Coronary heart disease in the Western Collaborative Group Study

J ChronDis 1970, Vol. 23, pp. 173490. Pergamon Press. Printed in Great Britain

CORONARY HEART DISEASE IN THE WESTERN COLLABORATIVE GROUP STUDY A

FOLLOW-UP

EXPERIENCE

OF

4

YEARS

RAY H. ROSENMAN,* M.D., MEYER FRIEDMAN,* M.D., REUBEN STRAUS,~M.D., C. DAVID JENKINS,$Ph.D., STEPHENJ. ZYZANSKI,~ Ph.D. and Mosns WURM,~M.D. (Received 24 September 1969; in revised form 29 January 1970)

PROSPEC~VEepidemiologic studies provide a valuable approach for determining many of the individual and environmental factors which precede the emergence of coronary heart disease (CHD) and which may raise the risk of its occurrence and recurrence. The Western Collaborative Group Study (WCGS), initiated in 1960-1961 in 3524 men employed in the San Francisco Bay Area and Burbank, is a continuing prospective epidemiologic investigation of this type [I]. The present report examines the relationship of 21 risk factors, considered singly and in various combinations, to the emergence of new CHD for the period from intake through the annual follow-up examination of 1965. The entering subjects were initially studied over an 18 month period in 1960-1961. The present period of follow-up for the men varied from 4 to 5 yr, with the mean period at risk for the total sample being 4 yr. Earlier studies from this laboratory indicated that a particular behavior pattern (labelled Behavior Pattern Type A) overtly characterized by excessive sense of time urgency, preoccupation with vocational deadlines and enhanced aggressiveness and competitive drive, bore a significant association with increased prevalence [2] and with increased incidence [3] of CHD. This behavior type also was found associated with a significantly greater degree of basic coronary atherosclerosis in a post-mortem study [4]. Conversely, subjects without such behavioral characteristics (labelled Behavior Pattern Type B) were found to possess a sharply lower incidence of clinical CHD [3, 51 and a relatively lesser degree of basic coronary atherosclerosis [4]. Supporting evidence has now been reported by two other research teams, which also found Behavior Type A to be associated with increased prevalence of CHD in cross-sectional studies. Keith, Lown and Stare utilized “blind” interviewing and rating procedures in a study of patients with CHD and other chronic diseases [6]. Guided *Harold Brunn Institute, Mount Zion Hospital and Medical Center, San Francisco, California, U.S.A. TResearch Laboratories, St. Joseph Hospital, Burbank, California, U.S.A. SDepartment of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, North Carolina, U.S.A. 173

174

RAY H. ROSENMAN, et al

by the methodological note by Cassel [7], examination of their tabulated data showed that for the total age range examined (35-55 yr), 47 per cent of the CHD patients were classed as Type A, whereas only 31 per cent of the non-CHD subjects were so classified. The trend for a higher percentage of coronary than non-coronary subjects to be called Type A prevailed for all age subgroups but was strongest in men under age 45. Two reports from the Benedictine-Trappist Monastery Study show Type A behavior to be highly associated with CHD prevalence [8, 91 whether initially expressed as angina pectoris or as myocardial infarction. METHODS

AND

MATERIALS

The methodology of the WCGS already has been reported in detail [l, 3, 51. Comprehensive data, including sociological, dietary, biochemical, clinical and behavioral tidings were obtained at intake in 1960-1961 and at annual intervals since 1961 among 3524 male participants, aged 39-59 yr at intake, employed in 11 California corporations in the San Francisco Bay Area and in Burbank. The present study describes some of the findings which have been observed in 3182 men during a mean follow-up period of 4 yr. Excluded from the present follow-up data were 78 subjects under or over the specified ages at intake, 113 subjects with CHD already manifest at intake, 106 employees of one of the 11 intake firms that subsequently excluded its group from further study, and 45 subjects that were lost to follow-up by relocation or noncardiac ceath. Among other things, the interval cardiac history and an electrocardiogram were obtained at each annual follow-up examination. The tracings were interpreted by an electrocardiographer* and then were submitted to the medical referee* who was solely responsible for any diagnosis of manifest CHD [l, 31. These diagnosticians were otherwise independent of the study. The analyses are based on the data obtained at intake into the study. For each of the 21 variables under consideration, men who subsequently developed CHD, were compared with men who remained free of CHD. Categorical and ranked data were analyzed by the Chi-square test with correction for continuity (Yates) when appropriate, and the continuous measures by Student’s t-test. The findings indicated a number of independent sociological, biochemical and behavioral variables to be “risk factors” for the occurrence of CHD, in that each, taken singly, was significantly associated with a higher incidence of CHD. In order to determine whether each of these variables made an independent contribution to the prediction of CHD or one that overlapped or merely reflected that made by some other variable, or was involved primarily in a synergistic interaction with another risk factor, the modified minimum ~2 method was utilized. Theoretical justification for this method is best represented by the procedures of Wald [lo] and Neyman [ll]. The equivalence of these two approaches for the type of analysis proposed here was shown by Bhapkar [12]. Computationally, the programmed solution used in this study was recently outlined in detail by Grizzle [13]. This particular approach to the analysis of categorical *Electrocardiograms were interpretedby Herman Uhley, M.D., of Mount Zion Hospital and Medical Center, San Francisco. Harold Rosenblum, M.D., Department of Medicine, Mount Zion Hospital and Medical Center. is the senior Medical referee.

