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The Lancet, Saturday 4 February 1967


PREVALENCE AND PATHOLOGICAL CHANGES OF ISCHAEMIC HEART-DISEASE IN A HARD-WATER AND IN A SOFT-WATER AREA


T. Crawford

M.D. Glasg., F.R.C.P., F.C.Path
Professor of Pathology, St. George's Hospital Medical School, London S.W.1

Margaret D. Crawford

M.D. Glasg.
Of the Social Medicine Research Unit of the Medical Research Council, London Hospital, N.1


Summary

A comparison has been made of cardiac lesions found m a very soft water area (Glasgow) and in a very hard water area (London) in two comparable series of medicolegal necropsies--men who had died from an accident and men who had died suddenly and unexpectedly from ischaemic heart-disease. In the accident series the prevalence of myocardial scars (healed infarcts) was greater in the soft than in the hard water area. At ages 30-44 there was more atheroma and there were more cases with lumen stenosis in the soft water area, but at ages 45-69 there was no difference in the prevalence of extensive atheroma or significant stenosis between the two areas; only "old occulsion" was commoner in the Glasgow cases. In the ischaemic-heart-disease series men who had died in Glasgow had less extensive coronary atheroma and lower scores for lumen stenosis, age for age, than those who died in London. The findings in both these series suggest an increased susceptibility of the myocardium in the soft-water area. Chemical analysis of the coronary arteries in the accident series indicated that, at ages under 40 years, there were more men in the soft-water area with very low values for calcium and magnesium suggesting content of the arteries is related to the mineral content of the drinking-water.

Introduction

Associationss have been found between hardness of drinking-water and mortality from cardiac disease in England and Wales (Morris, Crawford, and Heady 1961, 1962), in the U.S.A. (Schroeder 1960), and in Sweden (Biorck et al. 1965)--the softer the water the higher the mortality-rate from cardiovascular disease. Despite intensive search for possible confounding factors, there is no indication so far that hardness of water is merely reflecting other environmental or social factors. The possibility remains that there is a causal relationship between the mineral content of drinking-water and deaths from cardiovascular disease.

The death-rates in Glasgow for cardiovascular disease, including arteriosclerotic heart-disease, are about the highest in Britain and the city has a very soft water-supply: Greater London has very hard drinking-water and considerably lower mortality from these causes (table I). We have carried out an investigation in these two cities to consider these questions:

Lancet table 1

(1) Are the differences in cardiovascular death-rates reflected in the prevalence of cardiac lesions in the two populations?
(2) Are there any differences in the pathological features of the coronary arteries and myocardium in victims of ischaemic heart-disease in the two areas?
(3) Are there differences in the mineral content of the arteries related to differences in the mineral content of the drinking-water in the two areas ?

Material and Methods

Material

We enlisted the aid of pathologists carrying out medicolegal necropsies in London and Glasgow and compared the cardiac lesions in two series of cases of "sudden death": male victims of accidents who died within a short time of the accident and as a direct result of it (most of the cases in the series were from road accidents, but a few resulted from industrial accidents and accidental coal-gas poisoning) and sudden deaths in apparently healthy men who died before, or shortly after, coming under medical care and whose deaths were found at necropsy to have been due to ischaemic heart-disease.

Differences between England and Scotland in medicolegal procedure were minimised and can be ignored for the purpose of the study. Cases were as far as possible consecutive, and were unselected except that after a short time only cases under 60 years were included--thus the age-distribution is not representative of the whole population.

Information about length of residence in the area was obtained for most of the cases; 2 accident and 5 ischemic heart-disease cases were found to have moved from a soft to a hard water area or vice versa within the previous 10 years and were excluded; for the majority of the cases there was evidence that they had been at least 10 years in the same area.

Information about occupation was obtained and each case was graded in terms of the physical activity of the job (Morris and Crawford 1958). In the accident series there was no difference in the proportion of heavy workers between the Glasgow and London groups, but in the ischemic-heart-disease series there was a considerably higher proportion of "heavy workers" in the Glasgow group.

Methods

We were concerned solely with the findings in the heart. All the hearts were dissected and examined by T.C. who did not know the origin and other details of the specimens until after the findings had been recorded and assessments had been made. The coronary arteries were cut transversely at intervals of 5 mm. or less, examined under a dissecting microscope, and an assessment of disease was made in each of the three principal vessels -- the right coronary artery, the left trunk with anterior descending branch, and the circumflex artery.

