Tag Archives: calcium

Magnesium plays a critical role in heart disease

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The symposium proceedings on Oxidative Stress and Cardiovascular Injury of the Southern Society for Clinical Investigation presented during this year’s scientific session of the Southern Society for Clinical Investigation included an important paper on critical role of magnesium (Mg2+) deficiency in oxidative stress-induced cardiomyopathy.

“As emphasized by Weglicki and coworkers, Mg2+ deficiency is all too common and carries with it an increased risk of associated adverse cardiovascular events, including oxidative stress. Hypomagnesemia appears when dietary Mg2+ intake is restricted. It may also be the result of drug-induced Mg2+ wasting, such as occurs with loop diuretics and chemotherapeutics, or the neurohormonal activation that accompanies acute and chronic stressor states (ie, CHF, diabetes and the metabolic syndrome).”

The authors demonstrated that magnesium deficiency results in a rise in neurotransmitter substance P (SP) which in turn triggers a systemic inflammatory effect that includes cardiac and intestinal tissues. Elevations in substance P are sustained when the enzyme neutral endopeptidase (NEP) that is supposed to degrade it is impaired by reactive oxygen and nitrogen species. Importantly…

“An associated increase in intestinal permeability with evidence of mucosal invasion by inflammatory cells and accompanying fall in mucosal barrier function with endotoxemia are seen with Mg2+ deficiency. Endotoxin can stimulate the secretion of tumor necrosis factor-α from diverse cellular sources, including macrophages and cardiomyocytes, and can be attenuated by SP receptor blockade. Thus, this neurogenic signal-transduction pathway involving SP, endotoxemia and elevated tumor necrosis factor-α can contribute to the progressive nature of heart failure, including a decline in myocardial contractility.”

In other words, magnesium deficiency is a potent promoter of inflammatory damage to the heart (and the intestinal lining). This further explains why antagonizing magnesium with calcium supplementation can contribute to cardiovascular disease. Clinicians should bear in mind the concluding statement:

“The importance of careful monitoring of serum Mg2+ in the prevention and prompt correction of hypomagnesemia cannot be overemphasized.”

Readers may wish to read the previous posts on antacids and magnesium deficiency and increase in heart attack risk with calcium supplements.

A paper published only a couple months earlier in the journal Magnesium Research adds further emphasis. The authors state:

“Hypomagnesemia continues to cause difficult clinical problems, such as significant cardiac arrhythmias where intravenous magnesium therapy can be lifesaving. Nutritional deficiency of magnesium may present with some subtle symptoms such as leg cramps and occasional palpitation…We found that neuronal sources of the neuropeptide, substance P (SP), contributed to very early prooxidant/proinflammatory changes during Mg deficiency. This neurogenic inflammation is systemic in nature, affecting blood cells, cardiovascular, intestinal, and other tissues, leading to impaired cardiac contractility similar to that seen in patients with heart failure…Our findings emphasize the essential role of this cation in preventing cardiomyopathic changes and intestinal inflammation in a well-studied animal model, and also implicate the need for more appreciation of the potential clinical relevance of optimal magnesium nutrition and therapy.”

Clinical Pearl: serum and even erythrocyte membrane levels of magnesium reflect tissue levels poorly. Results of the intracellular x-ray fluorescence test (performed on cells scraped from the floor of the mouth) reliably correlate with heart, muscle and deep organ tissue mineral content.

 

The highest amounts of calcium intake increase the risk of fracture

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Patients are often surprised to learn that osteoporosis is not a calcium deficiency disorder but rather a failure to maintain the microarchitecture of the bone of which the protein matrix is a critical component. Moreover, earlier posts on magnesium and calcium have document the pro-inflammatory potential of calcium supplementation. Now fascinating research just published in the British Medical Journal offers evidence that calcium above the lowest quintile does not improve the risk of fracture of any type, while the highest levels actually increase the risk of fracture. The authors set out to…

“……investigate associations between long term dietary intake of calcium and risk of fracture of any type, hip fractures, and osteoporosis.”

They note that confusion regarding the issue of calcium requirements has been…

“…reflected by the wide range of daily calcium recommendations for individuals older than 50 years: at present 700 mg in the UK, 800 mg in Scandinavia, 1200 mg in the United States, and 1300 mg in Australia and New Zealand.”

The authors investigated 61,433 women born between 1914 and 1948 for 19 years for correlations between dietary intake of calcium and fractures of any type, hip fractures, and osteoporosis. They took into consideration vitamin D consumption, hormonal status, and other pertinent biological and lifestyle factors including physical activity. Perhaps not surprisingly in light of other evidence that has emerged recently about calcium, their data challenges the conventional wisdom:

“These findings show an association between a low habitual dietary calcium intake (lowest quintile) and an increased risk of fractures and of osteoporosis. Above this base level, we observed only minor differences in risk. The rate of hip fracture was even increased in those with high dietary calcium intakes.“

In others, amounts higher than the lowest level of calcium intake adequate to avoid gross insufficiency and compromised bone micoarchitecture there were not only no significant benefits, the highest levels of intake increased fracture risk. The authors comment:

“The present results may reflect a situation when a moderate intake of calcium* combined with adequate intake of other micronutrients is sufficient to meet the structural and functional demands of the skeleton. High levels of intake did not further decrease the rate of fracture, and might even increase the rate of hip fractures…Moreover, use of supplemental calcium has been associated with higher rates of hip fracture both in a cohort study and in randomised controlled trials…Furthermore, high calcium doses slow bone turnover and also reduce the number of active bone remodelling sites. This situation can lead to a delay of bone repair caused by fatigue, and thus increase the risk of fractures independent of bone mineral density.”

*Their data indicate that a total dietary intake of 700 mg of calcium per day is sufficient to prevent fracture and osteoporosis. The authors conclude:

“Incremental increases in calcium intake above the level corresponding to the first quintile of our female population were not associated with a further reduction of osteoporotic fracture rate.”

Considering that chronic inflammation can be a primary factor in causing loss of the protein ‘scaffolding’ of bone responsible for strength, resilience, and the matrix to which minerals attach, these findings invoke recollection of the recent evidence that calcium supplementation can increase the inflammation of  cardiovascular disease. In case you missed it, a recent research paper published in the British Medical Journal follows up on earlier reports of this association. The authors’ intent was…

“To investigate the effects of personal calcium supplement use on cardiovascular risk in the Women’s Health Initiative Calcium/Vitamin D Supplementation Study (WHI CaD Study), using the WHI dataset, and to update the recent meta-analysis of calcium supplements and cardiovascular risk.”

The examined the data from a randomised, placebo controlled trial of calcium alone or with vitamin D in 36,282 postmenopausal women over seven years for myocardial infarction, coronary revascularisation, death from coronary heart disease, and stroke. The data told an interesting story:

“In the WHI CaD Study there was an interaction between personal use of calcium supplements and allocated calcium and vitamin D for cardiovascular events…Calcium or calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.24 (1.07 to 1.45), P=0.004) and the composite of myocardial infarction or stroke (1.15 (1.03 to 1.27), P=0.009).”

Clinicians and patients need to appreciate that inflammation, a fundamental causal factor in both osteoporosis and cardiovascular disease, can be made worse by calcium supplements. The authors conclude:

“Calcium supplements with or without vitamin D modestly increase the risk of cardiovascular events, especially myocardial infarction, a finding obscured in the WHI CaD Study by the widespread use of personal calcium supplements. A reassessment of the role of calcium supplements in osteoporosis management is warranted.“

 

Proton pump inhibitors (antacid drugs) can cause severe magnesium deficiency

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Readers here are likely to know that magnesium is necessary for more than two hundred enzymes involved in cell metabolism including the production of ATP (the cellular ‘energy currency’). It is less well known that long term use of proton pump inhibitors (PPIs, such as omeprazole, aka Prilosec; Prevacid, Nexium, Protonix, etc.) can cause severe magnesium deficiencies. The authors of a study published in the journal Clinical Endocrinology set out to…

“…explore the mechanism underlying severe hypomagnesaemia in long-term users of proton-pump inhibitors (PPIs).”