Coronary HeartDiseasein theWe&em Collaberative Group Study

175

data by linear models initially defines u parametric functions of p, the expected cell probabilities in a contingency table, along with their estimates and their asymptotic covariance matrix. The method assumes that F(P)=X

P,

24.1 24.v v.1 where X is a known design matrix, which in this study is identical to the conventional design matrix employed in analysis of variance models, of rank vLu and l3is a vector of unknown parameters. The best asymptotic normal estimates of j3are computed and these are employed in developing a test of the fit of the linear model. A test of the c p=o hypothesis d.v v.1 d.1 is developed by conventional methods of weighted multiple regression, where C is a matrix of arbitrary constants depending on the specific contrasts of interest. The test statistic for the fit of the linear model is given by SS[F (p)]. This sum of squares has asymptotically a central ~2 distribution with u-v degrees of freedom, if the model fits. However, given the model, the test of the hypothesis CJ3=0 is given by SS(Cl3) which has asymptotically a central X*distribution with d degrees of freedom, if the Ho is true. A number of ‘risk factor’ variables, e.g. cholesterol and blood pressure, were dichotomized into high and low categories and various crossclassifications of these dichotomized variables were further crossclassified with CHD dichotomized as present and absent to form a number of 2 x 2 x 2 contingency tables. These tables constituted the input into the modified minimum x2 program. Since the CHD proportions per subgroup were quite small an arc sine transformation was deemed unfeasible due to the disproportionate subgroup samples sizes. The analysis was therefore performed on the log of the observed CHD proportions. An additional analysis employing the logit, i.e. the log of (p/l-p), was also carried out but due to the fact that the denominator in every cell was nearly 1 in most instances (because p was very small), the analysis of the logit was equivalent to the analysis of the log (p). This was confirmed in that the conclusions from both types of analyses were nearly identical, hence, only the log (p> analysis will be reported here. This modified minimum ~2 analysis attempts to fit a linear model as defined by the cross-classified variables to the log of the CHD proportions. If the hypothesis that the linear model fits the data cannot be rejected, this suggests that on this log scale no interaction exists and the tests of the variables comprising the classification can then be effected. In this study, twenty-six 25 analyses were performed for each of the two age groups, utilizing various combinations of significant risk variables in conjunction with CHD. Only a selected sample of these analyses is presented here. Each variable is dichotomized as indicated. However, it should be noted that the point of dichotomization does have some effect on the size of the observed ~2 statistic and it corresponding P-value. If alternate points of division were tried for each variable, an unmanageable number of analyses would have been required. Hence the points of division were set according to those commonly used in clinical practice and in epidemiological studies. The type of analysis employed here does take into account disproportionate cell sizes and in effect performs a weighted regression analysis. In addition, the X*statistic for each variable is computed adjusting for the effect of the other independent variable. For each of these analyses, the “lack of fit” term is computed first and is a test of the

176

RAY H. ROSENMAN, et al

appropriateness of the linear model. Ifit is found significant, the interpretation other effects is confounded [13].

of the

Given the observation that the relationship of Behavior Type A to incidence of coronary-disease may not be noticeably reduced by controlling for a wide range of other risk factors considered singly (Tables 6 and 7), the question may then be raised whether some combination of two, three, or more variables considered simultaneously might eliminate the power shown by Behavior Type A in the prediction of CHD. A regression procedure was used to examine this possibility. Men in each age decade were grouped by behavior pattern (Type A or Type B) and the influence of the associations of 12 demographic characteristics and CHD risk factors with CHD was removed statistically by utilizing the regression of CHD considered as a dichotomous variate (scored “1” for a CHD case and “0” for a non-case) on all of the variables. The 12 variables whose influence is statistically controlled in this analysis are: age, serum cholesterol, beta/alpha lipoprotein ratio, lipalbumin, systolic blood pressure, diastolic blood pressure, number of cigarettes currently smoked per day, ponderal index, rating of physical activity on the job, rating of amount of voluntary exercise, level of schooling, and level of income. The adjusted rates of CHD for men with Pattern A and men with Pattern B, incorportaing these multiple adjustments, were then tested for significance of difference by using the F-test. Adjusted CHD incidence rates, after adjustment for all 12 variables, are shown in Table 8. RESULTS

Incidence of CHD and relationship to single predictive factors

Clinical CHD occurred in 133 initially well men during the period of follow-up, averaging 4 yr for the total group. This yielded an annual incidence of 9.3/1000 men at risk. The annual incidence was 6.2 in the younger age group (39-49 yr at intake) and 16.8 in the older age group (50-59 yr at intake). The findings observed at intake into the study in the 133 men suffering CHD during follow-up are compared with the 3049 subjects who remained free of clinical CHD in Tables 1 and 2. Men in the 39-49 yr age group who developed CHD were about l+ yr older on the average than men in that decade who remained free of the disease. This was sign&ant statistically. Only an insignificant age difference appeared in the 50-59 decade. Men who developed CHD were similar to men remaining healthy in average height, but were heavier than the remaining men and exhibited smaller mean ponderal indices. These differences were significant only for the older age group. The rate of CHD was progressively higher as the ponderal index decreased in both age groups but the difference of distributions did not reach statistical significance. The level of education was significantly associated with the rate of CHD in both age groups. Men of high school or less education had significantly higher rates than did college graduates. However, annual income was not related to CHD rates. Men who reported moderate to heavy work activity (a relatively small fraction of the subjects studied) and men who reported regular daily exercise habits (purposeful calisthenics and/or walking or hobby exercise) had CHD rates lower than those with sedentary to light occupational activity and with none to occasional avocational exercise. However, the differences were slight and did not reach significance.