The extent of atherosclerosis was assessed by the rough quantitative method used in previous studies (Crawford et al. 1961, Crawford 1966( -- i.e., the length of each of the main vessels involved by confluent atherosclerosis was measured in centimetres, and the three figures were combined to give a numerical assessment of the extent of the disease. This assessment is clearly only approximate and underestimates the total extent by neglecting involvement of other branch arteries and ignoring areas showing only discrete plaques. But it is a useful index for comparison between groups.

Stenosis was assessed by estimating the area of the residual lumen and expressing it as a fraction of the original cross-sectional area of the vessel; thus stenosis to a quarter implies that the cross-sectional area of the remaining lumen has been assessed as a quarter of the original lumen. The highest degree of stenosis in each of the three main arteries was graded as follows: no stenosis or lumen nowhere less than two-thirds of normal (0), lumen two-thirds to a third of normal (1), lumen a third to a quarter of normal (2); or lumen reduced to a quarter or less (i.e., near complete or complete occlusion) (3). A stenosis "score" calculated for the three arteries in each case could, therefore, range from 0 to 9. Reduction of the lumen to a third or less -- i.e., grades 2 and 3 -- is used as the criterion of significant stenosis.

Old and recent occlusions were recorded: segments showing occlusion, or those with maximal stenosis were processed through paraffin for microscopial confirmation of the findings. Lesions were regarded as "old occlusions" when the lumen was plugged with granulation or fibrous tissue or when organisation had led to the formation of two or more recanalising channels. Only in such circumstances is it possible to be certain of the occlusive nature of a lesion, though the probability is that many eccentric stenoses result from retraction and organisation of large occluding thrombi. It is likely therefore that the figures presented underestimate the frequency of old occlusions. Occlusions were regarded as recent when fibrin and other components of thrombus still formed a conspicuous part of the occluding mass; in a few instances atheromatous debris and lipid formed part of the occluding plug.

The myocardium was inspected for the presence of recent infarcts, scars, or "healed infarcts" (areas of fibrosis with one measurement exceeding 1 cm.) and smaller areas of fibrosis.

Finally, the coronary arteries were dissected out and analysed for calcium and magnesium: the results are given in mg. per 100 g. wet weight.

Results

The number and age-distribution of the cases in each series are shown in table II.

Lancet table 2

Accident Series

The prevalence of coronary disease and myocardial fibrosis in the London and Glasgow cases is shown in table III: under 30 years of age disease was minimal in both groups and such cases are not included in this table. Ages of the two groups remaining are closely matched (table II). In the younger men, aged 30-44 the average extent of confluent atheroma was greater, and there was a higher prevalence of stenosis in the Glasgow cases but numbers are too small for the differences to be statistically significant. In the older group (45-69 years) the prevalence of coronary-artery disease was much the same for the two areas, only the index "old occlusion" had higher figures for Glasgow than for London. There is, however, a striking difference in the prevalence of myocardial scarring in the two areas, there being 6 healed infarcts among the Glasgow cases and none among the London cases. The scars were distributed throughout the age range in the Glasgow cases and the difference is statistically significant (P <0.02).

Lancet table 3

In so far as these accident cases reflect what is happening in the general population, the findings suggest that there is more ischemic heart disease in the Glasgow than in the London population. The known differences in cardiovascular mortality (table I) are thus reflected in the myocardial lesions; and this suggests that they are "real" and not merely the result of differences in diagnostic criteria or certification. Glasgow men under 45 years had more coronary atheroma and stenosis, but over 45 years the prevalence of coronary-artery disease, as estimated by the indices used in the present study, was the same in Glasgow as in London.

