Europ.J.clin.Invest. 5, 507-514 (1975)

Ischaemic Heart Disease and Associated Risk Factors in 40Year Old Men in Edinburgh and Stockholm M.F. Oliver1, I.A. Nimmol, Margaret Cookel, L.A. Carlson2, and A.G. Olsson2 ]Departments of Cardiology and Medicine and the Lipid Research Laboratory, Royal Infirmary, Edinburgh and k i n g Gustaf V Research Institute, Karolinska Hospital, Stockholm Received: November 2 2 , 1974, and in revised form: April 2 1 , 1975 ~~

~~

Abstract. The incidence of ischaemic heart disease in men in their early forties is approximately three times greater in Edinburgh than in Stockholm. To gain more information about some of the possible reasons for this striking difference, a random sample of apparently healthy men aged 40 was selected from each city. Identical clinical and biochemical measurements were made and interlaboratory variations were eliminated by making each analysis in the same laboratory. Serum triglycerides were higher in Edinburgh men than in Stockholm men, and the shapes of the-distribution curves were significantly different. Serum cholesterol concentrations were similar in the two cities. Fasting plasma glucose concentrations were the same in the two cities. After a standardised glucose load, the mean plasma glucose decreased in men in both cities and significantly more in Edinburgh. There were significantly more men in Edinburgh with high insulin values. There were significantly more cigarette smokers in Edinburgh. This is possibly the most clear-cut difference between the cities. Edinburgh men were shorter than Stockholm men. Analysis of the distributions of high risk characteristics showed that Edinburgh had more putative high risk individuals for ischaemic heart disease. This study is exploratory in nature and the differences found cannot by themselves explain the greater incidence of ischaemic heart disease in Edinburgh compared with Stockholm. Nor are they likely to be independent of such influences as diet, physical activity and ethnic origin. The fact that such marked differences can be found emphasises the potential value of studying in this way populations with dissimilar incidence of disease.

Key words: Ischaemic heart disease, epidemiology, young men, triglycerides, insulin, smoking.

Introduction An impression was gained during various exchanges between investigators in Edinburgh and Stockholm that the incidence of ischaemic heart disease (IHD) in young men is greater in Edinburgh than in Stockholm. This report substantiates the impression and presents the results of a pilot survey designed to campare the prevalence of major risk factors hyperlipidaemia, hypertension and cigarette smoking in young healthy men in the two cities.

-

-

Incidence of Ischaemic Heart Disease in Edinbtcrgh and Stockholm The greater incidence of H I D in Edinburgh compared with Stockholm can be shown by contrasting -the findings of two recent counnunity surveys ( 1 , 2 ) . The survey in Edinburgh was prospective in conduct. For one year all new myocardial infarcts and sudden cardiac deaths were notified by family doctors, hospitals and police surgeons to a special cardiac clinic. Diagnoses were confirmed by electrocardiograms,

serum enzyme levels, hospital reports and death certificates. A total of 1218 new cases was recorded for men aged 30 - 69, including 397 deaths. The Stockholm survey was a retrospective analysis of death certificates supplemented by hospital and autopsy data. It was conducted at the same time as the Edinburgh investigation and also lasted for one year. The number of deaths from IHD for men aged 30 - 69 was 699. The main findings of these two surveys are sunrmarised in Table la and Ib. The category described as medically unattended deaths was regarded by the doctor responsible for the study as approximating to sudden cardiac deaths: and the great majority of them occurred within one hour of the onset of symptoms or of the individual last being seen alive. The data in Table Ib incorporate those in Table la and represent the overall IHD mortality rates from the two cities. The numbers of recorded deaths under 49 were small and there were differences in the design of the two studies which could weaken the value of any statistical assessment of the difference in overall mortality between the cities (30 - 39: P = 0.03; 4 0 - 49: P < 0 . 0 0 1 ) , but these figures strongly suggest that deaths from IHD in younger

M.F. Oliver et a l . : Ischaemic Heart Disease and Associated Risk Factors

508

Table la. Medically unattended death rates from ischaemic heart disease in Edinburgh1 and Stockholm2 for men aged 30 - 69 years during one year (1970) Age years