Coronary Heart Disease in the Westem Collaborative Group Study

177

A history of CHD in either parent was associated in both age groups with sharply increased CHD rate, as was a history of either hypertension or diabetes, although the latter condition was small in this population. (In addition to obtaining the history of diabetes, all surviving subjects with CHD also were tested by obtaining a postprandial blood sugar.) The association of smoking habits with the rate of CHD is shown in Table 1. The relation of current or former cigarette smoking to enhanced CHD rate was observed in both age decades, but was found to be significant only in the younger age group. However, when the CHD rates for current cigarette smokers were tested against all men not smoking cigarettes at intake (not shown in the table) the higher CHD rates observed in the current smokers were found to be sign&ant (P=O.Ol) in both age groups. Higher rates of CHD also were observedamongformer cigarette smokers than among men who had never smoked and the differences againwere significant (P=O.OS) in both age groups. When the subjects were categorized by reported current number of cigarettes smoked daily, higher CHD rates were observed among heavier than lighter smokers. The differences were statistically significant only in the younger age group. The relationship of smoking habits to other CHD risk factors and to the emergence of CHD itself in this study population is discussed elsewhere in more detail [14]. The clinical and laboratory findings obtained at the intake examination are shown in Table 2. The fasting serum triglycerids, however, were not initially obtained until the tist follow-up examination in 1962. Accordingly, the sample size for the triglyceride analysis was 3030 instead of the intake sample size of 3182. The incidence of CHD in both age groups was found to be significantly related to the systolic and diastolic blood pressures and to the serum concentrations of.cholesterol, triglyceride, lipalbumin, beta lipoprotein and beta/alpha lipoprotein ratio. The behaviour pattern of the subjects was classified at intake into the WCGS by means of a structured interview whose reliability has been established [l, 151. Subjects were classified as exhibiting Pattern A or Pattern B [l, 31. Higher CHD rates were observed in all Type A than Type B men and the differences were significant in both age groups. In addition, an attempt was made further to subdivide the two patterns into completely and incompletely developed subtypes, respectively labelled Pattern Al and B4 (the two extremes) and Pattern A2 and B3 (incompletely developed forms). The attempted four-way division of behaviour types in correlation with CHD rates however was statistically significant only in the younger age groups. It is of interest that the highest rates in the younger men were observed among those with Pattern A2, an association which is under further investigation. Relationship of the predictive factors to the incidence of CHD with d@erent initial manifestations The advent of clinical CHD was observed in 133 subjects and was initially mani-

fested by clearcut angina pectoris in 29 of these men. Acute myocardial infarction occurred in 104 instances but was symptomatic in only 73 of such subjects. Definitive electrocardiographic evidence of myocardial infarction occurred in the remaining 31 instances but the infarction was either ‘silent’ or clinically unrecognized. The incidence rates of the various types of manifest CHD among subjects with and without various predictive factors are shown in Table 3. The two age groups have been combined

9;::

Hx diabetes (“/o) Without above (%)

45.6 40.2 14.2

7.2 92.8

Hx Hypertension (%) Without above (%)

Annual income

42.9 57.1

15.0 85.0

Medical history Parental CHD (%) Without above (%)

yr

6.1 6.6 5.6

N.S.

P=O.OOl

52.3 5.9 >

4.8 95.2

44.4 42.9 12.7

P=O.OOl

17.1 5.3 >

20.6 79.4

P=O.O2

N.S.

N.S. -

0.001 N.S.2 N.S.

~Signitkance

P=O.OOl

8.3 8.1 3.6 1

1.5 7.3 5.9 4.6

6.2 -

*Annual incidence

39-49

16.8 4.2 )

58.7 15.9 25.4

43.6 12.1 44.2

Schooling High school or less (%) Some college (%) College graduate (%)

12.58 9.5 34.9 41.3 14.2

17xT

69.8

2.9

2x 4312 19.6

12.65

2195 43.3 69.9 i70.4

CHD present

Ponderal index Age-adjusted mean Under 12.00 (%) 12.00-12.49 (“/,) 12.50-12.99 (%) Over 12.99 (%)

---No. of subjects Mean age (yr) Mean height (in) Moan weight (Ibs)

CHD absent

Ages

41.8 33.5 24.7

0.8 99.2

8.8 91.2

15.3 84.7

52.3 12.1 35.6

12.60 8.6 31.4 41.6 18.5

854 53.6 69.4 16m

CHD absent

TABLE 1. SUMMARY OF PROSPECTIVEHISTORY

30.0 42.9 27.1

4.3 95.7

22.9 77.1

57.1

42.9

25.7 21.4

52.9

12.46 12.9 35.7 44.3 7.1

70 54.1 69.7 175.9

CHD present

12.4 21.2 18.4

66.7 16.3

40.4 14.4 )

41.4 1 11.6 J

17.0 33.1 10.4 >

24.4 1 19.0 1 17.8 t 6.8 J

-

16.8 -

*Annual incidence

Ages SO-59 yr

N.S.

P=O.Ol

P=O.Ol

P=O.ool

P=O.Oi

N.S.

P=O.O2

0.01 -

N.S.

N.S.$

tSignificance

2

( %)

15.9

68.3

10.4

47.0

19.0 31.7 7.9 28.6 31.7

4.8

18.3

11.4 53.3 9.4 19.0 18.3

11.1

20.6 79.4

14.3 85.7

24.3

28.9 71.1

15.4 84.6

3.7 5.3 -! I

8.9 I

9.3

1.6

2.9

4.5 6.9 >

5.8 6.3 >

P=OOOl .

P=O.OOl

P =O.OOl

N.S.

N.S.

* Rate of CHD/lOOO men at risk t Underlined significant levels P-values) are based on t-test of means and others on chi-square. $ N.S.=Not Significant at P=O.O5

Mean per day Smoking 0 per day ( %) Smoking 1-15 per day (%) Smoking 16-25 per day (%) Smoking 26 and over (%)

Current cigarettes

Never smoked ( %) Current and former pipe or cigar only ( %) Former cigarette smoker (%) Current cigarette smoker (%)

Smoking habits

Nonwxcasional Regular ( %)

Exercise habits

Sedentary-light (%) Moderate-heavy (%)

Physical work activity

41.4 8.6 27.1 22.9

Mean values are also underlined

53.2 12.1 17.1 17.7

15.7

58.6

47.2

11.1

12.8

15.7

12.8

75.7 24.3

82.9 17.1

15.0

17.6

20.3

68.9 31.1

80.0 20.0

12.2 13.3 25.6 22.3

20.5

14.6

15.2

11.0

18.4 13.4

17.4 14.7 >

N.S.

P=O.Ol

N.S.

N.S.

