Fundamentals of clinical cardiology The importance of magnesium deficiency in cardiovascular disease G. E. Butch, M.D. T. D, Giles, M.D. New Orleans, La.
The role of magnesium in cardiovascular disease is not fully known primarily because magnesium measurements in patients have not been regularly obtained. Physicians fail to appreciat e the importance of this element in biology and medicine. Although a spectroscopic method for rapid, extremely accurate determination of small ampunts of magnesium in body fluids1 has been available for many years, magnesium data are lacking. The more recent-intr0duction of atomic absorption spectroscopy has facilitated the study of this major cation in the human body. A normal metabolism requires proper amounts of available magnesium; and previous studies from our laboratory have revealed magnesium to be an extremely kinetic element in man. 2 Although magnesium is vital to the proper metabolic function of all cells of man, the brief discussion to follow deals principally with selected aspects of magnesium deficiency in cardiac disease. Distribution of magnesium
The role of magnesium in metabolism has been well summarized recently.3'~ Magnesium is the fourth most plentiful cation in the body (approximately 2,000 mEq. in a 70 kilogram man), following calcium (60,000 mEq.), sodium (5,500 mEq.) and potassium (3,000 mEq.). Approximately 50 per cent of body magnesium is in bone and is not
From the Department of Medicine of Tulane University School of Medicine. and the Charity Hospital of Louisiana, New Orleans, La. Supported by grant HL-14789 from the National Heart and Lung Institute of the United States Public Health Service, the Rudolph Matas Memorial Fund for the Kate Prewitt Hess Laboratory, the Rowell A. BiUups Fund fur Research in Heart Disease, and the Feazel Laboratory. Received for publication July 29, 1976. Reprint requests: George E. Butch, M.D., Tulane University School of Medicine, 1430 Tulane Ave., New Orleans, La. 70112.
November, 1977, Vol. 94, 5/o. 5, pp 649-657
readily available as a dynamic reservoir for use in other body tissues. Like potassium, only a small part (1 per cent)of magnesium is in the extracetlular fluid compartment. The largest~ amount of magnesium which is active in magnesiokinetics is within the cells of the body in a c0ncentration of about 28 mEq. per liter. Normally, serum magnesium values are between 1.6 and 2.0 mEq. per liter. Cardiac muscle has a high concentration of magnesium (!7.4 to 19.8 mEq./liter)2.6 A higher concentration of magnesium is found in the ventricles than in the atria of the dog2 There are no significant differences between magnesium concentrations in the right and left ventricles or the interventricular septum: 6 One third of the 20 to 25 mEq. of magnesium present in a normal diet is absorbed in the small intestine, 3'* the remainder being excreted in the feces.2 Absorbed magnesium is excreted primarily by the kidney, the amount excreted in the stool over two to three days being less than 1,4 per cent of the amount given, 2 A diagram indicating the daily body turn0ver of magnesium in a female is shown in Fig. 1. Studies with Mg '-'s revealed that the rate of excretion through the urine falls during the first 15 to 20 hours and then remains relatively stable up to 70 hours:" The cumulative excretion of Mg~-~in the urine was as high as 10.7 per cent of the administered amount during the 70.hou~ observation period (Fig. 2):2 The kidney is capable of reducing renal magnesium loss to less than: 1 mEq. per day when intake is nil2' ~ A!dosterone increases the renal excretion of magnesium, v~hereas parathormone reduces excretion. Als0, parathyroid hormone regulates, i n part, bo~h calc!um and magnesium excretion and metabo, lism, An increase in the blood magnesium cation reduces parathormone secretion, and vice versa,
American Heart J o u r n a l
649
Butch and Giles Oral intake 163 mFq \ ~ , \
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/M.M. Hours Fig, 2. Time course curves of cumulativeexcretionof Mg~sfor two control subjects and four patients with idiopathic cardiomyopathyand congestiveheart failure,who were given intravenous injections of the tracer element. (From Yun, T. K., Lazzara, R., Black, W. C., Walsh,J. J., and Butch, G. E.:The turnover of magnesium in control subjects and in patients with idiopathic cardiomyopathyand congestiveheart failure studied with magnesium-28,J. Nucl. Med. 7:177, 19669Reproduced by permission9 Magnesium in normal biochemistry and physiology Magnesium activates m a n y enzyme systems. It is als0 a required co-factor for oxidative phospho, rylation?. 4 For example, magnesium activates alkaline phosphatase and pyrophosphatases, and the magnesium ion is a necessary co-factor when650
thiamine pyrophosphate is required. Enolases and leucine aminopeptidase also require magnesium for their enzymatic activity. These are extremely important enzymatic processes which are necessary for normal cell function and health. In addition, magnesium is involved in the structural integrity of ribosomal particles and protein synthesis. It is well known that a relationship exists between intracellular and extracellular sodium and potassium. A similar relationship exists between calcium and magnesium, In fact, an interdependent relationship with magnesium exists for most, if not all, ions present in the body. Moreover, there is a relationship among all four major cations, i.e., the intracellular ratios log (K+)/(Na § and log (Mg++)/(Ca§ are related2 There is evidence that membrane Na-K dependent adenosine triphosphatase (ATPase) requires magnesium2" Since this ATPase is necessary for the maintenance of a normal intracellular potassium, magnesium is directly involved in the regulation of potassium. A decrease in either calcium or magnesium serum concentration results in increased neuronal excitability and neuromuscular transmission. However, the effect of calcium is opposite to t h a t of magnesium in muscle. Magnesium in large doses or concentration has a curariform action on the neuromuscular junction 9 This action perhaps is produced by interference with the release of acetylcholine from motor nerve terminals? ~ November, 1977, Vol. 94, No. 5
Magnesium deficiency in cardiovascular disease
Magnesium in large doses can produce general anesthesia.
Myocardial disease in experimentally produced magnesium deficiency The effect of magnesium deficiency on the heart has been studied most extensively in the rat. In 1936, Greenberg and associates 8 described myocardial degeneration with fibrosis and polyblastic infiltration in rats that were fed a low magnesium diet from birth. Lowenhaupt, Schulman, and Greenberg 9 described in detail the basic histologic lesions of magnesium deficiency in the rat. They noted distinct, inflammatory and necrotic focal areas around small blood vessels. In the acute stage the lesions were characterized by a collection of inflammatory cells, with some areas progressing to necrosis and later scar formation. Ko, Fellers, and Craig, TM on the other hand, attached little significance to relatively few focal degenerative changes occurring in the hearts of magnesium-deficient rats. Heggtviet, Herman, and Mishra 1' studied myocardial lesions of magnesium-deficient rats using both light and electron microscopy. After 14 days of magnesium depletion, gross myocardial lesions ranging from small, pale yellowish-grey patches to large zones of necrosis and calcification were seen in 50 per cent of experimental animals. Light microscopy revealed focal areas of necrosis and exudative inflammation in most magnesium-deftcient rats after 10 days, particularly in subendocardial regionS. Muscle fibers adjacent to areas of necrosis showed increased sarcoplasmic eosinophilia, patchy loss of cross-striations, vacuolization, and accumulation of periodic acid-Schiff (PAS)-positive material. Calcification in the granulomatous lesions was seen in approximately one-half of the animals: Progression of the lesions to scarring was also observed. Electron microscopic evidence of myocardial damage was seen early (after five days on a magnesium-deficient diet). '' The mitochondria exhibited the earliest changes, consisting of swelling and vacuolization, compression and distortion of cristae, and accumulation of material (thought to represent early calcification) on and between the cristae. The myofibrillae were deranged and fragmented and were separated by accumulation of intracellular fluid. The M bands contained many dilated sarcoplasmic reticula, lipid droplets, glycogen particles and sarcoplasmic ground substance. Rupture of the sarcolemma and sepaAmerican Heart Journal
ration of myofibrils at intercalated discs were seen. Finally, nuclear changes occurred, consisting of marginal clumping of chromatin, loss of nucleoli, and vesiculation. Also, edema of the vascular endothelium was noted. The sequence of structural abnormalities suggested that interference with magnesiumdependent enzymes involved in oxidative phosphorylation played an important role in the pathogenesis of the lesions observed. 11 The lesions were not similar to those produced by potassium deficiency or ischemia. Several studies of magnesium deficiency have also been conducted in dogs. Vitale and associates TM reported calcification of the inner portions of the myocardium in magnesium-deficient puppies. Calcification of the aorta and medium sized arteries was also noted. Wener and associates ~3 observed no gross changes in the hearts of young dogs (three to eight months old) studied after receiving a magnesium-deficient diet for a mean of 87.2 days. Light microscopic findings showed only degenerativ e vascular changes in the hearts of these dogs. The endothelial cells of the intima showed pyknosis or absence of nuclei. There also was a suggestion of edema of the media. Segmental necrosis of some small coronary arteries was noted, b u t changes in larger coronary arteries were not as striking. Sections of myocardium revealed irregularly distributed, small patches of hyperchromatic staining myocardial fibers frequently located adjacent t o abnormal vessels. Necrosis Was seen in some areas of the myocardium, and there were small areas of calcification in a few animals. Electrocardiograms recorded from magnesiumdeficient dogs revealed ST segment depression with flattening of t h e T waves in the precordial leads. TM The electrocardiographic changes were interpreted as nonspecific and not related strictly to serum magnesium levels. The toxic effects of acetyl strophanthidin i n f u s i o n (100 mg./min.) were markedly increased in 19 mongrel dogs rendered hypomagnesemic by hemodialysis. ~ The arrhythmias resulting from digitalis toxicity were terminated by infusion of magnesium. Moore and colleagues 1~ observed focal cardiac necrosis and calcification in diet-induced magnesium deficiency in calves. Swelling of myofibrils and degeneration of Purkinje fibers were noted. Magnesium-deficient monkeys did not develop any histopathologic changes. TM However, magnesium-deficient monkeys were found to be more 651
Burch and Giles
Table I. Causes of symptomatic hypomagnesemia* I. Gastrointestinal disorders
a. Malabsorptionsyndromes,includingnontropical sprue b. Malabsorptiondue to extensivebowel resection c. Boweland biliary fistulas d. Prolongednasogastricsuction with administration of magnesium e. Free parenteral fluids f. Prolongeddiarrhea g. Protein-caloriemalnutrition h. Alcoholiccirrhosis i. Pancreatitis II. Endocrine disorders
a. Hyperparathyroidismand hypoparathyroidism b. Hyperaldosteronism c. Diabeticcoma III. Renal diseases
a. b. c. d. e.
