Metabolic Syndrome and Cardiovascular Disease

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