Magnes Trace Elem (1991-92;10:182-192
Department of Physiology, State University of New York Health Science Center at Brooklyn, N.Y., USA
Key Words. Atherogenesis - Coronary vasospasm Bioenergetics, cellular - Dietary Mg intake - Lipid accumulation- Modulation of Ca metabolism in cardiac and vascular muscle
Abstract. Hypertension and atherosclerosis are well-known precursors of ischemic heart disease, stroke and sudden cardiac death. Although there is general agreement that the atheroma is the hallmark of atherosclerosis and is found in coronary obstruction, there is no agreement as to its etiology. It is now becoming clear that a lower than normal dietary intake of Mg can be a strong risk factor for hypertension, cardiac arrhythmias, ischemic heart disease, atherogenesis and sudden cardiac death. Deficits in serum Mg appear often to be associated with arrhythmias, coronary vasospasm and high blood pressure. Experimental animal studies suggest interrelationships between atherogenesis, hypertension (both systemic and pulmonary) and ischemic heart disease. Evidence is accumulating for a role of Mg2+ in the modulation of serum lipids and lipid uptake in macrophages, smooth muscle cells and the arterial wall. Shortfalls in the dietary intake of Mg clearly exist in Western World populations, and men over the age of 65 years, who are at greatest risk for development and death from ischemic heart disease, have the greatest shortfalls in dietary Mg. It is becoming clear that Mg exerts multiple cellular and molecular effects on cardiac and vascular smooth muscle cells which explain its protective actions.
Globally, among the leading causes of death, hypertension and atherosclerosis rank at the top of the list. These cardiovascular diseases, obviously, are the forerunners or precursors of ischemic heart disease, stroke and sudden cardiac death. Among mortality and morbidity indices for man, ischemic heart disease ranks at the top of the list. In the industrialized world ischemic heart disease is the leading killer and accounts for approximately 35% of all deaths each year. The incidence of this disorder rises to 80% in people over 70 years of age. The most common cause of death results from insufficient coronary blood flow.
Some deaths can occur rather suddenly, for example, sudden-death ischemic heart disease. Possibly, as many as 40-60% of the latter may occur in the complete absence of any prior atherosclerosis, thrombus formations or cardiac arrhythmias [for review, see 1]. These syndromes are often referred to as nonocclusive sudden-death ischemic heart disease. Other forms of ischemic heart disease can result in death as a consequence of an acute coronary occlusion or ventricular fibrillation, whereas others are still thought to come about from slow, progressive occlusion of coronary vessels over a period of weeks to years.
Although there is general agreement that the atheroma is the hallmark of atherosclerosis and is found in coronary obstruction, there is no agreement at present as to either the characterization of the early intimal changes or their etiology.
Irrespective of the etiology of atheromas, the lesions usually consist of a fibrous cap containing smooth muscle cells, macrophages, foam cells and lymphocytes [for reviews, see 2, 31. In addition, there appears formation of dangerous necrotic centers consisting of cholesterol crystals, cholesterol esters, calcium ions and dying foam cells. What produces these characteristics is not completely known.
Although vascular smooth muscle cells in atheromas change from a contractile to a noncontractile state and become responsive to platelet-derived growth factor and elaborate connective tissue, no one knows how these cells are transformed. Finally, although T lymphocytes, platelets, neutrophils and macrophages are found in developing atherosclerotic plaques, it is not known what allows such cells to enter the vessel wall or be attracted to the potential plaque site.
Although many theories have been suggested in the etiology of hypertension, it is not known why peripheral blood vessels exhibit increased responsiveness to pressor substances [for review, see 4]. It is not known why peripheral blood vessels undergo vasoconstriction either. And, of course, it is not known why hypertension leads to a high incidence of strokes and sudden cardiac death.
Is it possible that the atherosclerotic and hypertensive events are related to the diet or the dietary intake of a particular food substance, metabolite or element? Are these vascular disease processes related to mineral metabolism, per se?
Why is the incidence of hypertension, atherosclerosis, sudden-death ischemic heart disease and stroke low, in South African Bantu natives, Bedouins in the Arabian desert, Aborigines in Australia and Greenlanders? And why, when these indigenous populations move to Western civilizations, do the incidences of these cardiovascular diseases equal those of Western civilized populations?