Glomerulonephritis Pyelonephritis Hydronephrosis Nephrosclerosis Renal tubular acidosis
IV. Alcoholism V. Diuretic therapy (mercurials, ammonium chloride and thiazides) VI. Malignant osteolytic disease VII. Porphyria with inappropriate secretion of antidiuretic hormone VIII. Excessive lactation IX. "Idiopathic" X. Cardiopulmonary bypass XI. "Soft" water *Modified from Wacker, W. E. C., and Parisi, A. F.: Magnesium metabolism, N. Engl. J. Med. 278:712, 1968. Reproduced by permission.
susceptible to the toxic effects of digitalis than control animals. It was proposed t h a t this latter effect was due to intracellular loss of potassium produced by magnesium deficiency, but this concept is certainly difficult to establish. Myocardial disease in magnesium deficiency in man There are many causes of magnesium deficiency in man {Table I). It has been shown t h a t magnesium deficiency in a healthy man is not very likely to be due to inadequate intake since an efficient mechanism is present for decreasing losses of magnesium in the urine and feces when intake is reduced." Severe magnesium deficiency in man is manifested by hyperexcitability and occasional behavioral disturbances? 8 Tetany, convulsive seizures, and other central nervous system disturbances
652
have been described. Manifestations of magnesium deficiency in man are much less clearly defined than those in experimental animals.~ ~ Nevertheless, magnesium deficiency does occur in man and may contribute to disease states. Chronic, low grade magnesium deficiency may be much more common than is conventionally considered since magnesium is not studied regularly in clinical medicine, as are sodium, potassium, and chloride. It is impossible in this presentation to consider all aspects of magnesium deficiency in man in relation to myocardial disease. Therefore, the remarks to follow are limited to alcoholic cardiomyopathy, electrocardiographic manifestations and disturbances in cardiac rhythm, and ischemic heart disease. However, the physician may readily think Of many other situations in which magnesium plays an important role in clinical medicine. Alcoholic cardiomyopathy. Chronic ingestion of alcoholic beverages is associated with hypomagnesemia and decreased skeletal muscle potassium.~O. 51 Since about 20 per cent of body magnesium is contained in skeletal muscles, a deficiency of magnesium in this tissue indicates a significant intracellular deficit throughout the body {including the heart). 22 A linear relationship exists between retention of infused magnesium and the increment of increase in skeletal muscle magnesium, -~1 supporting the reliability of skeletal muscle magnesium as an index of total body magnesium status. For obvious reasons, the state of myocardial magnesium metabolism remains little known in alcoholics even though electrocardiographic data suggest t h a t myocardial magnesium deficiency exists in alcoholics. ~3 Alcohol may increase renal excretion of magnesium by a direct effect on tubular resorption or by increasing production of some metabolic intermediates t h a t could bind magnesium ions as they are being excreted, s~ Other factors producing magnesium depletion in alcoholics include vomiting and diarrhea, hyperhydrosis, drugs, and hyperaldosteronism in patients with cirrhosis of the liver and ascites. ~~It is interesting t h a t relatively high rates of urinary excretion of magnesium continue in alcoholics during alcohol withdrawal states despite low serum levels of magnesium. '24 The mechanisms for the production of heart disease in association with excessive ingestion of alcohol by man include: (1) direct toxic injury by
November, 1977, Vol. 94, No. 5
Magnesium deficiency in cardiovascular disease
the alcohol to the myocardium, (2) nutritional disturbances (beri-beri), (3) toxic effects of substances contained in alcoholic beverages (e.g., cobalt), and (4) a combination of the above. 2~ Alcoholic cardiomyopathy is usually characterized predominantly by the symptoms and signs of left-sided heart failure when the cardiomyopathy is advanced and the myocardial damage extensive. ~ Initially, alcoholic cardi0myopathy has mild to subtle manifestations, often limited to the ECG. It is becoming well established that alcohol alone is sufficiently toxic to produce myocardial damage...,~. _~6The pathogenesis of alcohol induced cardiac injury may involve metabolites of ethanol (acetaldehyde), associated nutritional disturbances, or electrolytic disturbances (hypomagnesemia itself), along with direct toxic injury to the myocardium, The cardiac changes produced by experimental magnesium deficiency in the rat (vide supra) are similar in many ways to the changes found in mice fed large quantities of alcohol36.27.28 However, histologic and electron microscopically observed structural changes are not specific. Mitochondrial damage is prominent in both groups, as well as disruption of myofibres and swelling and dilatation of sarcoplasmic reticulum. Such ultrastructural changes have been observed in hearts of patients with alcoholic cardiomyopathy36. 2~, 36 T h e electrocardiograms recorded from alcoholic patients reflect changes of magnesium deficiency. 23 Evans 31 described the T wave changes associated with alcoholism to be of four types: (1) bifid or cloven, (2) spinous, (3) isoelectric, or (4) negative, Flink and colleagues 3~. 33 reported ECG changes associated with magnesium deficiency resembling those of hypokalemia. Only primary ST segment alterations were noted in acute alcoholism, and these changes could be corrected only with magnesium therapy24 Because electrolyte imbalance for any one electrolyte is associated with changes in all electrolytes, it becomes difficult to know which electrolyte is responsible for ECG changes2 ~' ~6 The early electrocardiographic manifestations of alcoholic myocardial disease are T wave and ST segment changes. As the disease advances in severity and duration, more extensive ECG changes reflecting diffuse myocardial damage occur. These include widening of the QRS complexes, conduction disturbances, and ar-
American Heart Journal
rhythmias such as atrial fibrillation. There is a need to study in detail the ECG changes associated with magnesium depletion and repletion in alcoholic cardiomyopathy. Beri-beri heart disease, which may be found in alcoholics, is characterized by a high cardiac output state, predominantly right-sided congestive heart failure (when congestive heart failure occurs), bounding pulses, and peripheral neuropathy. These changes have been attributed primarily to thiamine deficiency, but alcohol intoxication and disturbances in magnesium metabolism may be important associated contributing factors. Thiamine deficiency may also be associated with magnesium deficiencyY Because of the importance of magnesium in oxidative phosphorylation and as a cofactor for thiamine metabolism, magnesium deficiency may worsen the symptoms and signs of thiamine deficiency and, unless corrected, may even prevent or considerably lessen the therapeutic effects of thiamine administrationY
Electrocardiographic abnormalities and arrhythmias associated with magnesium deficiency The electrocardiographic changes of magnesium deficiency (Fig. 3) are different from those of potassium and calcium imbalance in experimental animals. However, there is a lack of agreement as to what ECG changes are characteristic of magnesium deficiency. This is not surprising since it is unlikely that magnesium deficiency ever occurs entirely alone. It has been ~shown that disturbances in balance of any one electrolyte result in changes of practically all the others.35.36 Magnesium does influence the con: centration and distribution of the other major cations as well as important metabolic processes. When children suffering from severe malnutrition are given nutrients without adequate magnesium supplementation, the ECG reveals sharply peaked, asymmetrical T waves and prominent U waves, 3s similar to patterns recorded by Vitale and associates 12for magnesium deficiency in dOgS. Prior to replacement therapy, flat or inverted T waves were recorded in children2 s Low-voltage P waves and QRS complexes have been recorded in magnesium-deficient patients. 39 T h e s e changes were reversed by magnesium administration/9 Thus, it would appear that "early" magnesium
653
Burch and Giles
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Fig. 3. Electrocardiographicchanges associated with magnesium deficiency. (From Seelig, M. S.:Electrocardiographic patterns of magnesium depletionappearing in alcoholicheart disease, Ann. N. Y. Acad. Sci. 162:906, 1969. Reproduced by permission.) deficiency is characterized electrocardiographically by tall, peaked T waves (not narrow as in hyperkalemia) and a normal QT interval2 ~ These changes probably reflect in part a relative increase in extracellular potassium. It is interesting that these T waves resemble the "spinous" T wave associated with alcoholism (Fig. 4). TM ~' Late or prolonged magnesium deficiency produces a prolonged PR interval, wide QRS complexes, ST segment depression, and low T waves2" Hypomagnesemia can contribute to disturbances in cardiac rhythm, especially when associated with digitalis administration. 7. ". ~ Both digitalis administration and hypomagnesemia tend to produce a loss of intracellular potassium. Hypokalemia produces electrical instability of the myocardium. Significant intracellular deficit of these cations can be produced by oral diuretic therapy2 3 It is not surprising, therefore, to find h y p o k a l e m i a and hypomagnesemia in patients with heart disease since these patients frequently receive both digitalis (often in excessive amounts) and oral diuretics. Administration of this combination of drugs contributes to the production of digitalis intoxication seen frequently in hospitals recently2 ~ Thus, in the presence of hypomagnesium, as with hypokalemia, the a m o u n t of digitalis required to produce toxicity is reduced. It is prudent to obtain magnesium levels in the serum of any patient with "digitalis-induced '~
654
Fig. 4. Electrocardiogramof a patient with alcoholic cardiomyopathy showing cloven and spinous T waves similar to those seen in magnesium deficiency.{From Burch, G. E., and Giles, T. D.:Diagnosis and treatment of cardiomyopathy, in Changing conceptsin cardiovasculardisease, the Proceedings of the American College of Cardiology, Baltimore, 1972, The Williams & Wilkins Company. Reproduced by permission.}
arrhythmias of any type and to administer magnesium in t r e a t m e n t when levels are low25 Such t r e a t m e n t has been shown to be effective in abolishing digitalis-induced ventricular bigeminy and ventricular tachycardia. Furthermore, when patients are hypokalemic, intracellular potassium will remain low unless the associated hypomagnesium is also corrected. Cardiac a r r h y t h m i a has been reported in patients with hypomagnesemia even when the patients were not on digitalis therapy2 ~ In one patient, a paroxysmal supraventricular tachycardia was abolished by the intravenous administration of magnesium sulfate. Ischemic heart disease
The possible role of magnesium in the production of disturbances in the cardiac state of ischemic heart disease has been r e v i e w e d f Ischemic heart disease appears to be more prevalent in areas where people consume soft water than in areas where hard water {high calcium and magnesium) is consumed28 Moreover, the reported incidence of sudden death is greater in areas with soft water t h a n in those with hard water. It has been shown in the rabbit t h a t magne-
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Magnesium deficiency in cardiovascular disease
slum protects against the development of dietary induced arteriosclerosis better than does calcium27 Also, magnesium decreases blood lipids and blood coagulability. The role of magnesium administration in ischemic heart disease, if any, probably relates to its cellular effects, e.g., counteracting adverse effects of intracellular calcium, protecting against loss of intracellular potas, slum, and maintaining the integrity of subcellular structure. Possibility of magnesium deficiency as a "conditioning factor." for heart disease
Because magnesium is so important in the metabolic function and physic0chemical state of cells, a deficiency of magnesium could render a cell more vulnerable to insults from viruses, toxins, radiation, and other noxious agents. For example, in alcoholic cardiomyopathy, magnesium deficiency may contribute to the development of viral infection, This concept of hypomagnesium or even hypermagnesium being conditioning factors for viral infections of the heart and other cardiac diseases needs investigation. Cardiopulmonary bypass and magnesium deficiency
A decrease in serum magnesium has been reported following cardiopulmonary bypass during open heart surgery, 49 even though intracellular magnesium has been reported to increase slightly2 ~ Importantly, conversion of cardiac arrhythmias following cardiopu!monary bypass may be assisted by magnesium therapy when hypomagnesemia is present29 Use of magnesium in management of cardiac disease
The need in clinical medicine to measure serum concentration of magnesium in all patient s with heart disease, as is the practice for sodium, potassium and calcium, cannot be overemphasized. Surely, attention should be directed to possible magnesium deficiency in patients receiving any, and especially oral, diureticsJ 0" ~3 Depletion of :magnesium occurs with the use of mercurial diuretics, ammonium chloride, and especially the thiazides with poor dietary intake.S0 Other drugs known to cause hypomagnesemia are capreomycin, viomyci n, and gentamicin. ~' ~ Large doses of gentamicin may also cause potassium loss,~i-53 possibly related to secondary aldosteronism. It is
American Heart Journal
Table II. Suggested guidelines for treatment of magnesium deficiency* Dose Intramuscular route (50% MgS04 solution)t 1 2 3-5
2.0 g r a m s {16.3 m E q . ) every 2 h o u r s for t h r e e doses a n d t h e n every 4 h o u r s for four doses 1.0 gram (8.1 m E q . ) every 4 h o u r s for six doses 1.0 g r a m every 6 h o u r s
Intravenous route (ampules of MgS03 1
2 3-5
6.0 g r a m s (49 m E q . ) in 1000 m L . s o l u t i o n
containing glucoseplus any other electrolytes and other medications as indicated-infuse in 3 hours, followedby 5.0 grams in each of 2 one-liter solutions administered throughout the day. A total of 6.0 grams (49 mEq.) divided equally in the total fluids of the day. The same as day 2
*From Flink, E. B.: Therapy of magnesium deficiency, Ann. N. Y. Acad. Sci. 162:901, 1969. Reproduced by permmslon. tThis supplies 32 grams or 260 mEq. of magnesium.
common clinical practice to order supplemental potassium therapy for patients receiving kaliuretic diuretics, particularly when digitalis preparations are also administered. Consideration should also be given to magnesium supplementation for such patients since hypomagnesemia also predisposes to digitalis intoxication. The supplemental dosage of magnesium, as well as of potassium, should not be empirical b u t should be based on each patient's need. In patients with congestive heart failure secondary to idiopathic cardiomyopathy, a significant correlation exists between daily cumulative balances and renal clearances of magnesium and potassium. 54 The kinetics of magnesium metabolism in normal people and in patients with congestive heart disease have been reported previously from our laboratoryJ Orally and intravenously administered Mg 2s was excreted very slowly (less than 5 per cent in the first 24 hours and less than 2 per cent per day thereafter) in patients with congestive heart failure and idiopathic cardiomyopathyJ The excretion of urinary magnesium in patients with congestive h e a ~ failure was primarily from the magnesium pool of the body, with less than 18 per cent o.f the daily urinary excretion being derived from newly absorbed magnesium. Most patients with magnesium deficiency will have a reduction of 1.0 to 2.0 mEq./Kg, of body weight25 Suggested replacement schedules, re-
655
Burch and Giles
gardless of the cause of the deficiency, are s u m m a r i z e d in T a b l e I I . AS m u c h a s 2 m E q . / K g . o f m a g n e s i u m Chloride c a n b e g i v e n o v e r 4 h o u r s a n d r e p e a t e d 24 h o u r s l a t e r 2 ~ H o w e v e r , r e p l a c e ment therapy should be determined by frequent evaluation of the patient with consideration of all aspects of the patient's health. There are not sufficient data to recommend the addition of magnesium to the drinking water of "soft water" areas even though the incidence of i s c h e m i c h e a r t d i s e a s e a n d s u d d e n d e a t h is g r e a t e r in t h e s e a r e a s t h a n in a r e a s w i t h h a r d water containing higher concentrations of magnesium. General remarks I t is a p p a r e n t t h a t m a g n e s i u m p l a y s a n i m p o r t a n t r o l e in c a r d i a c h o m e o s t a s i s a n d t h a t m a g n e s l u m d e f i c i e n c y is c a p a b l e o f p r o d u c i n g c a r d i a c d i s e a s e . P r o b a b l y o f m o r e i m p o r t a n c e is t h e ~ontributing role of magnesium deficiency to the pathogenesis of myocardial injury and the develb p m e n t of d r u g t o x i c i t y . M a g n e s i u m d e f i c i e n c y will b e f o h n d o n l y w h e n l o o k e d for, a n d t h u s t h e r e s p o n s i b i l i t y for p r e v e n t i o n , d e t e c t i o n , a n d treatment resides With the physician, The recogn i t i o n of t h e i m p o r t a n c e o f t h i s i o n l e a d s t o further realization that all elements contained within the body of man are important. REFERENCES 1. Maclntyre, I.i Flamephotometry, in Advances in clinical chemistry, vol. IV, 1961, p t. 2. Yun, T. K., Lazzara, R., Black, W. C., Walsh, J. J., and Burch, G. E.: The turnover of magnesium in control ~tlbjects and in patients with idiopathic cardiomyopathy and congestive heart failure studied with magnesium-28, J. NtiCl. Med. 7:177, 1966. 3. MacIrityre, I.: Maghesium metabolism, Adv. Intern. Mefl. 18:143, 1967. 4. Wacker, W. E; C., and Parisi, A. F.: Magnesium metabolism~ N. Engl. J. Med. 278:658, 1968. 5~ Gla~ei', W., and Brandt, J. L.: Further studies on the cardiac distribution of isotopic magnesium, Circulatio~i 18:724, 1958. 6. Lazzara, R., Hyatt, K., Love, W. D., Cronvich, J., and Butch, G. E.: Tissue distribution, kinetics a n d biologic half4ife of Mg"-'~in the dog, Am. J. Physiol. 204:1086, 1963. 7. Seller, R. H,: The role of magnesium in digitalis toxicity, AM. HEART J. ~2:551, 1971. 8. Greenberg, D. M:, Anderson, C, E., and Tufts, E. V.: Pathological chghges in the tissues of rats reared on diets low in magnesium, J. BiSl. Chem, 114:xliii, 1936. 9. Lowenhaupt, E., Schulman, M. P., and Greenberg, D. M.: Basic histologic lesions of magnesium deficiency in the ra~, Arch. Pathol. 49:427, 1950. 10. Ko, K. W., Fellers, F. X., and Craig, J. M.: Observations
656
11.
12. 13.
14. 15. 16.
17. 18, 19. 20. 21, 22. 23. 24. 25.
26. 27,
28.
29.
30. 31: 32.
on magnesium deficiency in the rat; Lab. Invest. 1 1:294, 1962. Heggtviet, H. A., Herman, L., and Mishra, R: K.: Cardiac necrosis and calcification in exPerimental magnesium deficiency; A light and electron microscopic study; Am. J. Pathol. 45:757, 1964. Vitale, J. J., Hellerstein, E. E., Nakamura, M.,'and Lown, B.: Effects of magnesium-deficient diet upon puppies, Circ. Res. 9:387, 1961. Wener, J., Pintar, K , Simon, M. A., Motola, R., Friedman, R , Mayman, A., and Schucher, R.: The effects of prolonged hypomagnesemia o9 the cardiovascula~ system in young dogs, AM. HEART J. 67:221, 1964. Seller, R. H., Cangiano, J., Kim, K. E., Mendelssohn, S,, Brest, A. N~, and SwartZ, C.: Digitalis toxicity and hypdmagnesemia, AM. HEART J. 79:57, 1970. Moore, L. A:, Hallman, E. T., and Sholl, L. B.i cardiovascular and other lesions in calves fed diets low in magnesium, Arch: Pathol: 26:820, 1938, Vitate, J. J., •etez, H., and Guzman, C.: The effect of hypothermla On the ECG of .magnesium deficient monkeys, in E, Bajusz, ed~: Electrolytes and cardiovascular diseaseS, Basel/Nev~ York, 1965, S: Karger, AG, pp. 237-247. Fitzgerald, M. G:, and Fourman, P.: An experimental study of magnesium deficiehcy in man, C1]n Sci. i 5:635, 1956. Wacker, W. E. C., and Parisi, A. F.:.Magnesium metabolism, N. Engl. J. Med. 278:712, 1968. Martin i H. Ei: Clinical magnesium deficiency, Ann. N. Y. Acad. Sci, 162:891, 1969. Wacker, W. E. C., and Parisi, A. F.: Magnesium metabolism, N. Engi. J. Med. 278,,772, 1968. Lira, P., and Jacob, E.:, Magnesium status of alcoholic patients, Metabolism 21:1045, 1972. Mac!ntyre, I,, Hanna, S., Booth, C. C., and Read, A. E.: Intracellular magnesium deficiency in man, Clin. Sci. 20:297, 1961. Seelig, M. S.: Electrocardiographic patterns of magnesium depletion appearing in alcoholic heart disease, Ann. N. Y. Acad. Sci. 162:906; 1969: Sullivan, J. F,, W01pert, P. W., Williams, R., and Egan, J. D.: Serum magnesium in chronic alcoholism; Ann. N. Y. Acad. Sci. 162:947, 1969. Burch, G. E., and Giles, T. D.- Alcoholic cardi0myopathy, in Benjamin Kissin and Henri Begleiter, eds,: The biology of alcoholism; v01. 3, Clinical Pathology, New York, 1974, Plenum Press. Burch, G. E., and Giles, T. D.: Alcoholic cardiomyopathy-Concept of the disease and its treatment, Am. J. Med. 50~141, 1971: Bureh, G, E., Colcoiough, H. L., Harb, J. M., and Tsui, C, Y.: The effect of ingestion of ethyl alcohol, wine, and beer on the myocardium of mice, Am. J. Cardiol. 27:522, 1971. Burch, G. E.: Harb, J: M:, C01colough, H. L., and TsUi, C. Y.: The effect 0f prolonged consumption of beer, wine and ethanol On the myocardium of ~he mouse, Johns Hopkins Med. J: 129:130, i971. Hibbs, R. G., Ferrans, V. J., Black, W: C.; Weilbaecher, D: G., Walsh, J. J., and Butch, G. E.: Alcoholic cardiomyopathy: An electron microscopic study, AM. HEART J. 69:766, 1965, Alexander, C. S . : Electron microscopic observations in alcoholic heart disease, Br. Heart J. 29:200, 1967. Evans, W.: Alcoholic cardiomyopathy, AM. HEART J. 61:556, 1961. Ftink, E. B., Stutzman, F. L., Anderson, A. R., Konig, T.,
November, 1977, Vol. 94, No. 5
Magnesium deficiency in cardiovascular disease
33. 34. 35.
36.
37. 38.
39. 40. 41.
42.
and Fraser, R.: Magnesium deficiency after prolonged parenteral fluid administration and after chronic alcoholism complicated by delerium tremens, J. Lab. Clin. Med. 43:169, 1954. Flink. E. B., McCollister, R., Prasad, A. S., Melby, J. C., and Doe, R. P.: Evidences for clinical magnesium deficiency, Ann. Intern. Med. 47:956, 1957 Smith. W. 0 , and Hammars~en, J. F.: Intracellular magnesium in delerium tremens and uremia, Am. J. Med. Sci. 237:413, 1959. Roberts. K. E., Magida, M. G., Satran, H.) and Ward, S.: Electrocardiographic alterations produced by a decrease in plasma pH, bicarbonate and sodium as compared with those produced by an increase m potassium, Circ. Res. 1:206, 1953. Magida, M. G,, Roberts, K. E.. and Satran, H.: Electrocardiographic alterations produced by an increase in plasma pH, bicarbonate and sodium as compared with those seen with a decrease m potassium, Circ. Res. 1:214, 1953. Zieve. L., Doizaki, W. M., and Stenroos, L. E.: Effect of magnesium deficiency on growth response to thiamine of thiamine-deficient rats, J. Lab. Clin. Med. 72:261, 1968. Caddell. J. L.: The effect of magnesium therapy on cardiovascular and electrocardiograph changes in severe protein-calorie malnutrition, Trop. Geogr. Med. 21:33, 1969. Bajpai, P. C.. Hasan. M., Gupta, A. K., and Kunwar, K. B.: Electrocardiographic changes in hypomagnesemia, Indian Heart J. 24:271. 1972. VanderArk. C. R., Ballantyne, F., III, and Reynolds, E. W., Jr.: Electrolytes and the electrocardiogram, Cardiovasc. Clin. 5(3):270, 1973. Butch, G. E., and Giles, T. D.: Diagnosis and treatment of cardiomyopathy, in Changing concepts in cardiovascular disease, the Proceedings of the American College of Cardiology, Baltimore, 1972, The Williams & Wilkins Company. Kim, Y. W., Andrews, C. E., and Ruth, W. E.: Serum magnesium and cardiac arrhythmias with special reference to digitalis intoxication, Am. J. Med. Sci. 242:87, 1961.