Edinburgh No Rate/l000

30 -

30

39

5

40 50 60

49

32 90 121

59

69 69

248

0.19 1.21

Stockholm No Rate/ 1000 4 35

3.17

95

5.68 2.42

230

0.06 0.46 1.31 4.60

364

1.40 -

Ib. Overall mortality rates from ischaemic heart disease in Edinburgh] and Stockholm2 for men aged 30 - 69 years during one year (1970) (includes Table la)

Age years

Edinburgh No Rate/1000

30 - 39 40 - 49 50 - 59 60 - 69

8 44 I41

69

30

-

Stockholm Rate / 1000

No

8 51 169

0.13 0.67

204

0.30 1.67 4.96 9.58

47 1

9.42

397

3.87

699

2.68

2.35

men are on a relative basis between 2.5 and 3 times more common in Edinburgh than in Stockholm. For men aged 6 0 - 6 9 the mortality rates were identical. This difference in mortality has been confirmed by an analysis of deaths due to acute myocardial infarction ( I C D 410) recorded through national statistics in the two cities. Considering the years 1969 and 1970 together, there is again a 3:l difference for men aged 4 0 - 44 years between Edinburgh (90/1000) and Stockholm (29/

cont ribut nts to the appar nt differen es in H I D between the cities, and it is possible that there could have been more 'false negatives'both in mortality and morbidity in Stockholm. But we considered that the evidence provided a prima facie case for believing that the differences are real and for proceeding further.

1000).

Because the incidence of IHD differs between Edinburgh and Stockholm, surveys were made of randomly selected men in each city. As the difference in incidence seemed to be greatest in the age range 30 49, men born in 1933 were chosen for the surveys: this restriction also enhanced the homogeneity of the two groups. The surveys were conducted simultaneously between July and September 1973. In Edinburgh, the random samples were selected through the Census (1971) Office and a letter was sent from the Department of Cardiology in the Royal Infirmary of Edinburgh with the authority of the Census Office and Registrar-General to 207 men born in 1933 and recorded in two years before this study as living in the city: of these men, 103 agreed to participate in the survey, 24 refused, 45 did not reply and 35 had "gone away". There was no statistically significant bias in those who volunteered compared with the original random sample in respect of marital status or socioeconomic group. Ultimately, 89 of the 103 were interviewed and examined. The other 14 indicated their willingness to attend, but were unable to

The total mortality in the two cities is greater in Edinburgh and deaths from IHD contribute approximately the same proportion in each city. This is to be expected, since IHD deaths are such a large component of total mortality. Total mortality usually changes in parallel with IIID mortality and, in this study, could mean that a greater force of mortality exists in Edinburgh. It is possible that the differences in mortality between the two cities is due to a difference in the proportion of infarcts that were fatal rather than in the total number of infarcts (i.e. fatal and non-fatal). This likelihood was taken into account by assessing the number of patients aged 4 0 or less admitted in each city into Coronary Care Units with nonfatal myocardial infarction. There was an excess in Edinburgh in the region of 5-6:l. These findings for morbidity support the view that the observed differences in mortality are real. We cannot, however, eliminate differences in diagnostic customs or in the coding of deaths as

Survey of Population

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M.F. Oliver et al.: Ischaemic Heart Disease and Associated Risk Factors

do so within the period specified for the duration of the survey. We have considered carefully the degree to which the 89 can be regarded as representative of the original random sample of 207 men. Since nothing was known, or could be traced, of the 4 5 who did not reply, these have been grouped with the 35 who had definitely left Edinburgh, leaving a denominator of 127: thus the 89 interviewed can be regarded as representing 70 Z of the original sample. In Stockholm, the random sample of men born in 1933 was obtained through the electoral r o l l s : 108 were approached, of whom 103 agreed to take part in the study and 96 (88 X ) were examined; 7 could not come during the time specified for the study. There was no difference with regard to marital status for those who were investigated compared with the initial group. The subjects gave their occupation status, smoking habits and family history of vascular disease. Questionnaires were used to assess effort chest pain, and intermittent claudication ( 3 ) . Height and weight, and blood pressure using a zero muddler were measured, and the presence or absence of xanthomata and of patent foot pulses was noted. In Edinburgh only, triceps and subscapular skinfolds and a 12 lead resting electrocardiogram were also recorded. A blood sample was taken after an overnight fast for the estimation of serum cholesterol

Table

2.

