Clinical communications Primary risk factors in patients with myocardial infarction Dag Elmfeldt, M.D. Lars Wilhelmsen, M.D. Hans Wedel, Ph.D. Anders Vedin, M.D. Claes Wilhelmsson, M.D. G6sta Tibblin, M.D. GSteborg, Sweden

Most prospective epidemiological studies have shown significant relationships between myocardial infarction and the level of serum cholesterol, blood pressure, and smoking, and that these factors increase the risk independently?, ~ Increasing age, male sex, diabetes, and some other factors have also been associated with increased risk of suffering myocardial infarction. It has also been shown that approximately 50 per cent of cases of coronary heart disease have relatively low predicted risk based on serum cholesterol, systolic blood pressure, and smoking? This and other findings have led to the assumption t h a t there are other, hitherto undefined, factors associated with coronary heart disease. Prospective studies are generally most suitable for detection of risk factors. This type of study is, however, very time-consuming and expensive and is therefore not suitable for research aimed at developing new hypotheses. A group of individuals who have already suffered the disease may be chosen instead but the disease may alter certain factors, for example, the blood pressure after myocardial infarction, and the patients may be selected, for example, due to death. The advantage of studying patients who already suffer from the disease is that a sufficiently large series of patients can be relatively rapidly collected for study even of variables which occur with low From the Section of Preventive Cardiology, Department of Medicine I, Sahlgren's Hospital, 8-413 45 G6teborg, Sweden. Received for publication Nov. 13. 1974. Reprint requests: Lars Wilhelmsen, M.D.. Department of Medicine I, Sahlgren's Hospital. S-413 45 G6teborg, Sweden.

412

frequency and probably have varying significance in different age groups. The aim of the present investigation was to study the distribution of retrospectively allocated risk among men who had survived a myocardial infarction and to compare these patients with random population samples. It was also planned to analyze in detail patients who had a relatively low predicted probability of myocardial infarction in order to identify any variables not included in the risk function t h a t might "explain" why these patients had suffered myocardial infarction. Thus, the following variables were studied: Registration by a Temperance Board, low physical activity at work and during leisure time, psychological stress, diabetes, gallstone, kidney stone, dyspnea on exertion, and triglycerides.

Study population and methods Since Jan. 1, 1968, all cases of acute myocardial infarction occurring in the population of G6teborg in certain age groups have been registered by a special organization. 4 The registration comprised 90 per cent of all surviving, diagnosed cases of myocardial infarction in GSteborg in the age groups concerned. Patients discharged from hospital alive have been systematically followed up at a special clinic-The Post-Myocardial Infarction Clinic.5, ~ During the years 1968-69 all patients aged 55 years or below were included and in 1970 all patients aged 67 years or below were included with the exception of a randomly selected 30 per cent sample in the age group 57-67

April, 1976, Vol. 91, No. 4, pp. 412-419

The ECG of constrictive pericarditis--Pattern resembling right ventricular hypertrophy Elliot Chesler, M.D., F.R.C.P., F.A.C.C. Abdul S. Mitha, M.R.C.P.(Lond.). R o d n e y E. Matisonn, M.B,, Ch.B., F.C.P.(S.A.). Durban, South Africa

Even in the subacute phase of constrictive pericarditis, where the h e a r t is large and m a y simulate cardiomyopathy, the correct diagnosis can almost invariably be m a d e b y careful clinical evaluation at the bedside. In regions where constrictive pericarditis and c a r d i o m y o p a t h y are prevalent, this diagnostic problem f r e q u e n t l y arises and a great deal of reliance is placed upon the electrocardiogram (ECG). In constrictive pericarditis the E C G shows classic abnormalities in at least 90 per cent of cases, b u t m a y be n o r m a l in the remainder. Characteristically, the QRS vector is n o r m a l l y directed with low voltage and t h e r e is widespread flattening or inversion of t h e T wave.' A u t h o r i t a tive textbooks 2. 3 have stated, however, t h a t the occasional tracing m a y show right axis deviation and right ventricular h y p e r t r o p h y - a p a t t e r n which has also been noted in association with a n n u l a r pericardial constriction. 4 In our experience we have also e n c o u n t e r e d cases of constrictive pericarditis where the ECG has shown unexpected evidence of right ventricular hypertrophy. T h e f r e q u e n c y of this confusing finding has not been d o c u m e n t e d or explained and this is the subject of this paper. Patients and Methods

T h e material consists of 122 patients with constrictive pericarditis, in whom an operation From the Cardiac Unit. Wentworth Hospital and the University of Natal, Durban. South Africa. Supported by a grant from the Medical Research Council of South Africa. Received for publication Feb. 5, 1975. Reprint requests: Professor E. Chesler, Cardiac Unit. Wentworth Hospital. P. B. Jacobs, Natal, 4026, Durban, South Africa.

420

was u n d e r t a k e n in all b u t one. Eighty-eight were male, 34 were female, and their average age was 33 years; 113 (93 per cent} were African, five Caucasian, three M u l a t t o , and one Asiatic. T h e etiology was tuberculous in all except six, in whom the cause was pyogenic in four and a result of amebiasis in the remaining two. Because of the virulence of tuberculosis in the African population the m a j o r i t y of our patients present with constriction in the s u b a c u t e stage of the disease. ~ Typically there is cardiomegaly and persistent pleural effusion, whereas pericardial calcification and atrial fibrillation are present in only 11 and 7 per cent of cases, respectively. At operation, the two layers of the pericardium are usually separated by fluid or caseous material and constriction is caused by thickened, fibrotic, visceral pericardium. This is in c o n t r a s t to the experience in Caucasians, of whom 75 per cent present in the chronic s t a t e with a n e a r - n o r m a l heart size, pericardial calcification in 70 per cent and atrial fibrillation in 35 per cent. 1 Twelve-lead ECG's were available in all cases and in most instances serial tracings were obtained. In all cases particular a t t e n t i o n was paid to the QRS voltage and the m e a n axis was plotted to within the nearest 10 degrees of the hexaxial reference system. Right ventricular h y p e r t r o p h y was diagnosed when there was reversal of the ratio of R / S in V1 to V3 ( R / S = > 1 ) and right axis deviation when the m e a n QRS was deviated to the right of + 100 ~ Left atrial enlargement was diagnosed when there was terminal negativity of the P wave of 1 mm. or more in depth with d u r a t i o n of 0.04 second or more in Lead V1. In 69 of the 122 cases cardiac c a t h e t e r i z a t i o n