N.S.

g Y

223.7 49.4 32.5 18.1

Serum totul cholesterol Mean (mg/lOOml) Under220 (a 220-259 (O/d 26Oand over (a

177 and over (%I

yJ,;y-$%)

22.9

146.0 28.5 48.6

81.3 92.4 3.1 4.5

Diastolic bloodpressure Mean (mm Hs) Under 95 (%) 95-99 (0%) 100 and over (“4

Feting serum trigrvcerides Mean (m&O0 ml)

127.2 26.6 71 .o 2.4

2195

Systolic blood pressure Mean (mm Hg) under 120 (0%) 120-159 (0%) Wand over (%)

No of subjects

CHD absent

164.4 12.1 51.7 36.2

247.6 22.2 36.5 41.3

84.3 81.0 4.1 14.3

132.7 17.5 69.8 12.7

63

CHD present

>

>

X:4” >

2.6

1:::

2.8

5::

4.1

6.2

*Annual incidence

Ages 3949 yr

TAB= 2. SUMMARY OF

P=O.Ol

P=O. 10

P=O.ool

P=O.ool

P=O.Ol

P=O.O2

P=O.OOl

P=O.Ol

tSign&ance

___

148.7 29.2 47.5 23.3

230.6 41.6 34.7 23.7

83.3 88.2 4.7 7.1

131.1 20.0 73.4 6.6

854

CHD absent

PROSPECTIVE EXAMINATION FINDINOS

174.9 20.3 37.5 42.2

247.8 xx 42.9 35.7

2;:;

88.6 72.9

140.3 11.4 70.0 18.6

IO

CHD present

11.4 12.8 27.4 >

2z.i 24:6

14.1 15.5 46.2

1X 41:9 >

16.8

*Annual incidence

Ages 50-59 yr

P=O.Ol

P=O.O5

P=O.Ol

P=O.OOl

P=O.OOl

P=O.OOl

P=O.Ool

P=O.Ool

tSignikance

z 0

alpha-2

Mean betat

Mean

12.4 46.8

53.2

Subtype B4 A)ftypeA

AlltypeB

2.32

28.5

7.9 71.5

6.4 65.1 20.6

6.0 55.7

3.9

16.9

17.5

42.8 9.5 47.6

5.4 10.0 3.2

9.8

4.6 4.9

-I

P=O.ool

d.f.=l

d.f.=3 P=O.W

P=O.Ool N.S.t: N.S. N.S. P=o.o5

P=O.Ol

P=O.O2

Rate of CID/1000 men at risk t Underlined significance levels (P-values) are based on t-test of means and others on chi-square. t: N.S.=Not Significant at P=O.O5

7.3 39.5 40.8

Subtype Al Subtype A2 Subtype B3

52.3

6.3

T-l

16.8

Mean alpha-l

29.4

Mean NF+

gamma

Mean lipalbumin

Behavior pattern

*

1.98

57.9 12.4 29.7

fraction.9 (in mean percentage of total)

Serum lipoprotein

Under2.01 (YJ 2.01-2.36 (%) 2.36and over (“/.)

Mean B/A ratio

lipoprotein

Serum betaldplra 2.06

2.53

30.0

15.7 54.3 24.3

Mean values are also underlined

43.6

9.1 56.3

11.6 44.7 34.5

53.6

59.8

11.8

10.8 20.5.

19.6 12.1

d.f.=l P=O.O5

d.f.=3 N.S.

P=O.OOl

P=O.Ol P=O.O5

3.4 5.4

6.1

4.0

P=O.ool

P=O.Ol

P=O.OOl

P=O.Ol

24.0

10.8 23.5 24.3 >

13.8

17.6

34.3 15.7 50.0

16.0

20.2

56.0 11.0 33.0

182

RAY

H. ROSENMAN, et al

for this analysis in order to provide a larger numerical base for statistical evaluation. While this might lead to some risk of confounding age with other risk factors, the alternative of splitting the sample by age in addition to clinical subtype leads to such small subgroups that statistical tests cannot easily be applied. For each risk factor, the total group of 133 CHD subjects and then each of the three clinical subgroups composing this total, was compared sequentially with the large group of men who remained healthy. Thus, four 2 by 2 chi-square tests were run to determine whether in the CHD group as a whole, or in any of the three clinical sub-categories of CHD, the proportion of men having an elevated risk factor was different from the proportion of men who had that risk factor elevated in the non-CHD group. As can be seen in Table 3, each of the seven predictive factors here tabulated was significantly associated with a higher overall rate of CHD, and specifically with a higher rate of symptomatic myocardial infarction. A parental history of CHD was TABLE3. INCIDENCE OFCHD BY TYPEOFINITIAL CLINICAL MANIFESTATION (ALLAGES39-59 YR COMBINED) Incidence of various types of CHD All cases of CHD

Myocardial infarction

Augina Symptomatic Unrecognized pectoris

No. of subjects at risk

No.

Rate

No.

Rate

No.

No. of subjects

3182

133

9.3

73

5.1

31

Parental history of CHD No Yes

2664 518

76 57

6.3 24.5t

42 31

3.5 13.3t

18 13

Cigarette smoking at intake No Yes

1674 1508

49 84

6.5 12.4t

23 50

3.1 7.4t

Diastolic blood pressure, mm Hg 94 and under 95 and over

2882 300

102 7.9 31 23.07

54 19

Serum cholesterol, mg/lOOml 259 and under 260 and over

2534 648

82 51

7.2 17.5t

Serum triglycerides, mg/lOOml 176 and under 177 and over

2313 714

74 48

Beta/alpha lipoprotein ratio 2.35 and under 2.36 and over

2188 994

Behavior Pattern Type B TypeA

1598 1584

Rate 2.2

No. Rate 29

2.0

1.5 5.6t

16 13

1.3 5.6t

13 18

1.7 2.7

13 16

1.7 2.4

1::x

25 6

1.9 4.4

23 6

1.8 4.4

42 31

3.7 10.6.t

23 8

2.0 2.7

17 12

1.5 4.1$

7.1 14.9t

34 29

3.3 8.5t

21 10

2.0 3.0

19 9

1.8 2.8

67 66

6.8 14.8.t

36 37

3.7 8.3t

16 15

1.6 3.4

15 14

1.5 3.1

39 94

5.4 13.2t

21 52

2.9 7.3t

13 18

1.8 2.5

5 24

0.7 3.4t

* Annual incidence of CHD/lOOOmen at risk. t P=O.OOl Probabilities associated with chi-square (d.f.= 1). 1 P=O.O5