American Heart Journal
43. Lim, P., and Jacob, E.: Magnesium deficiency in patients on long-term diuretic therapy for heart failure, Br. Med. J. 3"620; 1972. 44. Burch, G. E.~ Elegant digitalization for congestive heart failure, AM. HEARTJ. 83:543, 1972. 45. Szekely, P., and Wynne, N. A.: The effects of magnesium on cardiac arrhythmias caused by digitalis, Clin. Sci. 10:241, 1951. 46. Chadda, K. D., Lichstein, E., and Gupta, P.: Hypomagnesemia and refractory cardiac arrhythmia in a nondigitalized patient, Am. J. Cardiol, 31:98, 1973. 47. Seelig, M. S., and Heggtveit, H. A.: Magnesium interrelationships in ischemic heart disease: A review, Am. J. Clin. Nutr. 27:59, 1974. 48. Shaper, A. G.: Soft water, heart attacks, and stroke, J.A.M.A. 230:130, 1974. 49. Scheinman, M. M., Sullivan, R. W., and Hyatt, K. H.: Magnesium metabolism in patients undergoing cardiopulmonary bypass, Circulation 39 and 40 (Supp. 1):I235, 1969~ 50. Turnier, E., Osborn, J: J., Gerbode, F., and Popper, R. W.: Magnesium and open-heart surgery, J. Thorac. Cardiovasc. Surg: 64:694, 1972. 51, Vanasin, B., Colmer, M., and Davis, P. J.: Hypocalcemia, hypomagnesemia and hypokalemia during chemotherapy of pulmonary tuberculosis, Chest 61:496, 1972. 52. Bar, R. S., Wilson, H. E., and Mazzaferri, E. L.: Hypomagnesemic hypocalcemia secondary to renal magnesium wasting: A possible consequence of high-dose gehtamicin therapy, Ann. Intern. Med. 82:646, 1975. 53. Holmes, A. M., Hesling, C. M., and Wilson, T. M.: Druginduced secondary hyperaldosteronism in patients with pulmonary tuberculosis, Q. J. Med. 39:299, 1970. 54. Yun, T. K., Lazzara, R., Black, W. C., Walsh, J. J., and Burch, G. E.: Magnesium and potassium metabolism in patients with idiopathic cardiomyopathy and chronic congestive heart failure, Proc. Soc. Exp. Biol. Med. 120:110, 1965. 55. Flink, E. B.: Therapy of magnesium deficiency, Ann. N. Y. Acad. Sci. 162:901, 1969. 56. Ginn, H. E.: Treatment of potassium and magnesium abnormalities, Mod. Treatment 5:663, 1968.
657
The role of magnesium in cardiovascular disease is not fully known primarily because magnesium measurements in patients have not been regularly obtained. Physicians fail to appreciat e the importance of this element in biology and medicine. Although a spectroscopic method for rapid, extremely accurate determination of small ampunts of magnesium in body fluids1 has been available for many years, magnesium data are lacking. The more recent-intr0duction of atomic absorption spectroscopy has facilitated the study of this major cation in the human body. A normal metabolism requires proper amounts of available magnesium; and previous studies from our laboratory have revealed magnesium to be an extremely kinetic element in man. 2 Although magnesium is vital to the proper metabolic function of all cells of man, the brief discussion to follow deals principally with selected aspects of magnesium deficiency in cardiac disease. Distribution of magnesium
The role of magnesium in metabolism has been well summarized recently.3'~ Magnesium is the fourth most plentiful cation in the body (approximately 2,000 mEq. in a 70 kilogram man), following calcium (60,000 mEq.), sodium (5,500 mEq.) and potassium (3,000 mEq.). Approximately 50 per cent of body magnesium is in bone and is not
From the Department of Medicine of Tulane University School of Medicine. and the Charity Hospital of Louisiana, New Orleans, La. Supported by grant HL-14789 from the National Heart and Lung Institute of the United States Public Health Service, the Rudolph Matas Memorial Fund for the Kate Prewitt Hess Laboratory, the Rowell A. BiUups Fund fur Research in Heart Disease, and the Feazel Laboratory. Received for publication July 29, 1976. Reprint requests: George E. Butch, M.D., Tulane University School of Medicine, 1430 Tulane Ave., New Orleans, La. 70112.
November, 1977, Vol. 94, 5/o. 5, pp 649-657
readily available as a dynamic reservoir for use in other body tissues. Like potassium, only a small part (1 per cent)of magnesium is in the extracetlular fluid compartment. The largest~ amount of magnesium which is active in magnesiokinetics is within the cells of the body in a c0ncentration of about 28 mEq. per liter. Normally, serum magnesium values are between 1.6 and 2.0 mEq. per liter. Cardiac muscle has a high concentration of magnesium (!7.4 to 19.8 mEq./liter)2.6 A higher concentration of magnesium is found in the ventricles than in the atria of the dog2 There are no significant differences between magnesium concentrations in the right and left ventricles or the interventricular septum: 6 One third of the 20 to 25 mEq. of magnesium present in a normal diet is absorbed in the small intestine, 3'* the remainder being excreted in the feces.2 Absorbed magnesium is excreted primarily by the kidney, the amount excreted in the stool over two to three days being less than 1,4 per cent of the amount given, 2 A diagram indicating the daily body turn0ver of magnesium in a female is shown in Fig. 1. Studies with Mg '-'s revealed that the rate of excretion through the urine falls during the first 15 to 20 hours and then remains relatively stable up to 70 hours:" The cumulative excretion of Mg~-~in the urine was as high as 10.7 per cent of the administered amount during the 70.hou~ observation period (Fig. 2):2 The kidney is capable of reducing renal magnesium loss to less than: 1 mEq. per day when intake is nil2' ~ A!dosterone increases the renal excretion of magnesium, v~hereas parathormone reduces excretion. Als0, parathyroid hormone regulates, i n part, bo~h calc!um and magnesium excretion and metabo, lism, An increase in the blood magnesium cation reduces parathormone secretion, and vice versa,
American Heart J o u r n a l
649
Butch and Giles Oral intake 163 mFq \ ~ , \
I Taro. ] /
>~.
~
Stomoch
L
[Actively exchangingpool /
~
_
~
7
, ~, , -.-:':Obsor:ed15.2mEq
'
2 mE,
,,I
280mEq
~
#/j/
. / , 5 9 rnEq
)
I([(L/
Stool I.I mEq
Urine 4.8 mEq Fig. 1. Diagram illustrating the daily turnover of magnesium in a normal woman9The urinary excretion was determinedthroughintravenousadministrationofMg~. (From Yun, T. K., Lazzara, R., Black, W. C., Walsh,J. J., and Butch, G. E.iThe turnover of magnesiumin controlsubjects and in patients with idiopathiccardiomyopatl~y and congestiveheart failure studied with magnesium-28,J. Nucl9Med. 7:177, 1966. Reproduced by permission.)
dAf.
I0"
9
Jf
B.S. I~
Od
ever
--.-.""
J.M.,cemtrol
~JAT~.9~chronicCHF M•M• Stool
/M.M. Hours Fig, 2. Time course curves of cumulativeexcretionof Mg~sfor two control subjects and four patients with idiopathic cardiomyopathyand congestiveheart failure,who were given intravenous injections of the tracer element. (From Yun, T. K., Lazzara, R., Black, W. C., Walsh,J. J., and Butch, G. E.:The turnover of magnesium in control subjects and in patients with idiopathic cardiomyopathyand congestiveheart failure studied with magnesium-28,J. Nucl. Med. 7:177, 19669Reproduced by permission9 Magnesium in normal biochemistry and physiology Magnesium activates m a n y enzyme systems. It is als0 a required co-factor for oxidative phospho, rylation?. 4 For example, magnesium activates alkaline phosphatase and pyrophosphatases, and the magnesium ion is a necessary co-factor when650
thiamine pyrophosphate is required. Enolases and leucine aminopeptidase also require magnesium for their enzymatic activity. These are extremely important enzymatic processes which are necessary for normal cell function and health. In addition, magnesium is involved in the structural integrity of ribosomal particles and protein synthesis. It is well known that a relationship exists between intracellular and extracellular sodium and potassium. A similar relationship exists between calcium and magnesium, In fact, an interdependent relationship with magnesium exists for most, if not all, ions present in the body. Moreover, there is a relationship among all four major cations, i.e., the intracellular ratios log (K+)/(Na § and log (Mg++)/(Ca§ are related2 There is evidence that membrane Na-K dependent adenosine triphosphatase (ATPase) requires magnesium2" Since this ATPase is necessary for the maintenance of a normal intracellular potassium, magnesium is directly involved in the regulation of potassium. A decrease in either calcium or magnesium serum concentration results in increased neuronal excitability and neuromuscular transmission. However, the effect of calcium is opposite to t h a t of magnesium in muscle. Magnesium in large doses or concentration has a curariform action on the neuromuscular junction 9 This action perhaps is produced by interference with the release of acetylcholine from motor nerve terminals? ~ November, 1977, Vol. 94, No. 5
Magnesium deficiency in cardiovascular disease
Magnesium in large doses can produce general anesthesia.
