**Patient on ACS Pathway – Hypomagnesaemia a Contributory Factor to Myocardial Ischemia**

Ghulam Naroo, Tanveer Ahmed Yadgir, Bina Nasim and Omer Skaf

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55286

## **1. Introduction**

Magnesium is the 4th most abundant intracellular cation in the body. Normal adult plasma concentration ranges from 1.7 to 2.5 mg/dL. Most of the body's reserves are found in the skeletal bone mass.

Hypomagnesaemia is a common electrolyte abnormality seen in around 12% hospitalized patients and has an incidence as high as 60 to 65 % in Intensive Care Unit patients.

Clinical signs and symptoms are only possible in severe magnesium deficiency. Surprisingly, magnesium depletion can present despite a near normal serum magnesium level.

Common nutritional sources include green leafy vegetables, legumes, nuts, animal proteins, seafood and sea greens like kelp.

Absorption takes place in the upper small intestine, where nearly 30 to 50% of consumed magnesium is taken up depending upon the endogenous magnesium status.

Magnesium is excreted by the kidneys.

In circulation 33% is albumin bound (non-filterable), 12% complexed with anions & 55% is in the free ionized form (filterable fraction)

© 2013 Naroo et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **2. Magnesium at cellular level**

Magnesium serves as a cofactor for over 300 enzymes involved in Deoxyribonucleic Acid (DNA) and Ribonucleic Acid (RNA) synthesis, protein synthesis, energy metabolism and maintenance of electrical potential of nervous tissue and cell membranes.

Of particular importance is the role of this element in regulating potassium fluxes through Sodium (Na) Pottasium (K) ATPase pump and involvement in metabolism of Calcium. (*Magnesium is a natural calcium channel blocker)*

**Na K Pump** – the sodium potassium pump is activated by magnesium. With magnesium deficiency there is impaired pump activity, whereby insufficient potassium can be pumped into the cell, although the supply may be great enough.

The energy substrate for the transport activity of the sodium/potassium pump is represented by Adenosine Triphosphate (ATP) in form of its magnesium complex. This ATP-Mg++ complex is split by the ATPase delivering the transport energy and therefore it is said that the ATPase is directing the sodium/potassium pump.

**3. Causes of hypomagnesaemia**

**Figure 1.** ATP-Mg++ : Energy Supply for pumps and exchange

sium losses.

**•** Steatorrhea

Gastrointestinal Causes-

**•** Small bowel bypass

channel family.

Renal Causes-

**•** Acute/ Chronic Diarrhea

**•** Malabsorption syndromes

Pathologic effects of primary nutritional deficiency of magnesium is rare unless a relatively low magnesium intake is accompanied with prolonged diarrhea or excessive urinary magne‐

Patient on ACS Pathway – Hypomagnesaemia a Contributory Factor to Myocardial Ischemia

http://dx.doi.org/10.5772/55286

135

**•** Inborn errors of metabolism – autosomal recessive disorder, chromosome 9, selective defect in magnesium absorption due to a mutation in gene that encodes for a member of receptor

**•** Loop and thiazide diuretics – cause mild hypomagnesaemia, because volume contraction

**•** Hypercalcemia- increased filtered calcium load competes with magnesium in transport

**•** Loop of Henle & Distal tubule dysfunction – Barters Syndrome and Gitelmans syndrome.

**•** Alcoholics- Alcohol induced tubular dysfunction which is reversible within 4 weeks.

**•** Acute pancreatitis – Saponification of magnesium and potassium ions.

increase proximal sodium, water and magnesium reabsorption

**•** Nephrotoxins- Aminoglycosides, amphotericin B, cisplatin, cyclosporine

across the ascending limb of loop of Henle.

Furthermore with Magnesium deficiency there is not enough energy substrate. Hence the cell membrane shows increased permeability and the potassium gradient cannot be maintained.

*Potassium leaves the cell, in compensation sodium and hydrogen influx takes place passively. Magne‐ sium leaves the cell, if not enough ATP is present for forming the ATP-Mg complex and calcium influx will follow.*

**Calcium (Ca) Pump and Na/Ca exchange -** There are two possibilities for elimination of calcium out of the cell, but unfortunately both are impaired by magnesium deficiency:

They are the calcium pump and the sodium/calcium exchange.

**Calcium pump-** After muscle contraction calcium ions will be transported back again from the cytosol to the stores of the sarcoplasmatic reticulum by the calcium pump. The concentra‐ tion gradient at this action needs a high expense of energy: one ATP for two calcium ions. The calcium transport-ATPase is magnesium dependent.