Coronary Heart Disease in the Western Collaborative

Group Study

183

the only one of these risk factors significantly associated with the emergence of “silent” myocardial infarction. The incidence of angina pectoris was significantly associated with parental history of CHD, elevated serum cholesterol and the Type A behavior pattern but not with the other predictive factors. In part the failure of these risk factors to reach statistical significance may be influenced by the relatively small numbers of subjects in each clinical subgroup. Relationship of the incidence of CHD to combinations of predictive factors

For each bivariate analysis shown in Tables 4-7, 12 statistics testing each variable and the fit of the model are given in addition to the average annual CHD incidence rate for each cell. The first three analyses (Tables 4 and 5) involve serum cholesterol. In the younger age group serum cholesterol was found to be a strong independent predictor of CHD, the strength of which prevailed even when the influences of the beta/alpha lipoprotein ratio, the fasting serum triglycerides and the ponderal index TABLET.

CONTIUBCJTIONS TO RISK OF CORONARYHEART

DLWASE BYVARIOUSPAIRS

Ages 5@-59 yr

Ages 39-49 yr Cholesterol* Lo Lo Beta/alpha ratio*

3.7t (1387)

Modiied Effect Cholesterol Beta/alpha Lack of fit

Lo Triglyceride* Hi

12.0 (185)

13.7

minimum x2 summary d.f. x2 1 1 1

13.8 3.4 0.7

Cholesterol Lo

Hi

(l%)

&;

1 1 1

10.5 (507)

24.4 (91)

12.6

Hi

24.0 (185)

24.7 (135)

24.3

14.1

24.6

16.7

Modified minimum ~2 summary d.f. ~a

P

Effect

0.001 0.062 N.S.

Cholesterol Beta/alpha Lack of fit

1 1 1 Cholesterol Lo

4.9

2.7 5.2 2.9

P 0.099 0.021 0.087

Hi

Lo

10.9 (528)

17.3 (141)

12.3

Hi

25.6 (139)

30.6 (80)

27-4

14.0

22.1

16.0

Triglyceride 9.4

13.2

13.9 1.8 0.0

Beta/alpha ratio*

Hi

Lo

6.2

(‘3itj :p7jj

Modified minimum xs summary d.f. us

Cholesterol Triglyceride Lack of fit

4.7

9.8

4.2 Effect

Cholesterol Lo

Hi

Hi

4.5

OF RLVKFACTORS

5.9 P 0.001 0.171 N.S.

Effect

Modified minimum ~2 summary d.f. xa

Cholesterol Triglyceride Lack of fit

1 1 1

1.7 9.5 0.3

P 0.192 0.003 N.S.

* Cholesterol: Lo=259 and less, Hi=260 and over; beta/alpha lipoprotein ratio: Lo=2.35 and less, Hi=2.36 and over; Triglycerides: Lo=176 and less, Hi=177 and over. f Entries are average annual CHD incidence rates per 1000 men of specified age range. Figures in parentheses are number of subjects in subgroups.

RAY

184 TABLE 5.

H. ROSENMAN,et al

CCWTRIBUTIONS TO RJSK OF CORONARY HEART DISEASEBY VARIOUS PAIRS OF RISK FACTORS

Ages 39-49 yr Cholesterol* Lo

Ages 5&59 yr Cholesterol Lo

Hi 7.4

Ponderal Index*

Lo (Heavy)

Ponderal Index 5.5

4.5 Modiied Effect Cholesterol Ponderal Index Lack of fit

13.7

minimum x2 summary d.f. x” 19.3 1.0 0.6

: 1

Hi (Lean)

6.2

P

Effect

0.001 Cholesterol 0.3 18 Ponderal Index N.S. Lack of fit

20.4

13.3 (419)

19.0 (129)

14.6

14.4

24.6

16.9

: 1

4.9 1.9 0.5

P 0.025 0.160 N.S.

4.5

Lo

11.7 (608)

34.0 (85)

14.4

Hi

22.1 (191)

38.1 (35)

24.6

14.2

35.2

16.9

Cholesterol Hi

11.1 (381)

37.0 (42)

13.7

5.5

15.1

6.2

Modified minimum x2 summary d.f. ~a

Diastolic blood pressure Cholesterol Lack of fit

32.1 (97)

Diastolic blood pressure Lo Hi

Cholesterol

Effect

16.2 (274)

Modified minimum xa summary d.f. xa

Diastolic blood pressure* Lo Hi Lo

Hi

1 :

9.9 18.2 0.7

P 0.002 0.001 N.S.

Effect

Modified miniium xa summary d.f. xa

Diastolic blood pressure Cholesterol Lack of fit

1 1 1

12.6 4.4 1.0

P 0.001 0.035 N.S.

* Cholesterol: Lo=259 and less, Hi=260 and over; Ponderal Index: Lo=12.49 and less, Hi= 12.50 and over, Diastolic blood pressure: Lo=94 mm Hg and less, Hi=95 mm Hg and over. t Entries are average annual CHD incidence rates per 1000 men of specified age range. Figures in parentheses are number of subjects in subgroups.

are individually statistically eliminated. When the predictive effect of cholesterol is considered in this age group, neither the beta/alpha ratio, serum triglyceride nor ponderal index as here dichotomized are significantly associated with the rate of CHD. Although the independent effects of the beta/alpha lipoprotein ratio fail to reach statistical significance, comparison of the age-adjusted CHD rates for each of the four combinations of this pair of variables (See Table 4) reveals that for both high and low levels of cholesterol, men with higher beta/alpha ratios develop more CHD than men with low ratios. Similarly an elevated serum triglyceride appears to confer higher risk of CHD at both cholesterol levels, but the effect is pronounced only for men in the higher cholesterol group. The ponderal index was not found to be associated with risk of CHD when its association with cholesterol is statistically controlled.

