MAGNESIUM DEFICIENCY IN THE PATHOGENESIS OF DISEASE

Early Roots of Cardiovascular, Skeletal
and Renal Abnormalities

Mildred S. Seelig, M.D., M.P.H., F.A.C.N.

Goldwater Memorial Hospital
New York University Medical Center
New York, New York
1980

Contents

1 • Introduction: Consideration of Epidemiologic Factors

1.1. Ischemic Heart Disease
1.2. Concomitant Cardiovascular, Skeletal, and Renal Diseases
1.3. Changing Magnesium, Vitamin D, and Phosphate Intakes
1.4. Sex Difference in Magnesium Retention
1.5. Hard/Soft Water and Cardiovascular Disease
1.6. Epidemiologic Factors in Calcific Urinary Calculi
1.7. Genetic Factors in Cardiovascular, Skeletal, and Renal Diseases
(All figures and tables for Chapter 1)

Part I

Magnesium Deficiency during Gestation, Infancy, and Early Childhood

2 • The Role of Magnesium in Normal and Abnormal Pregnancy

2.1. Magnesium Balance in Pregnancy
2.2. Fetal Magnesium Requirements
2.3. Magnesium Serum Levels in Normal and Abnormal Pregnancy
2.3.1. Normal Pregnancy: Magnesium Levels
2.3.2. Preeclampsia and Eclampsia: Magnesium Levels and Treatment
2.3.2.1. Possible Contribution of Magnesium Deficiency to Eclamptic Pregnancy
2.3.2.2. Possible Contribution of Magnesium Deficiency to Placental and Coagulation Abnormalities
2.4. Magnesium Levels in Women with Recurrent or Imminent Abortion
(All figures and tables for Chapter 2)

3 • Consideration of Magnesium Deficiency in Perinatal Hormonal and Mineral Imbalances

3.1. Magnesium Deficiency during Gestation
3.1.1. Effects of Experimental Maternal Magnesium Deficiency on the Fetus
3.2. Perinatal Parathyroid Secretion: Interrelations with Magnesium and Calcium
3.2.1. Hyperparathyroidism of Pregnancy
3.2.2. Fetal Parathyroid Activity, and Phosphate, Calcium, and Magnesium Homeostasis
3.2.3. Hypoparathyroidism of Infancy
3.2.3.1. Hypocalcemia of Infancy
3.2.3.2. Magnesium Deficiency and Infantile Hypoparathyroidism
3.3. Calcitonin during Gestation; Interrelations with Magnesium and Calcium
3.3.1. Calcitonin during Pregnancy
3.3.2. Fetal Secretion of Calcitonin
3.3.3. Neonatal Calcitonin
3.4. Perinatal Hypervitaminosis D
3.4.1. Toxicity of Excess Vitamin D during Pregnancy
3.5. Summary of Maternal Factors That Might Contribute to Infantile Magnesium Abnormalities: Morbidity and Mortality
3.5.1. Genetic Hypoparathyroidism
3.5.2. Genetic Hyperparathyroidism
3.5.3. Reciprocal Maternal and Fetal Mineral Status
3.5.4. Maternal Age and Parity: Diabetes Mellitus
3.5.5. Eclampsia
(All figures and tables for Chapter 3)

4 • Magnesium Status in Infancy

4.1. Infantile Magnesium Deficiency: A Factor in Hypocalcemic Tetany, Seizures, and Respiratory Distress
4.1.1. Magnesium Deficiency in Metabolic Convulsions of Otherwise Normal Newborn Infants
4.1.2. Low-Birth-Weight Infants
4.1.3. Neonatal Hypoxia
4.1.4. Neonatal Infants of Diabetic Mothers
4.1.5. Neonatal Hypermagnesemia
4.1.6. Magnesium Depletion by Exchange Transfusions with Citrated Blood
4.1.7. Low Ionized Calcium and Hypomagnesemia
4.2. Treatment of Infantile Conditions Associated with Abnormalities of Magnesium
4.2.1. Correction of Neonatal Acidosis
4 2.2 Intensification of Magnesium Deficiency by Treatment of Hypocalcemia with Calcemic Agents
4.3 Influence of Infant Feeding on Magnesium Status Interrelations with Calcium, Phosphorus, and Vitamin D
4.3.1. Human versus Cows' Milk
4.3.1.1. Metabolic Balances of Infants Fed Human or Cows' Milk
4.3.1.2. Serum Magnesium, Calcium and Phosphorous Levels in Infants Fed Cows' and Human Milk
4.3.2. Risks of Excessive Vitamin D in Infancy
4.4. Primary Malabsorption of Magnesium
4.5. Acute and Protracted Gastroenteritis in Infancy and childhood
4.6. Protein Calorie Malnutrition (PCM)
4.7. Sudden Death in Infancy: Possible Role of Magnesium Deficiency
4.7.1. Sudden Infant Death Syndrome (SIDS)
4.7.1.1. Acute Magnesium Deficiency, Histamine Release, and Hypoxia in SIDS
4.7.1.2. Subacute Magnesium Deficiency and Cardiac Lesions in SIDS
4.7.1.3. SIDS and Hypoparathyroidism
4.7.1.4. Epidemiologic Factors in SIDS
(All figures and tables for Chapter 4)

