1 Introduction: Consideration of Epidemiologic Factors 1.1. Ischemic Heart Disease The most alarming trend in the past half-century has been the sharp increase in sudden deaths from ischemic heart disease (IHD), particularly in middle-aged men, and the increasing number of younger men who suddenly develop myocardial infarctions, cardiac arrhythmias, or arrests. That men in the prime of life are thus afflicted is the dramatic and tragic tip of the iceberg. Underlying these catastrophes is the widespread increase in incidence of atherosclerosis in young age groups, and in myocardial hyperexcitability and cardiomyopathy without notable coronary ath erosclerosis. It is proposed that magnesium deficiency or loss may be a common etiologic factor in the increased incidence of sudden infant deaths, infantile myocar dial infarction and arteriosclerosis, and the disease that becomes manifest later in life. It is also suggested that magnesium deficiency might also cause or predispose to some skeletal and renal diseases, all of which can coexist. The cardiac problem in men has been deemed of sufficient magnitude as to be termed an epidemic that has been increasing, particularly since the middle 1930s. It has led to widespread institution of therapeutic and prophylactic regimens on the basis of suggestive findings. For example, young women have a significantly lower incidence of ischemic heart disease than do young men (Fig. 1-1). Because their al,8-lipoprotein ratios differ from those of the more susceptible young men and especially from those of patients with peripheral or coronary atherosclerosis, there was a period during which estrogens were widely used in the treatment of patients with myocardial infarctions and given prophylactically to high-risk (hyperlipidemic) men and postmenopausal women. This approach has been largely discontinued, predominantly because of the resultant increase in risk of thrombosis: Another approach that was given a trial period was administration of excesses of unsaturated fatty acids; the incidence of atherosclerosis and IHD is lower in countries where more vegetable oils than saturated animal fats are consumed. A modification of the fatty-acid-supplement regimens that has been receiving extensive clinical trial is to M. S. Seelig, Magnesium Deficiency in the Pathogenesis of Disease © Plenum Publishing Corporation 1980 2 CHAPTER I 8 7 6 5 " - .... 3 E 2 .eQ ., )( VI 0·5 20 30 AO 50 Aqe 60 70 80 FIGURE I-I. Ratio of male to female cardiovascular death rates by 5-year age groups based on death rates for England and Wales. (From TW Anderson: New Scientist 9:374-376, 1978.) replace saturated with unsaturated fats. This approach has lowered blood lipids, but not the incidence of IHD. Because altering fat intakes of patients with established hyperlipidemia and atherosclerosis has not reduced the mortality from IHD, it has been recommended that the time to institute such a dietary modification might be in early infancy, a suggestion that has been disputed. 1.2. Concomitant Cardiovascular, Skeletal, and Renal Diseases Among women, the incidence of atherosclerosis and IHD increases with age, especially after the menopause, often in association with osteopenia or with calcific renal disease. The combined problem of bone wasting and extraskeletal calcifica tion (particularly renal and cardiovascular) is also encountered in renal osteodystro phy and in other conditions associated with hyperparathyroidism and phosphate treatment of hypercalcemia. Rarer forms of osteopenia, usually found in association with cardiac anomalies, arteriosclerosis, and renal calcinosis, are seen in infants oflow birth weight, or who have osteogenesis imperfecta or hypophosphatasia. The more common, but not widely known, arteriosclerosis and IHD of early infancy is also usually accompa nied by renal calcinosis, as is the later form that is accompanied by hyperlipidemia, hypertension and atherosclerosis. The latter type-some forms of which are asso ciated with aortic and pulmonary stenoses and atresias, and with endocardial fibro elastosis-has been attributed to hypervitaminosis D (Seelig, 1969b; Seelig and Haddy, 1976/1980) which contributes to loss of magnesium. These conditions are INTRODUCTION: CONSIDERATION OF EPIDEMIOLOGIC FACTORS 3 stressed in this volume because they support the supposition that atherosclerosis (and some renal and skeletal diseases) have their roots early in infancy and have put the onus on the absolute or conditioned magnesium deficiency