Myocardial disease in experimentally produced magnesium deficiency The effect of magnesium deficiency on the heart has been studied most extensively in the rat. In 1936, Greenberg and associates 8 described myocardial degeneration with fibrosis and polyblastic infiltration in rats that were fed a low magnesium diet from birth. Lowenhaupt, Schulman, and Greenberg 9 described in detail the basic histologic lesions of magnesium deficiency in the rat. They noted distinct, inflammatory and necrotic focal areas around small blood vessels. In the acute stage the lesions were characterized by a collection of inflammatory cells, with some areas progressing to necrosis and later scar formation. Ko, Fellers, and Craig, TM on the other hand, attached little significance to relatively few focal degenerative changes occurring in the hearts of magnesium-deficient rats. Heggtviet, Herman, and Mishra 1' studied myocardial lesions of magnesium-deficient rats using both light and electron microscopy. After 14 days of magnesium depletion, gross myocardial lesions ranging from small, pale yellowish-grey patches to large zones of necrosis and calcification were seen in 50 per cent of experimental animals. Light microscopy revealed focal areas of necrosis and exudative inflammation in most magnesium-deftcient rats after 10 days, particularly in subendocardial regionS. Muscle fibers adjacent to areas of necrosis showed increased sarcoplasmic eosinophilia, patchy loss of cross-striations, vacuolization, and accumulation of periodic acid-Schiff (PAS)-positive material. Calcification in the granulomatous lesions was seen in approximately one-half of the animals: Progression of the lesions to scarring was also observed. Electron microscopic evidence of myocardial damage was seen early (after five days on a magnesium-deficient diet). '' The mitochondria exhibited the earliest changes, consisting of swelling and vacuolization, compression and distortion of cristae, and accumulation of material (thought to represent early calcification) on and between the cristae. The myofibrillae were deranged and fragmented and were separated by accumulation of intracellular fluid. The M bands contained many dilated sarcoplasmic reticula, lipid droplets, glycogen particles and sarcoplasmic ground substance. Rupture of the sarcolemma and sepaAmerican Heart Journal
ration of myofibrils at intercalated discs were seen. Finally, nuclear changes occurred, consisting of marginal clumping of chromatin, loss of nucleoli, and vesiculation. Also, edema of the vascular endothelium was noted. The sequence of structural abnormalities suggested that interference with magnesiumdependent enzymes involved in oxidative phosphorylation played an important role in the pathogenesis of the lesions observed. 11 The lesions were not similar to those produced by potassium deficiency or ischemia. Several studies of magnesium deficiency have also been conducted in dogs. Vitale and associates TM reported calcification of the inner portions of the myocardium in magnesium-deficient puppies. Calcification of the aorta and medium sized arteries was also noted. Wener and associates ~3 observed no gross changes in the hearts of young dogs (three to eight months old) studied after receiving a magnesium-deficient diet for a mean of 87.2 days. Light microscopic findings showed only degenerativ e vascular changes in the hearts of these dogs. The endothelial cells of the intima showed pyknosis or absence of nuclei. There also was a suggestion of edema of the media. Segmental necrosis of some small coronary arteries was noted, b u t changes in larger coronary arteries were not as striking. Sections of myocardium revealed irregularly distributed, small patches of hyperchromatic staining myocardial fibers frequently located adjacent t o abnormal vessels. Necrosis Was seen in some areas of the myocardium, and there were small areas of calcification in a few animals. Electrocardiograms recorded from magnesiumdeficient dogs revealed ST segment depression with flattening of t h e T waves in the precordial leads. TM The electrocardiographic changes were interpreted as nonspecific and not related strictly to serum magnesium levels. The toxic effects of acetyl strophanthidin i n f u s i o n (100 mg./min.) were markedly increased in 19 mongrel dogs rendered hypomagnesemic by hemodialysis. ~ The arrhythmias resulting from digitalis toxicity were terminated by infusion of magnesium. Moore and colleagues 1~ observed focal cardiac necrosis and calcification in diet-induced magnesium deficiency in calves. Swelling of myofibrils and degeneration of Purkinje fibers were noted. Magnesium-deficient monkeys did not develop any histopathologic changes. TM However, magnesium-deficient monkeys were found to be more 651
Burch and Giles
Table I. Causes of symptomatic hypomagnesemia* I. Gastrointestinal disorders
a. Malabsorptionsyndromes,includingnontropical sprue b. Malabsorptiondue to extensivebowel resection c. Boweland biliary fistulas d. Prolongednasogastricsuction with administration of magnesium e. Free parenteral fluids f. Prolongeddiarrhea g. Protein-caloriemalnutrition h. Alcoholiccirrhosis i. Pancreatitis II. Endocrine disorders
a. Hyperparathyroidismand hypoparathyroidism b. Hyperaldosteronism c. Diabeticcoma III. Renal diseases
a. b. c. d. e.
Glomerulonephritis Pyelonephritis Hydronephrosis Nephrosclerosis Renal tubular acidosis
IV. Alcoholism V. Diuretic therapy (mercurials, ammonium chloride and thiazides) VI. Malignant osteolytic disease VII. Porphyria with inappropriate secretion of antidiuretic hormone VIII. Excessive lactation IX. "Idiopathic" X. Cardiopulmonary bypass XI. "Soft" water *Modified from Wacker, W. E. C., and Parisi, A. F.: Magnesium metabolism, N. Engl. J. Med. 278:712, 1968. Reproduced by permission.
susceptible to the toxic effects of digitalis than control animals. It was proposed t h a t this latter effect was due to intracellular loss of potassium produced by magnesium deficiency, but this concept is certainly difficult to establish. Myocardial disease in magnesium deficiency in man There are many causes of magnesium deficiency in man {Table I). It has been shown t h a t magnesium deficiency in a healthy man is not very likely to be due to inadequate intake since an efficient mechanism is present for decreasing losses of magnesium in the urine and feces when intake is reduced." Severe magnesium deficiency in man is manifested by hyperexcitability and occasional behavioral disturbances? 8 Tetany, convulsive seizures, and other central nervous system disturbances
652
have been described. Manifestations of magnesium deficiency in man are much less clearly defined than those in experimental animals.~ ~ Nevertheless, magnesium deficiency does occur in man and may contribute to disease states. Chronic, low grade magnesium deficiency may be much more common than is conventionally considered since magnesium is not studied regularly in clinical medicine, as are sodium, potassium, and chloride. It is impossible in this presentation to consider all aspects of magnesium deficiency in man in relation to myocardial disease. Therefore, the remarks to follow are limited to alcoholic cardiomyopathy, electrocardiographic manifestations and disturbances in cardiac rhythm, and ischemic heart disease. However, the physician may readily think Of many other situations in which magnesium plays an important role in clinical medicine. Alcoholic cardiomyopathy. Chronic ingestion of alcoholic beverages is associated with hypomagnesemia and decreased skeletal muscle potassium.~O. 51 Since about 20 per cent of body magnesium is contained in skeletal muscles, a deficiency of magnesium in this tissue indicates a significant intracellular deficit throughout the body {including the heart). 22 A linear relationship exists between retention of infused magnesium and the increment of increase in skeletal muscle magnesium, -~1 supporting the reliability of skeletal muscle magnesium as an index of total body magnesium status. For obvious reasons, the state of myocardial magnesium metabolism remains little known in alcoholics even though electrocardiographic data suggest t h a t myocardial magnesium deficiency exists in alcoholics. ~3 Alcohol may increase renal excretion of magnesium by a direct effect on tubular resorption or by increasing production of some metabolic intermediates t h a t could bind magnesium ions as they are being excreted, s~ Other factors producing magnesium depletion in alcoholics include vomiting and diarrhea, hyperhydrosis, drugs, and hyperaldosteronism in patients with cirrhosis of the liver and ascites. ~~It is interesting t h a t relatively high rates of urinary excretion of magnesium continue in alcoholics during alcohol withdrawal states despite low serum levels of magnesium. '24 The mechanisms for the production of heart disease in association with excessive ingestion of alcohol by man include: (1) direct toxic injury by
November, 1977, Vol. 94, No. 5
Magnesium deficiency in cardiovascular disease