Part II

Magnesium Deficiency in the Pathogenesis of Cardiovascular Diseases

5 • Failure to Reduce Incidence of Ischemic Heart Disease by Lowering Blood Lipids

5.1. Magnesium and Lipid Interrelationships
5.1.1. Influence of Fat on Magnesium Retention (Man)
5.1.1.1. Dietary Fat and Magnesium Balance
5.1.1.2. Steatorrhea and Magnesium Loss
5.1.1.3. Dietary Fat and Blood Lipids (Man)
5.1.1.4. Serum Magnesium and Cholesterol Levels in Cardiovascular Patients and High-Risk Populations
5.1.1.5. Clinical Use of Magnesium in Cardiovascular Disease with Hyperlipidemia
5.1.2. Blood and Cardiovascular Magnesium and Cholesterol in Experimental Dietary Atherogenesis and Cardiopathies
5.1.3. Magnesium/Lipid/Catecholamine Interrelationships
5.1.4. Estrogen, Lipids, and Magnesium; Interrelationships with Arteriosclerosis and Thrombosis
5.1.4.1. Estrogen Therapy of Ischemic Heart Disease
5.1.4.2. Estrogen, Cardiovascular Effects, and Magnesium
5.1.4.3. Magnesium, Estrogen, and Thrombotic Events
(All figures and tables for Chapter 5)

6 • Is Clinical Arteriosclerosis a Manifestation of Absolute or Conditioned Magnesium Deficiency?

6.1. The Arterial Wall and Arteriosclerosis
6.1.1. Mucopolysaccharides and Elastica in Arteriosclerotic Arteries
6.1.2. Pathology of Infantile Arteriosclerosis
6.1.3. Incidence of Infantile Coronary Arteriosclerosis
6.2. Factors Suggesting Magnesium Deficiency in Infantile Cardiovascular Disease
6.2.1. Experimental Arteriosclerosis of Magnesium Deficiency
6.2.1.1. Arterial Damage Caused by "Pure" Magnesium Deficiency
6.2.1.2. Arterial Damage of Magnesium Deficiency Intensified by High Calcium and Vitamin D Intakes
6.2.1.3. Arterial Damage of Magnesium Deficiency Intensified by High Fat Intakes
6.2.1.4. The Cardiovasopathic (CVP) Diet
6.2.1.5. Other Cardiovasopathic Models That Might Entail Relative Magnesium Deficiency
6.3. Catecholamine-Induced Arterial Damage; Magnesium Interrelationships
6.4. Magnesium Deficiency, Mast Cells, and Arteriosclerosis
6.5. Arterial Resistance, Blood Pressure, and Magnesium
6.5.1. Increased Arterial Resistance: Low Mg + K; High Ca + Na
6.5.2. Magnesium Deficiency and Decreased Blood Pressure; Refractoriness to Vasoactive Hormones
6.5.3. Clinical Magnesium Deficiency and Blood Pressure
(All figures and tables for Chapter 6)

7 • Magnesium Deficiency/Loss from Myocardium

7.1. Cardiac Magnesium Lability
7.2. The Magnesium Status of the Myocardium
7.3. Myocardial Changes with Magnesium Deficiency or Loss (Animal)
7.3.1. Experimental Magnesium Deficiency
7.3.2. Magnesium Loss from the Hypoxic Heart
7.3.3. Magnesium Loss from the Stressed Heart or in Association with Catecholamine Administration
7.3.4. Corticosteroid + Phosphate-Induced Myocardial Necrosis
7.3.5. Hereditary Cardiomyopathy of Hamsters
7.3.6. Stress and Free Fatty Acids/Myocardial Necrosis and Magnesium
7.3.7. Myocardial Loss of Magnesium after Parathyroidectomy and Sodium Phosphate Load
7.4. Cardiac Magnesium Loss: Central to Cardiac Dysionism, Disease, and Dysfunction
(All figures and tables for Chapter 7)

