Interrelationship of magnesium and congestive heart failure.

Congestive heart failure is a most arrhythmogenic disease that is responsible for many unexpected sudden deaths. Reduction of sudden cardiac death rates among patient populations receiving long-term diuretic therapy, when given potassium- and magnesium-sparing diuretics as well as magnesium supplements, substantiates the premise that maintenance of adequate magnesium status is important in the prevention and management of cardiovascular diseases that predispose to congestive heart failure.

Can one really measure magnesium deficiency using the short-term magnesium loading test?

OBJECTIVE: To compare a 1-h-version of a magnesium-loading-test (MLT) designed for outpatients in healthy controls with the 8-h standard; to establish the test in patients after renal transplantation prone to develop magnesium (Mg) deficiency; to correlate femur Mg-concentration and percentage retention of the given load. DESIGN: Comparison of mean values from healthy controls with respective from the literature; a prospective, randomized, controlled 4-month study; an intra-individual correlation of Mg-serum values and loading-test data with femur-Mg concentrations. SETTING: One centre study in a medical university; outpatients from the transplant unit; inpatients from the orthopedic unit. SUBJECTS: Twenty-four healthy controls aged 36.7 +/- 7.4 years; 34 patients after renal transplantation (46.5 +/- 14.3 years); 41 patients with hip replacement therapy (63.9 +/- 18.6 years). INTERVENTION: Baseline Mg values were measured by atomic absorption spectroscopy (AAS) in serum and urine. An intravenous Mg load with 0.1 mmol Mg-aspartate hydrochloride per kilogram bodyweight was given during 1 h. In 24 h-urine, the amount of excreted Mg was measured by AAS and the percentage retention of the given load calculated according to the formula: 1 - [Mg 24 h-urine/Mg test dose] x 100. Femur Mg was measured by AAS in a peace of the femur neck. Patients after renal transplantation were randomized after the first Mg load to either obtain daily 5 mmol Mg-aspartate hydrochloride per kilogram bodyweight, or placebo. Four months later a second loading-procedure was performed. MAIN OUTCOME MEASURE: Serum Mg, percentage retention of the given Mg load (%Ret) and femur Mg concentration. RESULTS: Mean serum Mg values were within the normal range. In controls, %Ret was -18 +/- 21 and not different from the literature. In the first MLT after renal transplantation, %Ret was 47 +/- 43. In patients under Mg medication it decreased significantly to 16 +/- 26, but was 58 +/- 27 in the placebo group. Femur Mg concentration was 62.6 +/- 20.9 mmol kg-1 dry substance and the corresponding %Ret was 14 +/- 28 with r = - 0.7093. CONCLUSION: The short-term version of the MLT is as good as the standard and was easily applied in outpatients. The indication from the good correlation between bone-Mg and %Ret and a marked decrease in %Ret in patients after Mg medication was that one can really measure magnesium deficiency.

Magnesium in acute myocardial infarction: still an open question.

Many activities of magnesium have justified randomized controlled trials of its role in acute myocardial infarction (AMI), which have shown reduction of short term mortality by 25% to over 50%. The Fourth International Study of Infarct Survival (ISIS-4) megastudy failed to confirm these findings, and, based on analysis of pooled findings, it was concluded that magnesium has no place in treatment of AMI. The fixed effects statistical model employed in ISIS-4 for evaluation of pooled data is inappropriate because the studies were not homogeneous. Among the differences between the earlier studies and the megatrial, the most significant was the time at which magnesium infusions were started relative to the time of reperfusion. Animal studies have shown that magnesium is protective only if present before or at the time of reperfusion. Unlike in earlier trials, in which magnesium infusions were started soon after the ischemic event or simultaneously with a lytic agent, in ISIS-4 magnesium treatment was withheld until after iatrogenic or spontaneous reperfusion occurred. This can explain poor therapeutic results in ISIS-4, but not the hypotension and bradycardia encountered in a minority of patients in that study. Dosage difference alone cannot explain this, even though the amounts given in the small studies were 40% to 25% less than that in ISIS-4, because the dose used in the Second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2) was only slightly lower than that used in ISIS-4. Administration of high dose magnesium with an angiotensin-converting enzyme inhibitor (which spares magnesium) or the vasodilating oral nitrate in arms of ISIS-4 may have contributed to adverse effects of hypermagnesemia. Also, the very low mortality rate of controls in ISIS-4 suggests that the patients may have been at relatively low risk, and it is in high risk patients that magnesium has been shown to be most effective. A large scale study of magnesium in such patients is being started.