that has become a problem during this century. Magnesium plays an important role in maintaining the integrity of the myocar dium, kidneys, and bone. Its deficiency has been shown to cause cardiomyopathy in several animal species, and to intensify myocardial lesions caused by a variety of modalities. Its deficiency has caused arteriosclerosis and has intensified formation of atheromata, or arteriosclerosis, thrombosis, and even myocardial infarction, induced by atherogenic diets, high intakes of vitamin D, calcium, phosphate, and fat. Its deficiency has caused renal lesions and intensified damage produced by vita min D, calcium, and phosphate. And its deficiency has been implicated in some forms of bone damage. Magnesium supplementation has prevented or reversed some of the lesions in the experimental models and been used clinically in cardio vascular disease and urolithiasis. 1.3. Changing Magnesium, Vitamin D, and Phosphate Intakes Examination of the changing nutritional intakes in America, particularly from the middle 1930s is disconcerting in light of these experimental findings. Although magnesium intakes have been gradually falling since the beginning of the century, there were sharply increased intakes of nutrients that increased its requirements [particularly high vitamin D and phosphorus intakes (Seelig, 1964, 1971) subse quently (Fig. 1-2)]. The rise in vitamin D intake began when the addition to each quart of milk of a sufficient amount (400 IU) to cure, rather than merely to prevent, rickets became widespread from the mid 1930s and was made mandatory in most states from the 1940s to 1950, either replacing cod liver oil, or taken in addition to it (Baldwin, 1953; Seelig, 1969b, 1970b). Fortification of many foods in addition to milk, including milk flavoring, oleomargarine, breakfast cereals, or "substitutes," led the Committee on Nutrition of the American Academy of Pediatrics to express concern about the total daily intake of vitamin D in the United States, which they calculated might range from 600 to 4000 IU/day from marketed fortified products (Table 1-1). A survey of 1000 Canadian children from 1 week to 51/2 years of age showed that 70% consumed more than 400 IU, and 30% consumed over 1000 IU of vitamin D daily (Broadfoot et al., 1972). Table 1-2 depicts the sources of vitamin D among those receiving over 1000 to 1800 IU of vitamin D per day. The major source of phosphorus derives from soft drinks that contain phosphoric acid, the consump tion of which has been rising markedly in the last quarter of a century (Henderson, 1972; Lutwak 1974). Although it is generally believed that the rise in blood lipids is due to increased intakes of saturated fats during this century, and that sugar consumption has also increased substantially, comparison of per capita intakes from 1909 to 1%5 shows relatively minor changes (Fig. 1-3). The average daily fat intake rose from 112 to 4 CHAPTER 1 .?,. .?,. •N• ? CHINA IN YOUNG AMERICANS (19411 FROM 1901 -19 76 171 ;N- t CHU(t9E~IAL 1901 -1922 1932-1939 1947-1957 1960-1967 1970-1975 - SURVEY' (I 1 FRIEND,I967; (21 WALKER a PAGE,I977 ·-BALANCE STUDY: (II BOGERT a TRAIL,I922; SCOULAR ET AL ,1957, (31 LEVERTON ET AL,I962. -"SEELIG,I964 t PROBABLE INTAKE}(SEELlG,I9691 tt MINIMAL INTAKE FIGURE 1-2. Changes in intakes of magnesium and nutrients that increase magnesium requirements (calcium, phosphorus, vitamin D). Z -l ~ 0 c:: (") -l 0 z (") 0 z a 00 ttl ;0 > -l 0 z 0 "T1 tIl :!! 0 ttl ::: 0 r-0 Cl ?i '"!j > (") -l 0 ;0 00 VI Total intake (IU/day) High Average SOO 1400 600 (1600) 2600 (3000) SOO (1200) 2900 (4700) 1200 2000 300 (SOO) 3250 (3400) 700 (1100) 4100 (4250) alues. v b Special candy bar or biscuit (400) (SOO) (100) (150) (150) ng these Da of Vitamin dividual food (IU/day) Special Breakfast breakfast cereal drink 200 400 200 (1000) 400 400 200 400 400 SOO ncluding and once excludi TABLE 1-1. Hypothetic Total Daily Intakes Amount of vitamin D contributed by in Vitamin Milk, Milk, Milk, Milk, upplement liquid evaporated powder flavoring Margarine A. Children in United States 400 400 1000 400 (1000) 300 100 1000 400 450 350 (400) 400 200 1000 400 500 600 B. Children in Canada 400 SOO 1000 1000 (400) 25 275 1000 450 400 SOO 25 275 (400) 1000 500 600 SOO on Nutrition of the American Academy of Pediatrics (1963). n parentheses, total intake of vitamin D has been calculated twice; once i Age of child Intake s 6mo Average High 3yr Average High S yr Average High 6mo Average High 3 yr Average High S yr Average