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Jlemrh00249 1.13Magnesium Research 2010; 23 (2): 1-13 Magnesium and cardiovascular system Leviev Heart Center, Chaim Sheba Medical Center, Tel Hashomern and the Sackler Facultyof Medicine, Tel Aviv University, Ramat Aviv, IsraelCorrespondence: M.Shechter, MD, MA, FESC, FACC, FAHA, FACN, Director, Clinical Research Unit, Leviev Heart Center, Chaim Sheba Medical Center, 52621 Tel Hashomer, Israel Abstract. Hypomagnesemia is common in hospitalized patients, especially in theelderly with coronary artery disease (CAD) and/or those with chronic heart failure.
Hypomagnesemia is associated with an increased incidence of diabetes mellitus,metabolic syndrome, mortality rate from CAD and all causes. Magnesium supple-mentation improves myocardial metabolism, inhibits calcium accumulation andmyocardial cell death; it improves vascular tone, peripheral vascular resistance,afterload and cardiac output, reduces cardiac arrhythmias and improves lipidmetabolism. Magnesium also reduces vulnerability to oxygen-derived free radicals,improves human endothelial function and inhibits platelet function, including plate-let aggregation and adhesion, which potentially gives magnesium physiologic andnatural effects similar to adenosine-diphosphate inhibitors such as clopidogrel.
The data regarding its use in patients with acute myocardial infarction (AMI) isconflicting. Although some previous, relatively small randomized clinical trialsdemonstrated a remarkable reduction in mortality when administered to relativelyhigh risk AMI patients, two recently published large-scale randomized clinical trials(the Fourth International Study of Infarct Survival and Magnesium in Coronaries)failed to show any advantage of intravenous magnesium over placebo. Neverthe-less, there are theoretical potential benefits of magnesium supplementation as acardioprotective agent in CAD patients, as well as promising results from previouswork in animal and humans. These studies are cost effective, easy to handle andare relatively free of adverse effects, which gives magnesium a role in treatingCAD patients, especially high-risk groups such as CAD patients with heart failure,the elderly and hospitalized patients with hypomagnesemia. Furthermore, magne-sium therapy is indicated in life-threatening ventricular arrhythmias such asTorsades de Pointes and intractable ventricular tachycardia.
Key words: magnesium, diabetes, nutrition, endothelium, myocardial infarction, heartdisease, hypertension, platelets The body magnesium distribution magnesium is located in high metabolic tissues suchas muscles, brain, heart, kidneys and liver and only 1% In a 70 kg human being there are 20-24 g of magne- of the total body magnesium is in the blood.
sium, 60% in bones [1, 2] a 1/3 of which is interchange- There is usually an equilibrium between intestine able and is part of the body magnesium reservoir magnesium absorption and renal elimination. About for high magnesium requirements. Almost 35% of 35-40% of daily magnesium intake occurs in thesmall intestine. Magnesium is eliminated mainlythrough the kidneys and accounts for 3-5% of the Presented in part at the 29 Magnesium-Symposium der Gesell- daily filtrated volume. More than 65% of the renal schaft für Magnesium-Forschung e.V. Samstag, 17 October magnesium reabsorption occurs through the thick ascending loop of Henle. 35% of serum magnesium the average daily intake of magnesium at the begin- is non-specifically bound to albumin, while the rest ning of the 20th century was 410 mg while today it is is in a ionic form .
only 200-300 mg. The reason for the reducedmineral consumption, including magnesium, in themodern menu, is mainly due to industrial food Magnesium measurements processing and over-utilization of fields dedicatedfor cultivating agricultural products .
Serum magnesium measurement Recommendations for magnesium are provided in As only 1% of total body magnesium is in the serum, the Dietary Reference Intakes (DRIs) developed by its measurement does not reflect its intracellular level.
the Institute of Medicine of the National Academy of While hypomagnesemia reflects low total body con- Sciences. "Dietary Reference Intakes" is the general tent, a normomagnesemia does not necessarily indi- term for a set of reference values used for planning cate normal or high total body magnesium [4, 5].
and assessing nutrient intake for healthy people.