Coronary Heart Disease in the Western Collaborative Group Study

185

A somewhat different pattern was observed in the older age group. When controlled for lower density lipoproteins as measured by the beta/alpha ratio and triglycerides, cholesterol appeared to lose its predictive association to a noticeable degree. On the other hand, when the cholesterol effect is removed, the serum triglycerides and beta/alpha ratio retain a significant association with the rate of CHD. It should also be noted that the combination of low serum cholesterol with low serum beta/alpha ratio in the older subjects tended to be associated with a lower CHD rate than would be expected if the two lipids operated additively. This trend, however, has an associated probability greater than 5 per cent. It would appear that the maximum CHD risk occurs in the younger subjects when both the serum cholesterol and beta/alpha lipoprotein ratios are elevated, but occurs in older subjects when either fraction is elevated, as herein defined. In the older age group, bivariate analysis of CHD rates by the serum cholesterol and triglycerides indicates that higher serum cholesterol confers added risk in association with either low or high serum triglyceride, but triglyceride appears clearly to be the stronger predictor of the two fractions. In the older age group ponderal index, when controlled for serum cholesterol, again was unrelated to CHD rates. When the joint relationship (not shown) of beta/alpha lipoprotein ratio and triglyceride to CHD rates was studied, the beta/alpha ratio was the only significant predictor in the younger age group, but in the older group both of these lipid entities were significant predictors, with triglyceride being the stronger. Two bivariate analyses involve the diastolic blood pressure (DBP). In the first analysis (Table 5) it was found that cholesterol and DBP are both strongly related to CHD rate. In addition to the independent influence of cholesterol and DBP on CHD risk it can be noted from Table 5 that an unusually high rate exists for those men in the younger age group with cholesterol and DBP both elevated. Since this cell is based on a small sample size, the weighted log analysis found no support for an interactive effect. In the older decade, strong independent effects of both variables on CHD risk again were observed. Ponderal index, previously found to be insignificantly related to CHD when lipid levels are controlled, was similarly insignificant in both age groups when DBP is controlled (Table 6). In the older age decade the “lack of fit” of the linear model is such as to raise the question (P=O. 09) of an interaction effect. For the population as a whole, lower ponderal indices (heavier weight, stockier build) are associated with higher CHD rates (see Table 1). The present bivariate analyses for both age groups show that this holds true only for normotensive subjects. Among men with DBP of 95 mm Hg or over, the direction of this relationship was reversed; thinner hypertensives developed more CHD than heavier ones. This reversal fails to reach statistical significance (‘lack of fit’ term), but in view of the sizable and consistent trend in both age groups it deserves further study. DBP shows a highly significant independent relationship with CHD in both age groups. Ponderal index alone then does not appear to be a useful predictor of CHD in either decade. Relationship of the incidence of CHD to the behavior pattern

In Table 1 it was found that the behavior pattern bore a significant association with the incidence of CHD. The behavior type has been much less widely studied in

186

RAY

H. ROSENMAN,et al

epidemiological surveys than have most risk factors discussed in this paper. For that reason it was thought important to submit it to a particularly rigorous examination to see if its predictive power could be “explained away” by some combination of other more commonly used indices. The association of the coronary-prone Type A behavior type to CHD was first examined by means of bivariate analyses to provide information as to whether the behavior pattern type makes an independent or interactive contribution to CHD risk or is merely a reflection of one or two of the traditional risk factors. Tables 6 and 7 show three of these analyses.

TABLE6.

CQNTRIBUTTONS

TO RISK OF CORONARY

Ages 50-59 yr

Diastolic blood pressure* Lo Hi

Diastolic blood pressure Lo Hi

Ponderal Index*

Eew)

124 (733)

Hi (Lean) (1Z)

18.8 (71)

5.5

14.9

6.2

5.5

Modified minimum x2 summary d.f. ~a

Diastolic blood pressure Ponderal Index Lack of fit

10.5 0.5 1.5

Behavior Type A Absent Parental CHD history

Effect

DISEASEBY VARIOUSPAIRS OF RISK FACTORS

Ages 39-49 yr

6.71

Effect

HEART

Present

8.3 (887)

Effect

0.002 N.S. 0.226

Y&u)

9.3

3.4

11.3 10.9 3.0

29.2 76

20.2

&;

45.5 (44)

14.6

14.1

35.2

16.8

Modified minimum x2 summary d.f. x”

Diastolic blood pressure Ponderal Index Lack of fit

5.0

10.3 (172)

;l;)

1 1 1

Behavior Type A

(12;

14.4 (185)

1 1 1

P

Ponderal Index

B

Modified minimum x2 summary d.f. x2

Behavior type Parental CHD Lack of fit

&vy) (E)

12.5

Parental CHD history

6.2 P 0.001 0.001 0.078

Effect

13.6 0.5 2.9

0.001 N.S. 0.086

B

Absent

17.5 (432)

11.4 (331)

14.9

Present

34.0 (98)

14.1 (63)

26.2

20.5

11.8

16.8

Modified minimum xz summary d.f. ~2

Behavior type Parental CHD Lack of fit

P

1 1 1

4.3 4.9 0.5

P 0.036 0.025 N.S.

* Diastolic blood pressure: Lo=94 mm Hg and less, Hi=95 mm Hg and over; Ponderal Index: Lo = 12.49 and less, Hi = 12.50 and over. t Entries are average annual CHD incidence rates per 1000 men of specified age range. Figures in parentheses are number of subjects in subgroups.

Coronary Heart Disease in the Western Collaborative

187

Group Study

The coronary-prone Type A behavior pattern and parental history of CHD are each strongly and independently related to risk of CHD in both age decades. When the Type A pattern is stratified by diastolic blood pressure (DBP), strong independent relationships to CHD again are found for both variables in both decades. In Table 7 it also can be seen that behavior type and serum cholesterol also are strongly and independently related to the risk of CHD. Thus, neither association can be “explained away” by the presence of the other. These relationships are much stronger in the younger decade than in the older, but both are significant risk factors in both decades. In other analyses (not shown), behavior type was found to have a significant main effect when stratified by triglycerides and by beta/alpha lipoprotein ratio. However, each of these lipids also remained strong independent predictors when behavior type was held constant. TABLE7.