April, 1976, Vol. 91, No. 4, pp. 420:424

The ECG of constrictive pericarditis

II:[~NI',i: ~ )

Fig. 1. ECG in a case of constrictive pericarditis with subpulmonic annular constriction showing marked right axis deviation and severe right ventricular hypertrophy. Right ventricular pressure 160 mm. Hg.

and angiographic findings were a v a i l a b l e a n d these confirmed the presence of pericardial constriction. For this group t h e a v e r a g e m e a n pressures were: right a t r i u m , 18 m m . Hg; p u l m o n a r y artery, 29 ram. Hg; p u l m o n a r y capillary wedge pressure, 20 m m . Hg. In no case did the difference b e t w e e n left a n d right atrial pressures exceed 6 m m . Hg. T h e m e a n cardiac index in these 69 cases was 2.8 L . / m i n . / M 2. A n g i o g r a p h y showed n o r m a l v e n t r i c u l a r c o n t r a c t i l i t y w i t h a characteristic a b r u p t h a l t in diastolic filling.

Results Following scrutiny of the E C G ' s t h e m a t e r i a l was divided into two groups.

Group A: 116 tracings compatible with constrictive pericarditis (95 per cent), T h e m e a n Q R S axis was normal; in one case t h e axis was - 3 0 ~ and in 115 it was between 0 ~ a n d 90 ~ Generalized T wave flattening or inversion was present in every instance. T h e voltage was decreased in 103 (89 per cent) a n d n o r m a l in 13. Sinus r h y t h m was p r e s e n t in 108 (93 per cent) and atrial fibrillation in eight. Left atrial e n l a r g e m e n t was present in 36 cases (31 per cent). Cardiac c a t h e t e r i z a t i o n d a t a were available in 63 of the 116 cases a n d in none was t h e r e evidence of mitral, pulmonic, or aortic stenosis suggestive of a n n u l a r constriction.

American Heart Journal

Group B: Six tracings showing right axis deviation or right ventricular hypertrophy or both (5 per cent). Six cases (5 per cent) showed evidence of right v e n t r i c u l a r h y p e r t r o p h y with a d o m i n a n t R wave in V1 a n d reversal of the R / S ratio; t h r e e tracings showed right axis deviation in addition. T wave flattening or inversion over precordial leads V4_~ was present in all six tracings. Sinus r h y t h m was present in five a n d atrial flutter in one. F o u r cases h a d evidence of left atrial e n l a r g e m e n t . Cardiac c a t h e t e r i z a t i o n d a t a were a v a i l a b l e in all six cases. In one p a t i e n t who presented in right ventricular failure the right v e n t r i c u l a r pressure was 160 m m . H g with pulsus a l t e r n a n s as a result of fibrous, noncalcific, s u b p u l m o n i c a n n u l a r constriction; the E C G showed an axis of +210 ~ and was c o m p a t i b l e with severe right v e n t r i c u l a r h y p e r t r o p h y (Fig. 1). T h i s p a t i e n t died following pericardiectomy and relief of the outflow t r a c t obstruction. A n o t h e r p a t i e n t whose E C G also showed right axis deviation a n d right ventricu lar h y p e r t r o p h y refused operative m a n a g e m e n t ; the h e m o d y n a m i c d a t a in this case were c o m p a r a b l e to those in the 63 catheterized cases in G r o u p A and there was no evidence to suggest a n n u l a r constriction (Fig. 2). Of the r e m a i n i n g four p a t i e n t s who h a d evidence of right v e n t r i c u l a r h y p e r t r o p h y ; one showed additional right axis deviation. T h e i r

421

Chesler, Mitha, and Matisonn

N

'!

~

t

ill

Fig. 2. ECG in a case of constrictive pericarditis showing sinus rhythm, right axis deviation ( + 120~), marked right ventricular hypertrophy with generalized T wave flattening and inversion. Right ventricular pressure 50 mm. Hg.

Fig. 3. ECG's in a case of constrictive pericarditis. The preoperative tracing (A) shows right axis deviation ( + 110~ and a dominant R in Lead V1. Right ventricular pressure 45 mm.Hg. A normal R/S ratio in V1 is present after operation (B}. h e m o d y n a m i c s w e r e also t y p i c a l o f c o n s t r i c t i v e pericarditis w i t h o u t a n n u l a r c o n s t r i c t i o n . F o l l o w ing pericardiectomy the QRS axis returned to normal and the evidence of right ventricular h y p e r t r o p h y regressed (Figs. 3 and 4).

