  4.1

Calcified
lesion

1.2
2.2
3.4


TABLE 3.-Continued.

Study

      Smoking data    Measure of
Population     source     atherosclerosis                              Results

Rhoads
et al.
(56-l

124
Japanese
American
males autop
sied as part
of the
Honolulu
heart study

Interview
with subject

Visual by
AHA panel
method

Correlation coefficients among selected autopsy and examination variables'

                            Aorta (N = 124). atherosclerosis grade

Age at death
Examination variables
Height (cm)
Relative wt. (%)
Cigarettes/day
Cholesterol (mg/dl)
Triglycerides (mg/dl)
Uric acid (mg/dl)
Glucose (mg/dl)
Hematocrit (%I
Vital capacity (liters)
Alcohol (pm,
Systolic pressure (mm Hg)
Diastolic pressure (mm Hgl
Mean coronary grade
Aorta grade

0.30 3

-0.12
a.10
0.14
0.243
0.14
-0.052
0.15
a.03
X1.23~
-o.08z
0.29 3
0.05
0.503 (96)'

I N= number of specimens.
sS~gniiicant at 0.05 level
a Significant at 0.01 level.

`When a correlation coeffXent is based on less than 95 percent of the ~pecmwns available (because of missing
data), the number of observations is indicated in parentheses. There were 96 autopsies with both aorta and
coronary vesel grades available. 13 wth coronary only. and 28 with aorta only


TABLE 3.-Continued.

Study

      Smoking data    Measure of
Population     SO"FX?     atherosclerosis                               ReSUlta

Auerbach    1,412 males  Family      Visual grading  Percentage of selected findings by smoking habits
and Garfinkel autopsied
(5)         at VA hos-                                              Percentage of cases'
       pita1                                            "Current" cigarette smokers

Findings

Never smoked 1 pack  l-2 pack3  2+ packs  Cigar  Excigarette
regularlv per day per day per day or pipe smoker

Thoracic aorta
Many or diffuse
  distribution of plaques
Moderate or advanced
  ulceration
Moderate or advanced
  calcification
Thrombus present
Abdominal aorta
Many or diffuse
  distribution of plaques
Moderate or advanced
  ulceration
Moderate or advanced
  calcification
Thrombus present

16       26      41       37      27      29

4        6      14       12      10       8

56       63      74       74      53      67
4        7      14       11      11       9

28       54      68       79      46      53

7       19      27       27      13      22

63       76      84       88      74      81
7       23      23       31      14      23

lPercentages are adjusted to distribution by age group of all men in study.


TABLE 3.-Continued.

Study

      Smoking data    Measure of
Population     source     atherosclerosis                               Results

Sternby
(71)

60        Interview    Visual grading   Smoking and atherosclerosis of the aorta
autopsies    with subject
from 703                                                                 Raised lesions in the
males enrol-                  Smoking category               Number                abdominal aorta
led in a
CHD study                        Non                         3                      26
in Malmo.                        ET.                          8                      43
Sweden                      Light                        18                      53
                             Heaw                        7                      83

Smoking and atherosclerosis m peripheral arteries

Femoral artery

Lower leg artery

Smoking

Iliac artery

Raised     Sterosis     RalSed    Stenosis

category      N      Raised lesions      lesions       (701      lesions     (70)

Non         3         17           20         0         2        0
EX         8         18           43        33        18       22
Light       18         29           29         6         3       11
Heavy       17         50           50        35        12       41


g   TABLE S.-Continued.

Study     Population

Smoking data    Measure of
  source     atherosclerosis                               Results

Tracy et al.   Autopsies    Interview     Visual exam   Means of observed minus expected raised-among-lesions GE), fatty streaks among flat surfaces (FaF),
(77)       of 1.380     with relatives          all types of lesions tATL1, and number of cases (N) by age, race, and cause of death according to
         white and                   smoking category I, abdominal aorta
         black males
       aged 2564                                         O-E                 Faf               ATL
         at death                      Age           0     l-24    25+     0     1-24    25+     0     l-24   25+

White basal
2534
3544
45-54
5.5-64

White CHD
25-34
35-44
45-54
55-64

Black basal
2634
3%44
4554
55-64

Black CHD
24-34
35-44
45.54
5564

-3.7      3.9    0.6    25.3    32.1    36.6    26.4     36.6   34.7
-7.3      5.0    12.7    22.8    30.8    35.5    27.9     48.1   64.7
77      6.1     3.6    21.3    28.9    31.4    47.3     57.3   65.8
-0.6      3.0    6.7    33.7    33.1    35.5    56.5     68.6   76.2

X      X     X      X      X     X     X      x x
-18.7     15.3    6.8    43.2    28.2    39.2    55.3     67.9   68.0
8.0      3.6     1.3    25.7    40.8    33.1    500     81.4   73.4
4.5      5.4     2.2    44.3    37.7    40.1    77.7     82.8   83.7

5.3     -3.5    -3.8    28.6    32.8    36.8    30.7     34.9   38.6
-16.9     -3.1    -3.9    26.5    31.8    33.0    27.8     43.9   45.6
-15.7     -7.3    -5.4    25.0    32.7    37.4    33.8     47.2   60.0
-9.5     a.3    -2.8    29.7    31.6    32.1    43.9     61.6   55.5

X       6.3    X      X      39.7    X     X      44.6   X
X      -2.7    9.3    X      28.0    29.9    X      55.1   61.8
X       4.6    4.8    X      34.2    386    X      72.4   73.0
-14.4     -2.8    2.5    41.9    35.8    40.7    62.5     66.2   81.4

' ATL as % fatty streaks (F) plus raised lesions (RI; FaF=F : (100 - R); O-E in percentage units explained in


TABLE 3.-Continued.

Study

      Smoking data    Measure of
Population     8oUrC.2     athercscleroeie                               ReSUlts

the text. X mdvxtes subgroups having fewer than live members

Sorlie
et al.
( 70)

139
autopsies
of 9.824

Interview     Visual
with subject   evaluation

Awxiation of atherosclerosis in aorta with antemortem characteristics. simple correlation coefficients
(Puerto Rican heart health program)

Puerto
Rican males

Correlation coefficients

aged 35-79

Characteristics
measured at exam 1

Total
(120)

Rural
(31)

Urban
(89)

Systolic blood pressure
Diastolic blood pressure
Serum cholesterol
Age, exam 1
Relative weight
Physical activity
Blood glucose
Hematcvxit
Education
Income
Cigarettes smoked
Calories (24.hour recall)
Starch (24-hour recall)
Alcohol (24.hour recall)
Total fats (24.hour recall)
Triglycerides (fasting)
Ventricular rate
Vital capacity

0.25             0.27          0.24
0.19             0.29          0.16
0.29             0.38          0.28
0.31             0.39          0.29
4.08            -0.22         4.06
-0.18            -lx21         -0.14
0.14             0.05          0.17
0.23             0.33          0.21
-0.08            a.23         a.03
0.01            -0.01         4.01
032             0.37          0.31
-0.24            -0`5.5         4 12
-0.19            a.45         -0.07
-0.18            4.39         AI 18
-0.19            4.49         a.11
0.11             0.53          0.04
0.07             0.11          0.05
-0.29            -0.28         -0.29


based on the findings in that study, as well as various interpretations
of those findings, have been published. Strong and Richards (74)
reported the basic findings on the association of cigarette smoking
and aortic atherosclerosis in 1,320 autopsied men in New Orleans, 25
to 64 years of age. Aortic lesions were evaluated visually in coded
specimens and objectively by analysis of radiographs. Interviewers
obtained estimates of cigarette smoking habits of the deceased men
from surviving relatives. Data were compared for black men and
white men, and also were analyzed in groups according to the
presence or absence of diseases thought to be associated with
smoking or with coronary heart disease (emphysema, lung cancer,
myocardial infarction, hypertension, diabetes mellitus, stroke, etc.).
Atherosclerotic involvement of the aorta was greatest in heavy
smokers and least in nonsmokers for both races in the total sample,
as well as in the basal group (those cases least influenced by the bias
of autopsy selection). The lesions were measured not only by visual
evaluation, but also by optical electronic scanning of radiographic
images of flattened arteries. Atherosclerotic lesions in the abdominal
aorta were more extensive in the heavy smokers than in the
nonsmokers, and there was an orderly trend of increased lesions
with increased smoking. In general, the magnitude of difference in
extent of lesions between nonsmokers and heavy smokers was
greater in the abdominal aorta than in the coronary arteries. A
variety of statistical analyses of smoking measures and atheroscle-
rotic lesions was applied to determine the significance of the various
differences and trends. All of the analyses confirmed that the
differences between the heavy smokers and the nonsmokers in
extent of raised atherosclerotic lesions were significant. A one-way
multivariate analysis of nine atherosclerotic variables indicated that
there were statistically significant differences among the three
categories of smokers (heavy, light to moderate, and nonsmokers) for
lesions in the abdominal aorta.