Three important types of reference values included Intracellular magnesium in the DRIs are Recommended Dietary Allowances(RDA), Adequate Intakes (AI), and Tolerable Upper The most accurate intracellular magnesium mea- Intake Levels (UL). The RDA recommends the surements, which also reflect the intramyocardial average daily intake that is sufficient to meet the muscle cell content, are lymphocytic (more accu- rate) and erythrocyte (less accurate and cell age healthy people. An AI is set when there is insuffi- dependent) magnesium levels [6, 7]. Recently the cient scientific data available to establish a RDA EXATM test, which measures intra epithelial cell for specific age/gender groups. AIs meet or exceed magnesium content from buccal tissue, has been the amount needed to maintain a nutritional state of highly correlated to intramyocardial magnesium adequacy in nearly all members of a specific age content . This method is disadvantageous as and gender group. The UL, on the other hand, is there is only one laboratory in the US which carries the maximum daily intake unlikely to result in out the test (IntraCellular Diagnostics Inc., CA).
adverse health effects. The current RDA for magne- Additionally, electrodes for the measurement of sium is 420 mg daily for males and 320 mg daily for free magnesium content are available, however, females above 31 years, and in stressful situations until now there has been no consensus regarding such as in pregnancy or physical growth, an addi- the normal and abnormal values in various popula- tion of 300 mg daily is recommended. Data from the tions and no standardization exits.
1999-2000 National Health and Nutrition Examina-tion Survey suggest that substantial numbers of Magnesium retention after oral magnesium adults in the United States (US) fail to get recom- or intravenous load test mended amounts of magnesium in their diets.
This test for measuring magnesium retention is Among adult men and women, the diets of Cauca- accurate but involves a 24 h urine collection [1, 9].
sians have significantly more magnesium than dothose of African-Americans. Magnesium intake islower among older adults in every racial and ethnic The magnesium in human nutrition group. Among African-American men and Caucasianmen and women who take dietary supplements, The main dietary magnesium sources are green the intake of magnesium is significantly higher than vegetables, cereals, nuts, soy beans, and shell fish,as well as over the counter (OTC) food supplements in those who do not. In a population-based study and vitamins.
of young Israelis of 30 years old, about 60% hadmagnesium deficiency [1, 10-14].
An accurate magnesium food content (or even high- magnesium food content) will keep people healthyand reduce the incidence of extreme or continuous The role of magnesium in coronary stress-induced sudden death, or hyperthermia- induced death, heart disease, atherosclerosis andvascular atherogenesis, vascular complications in Prior epidemiological trials from various countries, diabetics, early labor and congenital anomalies.
such as the US, South Africa, Finland, France, The magnesium content of food in the Western England, Canada, Germany and the Netherlands world is consistently decreasing. Data show that [1, 2, 15-17] demonstrated that water magnesium con- MAGNESIUM AND CARDIOVASCULAR SYSTEM tent is associated with the incidence and mortality inflammatory response while a reduction in the from CAD. Autopsies demonstrated high cardiac extracellular magnesium results in phagocyte and muscle magnesium concentration in high-(also called endothelial cell activation. Inflammation occurring "hard water areas") compared to low-magnesium in experimental magnesium deficiency is the mech-water areas (also called "soft water areas") and vice anism that induces hypertriglyceridemia and pro- versa [1, 12, 15-17].
atherogenic changes in the lipoprotein profile.
The Atherosclerosis Risk in Communities (ARIC) Endothelial cells actively contribute to inflamma- Study  with 13,922 healthy subjects without CAD tion in magnesium deficiency states. Magnesium on admission, after a 4-7 year follow-up, found that intake is inversely associated with markers of the highest risk for CAD occurred in subjects with systemic inflammation and endothelial dysfunction the lowest serum magnesium and vice versa, even in healthy  and postmenopausal women .
after controlling for the traditional CAD risk factors.
The available data suggest that a combination of The National Health and Nutrition Examination mechanisms may act additively or even synergisti- Survey Epidemiologic Follow-up Study  demon- cally to protect myocytes and constitute the rationale strated an inverse association of serum magnesium and mortality from CAD and all causes.
with heart disease [1, 3, 28-30] (table 1). Exogenic The Honolulu Heart Program  studied 7,172 administration of magnesium prevents intracellular men 45 to 68 years old during the years 1965-1968.
depletion of magnesium, potassium and high-energy In a 30-year follow-up low-magnesium in the food phosphates, improves myocardial metabolism, pre- was found to increase the incidence of CAD by 2.1 vents intramitochondrial calcium accumulation and compared to high magnesium concentration, even reduces vulnerability to oxygen-derived free radicals.
after controlling for traditional CAD risk factors Magnesium can impact on: and other food nutrients.