High From the Committee a • When values appear i 6 CHAPTER 1 TABLE 1-2. Vitamin D Intake Pattern of All Children Comsuming 1000-1799 IV and 1800 + IV Daily Average daily intake of vitamin D (IV) for children receiving Supplement and fortified foods Age Fortified foods only 1000- 1800 + Supplement only Source (months) (1000-1799 IU) 1799 IU IU (1000-1799 IU) Vitamin supplement 0-6 526 (56) 1200 (5) 1000 (9) 7-66 1045 (196) 1426 (17) 1000 (24) Milk 0-6 663 (56) 800 (5) 7-66 3W (4)a 71 (27) 317 (8) Margarine 0-6 7-66 442 (7) 85 (91) 166 (9) Cereal 6-6 7-66 478 (6) 173 (149) 182 (10) Milk flavorings 0-6 7-66 35 (4) 21 (81) 15 (6) Biscuits 0-6 1 (2) 7-66 5 (8) 28 (3) Fruit drinks 0-6 7-66 4 (5) TOTAL AVERAGE INTAKE 0-6 1190 (56) 2000 (5) 1000 (9) 7-66 1269 (7) 1404 (196) 2134 (17) 1000 (24) a The number of children receiving vitamin D from the source specified in the left margin is shown in parentheses. b Average intake of vitamin from this source for all children in the intake group. 130., u 520 120 480 110 440 100 400 ~ 90 360 ~ <t !of 80 320 :5 > a>- I- 70 280 I <t III "- 60 240 ~ u ~ 50 <t <::;I:l ~ 40 <t a: 30 120 <!) 20 80 10 40 oLJI~~IIfl~~~~~~~~~~~~~~ o 1935-1939 FIGURE 1-3. Fatty acid and carbohydrate intakes per capita per day from 1909 to 1965 (United States). (Adapted from Friend. 1967.) INTRODUCTION: CONSIDERATION OF EPIDEMIOLOGIC FACTORS 7 132, but most of the increase has been in unsaturated fatty acids. The total carbo hydrate intake dropped from 492 to 374, so that the greater percentage increase of sugar in 1965 reflects an increase of about 40 grams daily. Probably the sugar intake has risen more since the 1965 value (Fig. 1-2) among those who drink larger quan tities of sugar-sweetened, phosphorus-containing soft drinks. Largely disregarded is the possibility that the hyperlipidemia associated with atherosclerosis might be caused by hypervitaminosis D, which also causes hyper tension (Linden, 1977; Seelig and Haddy, 1976/1980), as well as the more widely recognized complications; cardiovascular and renal damage, and hypercalcemia (Seelig, 1969b). Much of the clinical data on the cardiovascular, skeletal, and renal damage caused by vitamin D derives from the use of massive doses of vitamin D a quarter of a century ago in the treatment of such diseases as rheumatoid arthritis, and from the lesser overdosage of European children at a time when administration of up to 4000 IV/day was not uncommon (Table 1-3; Seelig, 1969b). The sharp rise in vitamin D intake depicted for the 1947-1957 segment of Fig. 1-1 is presumed because of the probable consumption of large quantities of milk by the college stu dents studied-an impression suggested by their high calcium intake (Scoular et al., 1957), in contrast to the lower intake noted in a general diet survey (Friend, 1967). Since the amount of vitamin D needed by most adults is considered so small as to be met by exposure to sunlight and by ingestion of natural (unfortified) foods (Food and Nutrition Board, 1968), such high intakes must be considered well into the toxic range. As long ago as 1932, L. Harris reported that in the human, the toxic dose of vitamin D is not far removed from the therapeutic (antiricketic) dose. Stew art (1964) reported that there is a narrow toxic-therapeutic ratio. Furthermore, even most infants are protected against rickets by as little as 100 IU of vitamin D daily (Fraser, 1967), whereas a survey of young Americans showed that 50% ingested 400-800 IU daily, 10% usually consumed over 1000 IU daily, and occa sionally as much as 2900 IU were taken (Dale and Lowenberg, 1967). Epidemiologic data have correlated moderately high vitamin D intake with increased incidence of myocardial infarction, renal calcinosis, and urolithiasis (Linden, 1974a,b). In TABLE 1-3 (A). Fortification of National Dried Milka Date IV vitamin D per dry ounce Recommendation by 1945 280 Ministry of Health 1953 500 Ministry of Food 1957 90-100 Ministry of Health TABLE 1-3 (B). Calculated Daily Intake of Vitamin D (1956)a 1'k pints dried milk (460 V/dry oz.) 1725 IV I ounce cereal (l000-15OO/dry oz.) 1000-1500 IV 1 tsp. cod liver oil 700-800 IV TOTAL: 3525-4025 IV From Report of Subcomm. of Brit. Ped. Assoc., Lancet. 1956. U 8 CHAPTER 1 northern Norway, where intake of natural foods rich in vitamin D is common, the incidence of hypercholesterolemia and susceptibility to sudden death from ischemic heart disease and to calcific renal diseases, two conditions which are often found in the same patient (Linden, 1972, 1975/1977; Westlund, 1973), seems to be related to the amount of vitamin D ingested and to the individual sensitivity to solar irradia tion. Since magnesium deficiency is also associated with abnormal lipid distribu tion, and vitamin D excess causes magnesium loss, interrelations of protracted high intakes of vitamin D with magnesium requirements, and with the cardiovascular and renal lesions of each imbalance, deserve study (Seelig, 1977). Like magnesium deficiency and hypervitaminosis D, excess phosphate has also been implicated in cardiovascular, skeletal, and renal damage. The nature of the pathologic changes produced by dietary excesses of phosphorus depends upon its ratios to both calcium and magnesium. Figure 1-2 shows that the phosphorus intake increased sharply in the college studies during the periods analyzed in 1947-1957 (Scoular et al. 1957), and in the most recent survey of college diets (Walker and Page, 1977). The lower phosphorus level entered in the 1960-1967 block of columns derives from an extensive metabolic balance study in several colleges (Leverton et al., 1962). One can speculate that during these strictly controlled periods there was likely to have been less consumption of soft drinks containing phosphoric acid than during the self-selected dietary intakes reflected in the college diet surveys. The recommended phosphoruslcalcium (PICa) ratio is 1.5/1 (U.S. Department of Agriculture Report, 1972). In 1932-1939, the PICa ratio was about 1.2/1; it was estimated to be rising to as much as 411 among those who substitute sodas for milk (Lutwak, 1974). This shift in ratios was stressed as potentially harmful to bones, as a result of secondary hyperparathyroidism, on the basis of the effect of the osteo penia produced by comparable PICa dietary ratios in several species of animals, up to the monkey (Krook and Barrett, 1962; Krook et at., 1963, 1971; Henn :son et al., 1970; Draper et ai., 1972; Krishnarao and Draper, 1972; Krook et ai., 1975). However, the most recent dietary survey of college diets from fifty colleges (M. Walker and Page, 1977) showed that the mean PICa ratio was about 1.5/1, both phosphorus and calcium intakes having risen to 1200 and 1700 mg/day, respectively. What had dropped was the magnesium intake-to a mean of 250 mg/day. Such diets provide dietary ratios of Ca/Mg and P/Mg of almost 5/1 and almost 7/1, respectively. Since an excess of either phosphorus or calcium has been shown to increase mag nesium requirements and to intensify signs of magnesium deficiency (Reviews: See lig, 1964, 1971), such a dietary pattern-particularly when accompanied by high vitamin D and phosphate intakes by many-can be expected to produce either absolute or relative magnesium deficiency. 1.4. Sex Difference in Magnesium Retention Analysis of published metabolic balance studies (such as are done to establish a nutritional requirement, an amount sufficient to maintain equilibrium) has shown that young men require more magnesium in mg/kg/day than do young women (Fig. 1-4) (Seelig, 1964). The studies analyzed had been obtained from throughout the world, and showed that young Americans tended to ingest less magnesium on self- INTRODUCTION: CONSIDERATION OF EPIDEMIOLOGIC FACTORS 9 M ..M GNGE/SKICU . ..I. DIANYT AKE «0 .. 0-'" V 50-5 9 6 o· e 'D 70-100 > 100 SEX if '? 0' '? if ? if ? 0' '? if '? TOITNA L ALNLU ..... SBTEIRJ OID[SAY S 858 181 8., ',082 858 272 ••• 211 1,099 5' 171 16 NPUEMRa4E0AD S or" [o&PrAO L~,AT}NE.oOC E 105 1<6 167 176 95 53 55 32 59 6 43 < P£RC(NTAC( 15 .3 54 58 '6 ' 0 22 12 22 33 1< 0 BALANNECGEA TPIV[R[ IODS +IS 83 73 72 55 58 >3 31 28 3< 50 I. 0 AVERAGE DAILY MAGNESIUM BALANCE" 178 Me OF' MACNESIUM ~o PER OAY 40 20 AVERAGE PERCENT" OF INTAKE EXCRETED IN FECES 80 60 40 20 60 AVERAGE PERCENT" Of INTAKE EXCRETED IN URINE FIGURE 1-4. Influence of sex on magnesium balance and on percentage of intake excreted at different intakes of magnesium. *Figures are weighted by multiplying by number of days in each study. Only balance periods in which mg/kg intake can be calculated are included in analysis. (From MS Seelig: Am J Clin Nutr 14:342-390, 1964.) selected diets than did Orientals and, on average, tended to be in negative balance. This was particularly so for the young men, who on the average excreted more magnesium than they ingested on the typical American intake of 4-4.9 mg/kg/day. Young women on that typical intake, on the other hand, tended to remain in equi librium. The typical magnesium intake of