If one divides the US into Eastern and Western halves, you begin to see several interesting phenomena. First, the soil Mg content in the Eastern USA is about one third that of the Western USA (table 1). Second, the water hardness of the Eastern USA is one half that of the Western USA (table 1). Third, although the death rate for cardiovascular diseases in the Eastern USA is significantly higher than that of the Western USA, noncardiovascular death rates are equivalent (table 1). Similar phenomena have been observed in Canada, Finland and South Africa [6-11]. In 1983, Leary and Reves  published findings from 12 magisterial districts in South Africa demonstrating that as the concentration of Mg in the drinking water was found to be less and less, in various geographical regions, the death rate from ischemic heart disease was seen to rise more and more. Studies such as these and others like them [6-9, 11] suggest that maybe there is an important relationship between dietary Mg intake and the incidence of heart disease.
Approximately, 12 years ago, Karppanen et al.  in Finland published interesting findings in which it was suggested that the ratio of dietary calcium to magnesium may be linked to ischemic heart disease. According to the most recent USA dietary surveys, the Ca:Mg ratio in average American diets is rising [ 13].
During the past 10 years, a considerable number of studies have appeared which indicate that hospitalized patients have incidences of hypomagnesemia ranging from 7 to 60%, depending upon the type of patient [for reviews, see [1, 14]. What is particularly important to note here is that many of these patients are in acute coronary care units and intensive care units. Many of these patients present with numerous cardiovascular abnormalities including cardiac arrhythmias, atrial fibrillation, hypertension, strokes and myocardial infarctions.
Ever since the early studies of Iseri et al.  in 1952, there has been an increasing number of case reports and studies which indicate that hearts of patients who die of sudden-death ischemic heart disease exhibit deficits of Mg [for reviews, see 9, 11, 14]. On the average. there appears to be about a 20% deficit in cardiac Mg content in these patients.
Mg is the only metal to be decreased to this extent consistently. It is important to note that we and others have found that coronary arteries of such victims often exhibit deficits of 30-40% in total Mg content. These deficits in Mg content do not appear to be a consequence of cardiac necrosis for several reasons. First of all, nonnecrosed cardiac tissue areas clearly exhibit approximately the same 20% reduction in myocardial Mg, unlike the necrotic areas which can exhibit deficits of almost 50% in Mg content of [9, 11, 16-181.
It is rather interesting to note that patients with a history of angina on autopsy exhibit severe cardiac deficits in Mg, whereas patients without a history of angina appear to exhibit a near-normal myocardial Mg content . Is deficiency of myocardial Mg limited only to angina pectoris and sudden-death ischemic heart disease, or is Mg deficiency also found in other myocardial syndromes?
An examination of the literature reveals a growing body of evidence to indicate that loss of myocardial Mg is seen in a host of myocardial lschemic syndromes from myocardial infarction, arrhythmias, torsades de pointes to experimental and iatrogenic ischemic injuries [for reviews, see 9, 11, 14]. Many of these are clearly associated with prior histories of atherosclerosis and/or hypertension.
Is hypertensive disease associated with Mg deficiency in blood and/or tissues? If so, hypertensive disease should be brought about in some cases solely by Mg deficiency, and hypertension should be exacerbated by Mg deficiency. Finally, a variety of hypertensive syndromes should be amenable to treatment with Mg salts.
At this point, we would like to take the opportunity to review some of this evidence, including some of our own findings.
A number of studies in spontaneously hypertensive rats clearly demonstrate (except for one study by Overlack et al. ) that the serum content of total Mg is significantly reduced in hypertensive animals [for review, see 21].
An examination of most of the clinical studies on hypertensive patients, so far studied, who received diuretics, where blood pressure often continued to rise, demonstrates that serum Mg is clearly, reduced by about 15-20% [for review, see 21].
A few years ago, Resnick et al.  examined red blood cells from hypertensive subjects and found that the ionized Mg2+ determined by 31P nuclear magnetic resonance (NMR) spectroscopy was inversely related to the diastolic blood pressure. That is. the greater the elevation in diastolic blood pressure, the lower the ionized red blood cell Mg2+ content .
If all of this is so, then even salt-induced hypertension might be expected to be associated with Mg deficiency and should be treatable with Mg salts. We, therefore, utilized various groups of uninephrectomized male Wistar rats given weekly implants of deoxycorticosterone acetate in order to produce malignant salt-induced hypertension. Some animals were allowed to drink Mg aspartate HCl freely, daily, for periods up to 12 weeks. Others were allowed to drink the Mg salt 4 weeks after salt hypertension for an additional 12 weeks.
Table 2 summarizes some of our data. By 3 weeks, mean arterial blood pressure was elevated in all deoxycorticosterone acetate + salt groups. However, by 9 weeks, the groups which received Mg supplements exhibited significant lowering of blood pressure. Many of the untreated animals with malignant hypertension died at 4-7 weeks of blood pressure levels in excess of 245 mm Hg.
Figure 1 clearly shows that there is a deficit in serum Mg in uninephrectomized rats with salt-induced hypertension and that serum Mg levels are restored to normal in rats allowed to drink Mg. Interestingly, serum phosphate levels are also reduced in animals with malignant hypertension, whereas rats given Mg exhibit a restoration of phosphate to normal levels. Hypophosphatemia itself is known to produce high blood pressure. Whether or not this contributes to salt-induced hypertension in these animals is under investigation.
In view of these experiments, we wondered whether pulmonary hypertension is amenable to Mg therapy and whether the vascular remodeling that normally takes place in the pulmonary circulation in this syndrome can be ameliorated or prevented by Mg. Rats were administered 40 mg/kg of monocrotaline. This plant extract is known to produce specific pulmonary hypertension in all mammals so far investigated, and a pulmonary, vascular remodelling takes place within 14-21 days. We examined all animals 21 days after monocrotaline .
Animals which received monocrotaline exhibited significant elevation in pulmonary blood pressure . Controls and control animals which received oral Mg aspartate HCl exhibited no alteration in pulmonary pressure. However, monocrotaline-treated animals which received Mg aspartate HCl for 21 days exhibited a significant amelioration of pulmonary hypertension .
If true pulmonary hypertension is observed in human subjects or animals, the right ventricular to left ventricular ratio should be elevated. Our monocrotaline- treated animals clearly manifested a right ventricular to left ventricular ratio that was increased as expected . The monocrotaline-treated animals, however, which received Mg therapy, clearly exhibited reduction in the elevated right ventricular to left ventricular ratio suggesting a reversal of the pulmonary hypertension [23, 24]. If the latter is true, then we would expect to see attenuation of the pulmonary hyperplasia of the arterial wall normally seen in pulmonary hypertension.
Arteriolar and arterial walls clearly underwent significant hyperplasia, after monocrotaline, with encroachment of the lumens [23-25]. Mg therapy, reversed the monocrotaline-induced hyperplasia. Obviously, elevated levels of Mg must exert significant attenuating effects on collagen and elastin synthesis and smooth muscle cell hyperplasia [23-25]. These actions might therefore be of value in the treatment of atherosclerosis.
Is there any evidence to indicate that teenagers, that is children below the age of 20 years, may exhibit Mg deficits which could be a risk factor for the development of hypertensive vascular disease?
In the past 2 years, a group in Japan (headed by Shibutani in Hyogo Medical College) has begun to publish a number of reports which suggest that male children of parents with a genetic history of familial hypertension exhibit significant deficits in red blood cell Mg content . This may be the first study to clearly suggest that a predilection for high blood pressure could develop in young males if, genetically, they exhibit deficits in tissue Mg.
If atherosclerosis is a strong risk factor for hypertension, ischemic heart disease and stroke, and these are truly interrelated, then Mg should exert strong effects on atherogenesis. We, therefore, decided to examine rabbits given 1 or 2% cholesterol with varying Mg intake . The Mg intake was varied from 40% of normal to normal or 2.5 times the normal intake. The animals were followed serially for up to 10 weeks. Aortas were excised and stained with Sudan 4 and examined histologically for lesions.
No lesions could be found from rabbits ingesting normal chow with normal lipid and Mg intake or normal synthetic chow . High cholesterol intake in the presence of normal dietary Mg resulted in significant atherosclerotic lesions.
The animals receiving low dietary Mg and 2% cholesterol exhibited lesions far in excess of those observed with normal Mg intake . However, if the intake of Mg was raised to 2.5 times normal, despite the high cholesterol intake, the atheromas were greatly attenuated, suggesting that Mg intake can modulate atherogenesis. Overall, the data clearly indicate that the greater the lipid intake, the greater the number of atherosclerotic lesions . In addition, these data indicate that the lower the dietary intake of Mg, the greater the risk for developing atheromas. Stating this another way, it is also clear that the higher the intake of Mg, the less chance for developing atheromas despite high lipid intake.
Our data would seem to suggest that Mg must exert significant effects on smooth muscle, macrophage and monocyte accumulation of lipids and might affect chemotaxis and the activity of growth factors implicated in atherogenesis.
If this is all true, then dietary intake of Mg would be an important and maybe critical factor in the prevention of atherosclerosis, hypertension, cardiac disease, stroke and sudden cardiac death. In addition, such a hypothesis would suggest that a suboptimal dietary intake of Mg should put human subjects at risk for development of cardiovascular disease.
It is rather interesting that if one examines the intake of Mg over the past 90 years, we note that there is a progressive and alarming decline in Mg intake at the present time (table 3).
An examination of a recent US Department of Agriculture HANES dietary survey reported in 1985 indicates clear and significant shortfalls in dietary Mg, assuming an intake of 350 mg/day is needed for normal Mg balance . It is also clear from this survey that men over the age of 65 years, who are known to present the greatest risk for death from ischemic heart disease (vide supra), exhibit the greatest shortfalls for dietary Mg of all male age groups. This may be more than coincidental.
If Mg can ameliorate atherosclerosis and hypertension, and promote coronary vasodilation and unloading of the heart (8, 9, 11,14, 21], are these the primary mechanisms of the protective actions of magnesium ions against death from ischemic heart disease, or does Mg exert direct actions on myocardial bioenergetics as well [14, 21]? We will therefore present and discuss some of our recent experiments on intact perfused hearts which may have direct bearing on this question.
In order to get an assessment of cellular bioenergetics, we have employed 31P NMR spectroscopy and near-infrared spectroscopy [28, 29]. When the perfusate magnesium ion concentration is elevated to hypermagnesemic levels (2.4-4.8 mM), coronary flow, stroke volume, cardiac output and aortic pressure are seen to rise rather significantly, suggesting that Mg ions can exhibit inotropic-like effects. At the same time, the heart rate and rate-pressure product are decreased, suggesting that Mg unloads the heart and increases its efficiency.
The 31P NMR spectra for elevated magnesium indicated that elevated [Mg2+]o results in elevated phosphocreatine levels (by 22-40%). Second, inorganic phosphate levels were decreased, and there were chemical shifts in the 31P NMR spectra produced by elevated Mg [28, 29].
Clearly, elevated Mg resulted in spectral shifts, which suggest that alterations in myocardial intracellular, free Mg ions and intracellular pH must have occurred. Elevation in [Mg2+]o (i.e. 2.4-4.8 mM) clearly resulted in elevation of intracellular, free Mg ions and alkalinization of the cytosol. Elevation of the intracellular pH in the presence of elevation of intracellular, free Mg ions would increase the creatine kinase reaction, resulting in more phosphocreatine, contractile force and stroke volume, exactly as we have observed.
It was clear from our data that elevation in extracellular Mg ions to 4.8 mM resulted in a 40% rise in phosphocreatine.
Using a noninvasive near-infrared spectroscopic technique, we have clearly found that the mitochondrial levels of oxidized cytochrome aa3 and oxymyoglobin are increased by elevation in extracellular Mg ions 31P NMR . These data coupled with the data suggest that the efficiency of the myocardium is enhanced by Mg ions.
If, however, the extracellular Mg ions are reduced below normal, the cytosol becomes acidic and the intracellular free Mg ion level is significantly altered .
Preliminary experiments indicate that reduction in extracellular Mg ions or hypomagnesemia leads to rapid falls in oxymyoglobin levels. Finally, our recent near-infrared experiments indicate that subjection of intact rat hearts to hypomagnesemia clearly, results in increased mitochondrial levels of reduced cytochrome oxidase aa3.
It is becoming clear that a large body of epidemiologic data supports the idea that lower than normal dietary intake of Mg can be a strong risk factor for hypertension, cardiac arrhythmias, ischemic heart disease and sudden cardiac death. Lower than normal myocardial and coronary vascular Mg content seems to pose serious risks for angina, coronary vasospasm, ischemic heart disease and sudden cardiac death.
Deficits in serum Mg appear often to be associated with arrhythmias, coronary vasospasm and high blood pressure.
Experimental animal studies seem to suggest interrelationships between atherogenesis, hypertension and ischemic heart disease. Evidence is clearly accumulating to implicate a role for Mg in the modulation of serum lipids, lipid uptake in macrophages, smooth muscle cells and the arterial wall.
There clearly appear to be considerable shortfalls in dietary intake of Mg in Western world populations, and that men over the age of 65 years, who are at greatest risk for death from ischemic heart disease, have the greatest shortfalls in dietary Mg.
Although Mg clearly influences calcium uptake and distribution in vascular smooth muscle cells which can modulate vasomotor tone [3, 9, 14, 21, 28, 31-33], it is now becoming clear that Mg ions can directly alter myocardial cellular bioenergetics and influence (possibly dictate) efficiency of the myocardium. Noninvasive techniques such as 31P NMR spectroscopy, near-infrared spectroscopy and image analysis should aid in the clarification of the role of Mg as an important risk factor in cardiovascular disease.
The original work received herein was supported in part by NIAAA research grant AA-08674.
1 Altura BM: Ischemic heart disease and magnesium. Magnesium 1988;7:57-67.
2 Ross R: The pathogenesis of atherosclerosis. N Engl J Med 1986;314:488-500.
3 Lee KT, Onodera K. Tanaka K (eds): Atherosclerosis II. Recent Progress in Atherosclerosis Research. Ann NY Acad Sci 1990;598:1-589.
4 Laragh J, Brenner BM: Hypertension: Pathophysiology, Diagnosis and Management. New York, Raven Press, 1990, vol 1 and 11.
5 Masironi R: Geochemistry and cardiovascular diseases. Philos Trans R Soc Lond 1979;288:193-203.
6 Marier J, Neri LC, Anderson TW: Water hardness, human health and importance of magnesium, rep No 17581. Ottawa, Natl Res Council Canada,1979.
7 Marier J, Neri LC: Quantifying the role of magnesium in the interrelationship between human mortality/morbidity and water hardness. Magnesium 1985;4:53-59.
8 Altura BM: Magnesium and regulation of contractility: in Altura BM (ed): Advances in Microcirculation: Regulation of the Microcirculation. Basel, Karger. 1982, pp 77-113.
9 Altura BM, Altura BT: Magnesium-calcium interaction and contraction of arterial smooth muscle in ischemic heart diseases, hypertension and vasospastic disorders. in Wester P (ed): Electrolytes and the Heart. New York, Transmedica, 1983, pp 41-56.
10 Leary, WP, Reyes AJ: Magnesium and sudden death. S Afr Med J 1983;64:697-698.
11 Altura BM, Altura BT: New perspectives on the role of magnesium in the pathophysiology of the cardiovascular system. I. Clinical aspects. Magnesium 1985;4:226-244.
12 Karppanen HR. Pennanen R. Passinen L: Minerals, coronary heart disease and sudden coronary death. Adv Cardiol 1978;25:9-24.
13 Morgan KJ, Stampley GE, Zabik ME, Fischer DR: Magnesium and calcium intakes in the US population. J Am Coll Nutr 1985;4:195-206.
14 Altura BM, Altura BT: Magnesium and the cardiovascular system: Experimental and clinical aspects updated: in Sigel H, Sigel A (eds): Metal Ions in Biological Systems. New York, Dekker, 1990, vol 26: Compendium on Magnesium: Its Physiology, Biochemistry, and Nutrition. pp 359-416.
15 lseri LC, Alexander EC, MacCaughey RS, Boyle AJ, Meyers G: Water and electrolyte content of cardiac and skeletal muscle in heart failure and myocardial infarction. Am Heart J 1952;43:215-227.
16 Heggtveit MA, Tanser P, Hunt B: Magnesium content of normal and ischemic hearts. Proc 7th Int Congr Clin Pathol, Montreal, 1969, p 53.