422

Comment Of t h e 122 E C G ' s in t h i s s t u d y 95 per c e n t w e r e c o m p a t i b l e w i t h c o n s t r i c t i v e pericarditis, c h a r a c teristically showing a normally directed QRS axis and w i d e s p r e a d T w a v e i n v e r s i o n or f l a t t e n i n g ,

April, 1976, Vol. 91, No. 4

The ECG of constrictive pericarditis

Fig. 4. ECG's in a case of constrictive pericarditis. The preoperative tracing (A) shows sinus rhythm and a normal frontal plane axis with pattern compatible with right ventricular hypertrophy. Right ventricular pressure 49 mm. Hg. The R / S ratio in V1 and V~ reverts to normal after operation (B).

with low voltage in the majority. These findings are very helpful in the distinction from congestive cardiomyopathy, which may mimic constrictive pericarditis in the subacute stage. In congestive cardiomyopathy the ECG shows a fairly uniform pattern of left ventricular hypertrophy; conduction defects involving the left bundle occur in 25 per cent of cases and left bundle branch block and left anterior hemiblock occur with equal frequency.~ The normal QRS axis in constrictive pericarditis is also a useful diagnostic point in those cases of constrictive pericarditis which resemble rheumatic mitral stenosis. Both conditions may present with mid-diastolic murmurs, left atrial enlargement, or atrial fibrillation; however, in patients with mitral stenosis and "P mitrale" the mean QRS axis is frequently deviated to the right/ The presence of right axis deviation and right ventricular hypertrophy in constrictive pericarditis has been noted by Schrire '~ and by Fowler, ~ but the frequency and mechanism were not

American Heart Journal

stated. In our study we observed these findings in six cases (5 per cent) and in only one, with subpulmonic stenosis and a right ventricular pressure of 160 mm. Hg, could we find a ready explanation. Pericarditis is an unusual cause of obstruction to the right ventricular outflow tract and was first described by Mounsey. 4 In the five cases we have found reported in the literature, comment on the ECG was available in four, and all showed right axis deviation and right ventricu l a r hypertrophy. It is of interest that whereas four of these cases had previous inadequate pericardiectomies the fifth, like our case, had no previous operation2, 8-11 It is unlikely, however, that all the examples of. right axis deviation and right ventricular hypertrophy noticed by other observers can be explained on the basis of subpulmonic stenosis alone. Thus, in five of our six cases there was no evidence of annular constriction hemodynamically or angiographically, nor was this identified surgically.

423

Chesler, Mitha, and Matisonn

T h e usual causes of a d o m i n a n t R wave in Lead V1 are p u l m o n a r y hypertension, W o l f f - P a r k i n s o n White syndrome, and true posterior infarction, none of which can reasonably be invoked as an explanation in these cases. 12 Similarly, right axis deviation resulting from posterior hemiblock is unlikely, since the s u b e n d o c a r d i u m of the left ventricle is not involved by pericarditis. T h e fact t h a t myocardial h y p e r t r o p h y has never been d e m o n s t r a t e d pathologically in constrictive pericarditis and t h a t the p a t t e r n of right v e n t r i c u l a r h y p e r t r o p h y regresses after p e r i c a r d i e c t o m y m u s t imply a n o t h e r mechanism. M o u n s e y 4 noted t h a t the areas of the exterior of the surface of the h e a r t overlying the four valve rings are those at which the greatest m o v e m e n t takes place during the cardiac cycle. In the normal heart, m o v e m e n t of visceral u p o n the parietal layers of the pericardium m i g h t be expected to be greatest in these areas. In the presence of pericarditis, friction will be greatest here also, giving rise to a more intense inflammatory reaction and more fibrosis. This observation is in keeping with our experience, where the pericardium tends to be irregularly thickened b u t with a predilection for m a r k e d fibrosis at the base of the heart. A tentative explanation for the u n e x p e c t e d E C G findings m a y t h u s be t h a t in these cases heavy basal fibrosis (short of a n n u l a r constriction) leads to cardiac distortion and r o t a t i o n with an alteration of direction of the electrical forces producing a p a t t e r n simulating right v e n t r i c u l a r hypertrophy.

Summary The E C G changes in 122 cases of constrictive pericarditis have been reviewed. Ninety-five per cent of tracings were typical and showed a n o r m a l Q R S axis, low voltage, and generalized T wave

424

flattening or inversion. T h e remaining six tracings showed evidence of right v e n t r i c u l a r h y p e r t r o p h y and half of these showed right axis deviation in addition. In only one could these findings be readily accounted for by the presence of severe fibrotic a n n u l a r s u b p u l m o n i c constriction; the remainder are unexplained and it is p o s t u l a t e d t h a t cardiac rotation and distortion is causative since none of the other m e c h a n i s m s of right axis deviation or right ventricular h y p e r t r o p h y were operative.

REFERENCES 1. Wood, P.: Chronic constrictive pericarditis, Am. J. Cardiol. 7:48, 1961. 2. Fowler, N. D.: Disease of the pericardium, in Hurst, J. W., and Logue, F. B., editors: The heart arteries and veins, New York, 1970, McGraw-Hill Book Company, Inc., chap. 76. 3. Schrire, V.: Clinical cardiology, London, 1967, Staples Press, p. 457. 4. Mounsey, P.: Annular constrictive pericarditis, Br. Heart J. 21:325, 1959. 5. Schrire, V.: Pericarditis: Experience with pericarditis at Groote Schuur Hospital, Cape Town. An analysis of 160 cases over a six year period, S. Afr. Med. J. 33:810, 1959. 6. Chesler, E., and Beck, W.: Incidence of conduction defects in African and coloured patients with congestive cardiomyopathy, Br. Heart J. 35:779, 1973. 7. Surawicz, B., and Lasseter, K. C.: Electrocardiogram in pericarditis, Am. J. Cardiol. 26:471, 1970. 8. Portal, R. W., Besterman, E. M. M., Chambers, R. J., Sellors, T. H., and Somerville, W.: Prognosis after operation for constrictive pericarditis, Br. Med. J. 1:563, 1966. 9. Barros, J. L., and Perez-Gomez, F.: Pulmonary stenosis due to external compression by a pericardial band, Br. Heart J. 29:947, 1967. 10. McGaff,C. J., Haller, J. A., Leight, L., and Towery, B. T.: Subvalvular pulmonary stenosis due to a constriction of the right ventricular outflow by a pericardial band, Am. J. Med. 34:142, 1963. I i . Weglicki, W. B., Lee, J. F., Brown, I. W., and Whalen, R. E.: Infundibular pulmonic stenosis due to a pericardial band, Am. J. Cardiol. 16:262, 1965. 12. Grant, R.: Clinical electrocardiography, New York, 1970, McGraw-Hill Book Company, Inc., p. 79.