the alcohol to the myocardium, (2) nutritional disturbances (beri-beri), (3) toxic effects of substances contained in alcoholic beverages (e.g., cobalt), and (4) a combination of the above. 2~ Alcoholic cardiomyopathy is usually characterized predominantly by the symptoms and signs of left-sided heart failure when the cardiomyopathy is advanced and the myocardial damage extensive. ~ Initially, alcoholic cardi0myopathy has mild to subtle manifestations, often limited to the ECG. It is becoming well established that alcohol alone is sufficiently toxic to produce myocardial damage...,~. _~6The pathogenesis of alcohol induced cardiac injury may involve metabolites of ethanol (acetaldehyde), associated nutritional disturbances, or electrolytic disturbances (hypomagnesemia itself), along with direct toxic injury to the myocardium, The cardiac changes produced by experimental magnesium deficiency in the rat (vide supra) are similar in many ways to the changes found in mice fed large quantities of alcohol36.27.28 However, histologic and electron microscopically observed structural changes are not specific. Mitochondrial damage is prominent in both groups, as well as disruption of myofibres and swelling and dilatation of sarcoplasmic reticulum. Such ultrastructural changes have been observed in hearts of patients with alcoholic cardiomyopathy36. 2~, 36 T h e electrocardiograms recorded from alcoholic patients reflect changes of magnesium deficiency. 23 Evans 31 described the T wave changes associated with alcoholism to be of four types: (1) bifid or cloven, (2) spinous, (3) isoelectric, or (4) negative, Flink and colleagues 3~. 33 reported ECG changes associated with magnesium deficiency resembling those of hypokalemia. Only primary ST segment alterations were noted in acute alcoholism, and these changes could be corrected only with magnesium therapy24 Because electrolyte imbalance for any one electrolyte is associated with changes in all electrolytes, it becomes difficult to know which electrolyte is responsible for ECG changes2 ~' ~6 The early electrocardiographic manifestations of alcoholic myocardial disease are T wave and ST segment changes. As the disease advances in severity and duration, more extensive ECG changes reflecting diffuse myocardial damage occur. These include widening of the QRS complexes, conduction disturbances, and ar-
American Heart Journal
rhythmias such as atrial fibrillation. There is a need to study in detail the ECG changes associated with magnesium depletion and repletion in alcoholic cardiomyopathy. Beri-beri heart disease, which may be found in alcoholics, is characterized by a high cardiac output state, predominantly right-sided congestive heart failure (when congestive heart failure occurs), bounding pulses, and peripheral neuropathy. These changes have been attributed primarily to thiamine deficiency, but alcohol intoxication and disturbances in magnesium metabolism may be important associated contributing factors. Thiamine deficiency may also be associated with magnesium deficiencyY Because of the importance of magnesium in oxidative phosphorylation and as a cofactor for thiamine metabolism, magnesium deficiency may worsen the symptoms and signs of thiamine deficiency and, unless corrected, may even prevent or considerably lessen the therapeutic effects of thiamine administrationY
Electrocardiographic abnormalities and arrhythmias associated with magnesium deficiency The electrocardiographic changes of magnesium deficiency (Fig. 3) are different from those of potassium and calcium imbalance in experimental animals. However, there is a lack of agreement as to what ECG changes are characteristic of magnesium deficiency. This is not surprising since it is unlikely that magnesium deficiency ever occurs entirely alone. It has been ~shown that disturbances in balance of any one electrolyte result in changes of practically all the others.35.36 Magnesium does influence the con: centration and distribution of the other major cations as well as important metabolic processes. When children suffering from severe malnutrition are given nutrients without adequate magnesium supplementation, the ECG reveals sharply peaked, asymmetrical T waves and prominent U waves, 3s similar to patterns recorded by Vitale and associates 12for magnesium deficiency in dOgS. Prior to replacement therapy, flat or inverted T waves were recorded in children2 s Low-voltage P waves and QRS complexes have been recorded in magnesium-deficient patients. 39 T h e s e changes were reversed by magnesium administration/9 Thus, it would appear that "early" magnesium
653
Burch and Giles
NM
R
,~
/I
N i ........
I S~ ST ~. I~'~ interval i ~T
segment
I
1T
aV~
"
NORMAL R
ed T P
6ed
~oRss MODERATE Mg DEFICIENCY
S E V E R E Mg DEFICIENCY {Combined low K + & M g + ~
Fig. 3. Electrocardiographicchanges associated with magnesium deficiency. (From Seelig, M. S.:Electrocardiographic patterns of magnesium depletionappearing in alcoholicheart disease, Ann. N. Y. Acad. Sci. 162:906, 1969. Reproduced by permission.) deficiency is characterized electrocardiographically by tall, peaked T waves (not narrow as in hyperkalemia) and a normal QT interval2 ~ These changes probably reflect in part a relative increase in extracellular potassium. It is interesting that these T waves resemble the "spinous" T wave associated with alcoholism (Fig. 4). TM ~' Late or prolonged magnesium deficiency produces a prolonged PR interval, wide QRS complexes, ST segment depression, and low T waves2" Hypomagnesemia can contribute to disturbances in cardiac rhythm, especially when associated with digitalis administration. 7. ". ~ Both digitalis administration and hypomagnesemia tend to produce a loss of intracellular potassium. Hypokalemia produces electrical instability of the myocardium. Significant intracellular deficit of these cations can be produced by oral diuretic therapy2 3 It is not surprising, therefore, to find h y p o k a l e m i a and hypomagnesemia in patients with heart disease since these patients frequently receive both digitalis (often in excessive amounts) and oral diuretics. Administration of this combination of drugs contributes to the production of digitalis intoxication seen frequently in hospitals recently2 ~ Thus, in the presence of hypomagnesium, as with hypokalemia, the a m o u n t of digitalis required to produce toxicity is reduced. It is prudent to obtain magnesium levels in the serum of any patient with "digitalis-induced '~
654
Fig. 4. Electrocardiogramof a patient with alcoholic cardiomyopathy showing cloven and spinous T waves similar to those seen in magnesium deficiency.{From Burch, G. E., and Giles, T. D.:Diagnosis and treatment of cardiomyopathy, in Changing conceptsin cardiovasculardisease, the Proceedings of the American College of Cardiology, Baltimore, 1972, The Williams & Wilkins Company. Reproduced by permission.}
arrhythmias of any type and to administer magnesium in t r e a t m e n t when levels are low25 Such t r e a t m e n t has been shown to be effective in abolishing digitalis-induced ventricular bigeminy and ventricular tachycardia. Furthermore, when patients are hypokalemic, intracellular potassium will remain low unless the associated hypomagnesium is also corrected. Cardiac a r r h y t h m i a has been reported in patients with hypomagnesemia even when the patients were not on digitalis therapy2 ~ In one patient, a paroxysmal supraventricular tachycardia was abolished by the intravenous administration of magnesium sulfate. Ischemic heart disease
The possible role of magnesium in the production of disturbances in the cardiac state of ischemic heart disease has been r e v i e w e d f Ischemic heart disease appears to be more prevalent in areas where people consume soft water than in areas where hard water {high calcium and magnesium) is consumed28 Moreover, the reported incidence of sudden death is greater in areas with soft water t h a n in those with hard water. It has been shown in the rabbit t h a t magne-
November, 1977, Vol. 94, No. 5
Magnesium deficiency in cardiovascular disease
slum protects against the development of dietary induced arteriosclerosis better than does calcium27 Also, magnesium decreases blood lipids and blood coagulability. The role of magnesium administration in ischemic heart disease, if any, probably relates to its cellular effects, e.g., counteracting adverse effects of intracellular calcium, protecting against loss of intracellular potas, slum, and maintaining the integrity of subcellular structure. Possibility of magnesium deficiency as a "conditioning factor." for heart disease
Because magnesium is so important in the metabolic function and physic0chemical state of cells, a deficiency of magnesium could render a cell more vulnerable to insults from viruses, toxins, radiation, and other noxious agents. For example, in alcoholic cardiomyopathy, magnesium deficiency may contribute to the development of viral infection, This concept of hypomagnesium or even hypermagnesium being conditioning factors for viral infections of the heart and other cardiac diseases needs investigation. Cardiopulmonary bypass and magnesium deficiency
A decrease in serum magnesium has been reported following cardiopulmonary bypass during open heart surgery, 49 even though intracellular magnesium has been reported to increase slightly2 ~ Importantly, conversion of cardiac arrhythmias following cardiopu!monary bypass may be assisted by magnesium therapy when hypomagnesemia is present29 Use of magnesium in management of cardiac disease
The need in clinical medicine to measure serum concentration of magnesium in all patient s with heart disease, as is the practice for sodium, potassium and calcium, cannot be overemphasized. Surely, attention should be directed to possible magnesium deficiency in patients receiving any, and especially oral, diureticsJ 0" ~3 Depletion of :magnesium occurs with the use of mercurial diuretics, ammonium chloride, and especially the thiazides with poor dietary intake.S0 Other drugs known to cause hypomagnesemia are capreomycin, viomyci n, and gentamicin. ~' ~ Large doses of gentamicin may also cause potassium loss,~i-53 possibly related to secondary aldosteronism. It is
American Heart Journal
Table II. Suggested guidelines for treatment of magnesium deficiency* Dose Intramuscular route (50% MgS04 solution)t 1 2 3-5
2.0 g r a m s {16.3 m E q . ) every 2 h o u r s for t h r e e doses a n d t h e n every 4 h o u r s for four doses 1.0 gram (8.1 m E q . ) every 4 h o u r s for six doses 1.0 g r a m every 6 h o u r s
Intravenous route (ampules of MgS03 1
2 3-5
6.0 g r a m s (49 m E q . ) in 1000 m L . s o l u t i o n
containing glucoseplus any other electrolytes and other medications as indicated-infuse in 3 hours, followedby 5.0 grams in each of 2 one-liter solutions administered throughout the day. A total of 6.0 grams (49 mEq.) divided equally in the total fluids of the day. The same as day 2
*From Flink, E. B.: Therapy of magnesium deficiency, Ann. N. Y. Acad. Sci. 162:901, 1969. Reproduced by permmslon. tThis supplies 32 grams or 260 mEq. of magnesium.
