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