Adv. Cardiol., vol. 25, pp. 9-24 (Karger, Basel 1978)
Supported in part by the Yrjö Jahnsson Foundation,
Helsinki, and Medipolar Oy, Oulu (Finland).
A preliminary report of part of this work has been published .
The high incidence of some diseases in certain geographical areas can be explained by particular geological environments . Endemic goitre due to iodine deficiency in the soil is a well-known example of such an 'environmental or geological disease'. Great regional difference in the incidence of coronary heart disease (CHD) suggest that the causes could be environmental.
The interest in the possible role of various minerals in CHD was mainly created by reports that regional death rates from cardiovascular diseases in several countries are inversely related to the hardness and thus to the mineral content of the local drinking water [1-4, 9, 13-16, 28, 38-40, 42, 51, 52, 62, 67, 76]. Interestingly, goitre in Finland had its highest incidence in the same areas where the death rates from CHD are highest .
The high overall incidence, as well as the great regional differences in the incidence of CHD in Finland (fig. 1) offer good opportunities for studying the possible relation of geological factors to CHD.
In the present work, correlations between the hardness of drinking water and death rates from CHD in Finnish municipalities were studied. The soil contents of some minerals were also compared between the areas with the highest and lowest death rates from CHD in Finland.
Fig. 1. Relative age-adjusted death rates from CHD in different parts of Finland. The mortality rates are related to average mortality from CHD in the whole country (= 100). From PUSKA , by permission.
Water Hardness and Death Rates from CHD in Finnish Municipalities
The results of determinations of water hardness during the years 1971-1974 were obtained from all Finnish towns and some bigger population centres. The arithmetic mean of the determinations served as the hardness value for each municipality. Official statistics from the years 1969-1972 were used to calculate the death rates from acute or subacute CHD.
There is an inverse correlation between the hardness of drinking water and the death rates from CHD in Finnish municipalities (table 1). The linear dependence was statistically significant only for men in the age group 25-64 years. However, the correlation was statistically significant both for men and women in the 25-54 years age group as well as between 25-64 years, when the death rates were plotted against the logarithm of the hardness of water. Thus, the inverse statistical correlation between the hardness of drinking water and death rate from CHD was demonstrated also in Finland.
In Finland the contents of various minerals in arable soils have been extensively determined for agricultural purposes . The comparison between the areas with the lowest (area 1) and highest mortality (area 11) from CHD (fig. 1) shows that in the high mortality area in eastern Finland the soil contents of calcium, magnesium and potassium are lower than in the south-western area (table II). The difference is most pronounced, 2.7-fold, in the content of exchangeable magnesium. Also, over the whole country there appears to be an inverse correlation between the mortality from CHD and the soil content of magnesium. The soil contents of potassium and calcium show a very similar pattern to magnesium, but the differences between various parts of the country are not so marked as in the case of magnesium . The contents of copper and boron are, on the average, very similar in the two areas, whereas the content of manganese is higher in east Finland than in the south-west (table II).
Based on a smaller material it has also been reported that the soil content of selenium is lower in eastern Finland than in the other parts of the country. Even in the latter areas soil, selenium appears to be low in comparison with other countries (29]. Furthermore, in well-water samples the contents of chromium  and silicon  are lower in eastern Finland than in the west.
ANDERSON et al. [2, 3] in Canada ascribed the higher death rates in soft-water areas entirely to an excess of sudden deaths due to an increased susceptibility to lethal arrhythmias among residents of soft-water areas. A study in USA, which defined sudden death as occurring at home or on arrival at hospital, also indicated that a greater proportion of cardiovascular deaths were sudden in the towns with soft-water supplies . Recently, CRAWFORD et al. in England and Wales reported a higher death rate from all cardiovascular diseases including sudden deaths in the soft-water towns when subjects were classified by age or social class, and also during both winter and summer.
Provided that the correlation between water hardness and soil minerals on one hand and death rates from CHD on the other hand is causal and not a spurious one, one or more of the following mechanisms could increase mortality: (1) absolute decrease in the intake of cardioprotective minerals; (2) absolute increase in the intake of cardiotoxic minerals; (3) relative changes in the intake of minerals in favour of cardiotoxic factors.