April, 1976, Vol. 91, No. 4

Primary risk factors in myocardial infarction

years, which was omitted in order to form a control group. A total of 299 men with primary infarction were cared for during the years 1968 to 1970. It has been shown t ha t serum cholesterol and blood pressure as well as smoking habits change with myocardial infarction, but studies of a population sample examined before as well as after a myocardial infarction gave us the possibility of predicting certain of these changes. Thus, it was possible to retrospectively predict the probability (p) of suffering a myocardial infarction for the infarction patients of the present study. This was done with aid of a multiple-risk function developed from a multivariate, logistic analysis by Wilhelmsen, Wedel, and Tibblin. 2 This function gives the predicted probability for a 50-year-old man to suffer a myocardial infarction during 9 years and 4 months follow-up. T h e predicted probability will hereafter be called " t h e risk." T h e risk function was based on the factors serum cholesterol, systolic blood pressure, and tobacco smoking. For easy practical work, nomograms of the risk function were constructed for various tobacco consumption as follows: "never smoked," "ex-smokers," "smoke 1 to 14 Gm. daily," "smoke 15 to 24 Gm. daily," and "smoke > 25 Gm. daily," with serum cholesterol and systolic blood pressure on the horizontal and vertical axes, respectively {Fig. 1). Smoking habits prior to the infarction according to interview were used. According to earlier experiences, serum cholesterol has usually returned to preinfarction levels about 3 months after the infarction, ~-1~which is why these values were used. Since blood pressure has been shown to fall in connection with a myocardial infarction, ~ and this reduction of blood pressure cannot at present be predicted, two blood pressure groups were created. One group consisted of probable hypertensive patients and the other group of probable nonhypertensive patients. T h e group of probable hypertensive patients consisted of individualS who had been treated for hypertension prior to infarction, or who had manifest hypertension during the first year of follow-up, defined as systolic blood pressure > 160 mm. Hg a n d / o r diastolic blood pressure > 105 mm. Hg for patients up to 55 years of age, and diastolic pressure > 105 mm. Hg for patients above this age. In order to fulfill the criterion for manifest hypertension, two consecutive determinations, per-

American Heart Journal

Systolic blood pressure 200

mmHg

Systolic blood pressure

Never s m o k e d

o o

200~

mmHg

Stopped smoking

(o

,/o

150

150

:

100

:

:

200

:

: :100

300

400

~o'

i

i

@ ,"o

100

200

:

:

300

o~,, ~,s

Iso

.

:

I|

400

S m o k e 15-2/- g/d.__ay

o~,, 150

i

300

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200

i

200

: : 100

400

2 0

I

I 300

I

t , 400

S m o k e ->25 g/day

200

%

0

100

9

0

I 20O

J

; 300

I

0 ,40O

Cholesterol mg/lOOmt

Fig. 1. Nomograms for determination of predicted probability

(p) of a 50-year-old m a n without clinical signs of coronary heart disease suffering myocardial infarction before the age of 60 years. (According to Wilhelmsen, Wedel, and Tibblin: Circulation 48:950, 1973.)

formed within 2 to 4 weeks, were to give the above values. Determination of the blood pressure was performed in accordance with WHO's recommendationsi On the basis of the mean b l o o d pressure value for hypertension obtained in a primary preventive trial concerning cardiovascular disease and comprising 7,455 men examined in an intervention group, 12 the patients considered probably to be hypertensive were allocated a systolic blood pressure of 170 mm. Hg. T h e remaining patients were placed in the probably nonhypertensive group and allotted a systolic blood pressure of 150 mm. Hg, w h i c h was the mean value for persons without known hypertension in the primary preventive trial. Some bias was evidently introduced by this type of allocation to two groups, but by studying Fig. 1 it can be seen t hat the possible bias is acceptable. For 270 of the 299 men who had survived their first infarctions complete details concerning

413

E[mfeIdt e t eL1.

MEN

BORN

IN

1913

60-

40"

20

----~

0

- - 9

i,

0.05 0.10 0.15 0.20 0.25 0.~0 0'.~5 o.io 0.i5 0.50 p-value N

M.I.

-l

528

212

50

22

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3

4

3

2

I

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2

2

0

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2

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6

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INFARCTION < 45 YEARS

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20 84

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0

1

~89

R9, 2. Distribution of predicted probability (p value) of myocardial infarction for a population sample (men born in 1913) and for a representative series of men who survived myocardial infarction. The number of cases of infarction occurring during 9 years and 4 m o n t h s follow-up of the population sample is denoted.

414

April, 1976, Vol. 91, No. 4

P r i m a r y risk factors in m y o c a r d i a l infarction

Table I. Per cent distribution of certain variables by risk and age in men who survived myocardial

infarction compared to random population samples of men Men with infarction (45 yr.) Risk (p)

Population (50 yr.) 855*

Men with infarction (55-67 yr.)

