Metabolic Syndrome and Cardiovascular Disease

T. Barry Levine, Arlene Bradley Levine

• Publisher: Wiley-Blackwell
• Year: 2012
• Print ISBN: 9781405195751
• eBook ISBN: 9781118480076
• Edition: 2
• Topic: Medicine
• Subtopic: Cardiology

Trends indicate that the metabolic syndrome will become the leading risk factor for heart disease. Now more than ever you need an all-in-one reference that provides the tools and practical advice you need to:

• Identify at-risk patients
• Explain individual contributing factors
• Aid in patient education and motivation
• Direct comprehensive care and
• Choose the most appropriate interventions

Comprehensively revised to reflect leading-edge research and now organized to facilitate easy access to essential information and clinically-relevant guidance, Metabolic Syndrome and Cardiovascular Disease, 2e offers this and more. Not only will you receive a solid understanding of the pathophysiology underlying the metabolic syndrome and cardiovascular disease but also the rationale for today's most effective treatments.

What's new?

Filled with timely new content, this updated edition covers:

• New discoveries that have changed our understanding of the pathogenesis and interrelationship of metabolic syndrome, cardiovascular disease (CHD), and type 2 diabetes mellitus (DM)
• The relevance of mitochondria and telomeres
• Sleep and its impact on cardiometabolic health
• The pivotal interplay between insulin and forkhead transcriptionfactors
• Calorie restriction research
• Bariatric surgery experiences and outcomes

In addition, each chapter includes essential information on comorbidities, interventions, and pharmacotherapeutic options – an exclusive feature found only in the second edition!

Chapter 1

The Metabolic Syndrome: A Relevant Concept?

The concept of the “metabolic syndrome” arose from a research perspective. Epidemiologically, the term captures a confluence of clinical risk factors that tend to occur together, raising the question of whether these conditions have a single underlying cause.

Several different definitions of the syndrome have been proposed by various organizations, such as the International Diabetes Federation (IDF), World Health Organization (WHO), European Group for the Study of Insulin Resistance (EGIR), and the U.S. National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP), with various different constellations of risk factors. Although the detailed definitions differ among these organizations, the metabolic syndrome is generally diagnosed when a person presents with any three of the following findings: a generous waist circumference, ­elevated blood pressure, high triglyceride levels, low high-density lipoprotein (HDL) levels, or elevated fasting blood glucose.

However, beyond minor differences about specific components that make up the various definitions of the syndrome, there are significant disagreements as to the validity of naming this risk factor cluster as a separate condition and using it as a diagnostic tool for treatment. This controversy about the relevance of the metabolic syndrome has pitted diabetologists against cardiologists. In 2005, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) issued a statement discouraging the use of the term “metabolic syndrome.” In contrast, a few weeks later, the American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI) released statements encouraging the clinical use of that term. The controversy continues.

The EASD posits that no additional benefit derives from identifying the metabolic syndrome risk factor cluster over measuring and treating the individual risk factors. The EASD claims that there are no data to confirm that the metabolic syndrome is a true syndrome rather than a collection of co-aggregating cardiovascular risk factors; and that the collective association with cardiovascular disease is no more than the sum of its parts, much of the risk being linked to obesity, hypertension, glucose intolerance, and hyperglycemia. In short, diabetologists disagree with Aristotle that “the whole is greater than the sum of its parts.”

Since the syndrome may apply to 25 to 33% of the population, the organization also objects to applying a disease label to too many people. The 2005 EASD statement concluded: “There is much fundamental, clinically important, and critically missing information about the metabolic syndrome to warrant a more serious examination of whether medical science is doing any good by drawing attention to and labeling millions of people with a presumed disease that does not stand on firm ground.”

Other criticisms leveled at the concept of the metabolic syndrome are that there is no single therapy for such a syndrome. Rather, each risk factor has to be managed ­separately.

In truth, the metabolic syndrome concept is intellectually not rigorous and pathophysiologically not logical. One has a risk factor for inflammation (overweight) linked to a single manifestation of endothelial dysfunction (hypertension), associated with a manifestation of hepatic insulin resistance (dyslipidemia), coupled to pancreatic beta-cell failure (hyperglycemia). Furthermore, the Framingham Risk Score will perform better as a predictor of heart disease than the metabolic syndrome.

However, although there may be no synergy among the individual components of the metabolic syndrome on the risk of coronary outcomes, the risk of stroke and all-cause mortality associated with the metabolic syndrome appears to be significant, independent of its components. Also, as cardiologists, we find the metabolic syndrome a helpful concept: it is so readily recognized. How often do we not wonder if a person on the street or in the elevator has the metabolic syndrome? How often can we not just tell that an individual entering our office has the ­metabolic syndrome, only to confirm the diagnosis with easy, inexpensive testing? The most common presentation of the metabolic syndrome is in people with visceral fat, who are sedentary, and have poor dietary habits.