Calcium and magnesium are the main elements contributing to the hardness of the water. As calcium is usually present in larger amounts, there has been more attention paid to the possibility that calcium is the protective 'water factor' . Inverse correlations between the calcium content of water and CHD, between dietary calcium intake and CHD, and as well with total mortality have been observed [18, 27].
An increase in dietary calcium can lead to a decrease in serum lipids, probably by the formation of insoluble soaps in the gut . Calcium may also compete with lead for absorption from the gut. This has been advocated as an alternative mechanism by which a high intake of calcium may decrease mortality .
Under certain circumstances high intakes of calcium may increase rather than decrease the death rate from CHD . There is a highly significant positive correlation between death rates from CHD and estimated calcium to magnesium ratios of the average diets in OECD countries (fig. 2).
Fig. 2. Relationship between death rates from CHD and the average calcium to magnesium ratio of the diet in different OECD countries. Data adapted from KEYS  and VARO .
Since the daily intake of calcium is higher in Finland than in most other countries  the high death rate from CHD in this country cannot be attributed to a deficiency of calcium.
There is plenty of experimental, clinical and epidemiological evidence to suggest that magnesium may have important implications in CHD and sudden coronary death. Magnesium is one of the major inorganic constituents of the cell. It is essential for the activation of many enzymes and its plasma concentration in relation to that of calcium affects nerve transmission and muscular contraction. Magnesium participates in many of the most vital oxidative, synthetic and transport processes of the myocardial cells .
In clinical practice great emphasis is placed on potassium loss in the etiology and intensification of cardiac arrhythmias and cardiomyopathy. Recent evidence indicates that magnesium loss may also be an important factor in these conditions. Magnesium is necessary for the integrity of the mitochondrial system, which is responsible for the maintenance of cellular potassium as well as for the metabolic, processes . Magnesium loss from the heart, as from other tissues, interferes with the cellular machinery, without which cardiac potassium cannot be maintained . Magnesium loss thus predisposes to potassium loss.
Recent studies indicate that cellular loss of magnesium may be a basic biochemical mechanism in the evolution of arrhythmias and myocardial lesions of diverse etiology. Net loss of magnesium from the myocardium is a well-known phenomenon associated with oxygen deficiency. Loss of magnesium from hypoxic myocardium has been found both in several cardiomyopathic animal models and in patients who have died of myocardial infarcts [43, 59, 60, 62]. An early elevation of myocardial calcium is associated with a fall of myocardial magnesium both in experimental models of myocardial infarction and in human sufferers [59, 60, 62].
High doses of catecholamines cause myocardial necrosis, which is preceded by an elevation of myocardial calcium and a drop in myocardial magnesium , as well as a serious fall in the myocardial content of high-energy phosphates [19, 20]. These catecholamine effects are particularly interesting since psychogenic factors [49, 50] and the sympathetic nervous system  appear to be involved in sudden coronary death.
Both the fall of magnesium and elevation of calcium, which are associated with myocardial damage, may increase cellular excitability, thereby contributing to the development of ventricular arrhythmias .
Dietary magnesium deficiency in animals predisposes to ventricular extrasystoles (30, 73] and myocardial damage .
Prolonged therapy with thiazide diuretics is known to induce, in addition to hypokalemia, a marked magnesium deficiency in a considerable proportion of patients [17, 34]. Loss of magnesium and potassium and retention of calcium by thiazide diuretics increase the risk of arrhythmias . This might partly explain why the treatment of hypertension has not diminished the death rate from CHD, in spite of marked reduction in other complications. It has been suggested that patients on diuretics should be given magnesium together with potassium supplements . The administration of magnesium is especially important, since in magnesium deficiency there is refractoriness to potassium repletion . Moreover, administration of magnesium has also been shown to restore potassium stores .
On the basis of metabolic balance studies it has been concluded that occidental magnesium intakes are suboptimal [57, 69]. The amount of magnesium provided by hard water may be sufficient to correct a marginal deficit, thereby contributing to the lower death rates from ischemic heart disease in hard-water than in soft-water areas . Residents of soft-water areas have lower magnesium concentrations in heart muscle  and coronary arteries [141 than do residents of hard-water areas. Moreover, a diminished content of myocardial magnesium has been found after a sudden death from heart disease .
The results of an exhaustive work by ALLEN  in Ontario, Canada, suggest that the protective effect of hard water in CHD is due to the magnesium component. Magnesium was more effective than total hardness, which in turn was more effective than calcium in favourably influencing the rate of sudden deaths from CHD. The role of magnesium in maintaining a normal rhythm of the heart in the face of an ischemic insult might explain the difference in sudden cardiac death rates between hard and soft-water areas .