One of the most common symptoms of suboptimal magnesium is muscle spasms or cramps. In the subjects they examined, the deficiency was so severe that they were having hypocalcemic seizures (calcium utilization also depends on magnesium). What did they find?

“Both patients were severely magnesium-depleted and had avid renal magnesium retention, implicating a failure of intestinal magnesium absorption…The hypomagnesaemia could be partially corrected by high dose oral magnesium supplementation, and resolved on withdrawal of PPIs.”

In other words, the kidneys were trying their best to compensate for the failure of intestinal absorption due to the PPIs but it wasn’t enough. Clinicians and any individuals taking PPIs long-term should bear in mind the authors’ conclusions:

“PPI use can inhibit active magnesium transport in the intestine…Long-term PPI users who are highly adherent to treatment can eventually deplete total body magnesium stores and present with severe complications of hypomagnesaemia.“

There are often more physiological therapies effective for conditions such as gastroesophageal reflux disease (GERD) for which PPIs are commonly prescribed.

Magnesium deficiency and death from cardiovascular disease

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Magnesium deficiency is so common that it’s hard to find individuals with optimal levels. A study just published in the American Heart Journal adds to the growing body if evidence for the great importance of magnesium in cardiovascular disease. The authors state:

“We hypothesized that serum magnesium (Mg) is associated with increased risk of sudden cardiac death (SCD).”

They assessed risk factors and levels of serum Mg in 14,232 45- to 64-year-old subjects and followed them for an average of 12 years. During that time there were 264 cases of SCD that they used to evaluate the association of serum Mg with risk of SCD. The data made a clear statement:

“Individuals in the highest quartile of serum Mg were at significantly lower risk of SCD in all models. This association persisted after adjustment for potential confounding variables, with an almost 40% reduced risk of SCD in quartile 4 versus 1 of serum Mg observed in the fully adjusted model.”

This is a potent result, summed by the authors’ conclusion:

“This study suggests that low levels of serum Mg may be an important predictor of SCD.”

A whole body of emerging research is illuminating the mechanisms by which suboptimal magnesium levels can have this effect. In a study just published in the journal Diabetes Care the authors set out…

“To investigate the long-term associations of magnesium intake with incidence of diabetes, systemic inflammation and insulin resistance among young American adults.”

The authors followed 4,497 Americans aged 18-30 (who had no diabetes at the beginning) for 20 years. During that time they identified 330 cases of diabetes which they correlated with quintiles of magnesium intake. They also investigated the associations between magnesium intake and inflammatory markers including high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and fibrinogen, and the homeostasis model assessment of insulin resistance (HOMA-IR). What did the data show?

“Magnesium intake was inversely associated with incidence of diabetes after adjustment for potential confounders…Consistently, magnesium intake was significantly inversely associated with hs-CRP, IL-6, fibrinogen, and HOMA-IR; and serum magnesium levels were inversely correlated with hs-CRP and HOMA-IR.”

As you know, these are powerful markers for cardiovascular disease risk. As the authors state in their conclusion:

“This inverse association may be explained, at least in part, by the inverse correlations of magnesium intake with systemic inflammation and insulin resistance.”

An earlier paper published in the journal Magnesium Research documents how low magnesium in conjunction with high fructose consumption promotes inflammation associated with metabolic syndrome. The authors begin by observing:

“The metabolic syndrome is a cluster of common pathologies: abdominal obesity linked to an excess of visceral fat, insulin resistance, dyslipidemia and hypertension. This syndrome is occurring at epidemic rates, with dramatic consequences for human health worldwide, and appears to have emerged largely from changes in our diet and reduced physical activity. An important but not well-appreciated dietary change has been the substantial increase in fructose intake, which appears to be an important causative factor in the metabolic syndrome. There is also experimental and clinical evidence that the amount of magnesium in the western diet is insufficient to meet individual needs and that magnesium deficiency may contribute to insulin resistance.”