Is there a place for magnesium in the treatment of acute myocardial infarction?

Infusions of solutions of magnesium sulfate for patients with acute myocardial infarction were shown by a meta-analysis of seven small studies and a larger study of 2316 patients (LIMIT-2) to have clinical efficacy. However, the ISIS-4 study of 58,050 patients found no improvement in short-term mortality rates with magnesium therapy in patients with acute myocardial infarction. In this article we explore the following four differences between the ISIS-4 study and the earlier studies: (1) Time of initiation of magnesium treatment after acute myocardial infarction and thrombolytic therapy; (2) dosage of magnesium in the first 24 hours after acute myocardial infarction; (3) duration of magnesium infusion after acute myocardial infarction; and (4) differences in patient risks in control and treatment groups. These four differences may explain the different outcomes among these studies and indicate the type of additional studies that are needed to define the clinical utility of magnesium infusion in the treatment of patients with acute myocardial infarction.

ISIS 4: clinical controversy regarding magnesium infusion, thrombolytic therapy, and acute myocardial infarction.

Magnesium (Mg) infusions over 24 hours were given to patients with suspected acute myocardial infarction (AMI) at least 2 hours after thrombolysis. Patients showed no benefit and even some increased risk in contrast to reduction in mortality obtained by Mg therapy in smaller trials. Results of all of the studies were pooled and statistically analyzed, according to a fixed-effects model that is inappropriate for studies of different protocols. The panel concluded that further study of Mg in AMI is not needed. This conclusion has been questioned.

Consequences of magnesium deficiency on the enhancement of stress reactions; preventive and therapeutic implications (a review).

Stress intensifies release of catecholamines and corticosteroids that increase survival of normal animals when their lives are threatened. When magnesium (Mg) deficiency exists, stress paradoxically increases risk of cardiovascular damage including hypertension, cerebrovascular and coronary constriction and occlusion, arrhythmias and sudden cardiac death (SCD). In affluent societies, severe dietary Mg deficiency is uncommon, but dietary imbalances such as high intakes of fat and/or calcium (Ca) can intensify Mg inadequacy, especially under conditions of stress. Adrenergic stimulation of lipolysis can intensify its deficiency by complexing Mg with liberated fatty acids (FA), A low Mg/Ca ratio increases release of catecholamines, which lowers tissue (i.e. myocardial) Mg levels. It also favors excess release or formation of factors (derived both from FA metabolism and the endothelium), that are vasoconstrictive and platelet aggregating; a high Ca/Mg ratio also directly favors blood coagulation, which is also favored by excess fat and its mobilization during adrenergic lipolysis. Auto-oxidation of catecholamines yields free radicals, which explains the enhancement of the protective effect of Mg by anti-oxidant nutrients against cardiac damage caused by beta-catecholamines. Thus, stress, whether physical (i.e. exertion, heat, cold, trauma--accidental or surgical, burns), or emotional (i.e. pain, anxiety, excitement or depression) and dyspnea as in asthma increases need for Mg. Genetic differences in Mg utilization may account for differences in vulnerability to Mg deficiency and differences in body responses to stress.

Interrelationship of magnesium and estrogen in cardiovascular and bone disorders, eclampsia, migraine and premenstrual syndrome.