**Sodium calcium exchange-.** During the action potential calcium influx takes place along the slow calcium channels into the cell and induces the contraction process. The calcium influx will be compensated again by an exchange of three sodium ions into the cell. The energy for the exchange originates from the high extracellular sodium concentration, but these three sodium-ions must be removed again out of the cell by the sodium/potassium pump which requires one ATP. If the performance of the sodium/potassium pump is impaired, cellular sodium will increase and inhibit sodium/calcium exchange. This can be due to ATP deficiency, myocardial ischemia/ reperfusion injury, potassium/ magnesium deficiency.

Increasedsodiumwithinthecellresultsinhypertensionandtheincreasedcalciumwithinthecell increases the vascular tone in the smooth muscle of the artery to aggravate the hypertension.

**Figure 1.** ATP-Mg++ : Energy Supply for pumps and exchange

## **3. Causes of hypomagnesaemia**

Pathologic effects of primary nutritional deficiency of magnesium is rare unless a relatively low magnesium intake is accompanied with prolonged diarrhea or excessive urinary magne‐ sium losses.

Gastrointestinal Causes-


**2. Magnesium at cellular level**

134 Ischemic Heart Disease

(*Magnesium is a natural calcium channel blocker)*

is directing the sodium/potassium pump.

*will follow.*

into the cell, although the supply may be great enough.

They are the calcium pump and the sodium/calcium exchange.

calcium transport-ATPase is magnesium dependent.

Magnesium serves as a cofactor for over 300 enzymes involved in Deoxyribonucleic Acid (DNA) and Ribonucleic Acid (RNA) synthesis, protein synthesis, energy metabolism and

Of particular importance is the role of this element in regulating potassium fluxes through Sodium (Na) Pottasium (K) ATPase pump and involvement in metabolism of Calcium.

**Na K Pump** – the sodium potassium pump is activated by magnesium. With magnesium deficiency there is impaired pump activity, whereby insufficient potassium can be pumped

The energy substrate for the transport activity of the sodium/potassium pump is represented by Adenosine Triphosphate (ATP) in form of its magnesium complex. This ATP-Mg++ complex is split by the ATPase delivering the transport energy and therefore it is said that the ATPase

Furthermore with Magnesium deficiency there is not enough energy substrate. Hence the cell membrane shows increased permeability and the potassium gradient cannot be maintained.

*Potassium leaves the cell, in compensation sodium and hydrogen influx takes place passively. Magne‐ sium leaves the cell, if not enough ATP is present for forming the ATP-Mg complex and calcium influx*

**Calcium (Ca) Pump and Na/Ca exchange -** There are two possibilities for elimination of calcium out of the cell, but unfortunately both are impaired by magnesium deficiency:

**Calcium pump-** After muscle contraction calcium ions will be transported back again from the cytosol to the stores of the sarcoplasmatic reticulum by the calcium pump. The concentra‐ tion gradient at this action needs a high expense of energy: one ATP for two calcium ions. The

**Sodium calcium exchange-.** During the action potential calcium influx takes place along the slow calcium channels into the cell and induces the contraction process. The calcium influx will be compensated again by an exchange of three sodium ions into the cell. The energy for the exchange originates from the high extracellular sodium concentration, but these three sodium-ions must be removed again out of the cell by the sodium/potassium pump which requires one ATP. If the performance of the sodium/potassium pump is impaired, cellular sodium will increase and inhibit sodium/calcium exchange. This can be due to ATP deficiency,

Increasedsodiumwithinthecellresultsinhypertensionandtheincreasedcalciumwithinthecell increases the vascular tone in the smooth muscle of the artery to aggravate the hypertension.

myocardial ischemia/ reperfusion injury, potassium/ magnesium deficiency.

maintenance of electrical potential of nervous tissue and cell membranes.