The metabolic syndrome is not a disease. It is “individuals” or “people” that have the metabolic syndrome, not “patients.” However, over a lifetime, the metabolic syndrome is itself a powerful predictor for the incidence of chronic disease – not only of vascular disease, for which the Framingham Risk Score would serve well, but also of cardiomyopathy, diabetes mellitus (DM), cancer, renal disease, and dementia, that will turn “people” into “patients.” It is alarming that almost 40 million Americans have DM, that more than twice that number have prediabetes, and that by 2050 one-third of Americans will be diabetic. It is potentially devastating that in the U.S. at least half the population is overweight and 40% will have the metabolic syndrome and be at risk for such diseases. It is, therefore, of tremendous value to be able to easily identify people with this cluster of risk factors. It enables us to target this population for more aggressive lifestyle advice, and for therapy, if needed.

The construct of the metabolic syndrome may not be intellectually pleasing, but it is simple, and it works. Those at-risk individuals who are sedentary, eat unhealthily and excessively, and have visceral and/or ectopic fat, also develop mitochondrial dysfunction, telomere attrition, inflammation, endothelial dysfunction, and insulin resistance. Such individuals typically have elevated triglycerides, and rather than carry a laundry list of diagnoses, many cardiologists prefer to follow Pythagoras: “Do not say a little in many words but a great deal in a few.”

Aside from saying much with little, does it make a difference in clinical practice? We would argue that it does.

Physicians diagnosing only traditional risk factors will likely neglect borderline abnormalities as not relevant or not requiring attention. A slightly generous waist or mildly depressed HDL may not be addressed on a hypertension follow-up visit. Traditional risk factors will fail to capture those at risk in the population.

Physicians treating individual risk factors will prescribe their preferred treatments for each. One might choose a beta-blocker for hypertension; fibrates or ezetimibe might be prescribed for abnormal lipid findings, or a sulfonylurea for hyperglycemia.

In contrast, a physician thinking of the metabolic ­syndrome will focus on all abnormalities, even if they are of borderline concern. He/she will be aware of the common pathophysiology underlying the individual’s presentation: the role that inflammation, oxidative stress, mitochondrial dysfunction, endothelial dysfunction, and insulin resistance all play.

Finding the metabolic syndrome allows the physician to elucidate modifiable factors that contribute to the pathophysiology: Is the person stressed or sleep deprived? Does the individual suffer from some chronic inflam­matory process? In this context, overweight is no longer a cosmetic issue but a significant source of systemic inflammation; inactivity or an unhealthy diet are no longer ­lifestyles but factors that engender endothelial and mitochondrial dysfunction and insulin resistance.

The therapeutic approach chosen will be “holistic,” addressing the underlying pathophysiology. While tailored to an individual’s need, interventions will be chosen to synergistically impact on all components. The emphasis will be on aggressive therapeutic lifestyle changes: they do have a major impact on all factors underlying the metabolic syndrome, thus improving all individual risk factors.

With therapeutic interventions, the clinician dealing with the metabolic syndrome will identify therapies that make sense physiologically, that lower inflammation and oxidative stress, that improve mitochondrial and ­endothelial function, and that reduce insulin resistance. The aim is to have every drug chosen help the entire ­syndrome: thus a renin–angiotensin–aldosterone system (RAAS) antagonist will be more appropriate than a calcium channel blocker, an HDL-raising statin will be more beneficial than ezetimibe, an AMP-activated protein kinase (AMPK) activator will be more helpful than a ­sulfonylurea. In the presence of the metabolic syndrome, a clinician may consider prescribing aspirin.

Yes, the metabolic syndrome targets a large segment of the population; however, identifying the many affected individuals is a benefit. These individuals are not diseased. They are simply at higher risk of developing DM, heart disease, cancer, and dementia. The metabolic syndrome allows easy diagnosis and targeting of people for aggressive lifestyle advice. It is an early time in the pathophysiological process when lifestyle interventions are still very effective. Diet and exercise continue to be the cor­nerstone of any metabolic syndrome prevention-and-­treatment strategy, and individuals and society at large will benefit from a timely preventive intervention.

Chapter 2

Mitochondria

Mitochondria have traditionally been viewed as cellular organelles for energy production in response to changes in energy demand. However, mitochondria also function as active signaling organelles in a number of important intracellular pathways [1]. As such, mitochondria have a dichotomous role in controlling both life and death processes by playing a critical part in cellular function, stress response, cytoprotection, and apoptosis, as well as in reactive radical biology and calcium (Ca²⁺) ­homeostasis [2, 3].