Chemical analyses of the coronary arteries were available for most of the cases under 60 years of age, including the under-30-year age-group. Tle concentration of calcium in the coronary arteries increased with age and with the amount of disease in the arteries, as has been found by others (Lancing 1955, Blanenhorn 1963), disease being the main determinant because of the precipitation of calcium salts in advanced lesions. Figs.1 and 2 show the distribution of coronary calcium and magnesium in the accident cases from the hard and soft water areas. We had to divide the age-range at 40 instead of 45 in this analysis because of the amount of disease found in the Glasgow men at 40- 44 years. Under 40 years of age, when disease is minimal in both accident series, a greater proportion of the Glasgow men than of the London men had very low levels of calcium and magnesium. At ages over 40 and under 60 years, when coronary-artery disease was more prevalent, the distributions of the Glasgow and London cases are similar: the calcium distributions suggest the presence of second peaks. The distributions of magnesium values in men under 40 show the greatest differences between Glasgow and London -- of the Glasgow cases 5 out of 18 had values below 2 mg. while in London only 1 out of 23 had such a low value. Mean values for Glasgow men under 40 years were calcium 39 mg., magnesium 2.8 mg., and for the London men under 40 years calcium 47 mg., magnesium 4.2 mg. These findings if confirmed in a larger series, would suggest that the calcium and magnesium content of drinking-water is of importance in relation to the concentration of these elements in the tissues. There seems to be a paradox in the relation of these minerals and the arterial disease: low tissue concentration of calcium and magnesium are found in the area where disease appears earlier and is more lethal, but when disease is established the minerals are deposited in the lesions and very high values may be obtained.

Lancet figure 1

Lancet figure 2

Ischaemic heart-disease Series

Fig. 3 shows the frequency distribution of the extent of confluent atheroma in the coronary arteries of men from the two areas -- from under 5 cm. to over 20 cm. involvement. A higher proportion of the Glasgow cases had limited disease; a third of the Glasgow cases had less than 15 cm. of disease while only a sixth of the London cases were in this category. The age-distribution of the two groups are similar and the difference found is consistent within each 10-year age-group (p <0.001).

Lancet figure 3

Fig. 4 shows the distribution of stenosis scores. Again, there a "shift to the right" in the London group indicating more severe stenosis and more cases with multiple narrowing. The difference is significant (p <0.05).

Old and recent occlusions and occlusions in more than one artery were more frequent in the London cases, but the differences were small and not statistically significant.

In the age-group under 45 years there were more recent infarcts and myocardial scars (healed infarcts) among the Glasgow cases than among the London cases, but when all ages are compared the findings in the myocardium are similar for the two areas.

The chemical findings in the coronary arteries in this series are dominated by the amount of disease in the coronary arteries; very high values were obtained for calcium and magnesium in the majority of cases from both areas. In the age-group under 45 years, however, there were more men with low values for coronary calcium and magnesium among the Glasgow cases than among the London cases.

Table IV summarises the differences found between the Glasgow and London cases at ages under 45. The numbers are too small for the differences to be statistically significant.

Lancet figure 4

Discussion

Crawford et al. (1961) and Morris and Crawford (1961) found that in a proportion of men who had died of ischaemic heart-disease the coronary arteries showed only a limited extent of disease and that this proportion does not vary much with age. We have also found this, and it would seem that there are more of such cases -- i.e., fatal ischaemic heart-disease with only limited coronary atherosclerosis -- among men who died in a soft-water area (Glasgow) than among those who died in a hard-water area (London). The findings in the accident series seem to be similar, in that there is more ischaemic heart-disease, as evidenced by myocardial scarring, in the Glasgow cases without a higher prevalence of coronary atherosclerosis -- i.e., with the same amount of coronary atheroma and stenosis, myocardial disease seems more likely to develop in men in Glasgow than in London. The arterial disease does appear at an earlier age and there are more old occlusions in the Glasgow cases.

These findings raise several questions of importance which cannot be answered with the present limited numbers. For example, does the disease process develop more rapidly, is the myocardium more sensitive to minor degrees of ischaemia in Glasgow than in London? What other factors are involved? The differences cannot be explained by differences in physical activity: there were more physically active workers in the Glasgow than in the London groups so that less ischaemic heart-disease (Morris and Crawford 1958) might have been expected in Glasgow, not more. Different parts of the spectrum of coronary disease seem to be presenting in the two areas and there may be an opportunity here to dissociate "causes" of this multifactorial disease (Morris 1964). The epidemiological evidence on the distinction between "disease of the wall" and "disease of the lumen" has been given by Morris and Crawford (1961). Our findings suggest a third element, and there may be "causes" related to the myocardial lesion over and above those involved in the arterial disease.

The finding of an excess of men in the soft-water area with low values of magnesium in the coronary arteries may be important in relation to experimental work linking magnesium and myocardial disease (Vitale et al. 1959, Bajusz 1965, Goldsmith and Goldsmith 1966). The mechanisms for absorption, distribution in the tissues, and excretion of calcium and magnesium are interrelated and there is considerable ionic interchange between calcium and magnesium compounds in intermediary metabolism. In this way deficiency of one of these elements may affect the associations of the other. There is evidence that the range of dietary calcium may be greater than is appreciated; vegetables boiled in soft water lose an appreciable proportion of their calcium content to the water, while the calcium content of vegetables boiled in hard water may be greatly increased through precipitation on their surfaces from the water (Report of Government Chemist 1963). This could result in less readily available calcium in soft-water areas with corresponding effects on magnesium metabolism. In this country the fortification of bread with calcium makes an absolute dietary deficiency in calcium unlikely, but the more readily absorbed ionised calcium in drinking-water may make an important special contribution. An association between calcium intake and blood-lipid has been reported, and it has been shown that blood-cholesterol levels can be lowered by increasing calcium intake (Yacowitz et al. 1965). It is important to emphasise that the associations found between cardiovascular mortality and softness of drinking-water are not with ischaemic heart-disease only, but with all cardiovascular disease, including cerebrovascular disease; other factors, such as hypertension, or even a non-specific effect in cardiac failure, may be involved. We have no information about blood-pressure in the cases reported but in the accident series the average heart weight of the Glasgow cases was greater than that of the London cases and this was true within each 10-year age-group. Population studies of blood-pressure, blood-lipids, diet, and in particular, the minerals in the diet are needed in comparable groups in soft and hard water areas; in particular there is a need for serious investigation of the problem by chemists to help in the formulation of hypotheses and guide to further research. Large numbers of deaths are involved and elucidation of the mechanism producing the difference between the hard and soft water areas might be the key to more general problems in cardiovascular disease.

We thank the many pathologists in Glasgow and London for the collection of specimens, in particular, Dr. R.D. Teare, Dr. J.A. Imrie, and Dr. J.M. Cameron; Prof. N.H. Martin who supervised the chemical analyses; Prof. J.N. Morris, Dr. J.A. Heady, and Dr. M.R. Alderson for advice; the secretarial staff of the Social Medicine Research Unit, London Hospital, in particular Mrs. D. Greystoke; and the Medical Research Council for a grant to cover expenses. Requests for reprints should be addressed to T.C.

References

Bajusz, E. (1965) Nutritional Aspects of Cardiovascular Diseases. London.

Biorck, G., Bostrom, H., Widstrom, A. (1965) Acta med. scand. 178, 239.

Blankenhorn, D.H. (1963) in Evolution of the Atherosclerotic Plaque (edited by R.J. Jones); p 297. Chicago and London.

Crawford, T. (1966) in Second Symposium on Advanced Medicine (edited by J.R. Trounce); p 42. London.

Crawford, T., Dexter, D., Teare, R.D. (1961) Lancet, i, 450.

Goldsmith, N.F., Goldsmith, J.R. (1966) Archs envir. Hlth., 12, 607.

Lancing, A.I. (1955) inSymposium on Atherosclerosis. National Academy of Sciences: National Research Council, publication no. 338, p. 50.

Morris, J.N. (1964) Uses of Epidemiology. Edinburgh.

Morris, J.N., Crawford, M.D. (1958) Br. med. J. ii, 1485.

Morris, J.N., Crawford, M.D. (1961) Lancet, i, 47.

Morris, J.N., Crawford, M.D., Heady, J.A. (1961) ibid. p. 860.

Morris, J.N., Crawford, M.D., Heady, J.A. (1962) ibid. ii, 506.

Registrar General (1960, 1961, 1962) Statistical Review of England and Wales; part I, medical tables. H.M. Stationery Office.

Registrar General for Scotland (1960, 1961, 1962) Annual Report. Edinburgh.

Report of the Government Chemist (1963) H.M. Stationery Office.

Schroeder, H.A. (1960) J. Am. med. Ass. 172, 1902.

Vitale, J.J., Hellerstein, E.E., Hegsted, D.M., Nakamura, M., Farbman, A. (1959) J. clin. Nutr. 7, 13.

Yocowitz, H., Fleischman, A.I., Bierenbqaum, M.L. (1965) Br. med. J. i, 1352.


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