#### Renal Causes-


## **4. Effects of hypomagnesaemia on tissues**

**•** Hypokalemia- Hypokalemia induced due to deficiency of magnesium is refractory to potassium supplementation until magnesium deficiency is corrected.

association between serum magnesium and carotid intima-media thickness(12.). Low serum magnesium causes endothelial damage that accelerates the atherosclerotic process leading to ACS. Evidence links significant low serum magnesium to CHD in patient with Acute Myo‐ cardial Infarction (AMI) versus control [13] [14]. This cohort of 15,792 middle aged subjects were assessed over a four to seven year period as part of the Atherosclerosis Risk in Com‐ munities (ARIC) study [2]. The relative risk of CHD across quartiles of serum magnesium was 1.0 (in the lowest quartile), 0.92, 0.48 and 0.44. Both men and women who developed CHD had

Patient on ACS Pathway – Hypomagnesaemia a Contributory Factor to Myocardial Ischemia

http://dx.doi.org/10.5772/55286

137

lower mean baseline serum magnesium concentration than the disease-free controls.

prevention of CHD [17].

esis of diabetes or hypertension [18] [19].

increasing magnesium levels [20]

dium in patients of Unstable Angina:

limiting the reperfusion injury. **•** Dilating the coronary arteries. [21]

arrhythmias include the above and following:

**•** Reducing the after load. [22]

**•** Direct antiarrhythmic effect.

Another study of 50 patients with coronary heart disease found that oral magnesium supple‐ ment therapy improved endothelial function and exercise tolerance compared to placebo. Autopsy has shown that magnesium concentrations in cardiac muscle of individuals who died of heart disease is lower than those of accident victims [15] [16] One study, found a 20% reduction in magnesium in the non-infarcted and a 50% reduction in the infarcted myocardi‐ um. Also infarcted myocardium had a depressed magnesium/calcium ratio [16]. A prospective National Health and Nutritional Examination Survey (NHANES) I follow up study showed the important role of modifiable dietary and behavioral characteristics in the causation and prevention of coronary heart disease hospitalization and mortality. This study was done over a 10 years follow up of 8251 subjects. The study emphasized the role of modifiable dietary factors including magnesium as well as behavioral characteristics in the causation and

Another epidemiologic study showed an inverse association between dietary magnesium and incident CHD. These associations were present after adjustment for multiple confound‐ ing factors, including race, smoking, alcohol intake, life style & exercise, waist/hip ratio, fibrinogen & lipids level, diuretics use and HRT [17]. Diabetes and hypertension may merely be confounders but low magnesium concentration may contribute to the pathogen‐

ing green vegetables, nuts and whole grains may provide protection against CHD by

The following effects of magnesium might play an important role in protecting the myocar‐

**•** Reducing the ischemic myocardial death by reducing the intracellular calcium overload by

Other effects of magnesium beneficial in myocardial infarction and life threatening ventricular

**•** Inhibiting the platelet function by its effect on prostacyclin secretion.

**•** Attenuating the catecholamine release by reducing the sympathetic activity. [23]

High intake of foods rich in magnesium includ‐


## **5. Clinical manifestations of hypomagnesaemia**


Initial stage- widening of QRS Complex peaking of T waves

Later stage- prolongation of PR interval, progressive widening of QRS complex and diminu‐ tion of T wave.

## **6. Diagnosis of magnesium deficiency**

The serum magnesium level correlates poorly with total body stores. As a result, there have been several intracellular assays of magnesium from lymphocytes, red blood cells, and muscle biopsies. These assays include nuclear magnetic resonance (NMR) spectroscopy and ionspecific electrode measures. But since these tests are very expensive, therefore they are not clinically applicable at present. For these reasons, despite its limitations serum magnesium levels are commonly and easily carried out to evaluate the magnesium status. If the serum magnesium level is low, intracellular magnesium is also low but it is important to understand that many patients may have normal serum magnesium levels but may still be intracellularly depleted. [1]

#### **7. Discussion**

Low serum magnesium is an independent predictor of CHD in both gender. Although relation exist more in women and less in men. A cross-sectional cohort study has shown inverse association between serum magnesium and carotid intima-media thickness(12.). Low serum magnesium causes endothelial damage that accelerates the atherosclerotic process leading to ACS. Evidence links significant low serum magnesium to CHD in patient with Acute Myo‐ cardial Infarction (AMI) versus control [13] [14]. This cohort of 15,792 middle aged subjects were assessed over a four to seven year period as part of the Atherosclerosis Risk in Com‐ munities (ARIC) study [2]. The relative risk of CHD across quartiles of serum magnesium was 1.0 (in the lowest quartile), 0.92, 0.48 and 0.44. Both men and women who developed CHD had lower mean baseline serum magnesium concentration than the disease-free controls.