5c9

and of serum triglycerides ( 4 ) , and serum insulin (5), the sera being deep-frozen prior to analysis. Plasma glucose was also estimated (6): the samples were stored prior to analysis as deep-frozen protein-free perchloric acid extracts. There followed an oral glucose tolerance test (30 g glucose/m2 body surface area) with a second blood sample taken at 2 hours under standardised conditions for both cities. Serum lipids were analysed in Stockholm (the frozen samples from Edinburgh were transported there by air). Insulin was analysed in Newcastle and glucose in Edinburgh (the frozen samples from Stockholm being transported by air). The samples from both cities were randomised and analysed on consecutive days and in random order in each laboratory. Resu Zts

The data are summarised in Table 2 . In Edinburgh men, serum cholesterol levels were similar to those in their Stockholm counterparts while serum triglycerides were on overage higher, although not quite at the 5 Z level of significance. The striking similarity between cholesterol values in Edinburgh and Stockholm is well demonstrated in Fig. 1 while the greater occurrence o f high serum trig1yceri.de values in Edinburgh is seen in Fig. 2 .

Summary of mean values Edinburgh mean t SEM (n)

Serum cholesterol (nig/IOO ml) Serum triglycerides

249k5 ( 8 8 ) 2.39t0.28

(89)

Range 160

(88)

0.98

(mol/l)

Plasma fasting glucose 2h (mg/100 ml) 2h-fasting Serum insulin (pU/ml> Systolic blood pressure (m/Hg) Diastolic blood pressure (rmn/Hg) Cigarettes (No./day) Non-smokers+cigar/pipe smokers Height (cm Weight (kg) Relative weight

86.3k1.2 74.5k2.5 -11.822.2 7.7020.44

(85) (85) (85) (87)

124k1.6 ( 8 9 )

79.5f1.3 21.4fl.5

(89) (57)

-

400

-

25.4

- 22.2

55-6 117.2 28.8 163.5 -56.3 to +71.8 2.6 94

54 I

-

-

Stockholm SEM (n)

k

I .96k0.12

(95)

87. I k l . 1 (95) 84.623.4 ( 9 3 ) -2.253.0 ( 9 3 ) 6.68k0.29

(94)

117k1.5 ( 9 5 )

122

7 7 . 3 k 1 .2 ( 9 5 )

60

19.7k2.0

(96)

(41)

t

Range 143

254k6 ( 9 5 )

194

-

32 (89)

0.83

P

-

507

0.63

n.s.

-

9.25

1.87

< 0.10

0.04 2.43 2.32

< 0.02

71.6-151.7 35.7-261.7 -59.9 to 110.0

n.s. < 0.05

2.9-1 6 . 2

1.27

n.s.

81-154

3.02

< 0.01

52-1 14

I .23

n.s. n.s.

2- 8 0

Chi-square< 0.01

54 (95)

= 8.05

175.220.7

(89)

160.0

76.6k1.2

(89)

52.0

0.250t0.004

mean

( 8 9 ) 0.196

-

3.56

202.0

178.2M.6

(96)

162.5-1 9 3 . 5

105.0

78.0kl.1

(96)

58.0-121.7

0.63

0.186-0.334

0.46

- 0.359

0.246?0.003

(96)

< 0.00

n.s. n.s.

Relative weight = Quetlett's index The Mann-Wnitney test7 statistic t has been calculated without taking ties into account; ignoring ties makes the test conservative. Data are missing from this tabLe because measurements were occasionally not made for organisational reasons or treatment might have invalidated results.