The anticonvulsive and antihypertensive values of magnesium (Mg) in eclampsia, and its antiarrhythmic applications in a variety of cardiac diseases, have caused Mg to be considered only for parenteral administration by many physicians. In contrast, nutritionists have long recognized Mg as an essential nutrient, because severe deficiencies elicit neuromuscular manifestations similar to those justifying its use in eclampsia. More recently, this element has been used to favorably influence latent tetany with and without thrombotic complications, to delay preterm birth, to influence premenstrual syndrome, and to ameliorate migraine headaches. Most of these disorders exclusively or largely afflict women. The lesions of arteries and heart caused by experimental Mg deficiency have been well documented and may contribute to human cardiovascular disease. Estrogen's enhancement of Mg utilization and uptake by soft tissues and bone may explain resistance of young women to heart disease and osteoporosis, as well as increased prevalence of these diseases when estrogen secretion ceases. However, estrogen-induced shifts of Mg can be deleterious when estrogen levels are high and Mg intake is suboptimal. The resultant lowering of blood Mg can increase the Ca/Mg ratio, thus favoring coagulation. With Ca supplementation in the face of commonly low Mg intake, risk of thrombosis increases.

Increased need for magnesium with the use of combined oestrogen and calcium for osteoporosis treatment.

Prophylactic treatment of postmenopausal osteoporosis with oestrogen and calcium, often in combination, disregards the likelihood that an excess of each agent may increase magnesium requirements and decrease serum Mg levels. Relative or absolute Mg deficiency, which is likely in the Occident where the Mg intake is commonly marginal, can militate against optimal therapeutic bone response, Mg being important for normal bone structure, and can increase the risk of adverse effects. Although oestrogen has cardiovascular protective effects (expressed by the lower incidence of heart disease in premenopausal women than in men, and also in postmenopausal women given low dosage oestrogen replacement treatment), high dosage oestrogen oral contraceptives have caused increased intravascular blood clotting with resultant thromboembolic cardio- and cerebrovascular accidents. This might be contributed to by the oestrogen-mediated shift of circulating Mg to soft and hard tissues, which in persons with marginal Mg intakes may lead to suboptimal serum levels. If the commonly recommended dietary Ca/Mg ratio of 2/1 is exceeded (and it can reach as much as 4/1 in countries with low to marginal Mg intakes), relative or absolute Mg deficiency may result, and this may increase the risk of intravascular coagulation, since blood clotting is enhanced by high Ca/Mg ratios. Mechanisms by which Ca activates the various steps in blood coagulation that are also stimulated by oestrogen are considered here, as are the multifaceted roles of Mg that favourably affect blood coagulation and fibrinolysis, through its activities in lipoprotein and prostanoid metabolism.

Rapidly progressive glomerulonephritis in a patient with rheumatoid arthritis during treatment with high-dosage D-penicillamine.

A patient with advanced rheumatoid arthritis and severe clinical manifestations of rheumatoid vasculitis died of acute renal failure after 30 months of treatment with high-dosage D-penicillamine. She had had no signs of adverse drug reactions until the terminal illness. Although streptococcal pharyngitis was diagnosed late in her disease, penicillamine-induced immune complex glomerular damage is considered more likely than poststreptococcal glomerulonephritis, because her microscopic hematuria preceded diagnosis of pharyngitis. Postmortem examination disclosed findings suggestive of rapidly progressive glomerulonephritis of immune complex pathogenesis. The short period of microscopic hematuria and the rapidity of development of renal failure before death emphasize the need for frequent monitoring of renal function and prompt discontinuation of D-penicillamine treatment upon detection of otherwise unexplained hematuria. There is urgent need for early immunological evaluation, renal biopsy, and vigorous therapeutic measures.

Interactions of magnesium and potassium in the pathogenesis of cardiovascular disease.

The interactions of Mg and K in cardiovascular disease are diverse and complex. However, Mg deficiency and loss from the heart and arteries, caused e.g. by dietary deficiency or imbalance, or by diseases and their treatment, can contribute to cardiovascular damage, and to functional abnormalities. Although Mg deficiency interferes with K retention, it is seldom measured in routine clinical practice, and the need to correct low Mg levels, in order to replete K, is rarely considered. The heart, with its high metabolic activity, is particularly vulnerable to Mg deficiency or loss because of the importance of Mg in mitochondrial structure and enzymatic function. The need for Mg to activate Na/K ATPase has long been known. Mg has also been shown to be structurally part of the enzyme in cardiac mitochondria. Additionally, Na/K exchange occurs in association with phosphorylation and dephosphorylation, reactions that are also Mg-dependent. The demonstration that Mg modulates K+/proton (H+) exchange, and that cation selectivity in Na+ and K+ exchange for H+ is highly dependent on the concentration of Mg++, provides new insights into how Mg protects against K loss. The loss of myocardial K that results from Mg deficiency contributes to electrophysiologic changes, as can the Ca shifts of Mg loss. A high Ca/Mg ratio also predisposes to arterial spasms, and increases catecholamine release. Thus the arrhythmogenic potential of Mg deficiency can be related to imbalances between Mg and K or between Mg and Ca, or both. Electrical or K-induced catecholamine release is increased by a low Mg/Ca ratio, as are increased fatty acids and lipids and intravascular hypercoagulability. K or Ca loading of the patient with undiagnosed Mg inadequacy is not only often unsuccessful, but it may carry inherent risks. It can intensify the Mg depletion, the arterial contractility, and ECG abnormality. In the patient receiving digitalis, Mg deficiency can increase drug toxicity. In the case of myocardial infarction, Mg deficiency can increase the risk of malignant ventricular arrhythmias and sudden cardiac death. In the absence of alcoholism or gastrointestinal disease, the use of loop diuretic therapy for congestive heart failure, especially in elderly patients, is the most common cause of Mg depletion. A high concurrence of hypomagnesemia with hypokalemia, from whatever cause, has been documented. However, systemic Mg deficiency can exist despite normal Mg serum levels. Methodological difficulties hamper direct detection of cellular Mg deficiency, but patients can be indirectly evaluated by use of Mg-loading tests, which may be of combined diagnostic and therapeutic value.(ABSTRACT TRUNCATED AT 400 WORDS)

Diagnosis of systemic or visceral candidosis.

Although systemic or visceral candidosis can be diagnosed during life, it is usually discovered at autopsy. Early diagnosis is important since treatment with specific antifungal drugs is effective. The diagnosis should rest on all available clinical and laboratory evidence. Mucocutaneous lesions and chorioretinitis are important clinical findings in the presence of predisposing illness and iatrogenic factors. Repeatedly positive blood cultures for Candida in the absence of an indwelling intravenous line and Candida colony counts of 10 000/ml or greater in urine freshly obtained by catheter in the absence of an indwelling Foley catheter are very significant. Similarly significant is recovery of Candida from closed spaces (pleural, peritoneal, joint or subarachnoid). The agar gel diffusion test for Candida antibodies has a sensitivity and specificity of 85% or greater and can confirm the diagnosis in otherwise doubtful cases. The various antibody tests for Candida are not suitable for random screening because of the low prevalence of visceral or systemic candidosis in the general population.

Auto-immune complications of D-penicillamine--a possible result of zinc and magnesium depletion and of pyridoxine inactivation.

Long-term high-dosage penicillamine treatment of patients with advanced stages of diseases with autoimmune components has resulted in very few adverse reactions in a series of over 50 such patients also given selected nutrients: pyridoxine, zinc and magnesium (which penicillamine inactivates or chelates), and vitamins B1, B12, and E (which have sulfhydryl-protective activity). The patients on this regimen have been essentially free of the side effects that occur in about a third of patients treated with penicillamine without such supplements. Reports of myasthenia gravis--a disease with abnormalities of the thymus and of T-cells, as a side effect of penicillamine--suggest that zinc, magnesium, and pyridoxine might be the agents most likely to be protective. Pyridoxine is necessary for cellular accumulation of zinc and magnesium, deficiencies of which have caused thymic and other immunologic abnormalities. Whether the other vitamins administered contribute to the favorable results requires further study.