Intact mitochondrial function is central to good health and lifespan. Mitochondrial dysfunction and attenuation of cellular bioenergetics underlie a variety of diseases. Impaired mitochondrial function is thus closely associated with insulin resistance and contributes to the progression of diabetes mellitus (DM). Mitochondrial dysfunction plays a pivotal role in heart disease, diseases of the central nervous system, and aging [2, 4].

Background

Derivation

In many respects, mitochondria are akin to prokaryotic cells like bacteria. In fact, mitochondria have a unique evolutionary origin [5]. Whole-genome analyses suggest that mitochondria are descended from formerly free-living bacteria. Atmospheric oxygen appeared approximately 2.3 billion years ago. Prokaryotic cells evolved to harness the energy in oxygen. Mitochondria may be the evolutionary descendants of such oxygen-scavenging prokaryotes that established an endosymbiotic relationship within the cytosol of eukaryotes one-and-a-half to two billion years ago. Over time, mitochondria evolved into primary ­control centers for energy production and cellular life-and-death processes in eukaryotes. In effect, the history of eukaryotic development entails the fusion and coevolution of host and endosymbiont genomes [6–8].

Implications of life with mitochondria

The symbiotic relationship of mitochondria with eukaryotic cells may have been a turning point in the evolution of life, enabling the development of complex organisms [9].

Since mitochondria provide the energy for living, the enhanced mitochondrial supply of energy has permitted organisms to develop from single-celled entities into complex and sophisticated life forms. On the other hand, the requirements of mitochondria have modulated anatomy and physiology. As 98% of inhaled oxygen is consumed by mitochondria, their oxygen requirement has driven the need for the development of oxygen uptake membranes, such as lungs or gills. Mitochondrial fuel needs have also driven the development of gastrointestinal organs. Blood and the circulatory system serve to disseminate oxygen and energy substrates to the mitochondria within the cells of all tissues [2].

Structure

Mitochondria are membrane-enclosed, subcellular organelles distributed throughout the cytosol of most eukaryotic cells. Their shape is quite variable, ranging from small and spherical in adipocytes to oblong in hepatocytes, cylindrical, or thread-like and interconnected, depending on the cell type. They are approximately 0.5 µm wide and from 0.5 to several micrometers long, approximating the size of bacteria [6].

Mitochondria are highly organized structures. Different enzymes and reactions are confined to discrete membranes and aqueous compartments [10]. Specifically, in the mitochondria:

• the outer membrane separates the mitochondrion from the cellular cytosol;
• the inner membrane, subjacent to the outer membrane, encloses the interior compartment or matrix;
• invaginations of the inner membrane, the “cristae mitochondrialis”, project into the mitochondrial interior, the matrix;
• the matrix is of gel-like consistency, containing about 50% protein in a reticular network attached to the inner membrane; it also holds deoxyribonucleic acid (DNA) and ribosomes;
• the intermembrane space separates the outer membrane from the inner membrane [6].

Mitochondria contain about 2000 proteins. Many of these are hydrophobic membrane-based proteins. Mitochondrial proteins derive from the synthesis of macromolecules within the mitochondria, together with the import of proteins and lipids synthesized outside the organelle [11].

The outer membrane

Proper cell function is contingent on the integrity of the outer mitochondrial membrane separating cytosolic from mitochondrial factors. The outer mitochondrial membrane is smooth, but it contains a number of proteins that can form channels to facilitate the transmembrane movement of ions and molecules [6]. Passage of metabolites through the outer mitochondrial membrane seems to occur through a voltage-dependent anion-selective channel. This channel exhibits gating between a non­conducting state and various subconductance states controlling the permeability of molecular species via ­differing cutoff sizes [12].

The inner membrane

The inner mitochondrial membrane is often highly folded. Those folds, which project into the...

Table of contents

• Cover
• Title page
• Copyright page
• Preface
• List of Abbreviations
• Chapter 1: The Metabolic Syndrome: A Relevant Concept?
• Chapter 2: Mitochondria
• Chapter 3: Telomeres
• Chapter 4: The FoxO Transcription Factors and Sirtuins
• Chapter 5: Insulin and Insulin-Like Growth Factor
• Chapter 6: Oxidative Stress
• Chapter 7: Mental Stress
• Chapter 8: Sleep
• Chapter 9: Inflammation
• Chapter 10: Adipose Tissue and Overweight
• Chapter 11: Weight Loss and Diet
• Chapter 12: Skeletal Muscle and Exercise
• Chapter 13: Lipids, Atherogenic Dyslipidemia, and Therapy
• Chapter 14: The Endothelium, Cardiovascular Disease, and Therapy
• Chapter 15: Insulin Resistance, Metabolic Syndrome, and Therapy
• Index