M.F. Oliver e t a z . : Ischaemic Heart Disease and Associated Risk Factors

510

Fig. 1 . Cumulative frequency distribution curves for serum total cholesterol

SERUM TOTAL CHOLESTEROL

CUM U LATl V E FREQUENCY

-

EDINBURGH ( n = 8 8 )

a!

i

I

I

100

0

200

LOO

300

S E R U M CHOLESTEROL (mg/100 m l )

-

Fig. 2 . Cumulative frequency distribution curves for serum total triglyceride. The Edinburgh curve is more skewed towards high values (see Table 3)

SERUM TOTAL TRIGLYCERIDE

CLIMULATIVE :REQUE NCY

0

0-0

EOINBURGH ( n = 88 I STOCKHOLM ( n = 95 I

2 3 4 5 SERUM TRIGLYCERIDE ( m m o l l L )

1

6

7

PLASMA GLUCOSE : 2hr AFTER GLUCOSE LOAD JM U LATl VE

R E W E NCY 'I.

0--o

EDINBURGH (n = 8 5 ) STOCKHOLM (n.93)

Fig. 3 . Cumulative frequency distribution curve. for plasma glucose concentrations 2 hours after a glucose load. The Edinburgh curve is displaced to the left of the Stockholm curve

M.F. Oliver e t aZ.: Ischaemic Heart Disease and Associated Risk Factors

Cumulative Frequency

0-0

51 I

Fig. 4 . Cumulative frequency distribution curve for fasting serum insulin. The Edinburgh curve is more skewed towards high values (see Table 3)

FASTING INSULIN EDINBURGH ( n =87) STOCKHOLM ( n = 94 1

( %I

INSULIN (pU/rnll

Fig. 5 . Cumulative frequency distribution curve for systolic blood pressure. The Edinburgh curve is displaced to the right of the Stockholm curve

SYSTOLIC BLOOD PRESSURE CUM ULA1IV E

FREQUENCY 100-

0--0

50

EDINBURGH ( n = 8 9 ) STOCKHOLM (n = 951

-

0

* . d

0

50

1

100

1

8

200

150

sample 100

80

x of

60

smokers

Edinburgh

1 40

40

30

20

20

10

Edinhrgh

Stockholm

1-15

16-25

>25

Cigarettes per day

Fig. 6. Histograms showing an excess of cigarette smoking in Edinburgh men, but no differences in the amounts smoked by smokers

512

M.F. Oliver et az.: Ischaemic Heart Disease and Associated Risk Fact:ors

The fasting plasma glucose concentration was the same in men in the two cities. Two hours after the standard glucose load, the mean plasma glucose concentration had decreased in both cities but more so in Edinburgh than in Stockholm (Table 2 and Fig. 3). The mean fasting plasma insulin concentrations did not appear to differ significantly, although the Edinburgh values tended to be higher (Table 2, Fig. 4 ) . Edinburgh men had a greater mean.systolic blood pressure (Fig. 5) but there was no significant difference in diastolic blood pressure (Table 2). There were significantly more cigarette smokers in Edinburgh (Table 2), but there was no inter-city difference in the number of cigarettes smoked per day by the smokers (Fig. 6 ) . Cigar and pipe smokers were scored as nonsmokers, Only current smoking habits were analysed. Details of duration of smoking and inhalation were not recorded. Edinburgh men were shorter than Stockholm men, but had the same relative weight using Quetlett's Index, defined as weight (kg) /height2 (dm) (7), (Table 2). Differences in the two cities between mean values of any of the above variables could be due to a difference in the shapes of the underlying distribution as well as to a difference in their locations. For each of the variables the shapes of the distributions were therefore compared as follows. All the values from the two cities were pooled and then ranked in order of increasing magnitude, and the number of men from each city falling below the lowest quintile (i.e. the bottom 20 Z) and above the highest quintile (i.e. the top 2 0 X) of the pooled values was determined. If the underlying distributions differed in location, but not in shape, there might be significantly more men from one of the cities below the lowest quintile: and correspondingly more men from the other city above the highest one. On the other hand, if one of the distributions were more skewed than the other (for example, towards the higher values), there might be similar numbers of men from the two cities below the lowest quintile but significantly different numbers above the highest quintile. The results of comparing the shapes of the distributions in this way are shorn in Table 3. It can be seen that Edinburgh had significantly more men with relatively high values of triglycerides and insulin, while the cholesterol distributions did not differ. These statistical analyses thus confirm the visual impressions from Figs. I , 2 and 4 . On the other hand, Stockholm had more men with a relatively large rise in plasma glucose after the glucose load, and with low systolic blood pressure. There were no significant differences for fasting plasma glucose, diastolic blood pressure or relative weight. A comparable analysis to that presented in Table 3 was also made for the 10th and 90th centiles and, with the exception of systolic

