Magnesium Deficiency in the Pathogenesis of Disease : Early Roots of Cardiovascular, Skeletal, and Renal Abnormalities

There is a large and rapidly growing body of literature on the importance of mag­ nesium in biochemical and physiological processes. There is also much evidence that magnesium deficiency, alone and in combination with agents that interfere with its utilization, is associated with functional and structural abnormalities of mem­ branes, cells, organs, and systems. The manifestations of the changes caused by magnesium deficiency depend upon its extent and duration and on variable factors. Among the conditions that increase the risk of magnesium deficiency are (1) meta­ bolic factors that affect the absorption, distribution, and excretion of this mineral; (2) disease and therapy; (3) physiologic states that increase requirements for nutrients; and (4) nutritional imbalances. Excesses of nutrients that interfere with the absorption or increase the excretion of magnesium-such as fat, phosphate, sugar, and vitamin D-can contribute to long-lasting relative magnesium deficiency. All have been implicated in several of the diseases considered in this book. Whether their influence on the need for magnesium is a common denominator remains to be investigated further.

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.- 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.- 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.- 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 Deficiency1.- 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.- 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.- 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.- 7 • Magnesium Deficiency/Loss from Myocardium.- 7.1. Cardiac Magnesium Lability.- 7.7. 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.- 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.- 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.- 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.- 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.- 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.