Another study of 50 patients with coronary heart disease found that oral magnesium supple‐ ment therapy improved endothelial function and exercise tolerance compared to placebo. Autopsy has shown that magnesium concentrations in cardiac muscle of individuals who died of heart disease is lower than those of accident victims [15] [16] One study, found a 20% reduction in magnesium in the non-infarcted and a 50% reduction in the infarcted myocardi‐ um. Also infarcted myocardium had a depressed magnesium/calcium ratio [16]. A prospective National Health and Nutritional Examination Survey (NHANES) I follow up study showed the important role of modifiable dietary and behavioral characteristics in the causation and prevention of coronary heart disease hospitalization and mortality. This study was done over a 10 years follow up of 8251 subjects. The study emphasized the role of modifiable dietary factors including magnesium as well as behavioral characteristics in the causation and prevention of CHD [17].

Another epidemiologic study showed an inverse association between dietary magnesium and incident CHD. These associations were present after adjustment for multiple confound‐ ing factors, including race, smoking, alcohol intake, life style & exercise, waist/hip ratio, fibrinogen & lipids level, diuretics use and HRT [17]. Diabetes and hypertension may merely be confounders but low magnesium concentration may contribute to the pathogen‐ esis of diabetes or hypertension [18] [19]. High intake of foods rich in magnesium includ‐ ing green vegetables, nuts and whole grains may provide protection against CHD by increasing magnesium levels [20]

The following effects of magnesium might play an important role in protecting the myocar‐ dium in patients of Unstable Angina:


**4. Effects of hypomagnesaemia on tissues**

further contributes to Hypocalcaemia.

**•** Cardiac Effects - Arrhythmias, Heart Disease

**6. Diagnosis of magnesium deficiency**

**•** ECG Changes-

136 Ischemic Heart Disease

tion of T wave.

depleted. [1]

**7. Discussion**

**5. Clinical manifestations of hypomagnesaemia**

Initial stage- widening of QRS Complex peaking of T waves

**•** Hypokalemia- Hypokalemia induced due to deficiency of magnesium is refractory to

**•** Hypocalcaemia- due to diminished secretion of Parathyroid hormone and resistance to the effect of parathyroid hormone at the receptor level. Parathyroid hormone (PTH) induced

**•** Vitamin D Deficiency- Low plasma level of Calcitriol is noted in Hypomagnesaemia which

**•** Neurological Effects– Headache, paresthesias, tremors, muscular spasms, tetany, convul‐

Later stage- prolongation of PR interval, progressive widening of QRS complex and diminu‐

The serum magnesium level correlates poorly with total body stores. As a result, there have been several intracellular assays of magnesium from lymphocytes, red blood cells, and muscle biopsies. These assays include nuclear magnetic resonance (NMR) spectroscopy and ionspecific electrode measures. But since these tests are very expensive, therefore they are not clinically applicable at present. For these reasons, despite its limitations serum magnesium levels are commonly and easily carried out to evaluate the magnesium status. If the serum magnesium level is low, intracellular magnesium is also low but it is important to understand that many patients may have normal serum magnesium levels but may still be intracellularly

Low serum magnesium is an independent predictor of CHD in both gender. Although relation exist more in women and less in men. A cross-sectional cohort study has shown inverse

potassium supplementation until magnesium deficiency is corrected.

release of calcium from bone is impaired when plasma Mg < 0.8 mg/ dL.

**•** Metabolic Effects - Hypokalemia, Hypocalcemia, Diabetes, Osteoporosis

sions, migraine, irritability, anxiety, weakness, mood swings, depression.


Other effects of magnesium beneficial in myocardial infarction and life threatening ventricular arrhythmias include the above and following:

**•** Direct antiarrhythmic effect.


Magnesium has been shown to inhibit calcium influx in the cell, it reduces the mitochondrial calcium overload, conserves the intracellular ATP as Mg2+-ATP, and raising extracellular magnesium has been shown to be protective in ischemia. Magnesium inhibits the spasm of the coronary arteries [21], increases the coronary blood flow, and decreases the coronary vascular resistance in patients of Variant Angina. This can be a direct effect of magnesium on coronary vasculature or it can be an indirect effect by reducing the catecholamine release.

This study concluded that magnesium infusion reduces the ischemic ECG changes, cardiac markers, and urinary catecholamine excretion in the acute phase of unstable angina. Therefore

Patient on ACS Pathway – Hypomagnesaemia a Contributory Factor to Myocardial Ischemia

http://dx.doi.org/10.5772/55286

139

Among the other studies which have suggested that magnesium may reduce mortality and serious arrhythmias post acute myocardial infarction is the Second Leicester intravenous magnesium intervention trial (LIMIT-2) study [27], which was a double-blind randomized trial of 2316 patients with suspected acute MI who received either intravenous magnesium sulfate or placebo along with other currently accepted therapies for MI, including thrombolysis. Thirty-five percent of the patients received a fibrinolytic agent, usually streptokinase, and 66 percent received aspirin. The presence of an acute MI was confirmed in 65 percent of cases.

An important design feature of this trial was that magnesium was administered **prior** to a fibrinolytic agent. A treatment effect was observed in all subgroups, including those receiving thrombolysis and it showed a 24% reduction in mortality, 25% reduction in the incidence of left ventricular failure and 21% reduction in the mortality from ischemic heart disease.

In another small trial which revealed a positive association of magnesium to coronary heart disease, 194 patients with an acute MI who were not considered candidates for fibrinolytic therapy were randomized to receive either intravenous magnesium sulfate or placebo. In this study the benefits of magnesium compared to placebo showed a reduction in the in-hospital mortality especially in the elderly and a lower incidence of both arrhythmias and left ventric‐

However, this was not supported by the results of International Study of Infarct Survival (ISIS-4) study [28] which showed that a 24-h infusion of magnesium has no beneficial effect in those receiving thrombolysis for acute myocardial infarction. In this study, patients were randomized after the thrombolytic agent had been administered, a mean of 8 h after the onset of pain, compared to a median of 3 h in the Leicester intravenous magnesium intervention trial (LIMIT-2) trial, in which iv magnesium was given prior to thrombolysis. Animal studies have shown that the effect of magnesium is greatest if given before spontaneous or induced reperfusion, as this reduces the reperfusion induced myocardial injury, and this may account,

in part, for the lack of benefit seen in International Study of Infarct Survival (ISIS-4).

Data suggest that hypomagnesemia may precede CHD. The U.S. National Academy of Sciences has estimated that a nation-wide initiative to add calcium and magnesium to soft water might reduce the annual cardiovascular death rate by 150,000 in the United States. [7]. It is recommended to design further observational and interventional studies to

magnesium is useful in these patients.

ular dysfunction.

**8. Conclusion**

substantiate the link.

High catecholamine levels play an important role in the pathogenesis and prognosis of unstable angina and are closely related to the extension of an infarct [24]. Magnesium tends to inhibit the release of catecholamines from the adrenal medulla and reduces the sensitivity of a- adrenergic receptors to catecholamines, thereby reducing the arrythmogenic and the pressor effects of the catecholamines [25]. Deficiency of magnesium therefore enhances the sympa‐ thetic activity and increases the catecholamine induced myocardial damage.

A double blind randomized placebo controlled study was conducted to assess the 24 hour infusion of magnesium in patients of unstable angina [26]. In this study the patients who presented with unstable angina and had electrocardiographic changes were randomized to receive 24hour intravenous infusion of magnesium or placebo within 12hr of admission. The chosen primary endpoints in this study included ECG changes as assessed by 48h Holter monitoring, resting 12 lead ECGs, CK-MB release and urinary catecholamine levels.

In this study patients were followed for 1month. Thirty-one patients received magnesium sulphate and 31 placebo. Baseline characteristics and extent of coronary disease were similar in both groups. On 48 h Holter monitoring, 14 patients(50%) were found to have transient ST segment shifts in the magnesium group versus 12 patients (46%) in the placebo group. However, there were fewer ischemic episodes in the magnesium group (51 versus 101, P<0001) and there was a trend towards an increase in the total duration of ischemia in the placebo group compared to the magnesium group in the second 24 h. It was found that regression of T wave changes on the 24 h ECG and reduction in the ST segment changes in the 12 lead ECG, occurred more frequently in patients who received magnesium compared to those treated with placebo (11 patients versus 0 patients respectively, P<0005).

Creatine kinase-MB release was significantly less at 6 and 24 h in patients who received magnesium compared to those treated with placebo. Catecholamine excretion was lower in patients treated with magnesium than in those treated with placebo in the first 12 h sample, *P<005).* On continuous ECG monitoring, a similar proportion of patients in each treatment group had evidence of myocardial ischemia in the first 24 h of recording. However, the number of episodes was significantly less in the magnesium group and the number of patients with transient myocardial ischemia in this group fell from 11 patients (39%) to five (18%) in the second 24 h of recording with no change in the placebo group (10 patients [39%] in both the first and second 24 h).

This study concluded that magnesium infusion reduces the ischemic ECG changes, cardiac markers, and urinary catecholamine excretion in the acute phase of unstable angina. Therefore magnesium is useful in these patients.

Among the other studies which have suggested that magnesium may reduce mortality and serious arrhythmias post acute myocardial infarction is the Second Leicester intravenous magnesium intervention trial (LIMIT-2) study [27], which was a double-blind randomized trial of 2316 patients with suspected acute MI who received either intravenous magnesium sulfate or placebo along with other currently accepted therapies for MI, including thrombolysis. Thirty-five percent of the patients received a fibrinolytic agent, usually streptokinase, and 66 percent received aspirin. The presence of an acute MI was confirmed in 65 percent of cases.

An important design feature of this trial was that magnesium was administered **prior** to a fibrinolytic agent. A treatment effect was observed in all subgroups, including those receiving thrombolysis and it showed a 24% reduction in mortality, 25% reduction in the incidence of left ventricular failure and 21% reduction in the mortality from ischemic heart disease.

In another small trial which revealed a positive association of magnesium to coronary heart disease, 194 patients with an acute MI who were not considered candidates for fibrinolytic therapy were randomized to receive either intravenous magnesium sulfate or placebo. In this study the benefits of magnesium compared to placebo showed a reduction in the in-hospital mortality especially in the elderly and a lower incidence of both arrhythmias and left ventric‐ ular dysfunction.

However, this was not supported by the results of International Study of Infarct Survival (ISIS-4) study [28] which showed that a 24-h infusion of magnesium has no beneficial effect in those receiving thrombolysis for acute myocardial infarction. In this study, patients were randomized after the thrombolytic agent had been administered, a mean of 8 h after the onset of pain, compared to a median of 3 h in the Leicester intravenous magnesium intervention trial (LIMIT-2) trial, in which iv magnesium was given prior to thrombolysis. Animal studies have shown that the effect of magnesium is greatest if given before spontaneous or induced reperfusion, as this reduces the reperfusion induced myocardial injury, and this may account, in part, for the lack of benefit seen in International Study of Infarct Survival (ISIS-4).

## **8. Conclusion**

**•** Reducing free radical formation.

Magnesium has been shown to inhibit calcium influx in the cell, it reduces the mitochondrial calcium overload, conserves the intracellular ATP as Mg2+-ATP, and raising extracellular magnesium has been shown to be protective in ischemia. Magnesium inhibits the spasm of the coronary arteries [21], increases the coronary blood flow, and decreases the coronary vascular resistance in patients of Variant Angina. This can be a direct effect of magnesium on coronary

High catecholamine levels play an important role in the pathogenesis and prognosis of unstable angina and are closely related to the extension of an infarct [24]. Magnesium tends to inhibit the release of catecholamines from the adrenal medulla and reduces the sensitivity of a- adrenergic receptors to catecholamines, thereby reducing the arrythmogenic and the pressor effects of the catecholamines [25]. Deficiency of magnesium therefore enhances the sympa‐

A double blind randomized placebo controlled study was conducted to assess the 24 hour infusion of magnesium in patients of unstable angina [26]. In this study the patients who presented with unstable angina and had electrocardiographic changes were randomized to receive 24hour intravenous infusion of magnesium or placebo within 12hr of admission. The chosen primary endpoints in this study included ECG changes as assessed by 48h Holter

In this study patients were followed for 1month. Thirty-one patients received magnesium sulphate and 31 placebo. Baseline characteristics and extent of coronary disease were similar in both groups. On 48 h Holter monitoring, 14 patients(50%) were found to have transient ST segment shifts in the magnesium group versus 12 patients (46%) in the placebo group. However, there were fewer ischemic episodes in the magnesium group (51 versus 101, P<0001) and there was a trend towards an increase in the total duration of ischemia in the placebo group compared to the magnesium group in the second 24 h. It was found that regression of T wave changes on the 24 h ECG and reduction in the ST segment changes in the 12 lead ECG, occurred more frequently in patients who received magnesium compared to those treated with placebo

Creatine kinase-MB release was significantly less at 6 and 24 h in patients who received magnesium compared to those treated with placebo. Catecholamine excretion was lower in patients treated with magnesium than in those treated with placebo in the first 12 h sample, *P<005).* On continuous ECG monitoring, a similar proportion of patients in each treatment group had evidence of myocardial ischemia in the first 24 h of recording. However, the number of episodes was significantly less in the magnesium group and the number of patients with transient myocardial ischemia in this group fell from 11 patients (39%) to five (18%) in the second 24 h of recording with no change in the placebo group (10 patients [39%] in both the

monitoring, resting 12 lead ECGs, CK-MB release and urinary catecholamine levels.

(11 patients versus 0 patients respectively, P<0005).

first and second 24 h).

vasculature or it can be an indirect effect by reducing the catecholamine release.

thetic activity and increases the catecholamine induced myocardial damage.

**•** Enhanced collateral flow.

138 Ischemic Heart Disease

Data suggest that hypomagnesemia may precede CHD. The U.S. National Academy of Sciences has estimated that a nation-wide initiative to add calcium and magnesium to soft water might reduce the annual cardiovascular death rate by 150,000 in the United States. [7]. It is recommended to design further observational and interventional studies to substantiate the link.

#### **Author details**

Ghulam Naroo1 , Tanveer Ahmed Yadgir2 , Bina Nasim3 and Omer Skaf4

1 Emergency & Trauma Centre, Rashid Hospital Dubai, United Arab Emirates

2 Research & Accreditation Department, Dubai Corporation for Ambulance Services, Dubai, United Arab Emirates

[11] Redwood, S. R, Basir, Y, Huang, J, et al. Effect of magnesium sulphate in patients with unstable angina. A double blind,randomized,placebo-controlled study.Eu Heart

Patient on ACS Pathway – Hypomagnesaemia a Contributory Factor to Myocardial Ischemia

http://dx.doi.org/10.5772/55286

141

[12] Ma, J, Folsom, A. R, Melnick, S. L, Eckfeldt, J. H, Sharrett, A. R, Nabulsi, A. A, et al. Associations of serum and dietary magnesium with cardiovascular disease, hyper‐ tension, diabetes, insulin, and carotid arterial wall thickness: the ARIC Study. J Clin

[13] Singh, R. B, Rastogi, S. S, Ghosh, S, & Niaz, M. A. Dietary and serum magnesium lev‐ els in patients with acute myocardial infarction, coronary artery disease and noncar‐

[14] Kafka, H, Langevin, L, & Armstrong, P. W. Serum magnesium and potassium in acute myocardial infarction: influence on ventricular arrhythmias. Arch Intern Med

[15] Marier, J. R. Water hardness, human health and the importance of magnesium. Otta‐ wa: National Research Council of Canada. NRCC Series (1979). (17581), 65-84.

[16] Speich, M, Bousquet, B, & Nicolas, G. Concentrations of magnesium, calcium, potas‐ sium, and sodium in human heart muscle after acute myocardial infarction. Clin

[17] The role of modifiable dietary and behavioral characteristics in the causation and prevention of coronary heart disease hospitalization and mortality- NHANES follow

[18] White JR Jr. Campbell RK. Magnesium and diabetes: a review. Ann Pharmacother

[19] 31. Resnick, L. M. Cellular calcium and magnesium metabolism in the pathophysiol‐ ogy and treatment of hypertension and related metabolic disorders. Am J Med

[20] 48. Fraser, G. E, Sabate, J, Beeson, W. L, & Strahan, T. M. A possible protective effect of nut consumption on risk of coronary heart disease: the Adventist Health Study.

[21] Vigorito, C, Giordano, A, Ferraro, P, et al. Hemodynamic effects of magnesium sul‐

[22] Rasmussen, H, Larsen, O, Meier, K, & Larsen, J. Hemodynamic effects of intrave‐ nously administered magnesium on patients with ischemic heart disease. Clin Cardi‐

[23] James, M, Cork, R, Harlen, G, & White, J. Interactions of adrenaline and magnesium

fate on the normal human heart. AmJ Cardiol (1991). , 67, 1435-7.

on the cardiovascular system of the baboon. Magnesium (1988).

J (1997).

Epidemiol (1995). , 48, 927-40.

(1987). , 147, 465-9.

Chem (1980). , 26, 1662-5.

up study-1.

(1993). , 27, 775-80.

(1992). A):11S-20S.

ol (1988). , 824-8.

Arch Intern Med (1992). , 152, 1416-24.

diac diagnoses. J Am Coll Nutr (1994). , 13, 139-43.


#### **References**


[11] Redwood, S. R, Basir, Y, Huang, J, et al. Effect of magnesium sulphate in patients with unstable angina. A double blind,randomized,placebo-controlled study.Eu Heart J (1997).

**Author details**

140 Ischemic Heart Disease

Ghulam Naroo1

**References**

Heart J (1998).

Circulation.(2000).