the Orientals studied was between 7 and 10 mg/kg/day, and positive balance or equilibrium was the rule. In deriving the recommended magnesium intake from the data analyzed, the intake was selected at which equilibrium or positive balance was reached in at least three-fourths of the subjects. On this basis, the minimal daily requirement is 6 mg/kg/day. For a 140-lb woman, this comes to 385 mg of magnesium daily; for a 185-lb man, at least 500 mg/ day. Americans, and others in industrialized countries, tend to ingest diets rich in other nutrients (fat, protein, sugar, phosphorus, and vitamin D), all of which increase magnesium requirements (Seelig, 1964, 1971; Lindeman, 1976/1980). In addition, moderate to heavy ingestion of alcohol (even as "social" drinking) is not 10 CHAPTER 1 uncommon, and alcohol is magnesuretic (McCollister et al., 1958, 1963; Kalbfleisch et al., 1963). Thus, a magnesium intake of7-10 mg/kg/day might be preferable. On this basis, a 185-lb man might require 580-800 mg/day of magnesium, probably approximately twice as much as his diet normally delivers. Possibly a woman (unless she is pregnant or lactating) requires somewhat less. The most recent survey of college students (from 50 colleges) shows that less than the modest officially recommended amount [300 mg for women; 350 mg for men (Food and Nutrition Board, 1974)] is the amount usually ingested (M. Walker and Page, 1977). Actually, the mean daily magnesium intake of the college students (250 mg) may well be no more than halfthe amount required by the young women; it may be as little as one half to one-third the amount needed by large, athletic young men. In contrast to their inadequate magnesium intake, they ingest one and a half times the recom mended amount of calcium and twice the phosphorus allowance. Consumption by young college women of diets that provide suboptimal amounts of magnesium is not unique to the 50 colleges surveyed. N. Johnson and Philipps (1976/1980) surveyed the diets of pregnant women from different economic brackets, and found that their magnesium intakes ranged from 103 to 333 mg/day, with an average of 204 mg daily, an amount grossly inadequate for pregnant women. Ashe (1979) confirmed the inad equacy of prenatal magnesium intakes of 10 healthy white women from private practices in Tennessee by 7-day metabolic balance studies done at intervals throughout pregnancy. Their mean daily magnesium intakes were only 60% the recommended 450 mg/day, and mean balances were -40 mg/day. Only 3 of the 47 periods were positive. The investigators suggested that high calcium, phosphorus, and protein intakes might have intensified the severity of the negative magnesium balances. The significance of such low magnesium intakes during gestation, as regards the cardiovascular, skeletal, and renal status of infants of women with ges tational magnesium deficiency, is considered in Part I of this volume. Now that high fiber- (and phytate-) containing diets are increasingly being rec ommended, the effect of such diets on a magnesium intake that is otherwise meager should be explored. Review of metabolic studies of magnesium utilization by sub jects on diets rich in phytates-brown bread, brown rice, oatmeal, or white bread to which phytate had been added-showed poor percentage absorption of the mag nesium, particularly when the diet was first changed (Seelig, 1964). After several weeks on the phytate-rich diet, the absorption of magnesium tended to improve (A. Walker et al., 1948; Cullumbine et ai., 1950; Hathaway, 1962). McCance and Wid dowson (1942a,b) found that addition ofphytate to white bread caused greater fecal magnesium excretion, and removing phytate from brown bread greatly improved magnesium absorption. Reinhold et al. (1976) have recently confinued these obser vations, not only for magnesium but for trace metals. Thus, the higher magnesium content ofphytate-containing whole grain products may not be a reliable source, in terms of availability of magnesium. Whether adaptation to the phytate ingested, on its continued inclusion in the diet, will result in better utilization (as suggested in the early cited studies) remains to be investigated systematically. Long-term metabolic studies provide a more valuable index of adequacy of intake than do short-term studies. Figure 1-5 shows that on very low intakes « 4 mg/kg/day) the young men remained in negative balance for the average of 52 days of study, whereas the young women retained sufficient magnesium at the end of