common clinical practice to order supplemental potassium therapy for patients receiving kaliuretic diuretics, particularly when digitalis preparations are also administered. Consideration should also be given to magnesium supplementation for such patients since hypomagnesemia also predisposes to digitalis intoxication. The supplemental dosage of magnesium, as well as of potassium, should not be empirical b u t should be based on each patient's need. In patients with congestive heart failure secondary to idiopathic cardiomyopathy, a significant correlation exists between daily cumulative balances and renal clearances of magnesium and potassium. 54 The kinetics of magnesium metabolism in normal people and in patients with congestive heart disease have been reported previously from our laboratoryJ Orally and intravenously administered Mg 2s was excreted very slowly (less than 5 per cent in the first 24 hours and less than 2 per cent per day thereafter) in patients with congestive heart failure and idiopathic cardiomyopathyJ The excretion of urinary magnesium in patients with congestive h e a ~ failure was primarily from the magnesium pool of the body, with less than 18 per cent o.f the daily urinary excretion being derived from newly absorbed magnesium. Most patients with magnesium deficiency will have a reduction of 1.0 to 2.0 mEq./Kg, of body weight25 Suggested replacement schedules, re-
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gardless of the cause of the deficiency, are s u m m a r i z e d in T a b l e I I . AS m u c h a s 2 m E q . / K g . o f m a g n e s i u m Chloride c a n b e g i v e n o v e r 4 h o u r s a n d r e p e a t e d 24 h o u r s l a t e r 2 ~ H o w e v e r , r e p l a c e ment therapy should be determined by frequent evaluation of the patient with consideration of all aspects of the patient's health. There are not sufficient data to recommend the addition of magnesium to the drinking water of "soft water" areas even though the incidence of i s c h e m i c h e a r t d i s e a s e a n d s u d d e n d e a t h is g r e a t e r in t h e s e a r e a s t h a n in a r e a s w i t h h a r d water containing higher concentrations of magnesium. General remarks I t is a p p a r e n t t h a t m a g n e s i u m p l a y s a n i m p o r t a n t r o l e in c a r d i a c h o m e o s t a s i s a n d t h a t m a g n e s l u m d e f i c i e n c y is c a p a b l e o f p r o d u c i n g c a r d i a c d i s e a s e . P r o b a b l y o f m o r e i m p o r t a n c e is t h e ~ontributing role of magnesium deficiency to the pathogenesis of myocardial injury and the develb p m e n t of d r u g t o x i c i t y . M a g n e s i u m d e f i c i e n c y will b e f o h n d o n l y w h e n l o o k e d for, a n d t h u s t h e r e s p o n s i b i l i t y for p r e v e n t i o n , d e t e c t i o n , a n d treatment resides With the physician, The recogn i t i o n of t h e i m p o r t a n c e o f t h i s i o n l e a d s t o further realization that all elements contained within the body of man are important. REFERENCES 1. Maclntyre, I.i Flamephotometry, in Advances in clinical chemistry, vol. IV, 1961, p t. 2. Yun, T. K., Lazzara, R., Black, W. C., Walsh, J. J., and Burch, G. E.: The turnover of magnesium in control ~tlbjects and in patients with idiopathic cardiomyopathy and congestive heart failure studied with magnesium-28, J. NtiCl. Med. 7:177, 1966. 3. MacIrityre, I.: Maghesium metabolism, Adv. Intern. Mefl. 18:143, 1967. 4. Wacker, W. E; C., and Parisi, A. F.: Magnesium metabolism~ N. Engl. J. Med. 278:658, 1968. 5~ Gla~ei', W., and Brandt, J. L.: Further studies on the cardiac distribution of isotopic magnesium, Circulatio~i 18:724, 1958. 6. Lazzara, R., Hyatt, K., Love, W. D., Cronvich, J., and Butch, G. E.: Tissue distribution, kinetics a n d biologic half4ife of Mg"-'~in the dog, Am. J. Physiol. 204:1086, 1963. 7. Seller, R. H,: The role of magnesium in digitalis toxicity, AM. HEART J. ~2:551, 1971. 8. Greenberg, D. M:, Anderson, C, E., and Tufts, E. V.: Pathological chghges in the tissues of rats reared on diets low in magnesium, J. BiSl. Chem, 114:xliii, 1936. 9. Lowenhaupt, E., Schulman, M. P., and Greenberg, D. M.: Basic histologic lesions of magnesium deficiency in the ra~, Arch. Pathol. 49:427, 1950. 10. Ko, K. W., Fellers, F. X., and Craig, J. M.: Observations
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Magnesium deficiency in cardiovascular disease
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American Heart Journal
43. Lim, P., and Jacob, E.: Magnesium deficiency in patients on long-term diuretic therapy for heart failure, Br. Med. J. 3"620; 1972. 44. Burch, G. E.~ Elegant digitalization for congestive heart failure, AM. HEARTJ. 83:543, 1972. 45. Szekely, P., and Wynne, N. A.: The effects of magnesium on cardiac arrhythmias caused by digitalis, Clin. Sci. 10:241, 1951. 46. Chadda, K. D., Lichstein, E., and Gupta, P.: Hypomagnesemia and refractory cardiac arrhythmia in a nondigitalized patient, Am. J. Cardiol, 31:98, 1973. 47. Seelig, M. S., and Heggtveit, H. A.: Magnesium interrelationships in ischemic heart disease: A review, Am. J. Clin. Nutr. 27:59, 1974. 48. Shaper, A. G.: Soft water, heart attacks, and stroke, J.A.M.A. 230:130, 1974. 49. Scheinman, M. M., Sullivan, R. W., and Hyatt, K. H.: Magnesium metabolism in patients undergoing cardiopulmonary bypass, Circulation 39 and 40 (Supp. 1):I235, 1969~ 50. Turnier, E., Osborn, J: J., Gerbode, F., and Popper, R. W.: Magnesium and open-heart surgery, J. Thorac. Cardiovasc. Surg: 64:694, 1972. 51, Vanasin, B., Colmer, M., and Davis, P. J.: Hypocalcemia, hypomagnesemia and hypokalemia during chemotherapy of pulmonary tuberculosis, Chest 61:496, 1972. 52. Bar, R. S., Wilson, H. E., and Mazzaferri, E. L.: Hypomagnesemic hypocalcemia secondary to renal magnesium wasting: A possible consequence of high-dose gehtamicin therapy, Ann. Intern. Med. 82:646, 1975. 53. Holmes, A. M., Hesling, C. M., and Wilson, T. M.: Druginduced secondary hyperaldosteronism in patients with pulmonary tuberculosis, Q. J. Med. 39:299, 1970. 54. Yun, T. K., Lazzara, R., Black, W. C., Walsh, J. J., and Burch, G. E.: Magnesium and potassium metabolism in patients with idiopathic cardiomyopathy and chronic congestive heart failure, Proc. Soc. Exp. Biol. Med. 120:110, 1965. 55. Flink, E. B.: Therapy of magnesium deficiency, Ann. N. Y. Acad. Sci. 162:901, 1969. 56. Ginn, H. E.: Treatment of potassium and magnesium abnormalities, Mod. Treatment 5:663, 1968.
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