Metabolic Syndrome and Cardiovascular Disease

This new edition aims to explore the molecular mechanisms underlying insulin resistance and the metabolic syndrome, and to demonstrate how metabolic disorders such as diabetes, obesity, hypertension, and disturbances in lipid/carbohydrate metabolism, can be directly linked to cardiovascular disease. Secondly, it explains how therapeutic lifestyle changes and pharmacologic interventions are effective at improving insulin resistance and therefore reduce the threat of cardiovascular problems, and has sections highlighting the clinical outcomes of the various treatments. Fully comprehensive in both the science and research behind the metabolic syndrome, and also the treatments methods and preventative strategies used by clinicians when dealing with patients, this book is perfect for cardiovascular and endocrinologists alike, at both the bench and the bedside level. The book will be ideal equally for both cardiovascular and endocrinology clinicians and researchers. Researchers will use it to educate themselves in the current mechanistic insights on the derivation of the metabolic syndrome, insulin resistance and its comorbidities. Clinicians will use it to improve their prevention of metabolic disorders in patients and in order to treat and manage the syndrome and its complications according to current clinical guidelines.

T. Barry Levine, MD, FACC, is Chief Medical Officer, A.B.L.E. Medical Consulting. He is Professor of Medicine at Drexel University College of Medicine in Philadelphia, PA. Dr. Levine is a Fellow of the American College of Cardiology, a member of the Scientific Advisory Board of the International Academy of Cardiology, and a board member of the Tracleer International Scientific Advisory Board. In addition, he is a member of the American Federation for Clinical Research, the American Heart Association, the International Society for Heart and Lung Transplantation, the American College of Chest Physicians, and the Heart Failure Society of America. Dr. Levine has been recognized by his peers in "Best Doctors in America" and "Top Docs in Pittsburgh". Dr. Levine has participated in numerous clinical trials, authored many articles (138), and created a variety of media presentations on heart failure, hypertension, dyslipidemia, and metabolic syndrome. He along with Dr. Arlene B. Levine has written "A Patient's Guide to Heart Failure" and has authored a textbook, "Metabolic Syndrome and Cardiovascular Disease".

Arlene Bradley Levine, MD, FACC, is CEO, A.B.L.E. Medical Consulting. She is Assistant Professor of Medicine at Michigan State University and? is board-certified in Internal Medicine and Cardiovascular Disease. Dr. Levine is a Fellow of the American College of Cardiology. She is a member of the American Heart Association, the International Society for Heart and Lung Transplantation, the American College of Chest Physicians, and the Heart Failure Society of America. Dr. Levine has authored 45 articles, and has been recognized by her peers in "Best Doctors in America" and "Top Docs in Pittsburgh".