Following the initial report of Strong and Richards (74), there were
three additional publications from this study. Two of these were
directed toward interpretation of findings in regard to the effect of
cigarette smoking on fatty streaks (the earliest grossly visible lesions
of atherosclerosis) and raised atherosclerotic lesions (the more
advanced stage of the atherosclerotic process). The other study was
directed toward the interrelations of obesity, smoking, and athero-
sclerotic lesions in these same cases.

The original report by Strong and Richards (74) indicated that
raised lesions, the more advanced lesions, were greater in heavy
smokers than in nonsmokers. They also reported statistically
significant differences for fatty streaks in the abdominal aorta and
for fatty streaks in the coronary arteries, with the highest values in
the nonsmokers and lowest values in the heavy smokers. The well-

46


recognized problem of evaluating fatty streaks when more advanced
lesions of atherosclerosis are present made it difficult to interpret
the findings on fatty streaks. Pate1 et al. (54) approached this
problem by using a simple two-parameter model of fatty streaks
arising from a normal intimal surface at a constant rate and with
subsequent conversion to raised lesions at a constant rate. They
concluded that in the abdominal aorta, smoking enhances the
formation of fatty streaks as well as the subsequent conversions to
more advanced lesions, and in the coronary arteries, smoking seems
only to enhance the conversion of fatty streaks to fibrous plaques.
Tracy et al. (77) evaluated the same data from the New Orleans
study on smoking and atherosclerotic lesions. They approached the
problem using a different model: N = F -+ R, where N denotes
normal intima, F denotes fatty streaks, and R denotes raised lesions.
In this model, class A causes are viewed as promoting the process
from beginning to end, while class B agents act at the first or the
second step, but not at both. Their analysis and interpretation
suggest that cigarette smoking has a large class B effect. They
concluded that the target tissue of smoking is the fatty streak, and
the slowly progressing or regressing fatty streak (formed alike in
smokers and nonsmokers) is caused to progress more rapidly or to
cease to regress by smoking. Both of these studies, Pate1 et al. (54)
and Tracy et al. (73, agree that smoking has a role in the progr&ion
of fatty streaks to a more advanced stage of the atherosclerq$c
process.

Auerbach and Garfinkel in 1980 (5) published findings on smoking
habits and atherosclerotic lesions in over 1,400 aortas collected at
autopsy from male patients. The extent of atherosclerotic lesions
(plaques, ulcerations, and calcification) increased with number of
cigarettes smoked, and was also greater in excigarette smokers and
pipe smokers than in nonsmokers. The findings were more striking
in the abdominal aorta than in the thoracic aorta. Aortic aneurysms
were found eight times more frequently among those who smoked
one to two packs of cigarettes per day than in nonsmokers.

LifSc (37) reported on the relationship of cigarette smoking to
aortic lesions based on the Yalta sample from the World Health
Organization (WHO) autopsy study of five cities in Europe (87).
Information on cigarette smoking was obtained by means of inter-
views with the subjects' near relatives. The prevalence and extent of
atherosclerotic lesions were evaluated in autopsies of 865 men, aged
20 to 79 years, out of 1,220 deaths occurring in Yalta residents of this
age and sex group during the period of study. There were significant
positive relationships between smoking and the extent of fibrous
plaques, complicated lesions, and calcified lesions in the abdominal
aorta.

47


Aortic atherosclerosis has also been evaluated using autopsy
followup of prospective epidemiologic studies of cardiovascular
disease. Epidemiological studies in Puerto Rico and Honolulu
documented selected risk factors, including cigarette smoking habits,
during life and had standardized evaluation of atherosclerotic
lesions at autopsy (56, 70). Each of these studies reported findings on
the relationship of risk factors and aortic atherosclerotic lesions in
more than 100 deceased men from large cohorts that had been
examined and followed during life. A smaller study from Malmo,
Sweden, had some of the same features as these larger studies (71).
All of these studies found a significant positive relationship between
cigarette smoking and aortic atherosclerosis.

The prospective epidemiologic studies with autopsy followup
confirmed the relationship between smoking and atherosclerotic
aortic lesions found in earlier autopsy studies. The preponderance of
evidence suggests that cigarette smoking aggravates or accelerates
aortic atherosclerosis, and this effect on atherosclerosis may be more
pronounced in the aorta than in the coronary arteries.