United Arab Emirates

, Tanveer Ahmed Yadgir2

3 Rashid Hospital, Dubai, United Arab Emirates

tance. Patient Care (1994). , 10, 130-150.

, Bina Nasim3

2 Research & Accreditation Department, Dubai Corporation for Ambulance Services, Dubai,

[1] Altura, B. M, Brodsky, M. A, Elin, R. J, et al. Magnesium: growing in clinical impor‐

[2] Liao, F, Folsom, A. R, & Brancati, F. L. Is low magnesium concentration a risk factor for coronary heart disease? The Atherosclerosis Risk in Communities Study. Am

[3] Taneva, E. Hypokaliaemia and hypomagnesemia during acute coronary syndrome:

[4] Altura, B. M. Aimin Z Altura BT: Magnesium, hypertensive vascular disease, athero‐ genesis, subcellular compartmentation of calcium and magnesium and vascular con‐

[5] Paolisi, G. Barbagallo M: Hypertension, diabetes, and insulin resistance: the role of

[6] Chester Fox MD, Delano Ramsoomair, MD, and Cathleen Carter, PhD: Magnesium:

[7] http:/ / www.mgwater.com/, The Magnesium website.(2002). access dated- 27/11/12)

[8] Oral Mg therapy improves endothelial function in pt with ACSShechter M,Sharir

[9] The important role of modifiable dietary and behavioral characterisics in the causa‐ tion and prevention of coronary heart disease hospitalization and mortality; the per‐ spective NHANES follow up study, Gartside PS, Glueck CJ Jam Coll Nutr.(1995).

[10] 10. Antman, EM, Anbe, DT, & Armstrong, PW. ,et al. ACC/AHA guidelines for the

A- 661. European Journal of Anaesthesiology (2005). , 22-issue, 172.

intercellular magnesium. Am J Hypertension (1997). , 10, 346-355.

Its Proven and Potential Clinical Significance. South Med J. (2001).

management of patients with ST-elevation myocardial infarction.

tractility. Miner Electrolyte Metab (1993). , 19, 323-336.

1 Emergency & Trauma Centre, Rashid Hospital Dubai, United Arab Emirates

4 Dubai Corporation for Ambulance Services, Dubai, United Arab Emirates

and Omer Skaf4


[24] Penny, W. J. The deleterious effects of myocardial catecholamines on cellular electro‐ physiology and arrhythmias during ischaemia and reperfusion. Eur Heart J (1984). , 5, 960-73.

**Chapter 9**

**Cell Autophagy and Myocardial**

Suli Zhang, Jin Wang, Yunhui Du, Jianyu Shang,

**Ischemia/Reperfusion Injury**

Li Wang, Jie Wang, Ke Wang, Kehua Bai,

Additional information is available at the end of the chapter

Ischemic heart disease is a clinical syndrome resulting from myocardial ischemia and is characterized by an imbalance between the supply and demand of myocardial blood flow and myocardial oxygen metabolism. It is currently one of the major diseases that endanger human health. Early and effective reconstruction of ischemic myocardial blood perfusion is the fundamental measure taken to prevent the development of ischemic myocardial injury, reduce myocardial infarct size, and improve the clinical prognosis. However, several studies have discovered that in some cases, reperfusion of ischemic cells could cause further injury in the form of ischemia/reperfusion injury. The clinical manifestations of myocardial ische‐ mia-reperfusion injury include arrhythmia, myocardial stunning, and no-reflow. Although lethal reperfusion injury in clinical practice is more difficult to identify, it is the most serious consequence of ischemia/reperfusion injury and is also the main reason preventing the is‐ chemic myocardium recovery from effective reperfusion therapy. Therefore, studies on the modes of myocardial cell death after ischemia/reperfusion are of great significance. Previous studies suggested that myocardial cell death following myocardial ischemia/reperfusion in‐ jury were mainly necrosis and apoptosis. Apoptosis receives more attention due to its death program. However, in recent years, a number of studies have suggested that, another proce‐ dural manner of death---autophagy, type II programmed cell death, also plays a critical role in ischemia/reperfusion injury. The study of this death pathway may provide a new effec‐ tive way to block myocardial ischemia/reperfusion injury. Therefore, in this chapter, the roles and possible mechanisms of autophagy in myocardial ischemia/reperfusion injury will

> © 2013 Zhang et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

Tingting Lv, Xiao Li and Huirong Liu

http://dx.doi.org/10.5772/53442

**1. Introduction**

be reviewed.


**Chapter 9**