– vascular tone; Amighi et al.  followed 323 patients with periph- – platelet aggregation and coagulation system; eral artery disease and intermittent claudication for – endothelial function; 2 years. A low serum magnesium concentration was – infarct (scar) size; associated with a 3 fold increase of cerebrovascular – lipid metabolism; accident compared to those with high serum magne- – cardiac arrhythmias; sium levels.
– myocardial infarction.
Ka He et al.  followed 4,637 young Americans aged 18-30 without diabetes mellitus or metabolic Impact of magnesium on vascular tone syndrome. In a 16-year follow-up 608 (11%) subjectsdeveloped metabolic syndrome. Multivariate analy- Magnesium is considered to be nature's physiologic sis demonstrated a significant inverse association calcium blocker . It reduces the release of between food magnesium content and the incidenceof metabolic syndrome.
Table 1. Beneficial effects of magnesium in coronary While the magnesium content in food products in artery disease.
the USA has fallen over the last 2 decades, it iscurrently below the RDA, and the incidence of Antiplatelet effects CAD is increasing.
Coronary vasodilationSystemic vascular resistance reductionInhibition of calcium influx The rationale for magnesium in CAD Inhibition of vulnerability to oxygen free radicals There is a strong biological plausibility that the Inhibition of reperfusion injury effect of magnesium in cardiovascular disease Improvement of endothelial function prevention may be partly related to a decreased Inhibition of catecholamines inflammatory response. In animal models, experi- Improvement of lipid profile mental magnesium deficiency induces a clinical Enhanced angiogenesis inflammatory syndrome characterized by leukocyte Reduced cardiac arrhythmias and macrophage activation, release of inflammatory Mild reduction of blood pressure cytokines and acute phase proteins in addition to Improvement of exercise duration time and cardiac excessive production of free radicals [23-25]. An Improvement of quality of life increase in extracellular magnesium decreases the calcium from and into the sarcoplasmic reticulum magnesium sulfate was widely used as a muscle and protects the cells against calcium overload relaxant, and it was seen that the blood of patients under conditions of ischemia [31-44]. Magnesium examined post mortem after such treatment was reduces systemic and pulmonary vascular resis- unclotted . In 1959 Anstall et al.  demonstrated tance, with a concomitant decrease in blood pres- that magnesium inhibits human blood coagulation.
sure and a slight increase in cardiac index [31-33].
Adams and Mitchel  found that magnesium Elevation of extracellular magnesium levels reduces both topically and parenterally, suppressed thrombus the arteriolar tone and tension in a wide variety of formation and increased the concentration of ADP, arteries [34-36] and potentiates the dilatory action which was required to initiate thrombus production of some endogenous (adenosine, potassium and at human minor injury sites. Some experimental some prostaglandins) and exogenous (isoproternol studies have demonstrated the antiplatelet effects and nitroprusside) vasodilators [34, 35, 37, 38]. As a of magnesium, which may prevent the propagation result, magnesium has a mild reducible effect on of coronary artery thrombi or re-occlusion of the systolic and diastolic blood pressure , may act infarct-related coronary artery after spontaneous or as afterload reduction and thus unload the ischemic fibrinolysis-induced recanalization [63-66]. Recently ventricle. Kugiyama et al.  demonstrated that some studies have demonstrated that magnesium exercise-induced angina is suppressed by intrave- reduces platelet aggregation in healthy volunteers nous magnesium in patients with variant angina, . High magnesium levels inhibit blood coagula- most probably as a result of an improvement in tion  and thrombus formation in vivo , dimin- regional myocardial blood flow by suppression of ish platelet aggregation [65-67], reduce the synthesis coronary artery spasms. Altura and Altura  of platelet agonist thrombaxane A2 , and inhibit found in an experimental vascular smooth muscle the thrombin-stimulated calcium influx .
model, that magnesium deficiency, through potenti- Platelet activation is a key element in acute ation of increased cellular calcium activity, may vascular thrombosis, which is important in the be responsible for the arterial hypertension that pathogenesis of acute myocardial infarction and accompanies toxemia of pregnancy. The proven complications of coronary balloon angioplasty and effectiveness of parenteral magnesium therapy in stenting. Studies have demonstrated that magnesium toxemia of pregnancy [35, 46] is most likely the can suppress platelet activation by either inhibiting result of its calcium antagonist action.