0.10

0.10-0.19

0.20

14

10

6

9Olt r

60

62

29

Population (62 yr.) 95

21 60

30 78

50 25

21" 68t

13 76

21 69

11 76

80

67

100

84t

92

98

43 14 14 0 50

70 0 10 20 30

17 0 0 33 16

14t 2t 5* 7* 23*

45 7 12 20 32

38 2 11 11 39

No.

Registered by Temp. Board Low physical activity at work (1-2 points) Low physical activity during leisure time (1-2 points) Stress (5-6 points) Diabetes Gallstone Kidney stone Dyspnea on exertion

Men with infarction (45-54 yr.) 0.10

0.10-0.19 ] 0.20

0.10

0.10-0.19

0.20

62

21

6

27 61

87

57

67

84

92

92

86

0

25 0 14 14 38

11 2 6 7 33

7 15 24 76

5 14 0 81

0 0 17 100

*Men born in 1913. tMen from the primary preventive trial.

T a b l e II. S e r u m t r i g l y c e r i d e s ( m g . / 1 0 0 m l . ) b y r i s k a n d a g e in m e n w h o s u r v i v e d m y o c a r d i a l i n f a r c t i o n

c o m p a r e d t o m a l e p o p u l a t i o n s a m ~les Men with infarction (45 yr.) Risk (p)

0.10

0.10-0.19

0.20

N

14

10

6

Normal population (50yr.) 853*

Triglycefides Mean S.D.

146 59

143 64

192 48

108 65

Men with infarction (45-54 yr.)

Men with infarction (55-67 yr.) 0.10

0.10-0.19

0,~0

27

Normal population (62 yr.) 91

60

20

6

197 65

140 112

157 63

153 56

318 281

0.10

0.10-0.19

0.20

60

59

138 70

158 88

*Men born in 1913. serum cholesterol, systolic blood pressure, and tobacco smoking were available. Eleven men had d i e d w i t h i n 3 m o n t h s a f t e r t h e i n f a r c t i o n a n d in 18 c a s e s i n f o r m a t i o n o n o n e o f t h e v a r i a b l e s o f t h e risk function was lacking. T h e 270 p a t i e n t s w e r e a l l o c a t e d a r i s k (p) in accordance with the nomograms. The patients were a r b i t r a r i l y a l l o c a t e d t o o n e o f t h e t h r e e g r o u p s a c c o r d i n g t o risk; p < 0.10, p = 0.10 t o 0.19, a n d p _> 0.20. C e r t a i n v a r i a b l e s w e r e c o m p a r e d in t h e p a t i e n t series a n d in r e p r e s e n t a t i v e p o p u l a t i o n s a m p l e s o f m e n a g e d 50 a n d 62 y e a r s , r e s p e c t i v e l y . D a t a f o r 50-year-old men were taken either from the study of " M e n b o r n in 1913 "13, 1, o r f r o m o n e a g e g r o u p of m e n in t h e p r i m a r y p r e v e n t i v e t r i a l . 15 T h e f i r s t s t u d y c o m p r i s e d 855 m e n b o r n in 1913 a n d e x a m -

American Heart Journal

i n e d i n 1963. T h e y i n c l u d e d 88 p e r c e n t o f a l l m e n registered in GSteborg and born on dates which a r e e v e n m u l t i p l e s o f 3, i.e., 3, 6, 9, 12, etc. T h e men from the primary preventive trial were a r a n d o m l y s e l e c t e d t h i r d o f p e r s o n s b o r n in 1921 o f w h o m 80 p e r c e n t o r 901 m e n p a r t i c i p a t e d in t h e e x a m i n a t i o n , 1G O n e o r t h e o t h e r o f t h e g r o u p s o f 50-year-old men was chosen depending on availability of data. The 62-year-old men consisted of m e n r e g i s t e r e d in G S t e b o r g a n d b o r n in 1906 o n the fifteenth or thirtieth day of each month. They p a r t i c i p a t e d in a c r o s s - s e c t i o n a l s t u d y p e r f o r m e d in 1972 a n d c o m p r i s i n g 96 i n d i v i d u a l s . A d e s c r i p tion of the study and an analysis of nonparticipants have been presented previously." Both the patients and the population sample were investigated and interviewed according to

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standardized methods. TM 15., The variables subjected to special study in the present investigation were the following: registration by the Temperance Board, physical activity during work and leisure time, mental stress, diabetes, gallstone, kidney stone, dyspnea, and serum triglycerides. Information was obtained from the Temperance Board in G6teborg as to whether or not the person in question was known to the Board in connection with intemperance. Physical activity was estimated on a four-point scale~ Low physical activity was considered to be present for subjects allocated one or two points. 18 Mental stress was operationally defined according to a six-point scale, a high degree of stress corresponding to the constant experience of stress during the past year (five points) or past 5 years (six points). Diabetes, gallstone, and kidney stone were considered to be present in subjects who had been informed by a physician that they had the condition concerned. Dyspnea was considered to be present when the subject reported breathlessness when walking rapidly on level ground or climbing a small hili (or upon less exertion). For the infarction patients the history concerned the time before their infarction. Triglycerides were analyzed according to a method described by Carlson. 19 Results

Fig. 2 shows the distribution of risk for suffering myocardial infarction according to the multiple risk function for a representative sample of m e n - " M e n born in 1913"-and for the 270 men with primary infarctions divided into three age groups. The figure also shows the number of cases of infarction during 9 years and 4 months of follow-up among men from the population sample. Low risk, defined as p < 0.10, was found in 88 per cent of the population sample. In the infarction patients there was a definite tendency to higher risk than in the population, but p < 0.10 was found in 46 per cent of men below age 45 years, 41 per cent among patients aged 45 to 54 years, and 70 per cent in patients aged 55 to 67 years. Thus, a tendency to lower risk according to these variables was found among infarction patients in the highest age group, as compared to lower age groups. Table I shows the distribution of some variables, which were not included in the risk function. The values for serum triglycerides are shown in Table II. In the three age groups, patients with

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low (p < 0.10), moderate (p = 0.10 to 0.19), and high risk (p > 0.20) are analyzed. For the infarction patients aged 45 to 54 years the biggest population samples are available. In this age group registration by the Temperance Board was less common among surviving patients t h a n in the 50-year-old population sample. There was no tendency toward a continuously increased or decreased proportion of individuals registered by the Temperance Board between the risk groups of patients. Low physical activity at work was somewhat more common among patients but there was no tendency toward differences between the risk groups. Low activity during leisure time was more common among the patients but there was no tendency toward differences between the risk groups. As regards stress, the patient group as a whole was more exposed to stress than the population sample and there was a tendency for those with the lowest risk to contain the highest proportion of patients with a high degree of stress (45 per cent), and those with the highest risk to have the lowest proportion of patients with high degree of stress (25 per cent). The same relationship was found for diabetes, which was found in 7 per cent of the patients with the lowest risk, whereas none of the patients with the highest risk had diabetes. Gallstone and kidney stone were more common among the patients than in the population. However, there was no tendency toward a continuously increased or decreased proportion of individuals with gallstone or kidney stone between the risk groups. The situation was the same with respect to dyspnea upon exertion. For patients in the age group below 45 years it is difficult to draw conclusions due to the small numbers of patients in the different risk groups and the lack of reference groups. It is worthy of note, however, that a high degree of stress showed the same distribution tendency as in the age group 45 to 54 years and t h a t diabetes and gallstone as well as dyspnea upon exertion occurred more frequently than in the population of 50year-old men. These variables were more common among patients with low risk t h a n among those with high risk. Diabetes, gallstone, and kidney stone were also found more frequently than expected in the age group 55 to 67 years, particularly in the low-risk group. Dyspnea was found considerably more often among the patients than in the population sample, There was a tendency for the proportion

April, 1976, Vol. 9], No. 4

Primary risk factors in myocardial infarction

of patients with dyspnea upon exertion to increase with increasing risk. The triglycerides in the patient group with low risk in the age group 45 to 54 years were higher than in the population sample (138 and 108 mg. per 100 ml., respectively). In the age group below 45 years the triglycerides in the lowest risk group were also much higher than expected in the corresponding age in the population sample. The same was true for the age group 55 to 67 years, Discussion

In the prospective studies of suspected risk factors difficulties have been encountered in assessing the importance of factors which occur infrequently in the population. This is, for example, true of diabetes, though there is a great deal of clinical evidence suggesting t h a t this disease carries an increased risk of ischemic heart disease. A representative, large material of infarction patients in a defined population gives greater possibilities of studying factors which occur with low frequency and which may be associated with an increased risk of infarction. The significance of the 10 per cent dropouts among the patients is a matter of conjecture. None of the variables included in the risk function, the risk factors, has been shown to be of importance for death during the f i r s t 3 months after an infarction,s~ The deletion of t h e 11 subjects who died within 3 months can therefore not have any great influence on the results. For the 18 individuals for whom information on one of the variables included in the risk function was lacking, a special analysis was performed. It was found that they did not differ systematically with respect to existing variables from the remaining 270 infarction patients. The minor significance of the dropouts and the justifiability of the method used have been confirmed by a special analysis. The representative population sample of 50-year-old men was added to the patients in the age group 45 to 54 years. The multiple risk function was applied to the composite material and the good predictability was confirmed. There was no tendency toward concentration of patients from either of the original groups in any particular risk area. In the present study it has been shown t h a t a not inconsiderable number of patients have suffered myocardial infarction despite relatively low risk (p < 0.10)according to the multiple risk

American Heart Journal

function. It is improbable t h a t this is essentially due to the fact t h a t the function is based on a single observation of the variables included-serum cholesterol, systolic blood pressure, and tobacco smoking. Whether or not repeated d a t a with respect to these three variables would give a significant improvement in predictability is n o t known, but is of course an interesting question. It is more probable, however, t h a t several other factors, perhaps not yet studied, are of great importance for the risk of suffering infarction. The results of this study strongly suggest t h a t mental stress, diabetes, dyspnea u p o n exertion, and raised serum triglycerides partly "explain" the occurrence of infarction in patients with low risk (p < 0.10) who survive myocardial infarction, at least in the age groups up to 54 years. In addition, low physical activity during leisure time may be of some importance. It is possible t h a t the stress variable used is associated with type of personality, "life changes," etc., but the latter variables require further study. It must be emphasized that the variable mental stress is sensitive to the retrospective method used during the interview of the patients. T h e same criticism against the retrospective method may apply to t h e evaluation of physical activity and possibly also to dyspnea on exertion. A high prevalence of diabetes in patients who survive myocardial infarction, whether the case history or a pathological oral or intravenous glucose tolerance test is used as the diagnostic criterion, has been reported in a large number of studies during more than 30 years.21-26 Prospective studies have shown t h a t diabetic p a t i e n t s or persons with asymptomatic hyperglycemia have a higher incidence of ischemic heart disease than those without diabetes. 27-29 This higher incidence has been particularly pronounced in persons who also have high blood pressure. 3~ Dyspnea on exertion was in all age groups more common among the patients than in the population sample which has been reported in more detail in another paper. 31In the youngest patients the occurrence of dyspnea decreased with increasing risk, which suggests t h a t dyspnea is an independent risk factor, which was also shown in multivariate analyses by Wilhelmsen and associates. 2 In older patients, however, the occurrence of dyspnea increased with increasing risk. It is possible that the significance of dyspnea varies in

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different ages. A m e t h o d o l o g i c a l source of bias m a y be suspected. T h u s , p a t i e n t s m a y n o t be able to differentiate b e t w e e n angina pectoris a n d dyspnea. P a t i e n t s a n d m e n in t h e p o p u l a t i o n samples were, however, interviewed b y t h e s a m e physicians a n d t h e y were a w a r e of this p r o b l e m . I n m o s t cases t h e chest s y m p t o m s could n o t be classified as angina pectoris b u t as dyspnea. T h e high prevalence of d y s p n e a a m o n g p a t i e n t s in t h e present s t u d y m a y p a r t l y be explained b y t h e f a c t t h a t a m a j o r i t y of p a t i e n t s were s m o k e r s a n d s o m e w h a t less physically active. D y s p n e a has, however, been shown, b y m u l t i v a r i a t e analyses, to be associated with a n increased risk of m y o c a r dial infarction, irrespective of o t h e r risk factors. 2 T h e finding m a y be explained b y t h e f a c t t h a t dyspnea is a s y m p t o m of m y o c a r d i a l d i s t u r b a n c e , even prior to infarction. T h i s m a y be due to either ischemia or to some other, a t p r e s e n t u n k n o w n , factor. 32 As regards s e r u m triglyceride values, these varied in parallel with the risk function, so t h a t high risk was associated w i t h higher triglyceride values. This was in principle t r u e for all t h r e e age groups a n d m a y p a r t l y be explained b y t h e correlation between cholesterol a n d triglycerides. ~ In the m u l t i v a r i a t e a n a l y s e s it was also found t h a t inclusion of s e r u m triglyceride did n o t improve t h e possibilities of prediction in t h e s e middle-aged men. ~ T h e r e are evidently o t h e r factors which could h a v e been studied in addition to those m e n t i o n e d in the present paper. T h u s , we were i n t e r e s t e d in finding a n y useful d a t a indicating a genetic predisposition to c o r o n a r y h e a r t disease. I t t u r n e d out, however, t h a t t h e knowledge of p a r e n t s ' cause of d e a t h was limited. In a prospective s t u d y there was, however, f o u n d a t e n d e n c y for earlier d e a t h a m o n g p a r e n t s of those w h o l a t e r suffered m y o c a r d i a l infarction. 33 I t should be observed t h a t t h e results o f t h e present s t u d y are based on an analysis of surviving m a l e patients. O t h e r factors m a y be of i m p o r t a n c e for, or be associated with, increased risk of dying of ischemic h e a r t disease. An example of this is the finding t h a t alcoholic problems occurred m o r e f r e q u e n t l y a m o n g m e n with f a t a l t h a n those with n o n f a t a l m y o c a r d i a l infarction."

Summary A predicted p r o b a b i l i t y of suffering m y o c a r d i a l infarction ,based on a m u l t i p l e risk f u n c t i o n 418

involving s e r u m cholesterol, systolic blood pressure, a n d tobacco c o n s u m p t i o n , w a s allocated retrospectively to 270 m e n w h o survived a p r i m a r y m y o c a r d i a l infarction. T h e infarction p a t i e n t s were r e p r e s e n t a t i v e of all surviving, diagnosed cases of p r i m a r y infarction in m e n in certain age groups in G6teborg, Sweden, d u r i n g the years 1968-70. T h e p a t i e n t s were divided i n t o three g r o u p s - l o w , m o d e r a t e , a n d high risk. A large n u m b e r of p a t i e n t s h a d suffered infarction despite relatively low risk, b u t t h e p a t i e n t s showed a tendency t o w a r d higher risk in c o m p a r ison with the risk distribution in a r e p r e s e n t a t i v e population sample. I n order to s t u d y w h e t h e r o t h e r variables, n o t included in t h e risk function, could "explain" the infarction in p a t i e n t s w i t h relatively low risk, the different risk groups were compared. A high degree of m e n t a l stress, diabetes mellitus, a n d d y s p n e a on exertion, a n d possibly also raised triglycerides, c o n t r i b u t e d to "explain" the infarctions in t h e low-risk group. Low physical activity during leisure t i m e w a s p r o b a b l y also of i m p o r t a n c e .

REFERENCES 1. Truett, J., Cornfield, J., and Kannel, W.: A multivariate analysis of the risk of coronary heart disease in Framingham, J. Chron. Dis. 20:511, 1967. 2. Wilhelmsen, L., Wedel, H., and Tibblin, G.: Multivariate analysis of risk factors for coronary heart disease, Circulation 48:950, 1973. 3. Keys, A., Aravanis, C., Blackburn, H., van Buchem, F. S. P., Butzina, R., Djordjevic, B. C., Fidanza, F., Karvonen, M. J., Menotti, A., Puddu, V., and Taylor, H.: Probability of middle-aged men developing coronary heart disease in five years, Circulation 45:815, 1972. 4. Elmfeldt, D., Wilhelmsen, L., Tibblin, G., Vedin, J. A., Wilhelmsson, C. E., and Bengtsson, C.: Registration of myocardial infarction in the city of G6teborg, Sweden-a community study, J. Chron. Dis. 28"173, 1975. 5. Wilhelmsen, L.: The myocardial infarction clinic in G6teborg-organization and preliminary results, Pehr. Dubb. J. (III) 4:43, 1969. 6. Elmfeldt, D., Wilhelmsen, L., Tibblin, G., Wilhelmsson, C. E., Vedin, J. A., and Bengtsson, C.: Postmyocardial infarction clinic - follow-up of MI patients in a specialized out-patient clinic, Acta Med. Scand. 197:497, 1975. 7. Wilhelmsen, L., Elmfeldt, D., Tibblin, G., Vedin, J. A., and Wilhelmsson, C. E.: Blood pressure and cholesterol before and after myocardial infarction in a random population sample. To be published. 8. Tibblin, G., and Cram$r, K.: Serum lipids during the course of an acute myocardial infarction and one year afterwards, Acta Med. Scand. 174.'451, 1963. 9. Cotton, S. G.: Plasma cholesterol after myocardial infarction, Postgrad. Med. J. 46.'551, 1970. 10. Fyfe, T., Baxter, R. H., C0chran, K. M., and Booth, E. M.: Plasma-lipid changes after myocardial infarction, Lancet 2:997, 1971. 11. Rose, G., and Blackburn, H.: Cardiovascular survey methods, World Health Organization, Geneva, 1968. April, 1976, Vol. 91, No. 4

P r i m a r y risk factors in myocardial infarction

12. Wilhelmsen, L.: Treatment of hypertension in a Swedish Community-the problem of borderline hypertension, Acta Med. Scand. 576"99, 1975. 13. Tibblin, G.: A population study of 50-year-oid men. An analysis of the non-participation group, Acta Med. Scand. 178:453, 1965. 14. Tibblin, G.: High blood pressure in men aged 5 0 - a population study of men born in 1913, Acta Med. Scand. (Suppl.) 470, 1967. 15. Wilhelmsen, L., Tibblin, G., and WerkS, L.: A primary preventive study in Gothenburg, Sweden, Preventive Med. 1:153, 1972. 16. Wilhelmsen, L., Ljungberg, S., Wedel, H., and WerkS, L.: A comparison between participants and non-participants in a primary preventive trial, J. Chron. Dis. In press 1975. 17. Elmfeldt, D., Wilhelmsson, C. E., Vedin, J. A., Tibblin, G., and Wilhelmsen, L.: Characteristics in representative male survivors of myocardial infarction compared to representative population samples, Acta Med. Scand. In press 1975. 18. Wilhelmsen, L., and Tibblin, G.: Physical inactivity and risk of myocardial infarction.-The men born in 1913 study, in Larsson, O. A., and Malmborg, R. 0., editors: Coronary heart disease and physical fitness, K6penhamn, 1971, Ejnar Munksgaards Forlag, p. 251. 19. Carlson, L. A.: Determination of serum triglycerides, Acta Soc. Med. Ups. 64:208, 1959. 20. Vedin, J. A.: Hj~irtinfarkt i G6teborg 1968-1970. D6dsfall, infarktrecidiv och prognosfaktorer under tv~ ~rs uppf61jning av patienter som 6verlevt sjukhusvistelsen (in Swedish), Elanders, 1974, Kungsbacka. 21. Master, A. M., Dack, S., and Jaffe, H. L.: Age, sex and hypertension in myocardial infarction due to coronary occlusion, Arch. Intern. Med. 64:767, 1939. 22. Sievers, J.: Myocardial infarction. Clinical features and outcome in three thousand thirty-six cases, Acta Med. Scand. (Suppl.) 406, 1963. 23. Hood, B., Tibblin, G., Welin, G., Orndahl, G., and Korsan-Bengtsen, K.: Myocardial infarction in early age. III. Coronary risk factors and their deficient control, Acta Med. Scand. 185:241, 1969.

American H e a r t J o u r n a l

24. Bengtsson, C.: Ischaemic heart disease in women, Acta Med. Scand. (Suppl.) 549, 1973. 25. Luft, R., Efendi6, S., and Cerasi, E.: Prediabetes, diabetes and arteriosclerosis, some considerations, in WaldenstrSm, J., Larsson, T., and Ljungstedt, N., editors: Early phases of coronary heart disease, Skandia International Symposia, Stockholm, 1973, Nordiska Bokhandeln, p. 223. 26. Lundbaek, K.: Diabetes and the heart. A sketch of the problem, in Waldenstrom, J., Larsson, T., and Ljungstedt, N., editors: Early phases of coronary heart disease, Skandia International Symposia, Stockholm, 1973, Nordiska Bokhandeln, p. 215. 27. Epstein, F~ H.: "Hyperglycemia": A risk factor in coronary disease, Circulation 36:609, 1967. 28. Garcia, M. J., Gordon, T., McNamara, P. M., and Kannel, W. B.: Morbidity and mortalityin diabetics in a general population. Sixteen-year follow-up experience in the Framingham Study, Diabetes 19:375, 1970. 29. Kannel, W. B., and Gordon, T.: Assessment of coronary vulnerability. The Framingham Study, in WaldenstrSm, J., Larsson, T., and Ljungstedt, N., editors: Early phases of coronary heart disease, Skandia International Symposia, Stockholm, 1973, Nordiska Bokhandeln, p. 123. 30. Stamler, J., Berkson, D. M., and Lindberg, H. A.: Risk factors: their role in the etiology and pathogenesis of the atherosclerotic diseases, in Wissler, R. W., and Geer, J. C. Editors: The pathogenesis of atherosclerosis, Baltimore, 1972, The Williams & Wilkins, Company, p. 41. 31. Elmfeldt, D., Vedin, J. A., Wilhelmsson, C. E.,Tibblin, G., and Wilhelmsen, L.: Morbidity in representative male survivors of myocardial infarction compared to representative population samples, J. Chron. Dis. In press 1975. 32. Wilhelmsen, L.: Early diagnosis of coronary heart disease, in Atherosclerosis-Proceedings of the Third International Symposium, Berlin, Heidelberg, New York, 1974, Springer Verlag, p. 705. 33. Tibblin, G., Wilhelmsen, L., and Werk6, L.: Risk factors for myocardial infarction and d e a t h due to ischemic heart disease and other causes, Am. J. Cardiol. 35:514, 1975.

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