Table 3. Composition of tails of distributions for combined Edinburgh and Stockholm data ~

Variable

Lowest 20 % (value)

Highest 20 % (va1ue)

Cholesterol

n.s. (207 mg/ I OOml)

n.s. (294 mg/100ml)

Triglycerides Glucose (2h - fasting)

(1.27 m o l / l )

n.s.

E' (2.61 mmo1/1)

n.s. (-24.0 mg/100ml)

(5.8 mg/100ml)

Insulin

E*

n.s. (4.5

(9.5

pU/rn1)

S**

Systolic BP Relative Wt.

S**

uU/ml)

(106 mm Hg)

n.s. (133 ran Hg)

n.s. (0.220 kg/dm2)

( 0 . 2 7 3 kg/dm2)

n.s.

E: Edinburgh men predominante S: Stockholm men predominante n.s.: No significant difference *: P < 0.025 * * : P < 0.01 Chi-square test of significance Table 4 . Occurrence of individuals having risk factors with high values (combined Edinburgh and Stockholm data I

No. of highvalue risk factors* 0 1

No. of men

Edinburgh observed expected 13 31 27

16.7 33.3 26 .O

9

Stockhol m observed expecte 33 36

18.0

4

7

10.4 2.3

3

36.0 28.1 11.2 2 4

5

1

0.3

2

0.3

6

1

0.01

1

0.0;

2 3

12 9

.

*An individual was said to have a risk factor with a hi value if he appeared in the top 20 96 of the CholesteroL Triglyceride, Insulin, Systolic BP or Relative Weight distributions: or the top 43 X of the Cigarette Smoking distribution (15 or more cigarettes per day).

blood pressure (more men with low values in Stockholm), there were no significant differences found between the two cities indicating that the differences seen for the 20th and 80th centiles were not determined by a few unrepresentative individuals at the extremes of the distributions. Cigarette smoking could be regarded as a risk factor for IHD largely independent of the other measurements considered. An analysis was

M.F. Oliver e t el.: Ischaemic Heart Disease and Associated Risk Factors made using the top two quintiles (61 - 80 X and 81 - 100 %> for differences in prevalence of other risk factors between smokers and nonsmokers. None was found. An attempt was made to find out if the, "highrisk" tails of the various distributions often contained the same individuals, or if men appeared in them at random. It is well established that risk increases with triglyceride and cholesterol concentrations, blood pressure and cigarette smoking and so the upper tails of these distributions were analysed. Relative weight and insulin were also included in this analysis. The results are given in Table 4. The number of men appearing in four or more of the six possible high risk tails is somewhat greater in Edinburgh than would be expected on the basis of chance alone. In Stockholm, there is an excess of men in the 0-tail category. These differences raise the possibility of a different pattern of intercorrelation among risk factors in the two cities. The results also suggest that Edinburgh may have more putative high-risk individuals.

Discussion The studies reported here are exploratory and pilot in nature. The differences uncovered by them are unlikely by themselves to explain the greater incidence of IHD in the Edinburgh men. Such important influences as diet (including alcohol intake), physical activity, ethnic differences and the mineral content of water have not been explored. It should, therefore, be clearly understood that no claim is made that the differences reported here are independent of these influences. We do not propose to speculate why the observed differences occur and prefer to confine our comments to their existence. The fact that differences in the prevalence of some risk factors can actually be found is of considerable interest, and emphasises the potential value of stUdying.Cnthis way populations with dissimilar incidence of IHD. The studies also indicate that merely to estimate population means for the various risk factors is not enough: the number of individuals thought to be particularly at risk should also be established. The unique aspects of the surveys are that both were conducted at the same time on random samples of apparently healthy subjects of the same age and sex, and that inter-laboratory variations cannot account for the results, since each analysis was undertaken in only one laboratory with samples being run at the same time and at random. The similarity between the Edinburgh and Stockholm values for serum total cholesterol implies that the difference in incidence of IHD is unlikely to be related to cholesterol: but, before this conclusion can finally be

513

dram, it must be shown ( 1 ) that not only are the total serum cholesterol values identical but also the cholesterol distribution on the different lipoprotein classes is the same and ( 2 ) that the two populations have the same ratio of free to esterified cholesterol and that the cholesterol esters are similar. On the other hand, the relative elevation of serum triglycerides in Edinburgh men may be important and ought to be examined in more detail - for example, by estimating the different classes of lipoprotein and investigating fat tolerance, the fatty acid composition of serum and adipose tissue lipids, the biochemical and morphological characteristics of adipose tissue and free fatty acid turnover. Similarly, the differences in response to a glucose load and in the fasting insulin concentration require further analysis. Possibly the most clear-cut distinction between the two populations is in cigarette smoking: on a relative basis there are nearly 50 X more smokers in Edinburgh. The average consumption of cigarettes per smoker was, however, similar. Since €or the smokers there was no correlation between smoking and any of the metabolic parameters examined, smoking seems to be an independent risk factor. One can speculate what the differences described here might mean. A higher incidence of IHD in Edinburgh presumably implies a higher prevalence of atheromatous disease there. This might be explained in terms of some of the risk factors considered above. For example, a high serum triglyceride level in association with a "better" insulin response might favour the deposition of lipid in the arterial wall. Cigarette smoking can increase the carbonmonoxy-haemoglobin content of blood and decrease its oxygen carrying capacity: and mobilise catecholamines with consequential haemodynamic and metabolic effects. Further studies are planned to consolidate and elaborate these findings. Much of the credit for the concept of this joint study must go to the late Dr. B.W. Lassers who worked in Edinburgh and Stockholm. We are particularly indebted to Mr. Lawson and his staff in the General Registrar Office for Scotland for the Edinburgh random sample and to Mr. Bengt Olinder, Stockholm Office of Statistics, for the Stockholm random sample. We are also grateful to the technicians in the laboratories in Edinburgh and Stockholm: and to Dr. T. Lind (Newcastle) for serum insulin estimations. This work was partly supported by a grant from the Secretary of State for Scotland through the Advisory Committee on Medical Research.

References 1. Armstrong, A., Duncan, B., Oliver, M.F.,

Julian, D.G., Donald, K.W., Fulton, M., Lutz, W., Morrison, S.L.: Natural history of acute

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M.F. Oliver et az.: Ischaemic Heart Disease and Associated Risk Factors

coronary heart attacks. A community study. Brit. Heart J. 34, 67 (1972) 2 . Wikland, B.: Medically unattended fatal cases of ischaemic heart disease in a defined population. Atta med. scand. Suppl. 524 ( I 969) 3. Rose, G.A., Blackburn, 8.: Cardiovascular Survey Methods. Wld. Hlth. Org. Geneva (1968) 4. Rush, R.L., Leon, L., Turrell, J.: Advances in Automated Analysis. Thurman Assoc. N.Y. 1, 503 (1971) 5. Lind, T., van D. de Groot, H.A., Brown, G.,

Cheyne, G.A.: Observations on Blood Glucose and Insulin Determinations. Brit. med. J. iii, 320 (1972)

6. N i m o , I.A., Kirby, B.J., Lassers, B.W.: Rapid oscillations in blood glucose and plasma free fatty acid concentrations in man. J. appl. Physiol. 34, 448 (1973) 7. Khosla, T., Lowe, C.R.: Indices of obesity derived from body weight and height. Brit. J. prev. soc. Med. 21, 122 (1967) 8. Sokal, R.R., Rohlf., F.J.: Biometry. San Francisco: W.H. Freeman 1969

Dr. Michael F. Oliver Department of Cardiology Royal Infirmary Edinburgh E M 9YW Scotland, U.K.

Ischaemic heart disease and associated risk factors in 40 year old men in Edinburgh and Stockholm.

Europ.J.clin.Invest. 5, 507-514 (1975) Ischaemic Heart Disease and Associated Risk Factors in 40Year Old Men in Edinburgh and Stockholm M.F. Oliver1,...
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