17 Speich M, Bousquet B, Nicholas G, Delajartre AY: Incidences de l'infarctus du myocarde sur les teneurs en magnesium plasmatique erythrocytaire et cardiaque. Rev Fr Endocrinol Clin 1979;20:159-163.
18 Speich M, Bousquet B, Nicholas G: Concentrations of magnesium, calcium, potassium and sodium in human heart muscle after acute myocardial infarction. Clin Chem 1980;26:1662-1665.
19 Johnson CJ, Peterson DR, Smith EK: Myocardial tissue concentration of magnesium and potassium in men dying suddenly from ischemic heart diease. Am J Clin Nutr 1979;32:967-970.
20 Overlack A, Zenzen JG, Ressel C, Muller HM, Stumpe KO: Influence of magnesium on blood pressure and the effect of nifedipine in rats. Hypertension 1987;9:139-143.
21 Altura BM, Altura BT: Role of magnesium in pathogenesis of hypertension. Relationship to its actions on cardiac and vascular smooth muscle: in Laragh JH, Brenner BM (eds): Hypertension: Pathophysiology. Diagnosis and Management. New York, Raven Press, vol 1, 1990, pp 1003-1025.
22 Resnick LM, Gupta RK, Laragh JH: lntracellular magnesium in erythrocytes of essential hypertension relation to blood pressure and serum divalent cations. Proc Natl Acad Sci USA 1984;81:6511-6515.
23 Mathew R, Gloster ES, Altura BT, Altura BM: Magnesium aspartate hydrochloride attenuates monocrotaline pulmonary artery hypertension in rats. Clin Sci 1988;75:661-667.
24 Mathew R, Altura BM: Magnesium and the lungs. Magnesium 1988:7:173-187.
25 Mathew R, Altura BT, Altura BM: Strain differences in pulmonary hypertensive response to monocrotaline alkaloid and the beneficial effect of oral magnesium treatment. Magnesium 1989;8:110-116.
26 Shibutani Y, Sakamoto MK, Katsuno S, Yoshimoto S, Matsura T: Serum and erythrocyte magnesium levels in junior high school students: Relation to blood pressure and a family history of hypertension. Magnesium 1988;7:188-194.
27 Altura BT, Brost M, Bloom S, Barbour RL, Stempak JK, Altura BM: Magnesium dietary intake modulates blood lipid levels. Proc Natl Acad Set USA 1990;87:1840-1844.
28 Altura BM, Barbour RL, Reiner SD, Zhang A, Cheng TP, Down JL, Gupta RK, Wu F, Altura BT: Influence of Mg2+ on distribution of ionized Ca2+ in vascular smooth muscle and on cellular bioenergetics and intracellular free Mg2+ and pH in perfused hearts probed by digital imaging microscopy, 31P NMR and reflectance spectroscopy: in Zhakari S, Witt E (eds): Imaging Techniques in Alcohol Research. Monograph 21, Washington, NIAAA, pp 235-272.
29 Barbour RL, Altura BM, Reiner SD, Dowd TL, Gupta RK, Wu F, Altura BT: Influence of Mg2+ on cardiac performance, intracellular free Mg2+ and pH in perfused hearts as assessed with 31P-NMR spectroscopy. Magnes Trace Elem 1992;10:99-116.
30 Barbour RL, Gupta RK, Dowd TL, Reiner SD, Wu F, Altura BT, Altura BM: Response of cardiac energetics to elevated and low magnesium in perfused rat hearts. J Magn Reson Imaging, in press.
31 Altura BM, Altura BT: Magnesium and vascular tone and reactivity. Blood Vessels 1978;15:5-16.
32 Altura BM, Altura BT: Magnesium, electrolyte transport and coronary vascular tone. Drugs 1984; 28(suppl 1): 120-142.
33 Altura BM, Altura BT, Carella A, Turlapaty PDMV: Ca2+ coupling in vascular smooth muscle: Mg2+ and buffer effects on contractility and membrane Ca2+ movements. Can J Physiol Pharmacol 1982;60:459-482.
Prof. Dr. B.M. Altura
SUNY Health Science Center 450 Clarkson Avenue
Brooklyn, NY 11203 (USA)
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