~NTRIBUTIONS

TO RISK

OF CORONARY

HEART

DISEASE

Lo

Hi

3.4

12.4

0.001

1 1

9.6 0.4

0.003 N.S.

18.5 (228) 9.4

Effect

(:;

Behavior type Cholesterol Lack of fit

10.2 (349)

14.1

Hi

41.5 (75)

24.7 (45)

35.2

20.5

11.8

16.8

1 1 1

Behavior type Diastolic blood pressure Lack of fit

11.9 17.4 0.1

P

1

4.3

0.037

:

12.6 0.0

0.001 N.S.

Behavior type A

B

4.5

Lo

18.6 (394)

$9;

14.4

13.7

Hi

26.5 (134)

21.7 (92)

24.6

20.6

11.9

16.9

3.4

Modified minimum x2 summary d.f. ~2

B

Modified minimum x3 summary d.f. ~2

B

Lo

Hi

Effect

1

Behavior type A

FACTORS

17.1 (455)

6.2

Modified minjmum x2 summary d.f. x2 P

Behavior Type Diastolic blood pressure Lack of fit

OF RISK

Lo Diastolic blood pressure

9.3

PAIRS

Behavior type A

B

Diastolic blood pressure*

Effect

VARIOUS

Ages SO-59 yr

Ages 39-49 yr Behavior type A

BY

6.2 P 0.001 0.001 N.S.

Effect

Modified minimum x2 summary d.f. ~2

Behavior type Cholesterol Lack of fit

1 1 1

4.2 4.8 1.1

P 0.039 0.027 0.296

* Entries are average annual CHD incidence rates per 1000 men of specified age range. Figures in parentheses are number of subjects in subgroups. t Diastolic blood pressure: Lo=94 mm Hg and less, Hi=95 mm Hg and over; Cholesterol: Lo= 259 and less, Hi=260 and over.

188

RAY

H. ROSBNMAN, et al

Although the behavior pattern type remained a strong independent predictor of CHD in this array of bivariate analyses, it is possible that it would not remain so if a broad series of effective risk predictors are simultaneously controlled. This hypothesis was tested by use of the multiple regression procedure described earlier. The results of this analysis are shown in Table 8. The combined influence of the 12 variables on TABLET. CHD

INCIDENCE

IN

BEHAVIOR TYPES A AND Bwrr~ CONTROLLED BY REGRESSION

TWELVE

OTHER

RISK FACTORS

Men aged 39-49 Regression analysis source Within ceils Regression on 12 variables* Behavior type

d.f.

Mean square

2226 12 1

0.027 0.123 0.265

F

P

4.60 9.93

0.001 0.002

Adjusted CHD rates : Behavior type A : 8.9/1OOO/yr Behavior type B: 4.O/lOOO/yr Men aged 50-59 Regression analysis d.f. Mean square

source Within cells Regression on 12 variables* Behavior type

902 12 1

0.066 0.251 0.134

F

3.79 2.02

P

0.081 0.155

Adjusted CHD rates: Behavior type A: 18.7/1OOO/yr Behavior type B : 13.2/1OOO/yr *The 12 variables are as follows: Age, serum cholesterol, beta/alpha lipoprotein ratio, lipalbumin, systolic blood pressure, diastolic blood pressure, number of cigarettes currently smoked per day, Ponderal Index, rating of physical activity on the job, rating of amount of voluntary exercise, amount of schooling, level of income.

CHD rate is highly significant in both age decades of subjects (P=O.OOl). With the intIuence of these variables removed, the impact of the coronary-prone behavior pattern remains highly significant in the 3949 yr old age group. The adjusted annual CHD rates for Type A and Type B men are 8.9 per 1000 and 4.0 per 1000, respectively. The Type A men had over twice the CHD risk of Type B men even when serum lipids, blood pressure, smoking, obesity, and the numerous other influences were statistically held constant. In the older group the adjusted annual CHD rates were 18.7 per 1000 for Type A men and 13.2 per 1000 for Type B men. Although the Type A men still appear to be at a clearly higher risk, the difference betweenTypes A and B is no longer statistically significant in the older decade when all of the other 12 variables are simultaneously controlled. The greater strength of the behavior pattern as a CHD risk factor in younger men as compared to older men has been reported before [l, 51. DISCUSSION

has been given during the past decade to certain factors found in prospective studies to be associated with increased incidence of coronary heart disease. These co-called risk factors variously include a family history of Considerable

emphasis

Coronary Heart Diseasein the Western CollaborativeGroup Study

189

coronary heart disease, elevated systolic and diastolic blood pressures, cigarette smoking and higher serum concentrations of cholesterol, beta lipoproteins and triglycerides [16]. The association of such factors with the incidence of CHD has been found to prevail mainly for subjects suffering myocardial infarction and in general has not been found to be significantly related to increased incidence of angina pectoris without infarction. The present tidings again con&m the prognostic importance of each of the above factors. A significantly increased rate of CHD was found to be associated with each of these risk factors, but this relationship was found to be strongest for men suffering symptomatic myocaridal infarction and was much weaker or not observed in subjects incurring “silent” infarction or angina pectoris without infarction. The findings raise the question whether different mechanisms underlie the occurrence of these different initial manifestations of CHD [17]. In addition to the above noted associations, the rate of CHD was found to be significantly related to the level of education, as noted by other investigators [18], and to the serum lipalbumin fraction as previously found by Straus et al. [19] The present results con&m the earlier follow-up study [3] by clearly indicating that the presence of a particular overt behavior pattern carries a profoundly significant prognostic relevance. Earlier studies have shown that men with the completely developed Pattern A exhibit higher serum lipids 12, lo], augmented postprandial hypertriglyceridemia [21], accelerated coagulation [2], and enhanced daytime excretion of catecholamines [22]. If the apparent pathogenetic effect of Pattern A is merely an artifact of the association of the behavior pattern with these or some other risk factor, statistical stratification by values of that factor should reduce the association of the behavior with CHD to insignificant levels. Accordingly each of the social and biological variables found to be associated with the incidence of CHD was controlled for, singly and together. In each such comparison Type A men suffered higher CHD rates than did men with the converse Type B behavior pattern. Thus the findings indicate that the association of the Type A behavior pattern with increased CHD risk is not an artifact of any association of Pattern A with some of the risk factors here considered, alone or in combination. These analyses thus indicate that Pattern A exerts a strong pathogenetic force and suggest that this force operates in significant part outside the mechanism of any of the variables herein considered. In any event, the present findings would appear to confirm the pathogenetic relevance of the central nervous system (including its neurohumoral capacities), to the occurrence of manifest CHD. This force may operate in part through the artherosclerotic process, as suggested both by the earlier pathological findings [4] and from the association of the behavior pattern both with acute infarction and uncomplicated angina pectoris (Table 3). The present findings take on added significance in view, of the recent conf%mation of the behavior pattern-CHD relationship in the large-scale epidemiologic survey by Quinland and colleagues [8, 91 and supporting work by Caffrey [23]. SUMMARY