Preface viii

List of Abbreviations ix

1 The Metabolic Syndrome: A Relevant Concept? 1

2 Mitochondria 3

Background 3

Cellular respiration 6

Modulation of mitochondrial metabolic activity 9

Factors that affect mitochondrial number and activity 10

Peroxisome proliferator–activated receptor gamma coactivator-1 11

Mitochondrial production of prooxidant species 12

Mitochondria and nitric oxide 15

Mitochondrial calcium homeostasis 17

The mitochondrial permeability transition 18

Apoptosis 22

Causes for mitochondrial dysfunction 22

Implications of mitochondrial dysfunction 27

Mitochondrial dysfunction and cardiovascular disease 27

Mitochondrial dysfunction and metabolic disease 29

Conclusion 32

Bibliography 34

3 Telomeres 40

Telomere structure 40

Telomere function 41

Telomere shortening 41

Telomere dysfunction 42

Physiologic age 42

Gender differences 43

Telomerase 43

Cell senescence and apoptosis 46

Telomeres in aging 49

Risk factors for cardiometabolic disease 51

Telomeres senescence and chronic disease 54

Cardiovascular disease 54

Insulin resistance and type 2 DM 57

Conclusion 58

Bibliography 60

4 The FoxO Transcription Factors and Sirtuins 64

Forkhead transcription factors 64

Functions of FoxO 68

Cardiovascular forkhead effects 70

Metabolic forkhead effects 72

Histone acetylation and deacetylation 75

Sirtuin deacetylases 76

Sirtuin regulation 78

Antiinflammatory cardiovascular and myocyte sirtuin effects 80

Sirtuin effects on metabolism 81

Sirtuins and cell longevity 83

Forkhead deregulation and insulin resistance 85

Paradoxical effect of nutrition versus stress on cell death suppression 87

Conclusion 89

Bibliography 90

5 Insulin and Insulin-Like Growth Factor 96

Anabolism and catabolism 96

Control of plasma glucose 96

Insulin 97

Insulin receptor location 98

Metabolic insulin signaling 101

Insulin-mediated glucose uptake 103

Nutrient storage and metabolism 104

Vascular and antiinflammatory effects 106

Mitogenic action 107

Insulin-like growth factor 108

Insulin and IGF impact on cell longevity 111

Amylin 113

Glucagon 113

Conclusion 113

Bibliography 114

6 Oxidative Stress 120

Free radicals 120

Oxidases 120

Sources for free radicals 123

Endogenous antioxidants 124

Physiologic functions of oxidative stress 126

Mechanisms of oxidative damage 127

Cellular stress-sensitive pathways 127

Cellular targets of oxidative stress 128

Oxidative stress-related diseases 129

Endothelial dysfunction with oxidative stress 129

Cardiovascular disease 130

Insulin resistance and type 2 DM 131

Conclusion 133

Bibliography 134

7 Mental Stress 139

Stress responses 139

Central stress pathways 139

Peripheral stress pathways 140

Fight-flight-fright responses to acute stress 142

Sequelae of sustained passive stress 142

Inflammatory effects of stress pathways 143

Vascular and lipoprotein effects of

stress pathways 143

Stress impact on body weight 146

Metabolic effects of stress pathways 146

Depression and other mood disturbances 149

Conclusion 152

Bibliography 153

8 Sleep 159

Stages of sleep 159

Cardiovascular parameters during normal sleep 160

Function of sleep 161

Sleep duration 164

Circadian rhythm 165

Examples of circadian regulation 166

Neurohormonal modulation of wakefulness 168

Neurohormonal modulation of sleep 170

Sleep–arousal transitions 172

Sleep deficit 174

Pathophysiologic effects of sleep debt 175

Sleep debt and risk of cardiometabolic disorder 177

Sleep disorders 179

Conclusion 182

Bibliography 183

9 Inflammation 192

Immune responses 192

Selected participants in the inflammatory response 193

C-reactive protein 198

The renin–angiotensin–aldosterone system and inflammation 199

Inflammation and chronic diseases 202

Inflammation endothelial and vascular dysfunction 202

Inflammation and atherosclerosis 205

Acute inflammation carbohydrate metabolism and dyslipidemia 210

Chronic inflammation and the metabolic syndrome 213

Causes for systemic inflammation 215

Conclusion 218

Bibliography 219

10 Adipose Tissue and Overweight 228

Energy storage 228

Diverse fat depots 230

Adipose tissue as immune organ 234

Adipose tissue as endocrine organ 236

Adipokines with beneficial cardiometabolic effect 237

Adipokines with detrimental cardiometabolic effect 244

Obesity comorbidities and cardiovascular disease 250

Obesity insulin resistance and diabetes 252

Conclusion 254

Bibliography 255

11 Weight Loss and Diet 266

Homeostatic responses to weight gain and weight loss 266

Adipose weight loss effects 267

Antiinflammatory vasculoprotective and metabolic effects of weight loss 267

Dietary intervention for weight loss 269

Calorie restriction 270

Surgical intervention 277

Diet 279

Exercise as adjunct to weight loss 289

Conclusion 289

Bibliography 291

12 Skeletal Muscle and Exercise 303

Myocyte structure and function 303

Metabolic adaptations in skeletal muscle 305

Energy sensors 311

Skeletal muscle in inflammation 317

Skeletal muscle in insulin resistance 318

Exercise effect on inflammation and oxidative stress 320

Exercise effect on metabolism in obesity 322

Exercise effect and cardiovascular health 322

Exercise and insulin resistance 325

Exercise and mortality 328

Exercise recommendation 331

Conclusion 332

Bibliography 334

13 Lipids Atherogenic Dyslipidemia and Therapy 347

Apolipoproteins 347

Lipoproteins 347

Apo A-containing lipoproteins 348

Apo B-containing lipoproteins 355

Apolipoproteins C D and E 360

The triglyceride lipase family 360

The normal metabolism of free fatty acids 363

Inflammation and hepatic insulin resistance 365

Atherogenic dyslipidemia in insulin resistance 369

Lipid-lowering therapy 372

The HMG CoA reductase inhibitors 374

Nicotinic acid 387

The fibric acid derivatives 388

Bile acid sequestrants 391

Ezetimibe 391

CETP inhibition 391

Conclusion 392

Bibliography 393

14 The Endothelium Cardiovascular Disease and Therapy 409

Endothelial function 409

Nitric oxide synthase and eNOS 409

Endothelial NO synthesis 410

Specific enhancers of NO synthesis 413

Functions of nitric oxide 415

Shear stress and vascular function 418

Mechanisms of endothelial dysfunction 420

Insulin insulin resistance and endothelial dysfunction 424

Implications of endothelial dysfunction 428

Assessment of endothelial function 430

Hypertension 432

Cardiomyopathy 434

Coronary and peripheral vascular disease 440

Pharmacologic antagonism of the renin–angiotensin–aldosterone system and endothelin-1 443

Beta-adrenergic blockade 448

Phosphodiesterase-5 inhibitors 449

Conclusion 450

Bibliography 451

15 Insulin Resistance Metabolic Syndrome and Therapy 468

Diagnostic criteria for the metabolic syndrome 468

Prevalence of the metabolic syndrome 470

Insulin resistance 470

Causes of insulin resistance 474

Pathways toward insulin resistance 476

Pharmacologic therapy to improve insulin sensitivity 480

Conclusion 483

Bibliography 484

Index 491

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Metabolic Syndrome and Cardiovascular Disease

Summary

Author Biography

Table of Contents

Supplemental Materials