The average content of magnesium in Finnish soils is low [31, 32]. This is especially true for the eastern areas where the death rates from CHD are very high. The low soil content is reflected in a very low content of magnesium in the drinking water and a lower intake of magnesium in eastern Finland compared with the south-western parts of the country.
In the past half century, magnesium intakes have fallen, whereas dietary contents of protein, fat, sugar, and calcium have risen . High intakes of these nutrients increase magnesium requirements and increase susceptibility to magnesium deficit [57, 58, 61, 62]. Due to the low content of magnesium in the drinking water, and possibly also in agricultural products, such a change may have more, serious consequence in eastern Finland than in most other areas. Moreover, the consumption of milk products is, on the average, higher in Finland than in any other country . The calcium to magnesium ratio in milk is about 12:1 . The high calcium concentration in the average Finnish diet is likely to inhibit the intestinal absorption of magnesium  and also to increase the loss of magnesium . Thus, because of the geochemical environment and dietary habits the occurrence of magnesium deficiency is more likely in Finland than in most other countries. However, it should be emphasised that no studies have been done to examine whether magnesium deficiency does exist in Finland.
If the relation of magnesium depletion to cardiac arrhythmias and myocardial damage is a causal one, magnesium administration should have a beneficial effect in these conditions. In fact, there is laboratory evidence that magnesium salts protect against hypoxic damage to the heart [5, 10, 62]. Magnesium chloride and calcium antagonists also protect against catecholamine-induced myocardial damage . In man, successful use of magnesium in the treatment of cardiac arrhythmias of various etiologies has been reported [34, 62, 63, 68, 78]. Correction of the magnesium deficit protects against cardiovascular lesions in several species of animals on atherogenic, magnesium-deficient diets [41, 62].
Potassium depletion predisposes to cardiac arrhythmias. The soil content of potassium is lower in eastern Finland than in Southwestern Finland, and potassium intake is probably lower in the high-mortality area. Since monovalent cations are easily absorbed from the gastrointestinal tract, a primary dietary deficiency of potassium seems unlikely. Decreased dietary intake is likely to predispose to potassium depletion in cases of increased loss due to diuretic therapy or gastrointestinal causes.
Little is known about the exact role of several other minerals upon CHD and sudden death in man and further studies are needed to establish their role. Chromium in cardiovascular diseases has been reviewed earlier . Chromium deficiency in rats induces atherosclerosis, and results of epidemiological studies indicate that chromium may also be related to cardiovascular disease in man. In populations with low incidences of cardiovascular diseases the chromium content of the heart, kidney and aorta is many times higher than in populations with high incidences of these diseases. Chromium is necessary for glucose and lipid metabolism. The decreased or absent aortic chromium in atherosclerosis may reflect the same thing in the coronary arteries, which leads to abnormal metabolism and plaque formation.
The concentration of chromium in drinking water was found to be lower in the high-mortality area of eastern Finland compared with the low-mortality area in the west Finland (44]. The urinary excretion of chromium of the two populations was similar and no consistent differences were found in urinary chromium excretion between groups with atherosclerotic diseases and reference groups . In population studies in Canada and UK, chromium, either in myocardial tissues or as a water constituent, has not been found to be associated with increased CHD or sudden deaths [4, 18].
Selenium has proved to be cardioprotective in several animal studies [21, 22, 37, 64, 65]. Death rates from cardiovascular diseases have been reported to be lower in a very high selenium area than in the low selenium area [651. The selenium content of the Finnish soil is low . The level of selenium is also low in the blood of Finns, suggesting possible selenium deficiency .
Results from silicon are contradictory. Silicon seems to protect the elastic state of the artery walls and has been claimed to maintain the intimal impermeable to lipid infiltration . Silicate-silicon may be the active agent in dietary fibre  which affects the development of atherosclerosis. Water appears to provide several times more silicon than food [531. Drinking water in east Finland contains less silicon than in west Finland [561.
A positive correlations between cardiovascular mortality and silicon content in drinking water, consistent with a harmful effect of this element, has been found . Moreover, when silicon in heart muscle from people who had died suddenly from ischemic heart disease and from controls in the same area was measured, it appeared that the cases of sudden death had higher concentrations of silicon than the controls, though the difference was not statistically significant .
Incidence and severity of aortic calcification have been found to be lower in areas supplied with highly fluoridated waters than in non-fluoridated areas . Addition of fluoride and magnesium to high sucrose, high phosphate diets prevented aortic calcification in rats [361. A lower incidence of cardiovascular disease in the areas with the highest concentrations of fluoride and magnesium in the drinking water compared with areas with low concentrations of these elements in water is found . However, the magnesium component may have played an important role in these results. On the other hand, it has been shown that high doses of fluorine produce focal myocardial necroses and lesions of the cerebral cortex in the rat .
Manganese has been reported to exert a beneficial effect on lipid metabolism in atherosclerotic patients, and to prevent the development of experimental atherosclerosis in rabbits . However, the content of manganese in soils is higher in the high-mortality area of eastern Finland compared to south-western Finland. Soft water also contains more manganese than hard water .
When administered to rats in doses which produced the tissue levels of cadmium found in North-American subjects, cadmium produced hypertension, hypertrophy of the left ventricle and sclerosis of the small arteries in kidneys, heart and other organs . A positive correlation between the cadmium content in the air and the incidence of hypertension and atherosclerosis in 28 North-American cities has been demonstrated. Cadmium is present in high concentrations in the kidneys and urine of hypertensive patients . In Kansas City, Kansas, the content of cadmium in drinking water is three times higher than in Kansas City, Missouri. The higher content of cadmium in water was associated with a tenfold higher content of this metal in serum, significantly higher systolic and diastolic blood pressures, and higher mortality from cardiovascular diseases in Kansas City, Kansas, than in Kansas City, Missouri . Due to corrosive properties of soft water, cadmium is dissolved from pipes so that content is usually higher in soft water than in hard .
Renal cadmium concentration is lower in populations relatively unexposed to industrial surroundings. Hence it seems probable that exposure to cadmium in the rural areas of eastern Finland is not high. Furthermore, in these high mortality areas a big proportion of drinking water is derived from private wells, either via short water pipes or without pipes. In spite of the water being soft, these local conditions diminish the risk of waterborne exposure to cadmium. On the other hand, it has been reported that the so-called 'muikku' fish (Coregonus albula) which is heavily consumed in eastern Finland, contains the highest cadmium concentration of all Finnish fish products . Another source of cadmium is cigarette smoke . Men, but not women, in eastern Finland are heavy smokers . This might partly explain the great difference in the death rates from CHD between men and women in this area. However, the body burden of cadmium in Finland is not known.
Lead is another metal which is present in higher concentrations in soft water than in hard . Fed in water to rats, lead causes myocardial damage . However, in South Wales any connection between lead content in water and mortality seems to be very slight .
Copper in the context of cardiac diseases has been reviewed earlier . Copper is present in higher concentrations in soft water than in hard. In patients suffering from myocardial infarction, serum copper was increased. In experimental animals the, addition of copper to the diet resulted in a higher degree of atherosclerosis. In atherosclerotic subjects the copper content of the aorta wall was found to be decreased, while that of the myocardium increased.
No significant correlation between the water content of copper and cardiovascular mortality was found in England and Wales . Also, the average soil content of copper in the areas with the highest and lowest rates from CHD in Finland are similar. Thus, at least in Finland, the regional differences in the death rates from CHD can hardly be attributed to different intakes of copper.
There is evidence that loss of myocardial magnesium and potassium, and rise in myocardial calcium predispose to ventricular arrhythmias and thus to sudden coronary death. Myocardial depletion of magnesium and potassium may be due to hypoxia, decreased dietary bioavailability, or increased loss of these minerals. In experimental animals, dietary magnesium deficiency also promotes the development of atherosclerosis. Deficiency of several trace elements, such as chromium and silicon, may also increase the risk of atherosclerosis. On the other hand, an increased body burden of cadmium may predispose to sudden coronary death by inducing hypertension.
In Finland the soil contents of several minerals, e.g. that of magnesium, are very low, especially in the eastern areas where the mortality rates from CHD are high. The low soil content of mineral in eastern Finland could lead to deficiency states which may be involved in the high mortality from CHD.
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H. KARPPANEN, MD, Department of Pharmacology, University of Oulu, SF-90100 Oulu 10 (Finland)
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