A prospective study of coronary heart disease (CHD) was initiated in 1960-1961 in 39-59 year old men. Some of the relevant tidings observed during a mean four and one-half year period of follow-up of 3182 subjects are presented. A significantly increased incidence of CHD was found to be associated with parental history of CHD,

190

RAY H. ROSENMAN, et al

elevated systolic or diastolic blood pressure, cigarette smoking, higher serum levels of cholesterol, triglyceride and beta lipoproteins, and the Type A behavior pattern. The association of the Type A behavior pattern with a significantly increased rate of CHD was not found to be ascribable to an association of the behavior pattern with other risk factors. Acknowledgement-This study was supported by National Institutes of Health, Research Grants HE-03429 and HE-10326 and grants from the American Heart Association and the Irwin Strasburger Memorial Medical Foundation of New York.

9.

10. 11. 12. 13. 14.

15. 16. 17. 18. 19. 20. 21. 22.

23.

REFERENCES Rosenman RH, Friedman M, Straus R, et al: A predictive study of coronary heart disease. JAMA 189: 15-22, 1964 Friedman M, Rosenman RH: Association of specific overt behavior pattern with blood and cardiovascular tindings. JAMA 169: 12861296, 1969 Rosenman RH, Friedman M, Straus R, et al: Coronary heart disease in the Western Collaborative Group Study: A follow-up experience of two years. JAMA 195: 86-92,1966 Friedman M, Rosenman RH, Straus R, et al: The relationship of behavior pattern A to the state of the coronary vasculature: A study of 51 autopsy subjects. Amer J Med 44: 525-537, 1968 Rosenman RH, Friedman M, Jenkins CD, et al: The prediction of immunity to coronary heart disease. JAMA 198: 1159-1162, 1966 Keith RA, Lown B, Stare FJ: Coronary heart disease and behavior patterns: An examination of method. Psychesom Med 27: 424-454, 1965 Cassel JC: Letter to the Editor. Psyehesem Med 28: 283-284, 1966 Quinlan CB, Barrow JG, Moinuddin M, et al: Prevalence of selected coronary heart disease risk factors in Trappist and Benedictine monks. Paper presented at the Conference on Cardiovascular Disease Epidemiology. Atlanta, Georgia, Amer Heart Ass, Feb 1968 Quinlan CB, Barrow JG, Hayes CG, et al: The association of risk factors and coronary heart disease in Trappist and Benedictine monks. Paper presented at the Conference on Cardiovascular Disease Epidemiology. New Orleans, Amer Heart Ass, Mar 1969 Wald A: Tests of statistical hypotheses concerning several parameters when the number of observations is large. Trans Amer Math Sot 54: 426-482, 1943 Neyman J: Contributions to the theory of the ~2 test. Proc Berkeley Symp Math Stat Probability. Berkeley and Los Angeles, University of California Press, 1949, pp 239-273 Bhapkar VP: A note on the equivalence of two test criteria for hypotheses in categorical data. J Amer Stat Ass 61: 228-235, 1966 Grizzle JE, Starmer FG, Koch GC: Analysis of categorical data by linear models. Biometrics 25: 489-504, 1969 Jenkins CD, Rosenman RH, Zyxanski SJ: Cigarette smoking: Its relationship to coronary heart disease and related risk factors in the Western Collaborative Group Study. Circulation 38:114&1155,1968 Jenkins CD, Rosenman RH, Friedman M: Replicability of rating the coronary-prone behavior pattern. Brit J Prev Sot Med 22: 16-22, 1968 Epstein FH: The epidemiology of coronary heart disease: A review. J Chron Dis 18: 753-774, 1965 Rosenman RH, Friedman M, Jenkins CD, et al: Clinically unrecognized myocardial infarction in the Western Collaborative Group Study. Amer J Cardioll9: 776783,1967 Hinkle LE, Christenson WN, Ulhnarm DS: Coronary heart disease, 3O-yr experience of 1160 men. Archs Environ Health 13: 312-321, 1966 Straus R, Wurm M, Kositchek RJ: Lipoproteins in serum. Lipids and the Steroid Hormones in Cllnieal Medicine. Philadelphia, H. B. Lippincott Co, 1960 Rosemrtan RH, Friedman M: Behavior patterns, blood lipids and coronary heart disease. JAMA 184: 934-938, 1963 Friedman M, Rosenman RH, Byers SO: Serum lipids and conjunctival circulation after fat ingestion in men exhibiting Type-A behavior pattern. Circulation 29: 874-885, 1964 Friedman M, St. George S, Byers SO, et al: Excretion of catecholamines, lFketosteroids, 17hydroxycorticoids and 5-hydroxyindole in men exhibiting a particular behavior pattern (A) associated with high incidence of clinical coronary artery disease. J Clm Invest 39: 758-764, 1960 Caffrey B: Reliability and validity of personality and behavioral measures in a study of coronary heart disease. J Cbron Dis 21: 191-204, 1968