8 • Clinical Cardiac Abnormalities and Magnesium

8.1. Cardiomyopathies Not Secondary to Disease of the Major Coronary Arteries or to Infection
8.1.1. Peripartum Cardiomyopathy
8.1.2. Infantile Cardiomyopathy
8.1.3. Alcoholic Cardiomyopathy and Magnesium Deficiency
8.1.4. Diabetic Cardiomyopathy
(There are no figures and tables for Chapter 8)

9 • Magnesium Deficiency and Cardiac Dysrhythmia

9.1. Electrocardiographic Changes of Experimental Magnesium Deficiency
9.2. Magnesium Interrelationships with Other Factors in Cardiac Rhythmicity
9.2.1. Magnesium/Potassium in Cardiac Rhythmicity
9.2.2. Catecholamine/Magnesium/Potassium Interrelationships
9.2.3. Postinfarction/Catecholamine/Free Fatty Acid/Magnesium Interrelationships with Arrhythmia
9.2.4. Blood Primes for Extracorporeal Circulation
9.3. Magnesium Deficiency in Clinical Arrhythmia
9.3.1. Experimental Magnesium Deficiency (Man)
9.3.2. Electrocardiographic Changes with Use of ACD Blood
9.3.2.1. Exchange Transfusion
9.3.2.2. Open-Heart Surgery
9.3.2.3. Surgery, Drainage, and Magnesium-Free Intravenous Infusions
9.3.3. Malabsorption and Magnesium-Deficient Arrhythmias
9.3.4. Arrhythmias of Starvation
9.3.5. Arrhythmias of Alcoholism
9.3.6. Dysrhythmia in Diabetes Mellitus
9.3.7. Arrhythmias and Abnormal ECGs in Toxemias of Pregnancy and Peripartal Cardiomyopathy
9.3.8. Infantile Arrhythmias and Cardiomyopathies
9.3.9. "Idiopathic" and Postinfarct ECG Abnormalities That May Be Related to Magnesium Deficiency or Loss
9.3.9.1. "Benign" Arrhythmias
9.3.9.2. Similarity to ECGs of Magnesium Deficiency
9.3.10. Heart Block of Dialyzed Uremic Patients
(All figures and tables for Chapter 9)

10 • Therapeutic Use of Magnesium in Cardiovascular Disease

10.1. Magnesium in the Treatment of Arrhythmias
10.1.1. Magnesium and Digitalis Arrhythmias
10.1.2. Magnesium Treatment of Ischemic Arrhythmia
10.1.2.1. Magnesium in Experimental Hypoxic Arrhythmia
10.1.2.2. Magnesium in Clinical Arrhythmias of Ischemic and Unknown Origin
10.1.2.3. Glucose Solutions and Insulin to Increase Myocardial Magnesium and Potassium Uptake
10.1.2.4. The Role of the Anion
10.2. Formulation of a Metabolic Therapeutic Program for Treating Cardiomyopathies and Arrhythmias
(All figures and tables for Chapter 10)

Part III
Skeletal and Renal Effects of Magnesium Deficiency

11 • Magnesium, Bone Wasting, and Mineralization

11.1. Mobilization of Bone Magnesium
11.2. Influence of High Vitamin D and High or Low Calcium Intakes
11.2.1. High Calcium: Decreased Mobilization
11.2.2. Low Calcium: Increased Mobilization
11.3. High Phosphate Intakes: Effects on Bones
11.3.1. Effects on Bone Magnesium
11.3.2. High P/Ca; P/Mg and Bone Wasting; Mineralization
11.3.2.1. Bone Wasting
11.3.2.2. Bone Mineralization
11.4. Influence of Metabolic Activity of Bone on Availability of Bone Magnesium
11.5. Influence of Age on Mobilization of Bone Magnesium
11.6. Physicochemical Exchange of Bone Magnesium and Calcium
11.7. Alkaline and Pyrophosphatases, Magnesium, and Mineralization of Bone
11.7.1. Magnesium Requirement for Phosphatase Activation and Synthesis
11.7.2. Alkaline Phosphatase and Skeletal Mineralization (All figures and tables for Chapter 11)