platelet-stimulating factors, such as thromboxane A2, Shechter et al.  found that the intra lymphocytic or by stimulating synthesis of platelet-inhibitory fac- magnesium levels in CAD patients after myocardial tors, such as prostacyclin (PGI2) [54-60, 64, 67, 68].
infarctions and/or coronary artery bypass operations Intravenous administration of magnesium to healthy were highly correlated to exercise duration time and volunteers inhibited both ADP-induced platelet cardiac performance and inversely correlated to the aggregation by 40% and the binding of fibrinogen or peak exercise double-product (heart rate x systolic surface expression of glycoprotein IIb-IIIa com- blood pressure). Thereafter, Shechter et al.  dem- plex GMP-140 by 30% . Thus, pharmacological onstrated in Austria, Israel and the US, that a 6-month concentrations of magnesium effectively inhibit platelet function in vitro and ex vivo.
improved exercise tolerance, exercise duration time, Using an ex vivo perfusion (Badimon) chamber ischemic threshold and quality of life in stable CAD , Shechter et al.  recently demonstrated that patients. Pokan et al.  reinforced Shechter's findings. They demonstrated that a 6-month oral increased in stable CAD patients with low mononu- magnesium supplementation significantly improved clear intracellular levels of magnesium, despite the intracellular magnesium levels, VO2max, left antiplatelet treatment with aspirin. Furthermore, Shechter et al.  found in a randomized, prospec- exercised-induced heart rate.
tive, double-blind, cross-over, placebo-controlledtrial that 3-months of magnesium oxide tablets (800-1,200 mg/day) significantly reduced the median platelet-dependent thrombosis by 35% compared to In 1943, Greville and Lehmann  found that a small placebo in stable CAD patients who were on aspirin amount of magnesium added to fresh unclotted therapy. The antithrombotic effect of magnesium human plasma prolonged the clotting time. In Ger- treatment was observed despite the 100% utilization many, during and shortly after the-2nd World War, of aspirin therapy.
MAGNESIUM AND CARDIOVASCULAR SYSTEM Gawaz et al. [57, 59] demonstrated that platelet Shechter et al.  recently demonstrated that aggregation, fibrinogen binding, and expression of endothelial function is significantly correlated to P-selectin on the platelet surface, are all effectively intracellular magnesium levels, measured in sublin- inhibited by intravenous magnesium supplementa- gual epithelial cells, in CAD patients and oral tion. Since glycoprotein IIb-IIIa is the only glycopro- magnesium 30 mmol/day (total magnesium 730 mg/ tein on the platelet surface that binds fibrinogen, day) for 6 months significantly increased intracellular Gawaz et al. speculated that magnesium supplemen- magnesium compared to placebo. In addition the mag- tation directly impairs fibrinogen interaction with nesium therapy resulted in a significant improvement the glycoprotein IIb-IIIa complex. Since fibrinogen in endothelial function, associated with improvement binding to the platelet membrane and surface in exercise duration, exercise-induced chest pain and expression of P-selectin requires previous cellular exercised-induced cardiac arrhythmias. Pearson et al.
activation, the inhibitory effect of magnesium  demonstrated that hypomagnesemia selectively might be a consequence of direct interference of impaired the release of nitric oxide (NO) from coro- the cation with the agonist-receptor interaction or nary endothelium in a canine model. Paravicini et al.
with the intracellular signal transduction event.
 demonstrated in a model of hypomagnesemia Fibrinogen- glycoprotein IIb-IIIa interaction is regu- that blood pressure significantly increased in low lated by divalent cations, and at pharmacological levels magnesium may inhibit the binding of fibrino- normal-high intracellular magnesium levels. The low gen to glycoprotein IIb-IIIa by altering the receptor intracellular magnesium levels were associated with conformation. This might be caused by the compe- tition of magnesium with calcium ions for calcium- decreased plasma nitrate levels and endothelial NO binding sites in the glycoprotein IIb subunit.
synthase expression when compared with normal- Rukshin et al.  recently demonstrated that high intracellular magnesium levels. Because NO is treatment with intravenous magnesium sulfate pro- a potent endogenous nitrovasodilator and inhibitor duced a time-dependent inhibition of acute stent of platelet aggregation and adhesion, hypomagnese- thrombosis under high-shear flow conditions with- mia may promote vasoconstriction and coronary out any hemostatic or significant hemodynamic thrombosis in hypomagnesemic states.
complications in an ex vivo porcine arteriovenous Endothelial cells actively contribute to inflamma- shunt model of high-shear blood flow, suggesting tion in magnesium deficiency states. Magnesium that magnesium inhibits acute stent thrombosis in intake is inversely associated with markers of animal model. Thereafter the same group  systemic inflammation and endothelial dysfunction demonstrated that intravenous magnesium sulfate in healthy  and postmenopausal women .
is a safe agent in acute coronary syndrome patientsundergoing non-acute percutaneous coronary inter- Impact of magnesium on infarct size vention with stent implantation, while magnesiumtherapy significantly inhibited platelet activation.
Hypomagnesemia may increase coronary and sys-temic vasoconstriction and afterload, leading to Impact of magnesium on endothelial function increased myocardial oxygen depth [3, 28, 29]. Lowconcentrations of magnesium in laboratory animals The vascular endothelium is an active paracrine, seem to potentiate catecholamine-induced myocardial endocrine and autocrine organ, which plays a necrosis and cardiomyopathy . Magnesium defi- critical role in vascular homeostasis by secreting ciency may adversely influence the healing and re- several mediators regulating vessel tone and diame- endothelialization of vascular injuries, the healing of ter, coagulation factors, vascular inflammation, cell myocardial infarction, and may also result in delayed proliferation and migration, platelet and leukocyte or inadequate angiogenesis [79, 80]. Such effects could interaction and activity and thrombus formation potentially lead to inadequate collateral development [66-73]. Endothelial dysfunction is therefore recog- and infarct expansion. Magnesium reduces vulnerabil- nized as a major factor in the development of athero- ity to oxygen-derived free radicals , reperfusion sclerosis, hypertension, and heart failure. Vascular injury and stunning of the myocardium.
endothelial dysfunction is an independent risk factorfor cardiovascular events, and provides important Impact of magnesium on lipids prognostic data in addition to the classic cardiovas-cular risk factors and may be a "crystal ball predic- Magnesium plays an interesting role in lipid regula- tion for enhanced cardiovascular risk" .
tion, although it is not yet fully understood [82-87].
Magnesium is an important cofactor of two enzymes duction . Zwillinger  in 1935 was the first that are essential in lipid metabolism: lecithin- to recognize the arrhythmic effect of magnesium, cholesterol acyltransferase (LCAT) and lipoprotein when used to convert paroxysmal tachycardia to lipase. In a rabbit animal model fed a normal diet or normal sinus rhythm. Later on it was successfully a high cholesterol diet supplemented with varying used in resistant ventricular tachycardias , ven- amounts of magnesium, the addition of supplemen- tricular arrhythmias induced by digitalis toxicity tal magnesium achieved a dose dependent reduc-  and episodes of torsade de pointes, a life threat- tion in both the area of the aortic lesions and the ening ventricular arrhythmia [92, 93].
cholesterol content of the aortas . The 1% Magnesium was also found to be effective in the termination of episodes of supraventricular arrhyth- cholesterol and triglyceride concentrations and mia, such as multifocal atrial tachycardia (MAT)  decreased high density lipoprotein (HDL) choles- and increased the susceptibility of atrial tachycardia terol concentration. Additional magnesium had no to pharmacological conversion with digoxin .
further effect on cholesterol and HDL cholesterol Magnesium has recently been recommended by concentrations, but it slightly decreased the rise in the American Heart Association as the third drug triglyceride concentration . Rats, on the other of choice (after Amiodarone and Lidocaine) in the hand, placed on diets severely deficient in magne- resuscitation of patients with pulseless ventricular sium, developed adverse lipid changes . In a rat tachycardias or ventricular fibrillation .
model, magnesium-deficient diets demonstrated an Magnesium therapy may correct resistant hypo- elevated plasma cholesterol level, low density lipo- kalemia, since it is a cofactor of ATP molecule .
protein (LDL) and triglycerides with a proportionatereduction in high-density lipoprotein (HDL) .