They present present experimental evidence showing that metabolic syndrome, high fructose intake and low magnesium diet may all be linked to the inflammatory response. The data they gathered showed that:

“…a few days of experimental magnesium deficiency produces a clinical inflammatory syndrome characterized by leukocyte and macrophage activation, release of inflammatory cytokines, appearance of the acute phase proteins and excessive production of free radicals. Because magnesium acts as a natural calcium antagonist, the molecular basis for the inflammatory response is probably the result of a modulation of the intracellular calcium concentration.”

These findings remind of the recent research linking calcium supplementation to increased heart attacks.  The authors conclude:

“Since magnesium deficiency has a pro-inflammatory effect, the expected consequence would be an increased risk of developing insulin resistance when magnesium deficiency is combined with a high-fructose diet. Accordingly, magnesium deficiency combined with a high-fructose diet induces insulin resistance, hypertension, dyslipidemia, endothelial activation and prothrombic changes in combination with the upregulation of markers of inflammation and oxidative stress.”

It goes without saying that these are primary inducers of cardiovascular disease. Another paper published last year in the same journal note the association of magnesium deficiency and C-reactive protein:

“Recent findings from epidemiologic studies support that magnesium intake is inversely associated with C-reactive protein concentration, an important marker of inflammation strongly associated with cardiovascular disease risk.”

A fascinating study published in the American Journal of the Medical Sciences investigates magnesium deficiency promotes inflammation and cardiovascular disease through neurogenic pathways:

“This review highlights some key observations that helped formulate the hypothesis that release of substance P (SP) [an inflammatory signalling molecule] during experimental dietary Mg deficiency (MgD) may initiate a cascade of deleterious inflammatory, oxidative, and nitrosative events, which ultimately promote cardiomyopathy, in situ cardiac dysfunction, and myocardial intolerance to secondary stresses.”

The authors further state:

“…SP-mediated events may…facilitate development of in situ cardiac dysfunction, especially with prolonged dietary Mg restriction.”

Additional intriguing research published in the British Journal of Anaesthesia adds even more evidence to the assertion that magnesium helps reduce cardiovascular disease by opposing calcium.  The authors begin by stating:

“Magnesium sulphate (MgSO4) has potent anti-inflammatory capacity. It is a natural calcium antagonist and a potent L-type calcium channel inhibitor. We sought to elucidate the possible role of calcium, the L-type calcium channels, or both in mediating the anti-inflammatory effects of MgSO4.”

And magnesium sulphate is not the most bioavailable form of magnesium supplementation. When the authors induced inflammation by exposure to lipopolysaccharide (LPS) as evidenced by macrophage inflammatory protein-2, tumour necrosis factor-α, interleukin (IL)-1β, IL-6, nitric oxide/inducible nitric oxide synthase, prostaglandin E2/cyclo-oxygenase-2, and NF-κB activation.

“MgSO4…significantly inhibited the LPS-induced inflammatory molecules production and NF-κB activation. Moreover, the effects of MgSO4 on inflammatory molecules and NF-κB were reversed by extra-cellular calcium supplement with CaCl2 and L-type calcium channel activator BAY-K8644.”

In other words, in addition to opposing inflammation, magnesium is nature’s calcium channel blocker. The authors conclude:

“MgSO4 significantly inhibited endotoxin-induced up-regulation of inflammatory molecules and NF-κB activation… The effects of MgSO4 on inflammatory molecules and NF-κB may involve antagonizing calcium, inhibiting the L-type calcium channels, or both.”

Magnesium reduces inflammation by opposing calcium

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A paper published last month in the journal Magnesium Research sheds light on the study reported in the last post offering evidence for the link between calcium supplementation and heart attacks. The authors investigated the role of magnesium deficiency in the calcium-activated inflammation of metabolic syndrome.

“The concept that metabolic syndrome is an inflammatory condition may explain the role of Mg [magnesium]. Mg deficiency results in a stress effect and..activates the hypothalamic-pituitary-adrenal axis (HPA) axis and the sympathetic nervous system. The activation of the renin-angiotensin-aldosterone system is a factor in the development of insulin resistance by increasing oxidative stress [and]…leads to an inflammatory phenotype.”