Cerebral Vasculature

The relationship between cigarette smoking and atherosclerosis in
the cerebral vasculature has not been extensively evaluated. Two
studies that have examined this question are summarized in Table 4.
Sternby (71) reported that cigarette smokers had more extensive
raised lesions in the basilar artery than had nonsmokers. This study
was based on 60 autopsy subjects from 703 men born in 1914 who
participated in a study of cardiovascular disease in Malmo, Sweden.
Holme et al. (29) reported a positive correlation coefficient between
raised lesions in the cerebral vessels and the number of cigarettes
smoked; this relationship was not statistically significant, however.

The limited amount of information available on the relationship
between cigarette smoking and atherosclerosis in the cerebral
vasculature does not allow a clear conclusion to be drawn at this
time.

Pathophysiologic Mechanisms of Tobacco Smoke
Studies of Components of Tobacco Smoke

The possible pathophysiologic mechanisms for the atherogenic
influence of cigarette smoking were reviewed in the 1971 Report of
the Surgeon General The Health Consequences of Smoking (80). The
major components of cigarette smoke considered in that review were
nicotine and carbon monoxide. Numerous investigators have studied
the effect of nicotine administration, either subcutaneously or
intravenously, upon experimentally induced changes in the aorta
and coronary arteries of animals. When administered alone, nicotine

48


TABLE 4.-Autopsy studies of atherosclerosis involving cerebral vasulation

Study            Population

Smoking data
  8ource

Measure of
atherosclerosis

Result.6

Sternby
(711

60 autoplied
subjects from
703 male8 in
CHD study in
Malmo. Sweden

Interview
with subject

Visual
inspection

Smoking and atherosclerosis m the basilar arteries

Smoking
category     Number   Basilar artery raised lesions

Non         3              1
EX          8              6
Light        18              3
Heavy       17              7

Holme et al.
(29)

129 autopsies
out of 16,200
men aged
4049 in
Oslo CHD
study

Interview
with subject

Visual grading

Correlation coefticlent between raised lesions in the cere-
bra1 vessels and number of cigarettes smoked per day is
0.090 (not statistically signifxantl.


induces certain degenerative or necrotic changes in the arterial wall,
but these are characteristically medial changes rather than the
intimal changes that characterize atherosclerosis. When nicotine is
administered in combination with a high cholesterol diet, it seems to
aggravate arterial damage, according to a preponderance of studies.
Some studies, however, do not report this synergism between
cholesterol feeding and nicotine (16, 84).

Schievelbein and associates (66) reported the effect of long-term
nicotine exposure on the development of arteriosclerosis in rabbits.
They administered nicotine to rabbits not being fed an atherogenic
diet. All animals had arteriosclerotic lesions in the aorta and
coronary arteries at the end of the experiment, but there was no
difference between the control group and the experimental animals
administered nicotine. They reviewed the experiments of several
authors who studied nicotine and their own animal experiments and
concluded that the evidence did not establish a causative role for
nicotine in the etiology of arteriosclerosis.

A recent report by Liu et al. (38) on experimental arterial lesions
in rhesus monkeys with various combinations of dietary hypercho-
lesterolemia, hypervitaminosis D(2), and nicotine indicated that the
combination of these three factors produced high scores for various
measures of arteriosclerotic changes in aorta, coronary, and limb
arteries of the monkeys. When the factors were administered singly,
however, very little arterial disease was demonstrated over the
period of the experiment. The group with all three factors was the
only group with significant coronary arteriosclerosis as well as
complicated lesions of the arteries of extremities.

Dooyse et al. (15) reported the effects of chronic oral consumption
of nicotine on the rabbit aortic endothelium. They found that fasting
serum levels of glucose, triglyceride, total cholesterol, and LDL
cholesterol were elevated in nicotine-treated rabbits as compared
with controls. They found no significant differences between the
experimental group and the controls for leukocyte, erythrocyte, and
platelet counts, or for hematocrit and hemoglobin. Endothelial cells
from the aortic arch of the nicotine-treated animals showed exten-
sive changes, such as increased cytoplasmic silver deposition, in-
creased formation of microvilli, and numerous focal areas of
"ruffled" endothelium. The authors concluded that nicotine adminis-
tered orally to rabbits has a demonstrable morphologic effect on
endothelial cells in the aortic arch.

While the evidence for and against a primary role for nicotine in
the development or acceleration of atherosclerosis is not conclusive,
nicotine is certainly one of the components of tobacco smoke for
which there are both some supporting data and a rational conceptu-
alization for a role in the pathogenesis of atherosclerotic lesions.
There is little doubt that nicotine alone or in combination with other

50