Clinical trials of magnesium in acute Rassmussen et al.  gave a daily dose of 15 mmol myocardial infarction magnesium hydroxide to humans and found a 27% In the last 2 decades, some relatively small prospec- reduction in triglycerides and very low-density tive, randomized, double-blind and controlled trials lipoprotein (VLDL) after 3 months of therapy and have been reported, comparing intravenous magne- reduction in apoprotein B and elevation of HDL. Davis sium to placebo in acute myocardial infarction et al.  demonstrated a significant improvement in (AMI) patients [96-105]. Morton et al.  published the ratio of HDL to LDL plus VLDL, by giving 18 mmol their study in 1984 and were the pioneers to show magnesium per day in a 4-month clinical trial.
that magnesium reduced the infarct size by 20% in Niemela et al.  showed that in men, but not in patients in Killip class I and in-hospital mortality in women, platelet intracellular magnesium levels AMI patients.
significantly inversely correlated with serum total The Second Leicester Intravenous Magnesium cholesterol (r = - 0.52, p < 0.02), LDL (r = - 0.54, Intervention Trial (LIMIT-2) , was the first p < 0.009) and apolipoprotein B (r = - 0.42, p < 0.04).
large clinical trial where 30% of the 2,316 patients These investigators also speculated that decreased received thrombolytic therapy. Intravenous magne- platelet intracellular magnesium level is a possible sium reduced congestive heart failure (CHF) by 25% marker for platelet membrane alterations that may and all-cause mortality by 24% at 28 days  and affect platelet involvement in thrombosis and athero- 20% reduction in ischemic heart disease-related genesis .
mortality over a mean follow-up of 4.5 years .
In mid 1990 Shechter et al.  demonstrated Impact of magnesium on cardiac arrhythmias that 22 g (92 mmol) of intravenous magnesium Magnesium deficiency is associated with intracellu- sulfate for 48 hours in 215 AMI patients who were lar hypopotassemia, hypernatremia and augmenta- considered unsuitable for reperfusion, reduced the tion of cell excitability . Magnesium has modest in-hospital mortality by almost 50% and the inci- electrophysiologic effects: It prolongs the actual dence of arrhythmias and CHF by 33% in elderly and corrected sinus node recovery time, prolongs patients above the age of 70 years.
the atrioventricular nodal function, relative and In the same era the Fourth International Study effective refractory periods, slightly increases the of Infarct Survival and Magnesium in Coronaries QRS duration during ventricular pacing at cycle (ISIS-4)  study was conducted with approxi- lengths of 250 and 500 milliseconds, and increases mately 58,000 AMI patients, of whom almost the atrial-His interval and atrial paced-cycle length 70% received thrombolytic therapy, and showed causing atrioventricular nodal Wenckebach con- no survival-benefit from intravenous magnesium MAGNESIUM AND CARDIOVASCULAR SYSTEM sulfate over placebo at 35-day and 1-year. The mag- (48 h vs 24 h). Furthermore, a significantly higher nesium dose was almost identical to that of the proportion of the MAGIC study population received LIMIT-2 study, but with an open control. However, aspirin, β-blockers and angiotensin-converting enzyme the time from onset of symptoms to randomization inhibitors than in the Shechter's study population, was substantially longer (median of 8 hours rather and as a result the postulated cardioprotective effects than 3). The 30% patients not given thrombolytic of magnesium could have been superseded by the therapy were randomized at a median of 12 hours effects of these medical regimens.
after symptoms onset. The low mortality rate in the Recently published random-effect meta analyses ISIS-4 control group, the late enrollment of patients, have demonstrated a significant reduction in early particularly those who did not receive thrombolytic mortality when comparing magnesium with placebo treatment, plus the fact that magnesium infusions (OR: 0.66, 95% CI: 0.53-0.82), especially in patients were delayed by 1-2 hours after thrombolytic ther- not treated with thrombolysis (OR: 0.73, 95% CI: apy, suggest the possibility that the majority of 0.56-0.94) and in those treated with < 75 mmol of patients in ISIS-4 were at low mortality risk and magnesium (OR: 0.59, 95% CI: 0.49-0.70) .
that an elevated magnesium blood level was not Following the data from the ISIS-4 and MAGIC reached until well beyond the narrow time window studies, the current guideline recommendation is for salvage of myocardium or prevention of reperfu- that magnesium should not be routinely adminis- sion injury suggested by experimental data [79, 80].
tered to all AMI patients. However, it should be an Shortly thereafter Shechter et al.  showed a adjunct therapy option in selected cases of high-risk significant long-term (mean follow-up of 4.5 years) AMI patients, such as elderly patients, those with mortality reduction of 40% in 194 AMI patients, con- left ventricular dysfunction and/or CHF, and/or sidered unsuitable candidates for reperfusion therapy patients not suitable for reperfusion therapy .
at the time of enrollment, who received intravenousmagnesium compared to placebo for 48 hours. The rest left ventricular ejection fraction, measured inall patients who survived the last year of follow-up, was significantly higher in patients who received [3, 28-30]. In all previous randomized controlled magnesium versus placebo. Thus, the favorable clinical trials only a few adverse effects were effects of intravenous magnesium therapy can last reported. In the ISIS-4 trial  with 58,000 several years after acute treatment, probably due to patients with suspected AMI, no overall increase in preserved left ventricular ejection fraction.
the incidence of second or third degree heart block In 2002, the Magnesium in Coronaries (MAGIC) was observed, although there was a slight but not trial  was published. The MAGIC trial random- convincingly significant excess during or just after ized 6,213 patients ≥ 65 years, of whom an unexpect- the magnesium infusion. These adverse effects were edly high percentage (45%) were female with acute ST not confirmed in the LIMIT 2 trial  with 1,500 elevation AMI < 6 hours who were eligible for reper- and in the MAGIC trial  with 6,200 AMI fusion therapy (median age 73 years) (stratum 1); or patients. Non-clinically significant sinus bradycar- patients of any age who were not eligible for reperfu- dia, however, was observed in some but not all ran- sion therapy (median age 67 years) (stratum 2), to a domized clinical trials. As magnesium is a physio- 2 g intravenous bolus of magnesium sulfate, adminis- tered over 15 minutes, followed by a 17 g infusion of (bolus) administration is prohibited as it can reduce magnesium sulfate over 24 hours (n = 3,113) or blood pressure. Therefore an intravenous bolus matching placebo (n = 3,100). The "magnesium com- dose of 1 g over 5 minutes is recommended .
munity" was very disappointed by the results which A patient with normal kidney function excretes demonstrated the null effects of magnesium on magnesium rapidly through the kidneys. Normally 30-day mortality or heart failure. In comparison to the kidneys filter approximately 2.5 g of magnesium the MAGIC trial, the study of Shechter et al.  and reclaim 95%, excreting some 100 mg/dL into the comprised thrombolysis-ineligible AMI patients, of urine to maintain homeostasis. Approximately 25-30% whom one third were > 75 years and therefore similar is reclaimed in the proximal tube through a passive to the MAGIC stratum 2 patients but differing in transport system that depends on sodium re- 2 aspects: the Shechter et al. study patients (a) absorption and tubular fluid flow. Usually, as serum received a higher dose of intravenous magnesium magnesium concentration increases, there is a linear sulfate (22 g vs 19 g); (b) for a longer period of time increase in urinary magnesium excretion, paralleling that of insulin. With normal kidney function, hyper- duction and secretion, while magnesium infusion magnesemia or magnesium intoxication does not decreases aldosterone production production by usually develop, even during high intravenous magne- inhibiting cellular calcium influx . Adamopoulos sium infusion [3, 28-30].
et al.  recently found that CHF in patients Additionally, oral magnesium supplementation (mainly New York Heart Association [NYHA] II-II) may cause diarrhea, soft stool, gastrointestinal irri- with low serum magnesium ≤ 2 mEq/L was associated tation, weakness, nausea, vomiting and abdominal with increased cardiovascular mortality (but had no association with cardiovascular hospitalization) com-pared to those with serum magnesium > 2 mEq/L in along-term follow-up of 36 months, suggesting that Reasons for magnesium deficiency most of these deaths were likely sudden (arrhythmic) The prevalence of hypomagnesemia in hospitalized in nature. Furthermore, Stepura and Martynow  patients ranges from 8 to 30% [1, 3]. Elderly patients, demonstrated that oral magnesium orotate used as particularly those with CAD and/or CHF, can have adjuvant therapy in severe NYHA IV CHF patients low body magnesium levels, the mechanisms of increased the 1-year survival rate and improved which are likely to be multi-factorial. Evidence sug- clinical symptoms and the patient's quality of life gests that the occidental "American-type diet" is compared to placebo.
relatively deficient in magnesium [1, 3, 10, 11],while the "oriental diet", characterized by a greater intake of fruit and vegetables, is richer in magnesium. It has also been observed that CAD patients Magnesium plays a vital role in many cellular pro- absorb more magnesium during magnesium loading cesses. Magnesium is essential for a number of tests than non CAD patients, suggesting that CAD is metabolic activities since it is associated with a associated with excessive magnesium loss and a variety of enzymes which control carbohydrate, fat, relative magnesium-deficient state .
protein end electrolyte metabolism. Several hundred Magnesium deficiency may usually be reflected in enzymes, directly or indirectly, are dependent on low-magnesium diet, blood loss, excessive sweat- magnesium. Most important among these enzymes ing, drug and/or alcohol abuse or due to certain are those which hydrolyze and transfer phosphate medication use (such as loop diuretics and thia- groups, including enzymes that are concerned with zides, cytotoxic drugs, aminoglycosides, digoxin, reactions involving energy production and ATP.
steroids), or some physiological conditions of over Magnesium deficiency, or reduction in the dietary utilization of magnesium such as pregnancy or intake of magnesium, plays an important role in the infancy growth. Mental stress can also lead to mag- etiology of diabetes and numerous cardiovascular nesiuresis due to high serum adrenalin [113, 114].
Diabetes mellitus is also associated with magnesium ischemic heart disease, myocardial infarction, hyper- deficiency, mainly due to urinary magnesium loss tension, cardiac arrhythmias and CHF in humans.
. Other diseases associated with magnesium defi- Magnesium deficiency may lead to reduced ener- ciency: liver cirrhosis, diseases of the thyroid and getic metabolite production and the sense of fatigue parathyroid glands, renal diseases. Moreover, diets and/or "chronic fatigue syndrome". Modern life styles rich in animal foods and low in vegetables induce and the Western industrial diet have enhanced the acidosis and increase magnesium urinary excretion.
reduction of magnesium in our food, which contri- Pure magnesium deficiency is characterized by a butes to marginal or absolute magnesium deficiency.
number of clinical features, including muscular The magnesium deficiency is mostly evidenced in the tremor, vertigo, ataxia, tetany, convulsions and elderly population, those with myocardial infarction organic brain syndrome.
and/or CHF, diabetics, patients with chronic airwayobstruction, pre- or toxemia of pregnancy, in post Magnesium and CHF transplantation patients (especially in heart trans-plantation), patients with malignancies who receive Patients with CHF are magnesium deficient. The acti- cytotoxic chemical therapy, in competitive athletes vation of the renin-angiotensin-aldosterone system and in metabolic syndrome patients.
and the use of diuretics are associated with depletion It should be noted that magnesium deficiency can of potassium and magnesium in CHF [1, 3, 28, 115].
easily be treated by magnesium supplementation if Magnesium deficiency stimulates aldosterone pro- we are aware of the situation. The best recommen- MAGNESIUM AND CARDIOVASCULAR SYSTEM dation is to increase consumption of magnesium- 7. Elin RJ. Status of the determination of magnesium in rich food. However, since magnesium deficiency is mononuclear blood cells in humans. Magnesium 1988; hard to treat only by increase consuming high- magnesium food products, it is recommended to 8. Haigney MCP, Silver B, Tanglao E, Silverman HS, Hill JD, take magnesium supplements which officially and Shapiro E, Gerstenblith G, Schulman SP. Noninvasive safely increase the magnesium in the body and measurement of tissue magnesium and correlation with correct the deficit.
cardiac levels. Circulation 1995; 92: 2190-7.
There are theoretical potential benefits of magne- 9. Cohen L. Physiologic assessment of magnesium status sium supplementation as a cardioprotective agent in in humans: a combination of load retention and renal CAD patients, as well as promising results from pre- excretion. IMAJ 2000; 2: 938-9.
vious work in animal and humans. Magnesium is anessential element in treating CAD patients, espe- 10. Seelig MS. The requirement of magnesium by the cially high-risk groups such as CAD patients with normal adult. Am J Clin Nutr 1964; 6: 342-90.
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Platinum Priority – Prostate Cancer Editorial by Derek J. Rosario, Liam Bourke and Nancy L. Keating on pp. 574–576 of this issue Cardiovascular Morbidity Associated with GonadotropinReleasing Hormone Agonists and an Antagonist Peter C. Albertsen , Laurence Klotz Bertrand Tombal , James Grady ,Tine K. Olesen Jan Nilsson a University of Connecticut Health Center, Farmington, CT, USA; b Division of Urology, University of Toronto, ON, Canada; c University Clinics Saint Luc/Catholic University of Louvain, Brussels, Belgium; d Ferring Pharmaceuticals, Copenhagen, Denmark; e Department of Clinical Sciences, Lund University,