They further describe how this develops an inflammatory milieu in blood vessels:

“One of the earliest events in the acute response to stress is endothelial [blood vessel 'lining'] dysfunction…Experimental Mg deficiency in rats induces a clinical inflammatory syndrome characterized by leukocyte and macrophage activation, synthesis of inflammatory cytokines and acute phase proteins, extensive production of free radicals. An increase in extracellular Mg concentration decreases inflammatory effects, while reduction in extracellular Mg results in cell activation. The effect of Mg deficiency in the development of insulin resistance in the rat model is well documented.”

They then elucidate how magnesium deficiency promotes atherosclerosis with the vascular inflammation characteristic of cardiovascular diseases including heart attacks:

“Inflammation occurring during experimental Mg deficiency is the mechanism that induces hypertriglyceridemia and pro-atherogenic changes in lipoprotein metabolism. The presence of endothelial dysfunction and dyslipidemia triggers platelet aggregability [stickiness], thus increasing the risk of thrombotic events [blood clots]. Oxidative stress contributes to the elevation of blood pressure. The inflammatory syndrome induces activation of several factors, which are dependent on cytosolic [inside the cell] Ca [calcium] activation. Recent findings support the hypothesis that the Mg effect on intracellular Ca 2+ homeostasis may be a common link between stress, inflammation and a possible relationship to metabolic syndrome.“

In other words, as calcium goes up in ratio to magnesium cardiovascular inflammation develops. This is important in light of the previous post on calcium supplementation and heart attacks.

The author of a review in the same issue of Magnesium Research notes:

“Hypomagnesemia is associated with an increased incidence of diabetes mellitus, metabolic syndrome, mortality rate from CAD [coronary artery disease] and all causes. Magnesium supplementation improves myocardial metabolism, inhibits calcium accumulation and myocardial cell death; it improves vascular tone, peripheral vascular resistance, afterload and cardiac output, reduces cardiac arrhythmias and improves lipid metabolism. Magnesium also reduces vulnerability to oxygen-derived free radicals, improves human endothelial function and inhibits platelet function, including platelet aggregation and adhesion, which potentially gives magnesium physiologic and natural effects similar to adenosine-diphosphate inhibitors such as clopidogrel [blood clot prevention].”

If you’re reading this, whether you are a man or woman it is highly likely that you have a functional deficiency of magnesium and should not be taking calcium.

Calcium supplements increase risk of heart attack

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Important research was just published in the British Medical Journal that adds more weight to the evidence that calcium supplementation is poorly advised for osteoporosis. The authors’ intent was to:

“…investigate whether calcium supplements increase the risk of cardiovascular events.”

They undertook a meta-analysis of cardiovascular events mined from a massive amount of data accumulated in numerous randomised trials of calcium supplements. When the numbers were crunched a 30% increase in myocardial infarctions (heart attacks) was associated with the calcium supplementation. Their conclusion is compelling:

“Calcium supplements (without coadministered vitamin D) are associated with an increased risk of myocardial infarction. As calcium supplements are widely used these modest increases in risk of cardiovascular disease might translate into a large burden of disease in the population. A reassessment of the role of calcium supplements in the management of osteoporosis is warranted.“

This is not surprising if you know that calcium has a competitive edge over magnesium for absorption. Magnesium is critically important for supporting parasympathetic nervous system tone and healthy heart rate variability. It has also been  called “nature’s calcium channel blocker” (a class of medications used to treat coronary artery spasm). Moreover, osteoporosis is not a calcium deficiency disorder—it is a problem of calcium utilization due to inflammation and an associated dysregulated hormonal milieu. The authors of an accompanying editorial in the same journal state:

“In the meantime, on the basis of the limited evidence available, patients with osteoporosis should generally not be treated with calcium supplements, either alone or combined with vitamin D, unless they are also receiving an effective treatment for osteoporosis for a recognised indication. Research on whether such supplements are needed as an adjunct to effective agents is urgently required.”