12 • Abnormal Bone in Magnesium Deficiency

12.1. Osteopenia of Magnesium Deficiency (Animals)
12.2. Abnormal Bone: Hypermineralization and Hyperplasia of Magnesium Deficiency
12.3. Bone Diseases Possibly Related to Magnesium Deficiency
12.3.1. Fetal Magnesium Deficiency and Bone Damage
12.3.1.1. Interrelationships with Parathyroid Hormone and Calcitonin
12.3.1.2. Interrelationships with Gestational Hypervitaminosis D
12.3.2. Magnesium Deficiency and Bone Disease in Low-Birth-Weight Infants
12.4. Magnesium Status and Vitamin D Requirements and Responses
12.4.1. Increased Vitamin D Requirements of Magnesium Deficiency
12.4.2. Vitamin-D-Refractory Rickets and Osteomalacia
12.4.2.1. Hypophosphatemic Hyperparathyroid Rickets
12.4.2.2. Hyperphosphatemic Hypoparathyroid Osteopenia
12.4.3. Other Abnormal Function of, or Response to, Parathyroids
12.4.4. Osteopetrosis or Osteosclerosis and Hyperreactivity to Vitamin D
12.4.4.1. High Vitamin D and Calcium/Low Magnesium
12.4.4.2. Magnesium/Calcitonin Interrelationships in Osteoporosis
12.5. Other Genetic Bone Diseases and Possible Role of Magnesium
12.5.1. Osteogenesis Imperfecta
12.5.2 Hypophosphatasia
12.6. Other Osteopenias Possibly Mediated by Magnesium Deficiency
12.6.1. Osteoporosis
12.6.2 Renal Osteodystrophy
12.7. Joint Diseases Possibly Mediated by Magnesium Deficiency
12.7.1. Osteochondrosis
12.7.2. Chondrocalcinosis and Osteoarthritis
12.8. Magnesium Deficiency and Dental Disorders

13 • Renal Damage Caused by Magnesium Deficiency

13.1. Experimental Magnesium Deficiency
13.2. Intensification of Magnesium Deficiency Renal Damage by Excess Vitamin D (Animal)
13.3. Intensification of Magnesium Deficiency Renal Damage by Excess Phosphates (Animal)
13.4. Mediation by Secondary Hyperparathyroidism; Protection by Parathyroidectomy
13.5. Tissue Magnesium Loss and Damage: Not Parathyroid-Mediated
13.6. Phosphatases and Extraskeletal Mineralization
13.7. Magnesium Effect on Precipitation of Calcium Crystals in Urine
13.8. Clinical Renal Diseases Possibly Related to Magnesium Deficiency
13.8.1. Renal Tubular Defects in Magnesium Reabsorption
13.8.1.1. Contributions to Clinical Renal Magnesium Wastage by Calcemic Factors and Phosphate Therapy
13.8.1.2. Contribution to Clinical Renal Magnesium Wastage by Malabsorption
13.8.1.3. Miscellaneous Factors in Renal Magnesium Wastage
13.8.2. Renal Damage during Pregnancy: Related to Magnesium Deficiency?
13.8.3. Diabetic Renal Disease: Contributed to by Magnesium Deficiency

14 • Intensification of Magnesium Deficiency by Calcemic and Phosphate Therapy

14.1. Calcemic Therapy during Pregnancy
14.2. Calcemic Therapy during Infancy
14.3. Calcemic Therapy for Osteopenias
14.4. Treatment for Hypercalcemia
14.4.1. Risks of Phosphate Therapy
14.5. Complex of Diseases to Which Magnesium Deficiency Contributes Especially When Complicated by Calcemic and Phosphate Therapy

Appendix • Tests for Magnesium Deficiency
Cases of Infantile Ischemic Heart Disease

A.1. Limitations of Serum or Plasma Magnesium Levels
A.1.1. What is the Normal Range
A.1.2. Bound and Free Magnesium in Plasma
A.2. The Importance of Cellular Magnesium Determinations
A.2.1. Erythrocyte Magnesium
A.2.2. Skeletal Muscle Magnesium
A.2.3. White Blood Cell Magnesium Determinations
A.3. Percentage Retention of Parenteral Magnesium Loads
A.3.1. Recommended Procedures for Determining Percentage Retention of Parenteral Magnesium Load
A.3.1.1. Adults: Intramuscular Load
A.3.1.2. Adults: Intravenous Load
A.3.1.3. Infants: Intravenous Load
A.3.1.4. Infants: Intramuscular Load
A.3.2. Evaluation of Renal Handling of Magnesium

Bibliography (A-D)
Bibliography (E_K)
Bibliography (L_R)
Bibliography (S_Z)

Index (Not reproduced in this online version) Please search either the book or The Magnesium Web Site: