Metabolic Syndrome and Cardiovascular Disease is a comprehensive text addressing the cardiovascular risk factors and consequences associated with this important condition, a concept that has evolved over much of the past century, but which has received renewed and heightened attention over the past decade. It has been known for several decades that risk factors for atherosclerotic cardiovascular disease often cluster together. This knowledge is the basis for multifactorial algorithms to predict risk for cardiovascular disease.  The Framingham Heart Study produced the first risk-prediction algorithms, but more recently, similar risk engines have been created from other databases of prospective studies.  These risk-prediction tools have included all of the established atherosclerotic cardiovascular disease risk factors and provide the basis for estimates of global risk.

Only recently have efforts been made to identify particular patterns of risk factors that have a common origin. The metabolic syndrome is one such pattern that has generated much interest in recent years.

Two lines of evidence have merged to produce the metabolic syndrome concept. These different origins have not been fully integrated and account for much of the debate that surrounds the syndrome. The first of these has been the recognition that obesity is strongly associated with multiple risk factors and undoubtedly contributes significantly to them. These include hypertension, hyper-cholesterolemia, hypertriglyceridemia, low levels of high-density lipoproteins, and hyperglycemia.  In spite of much research on these metabolic complications of obesity, researchers in this field never consolidated all of them into a syndrome.

But certainly it was recognized that prevention and treatment of obesity is the foundation of management of these risk factors.

During this same period, researchers in the diabetes field identified a metabolic state called insulin resistance.  It was characterized by resistance to the actions of insulin and hyperinsulinemia. Insulin resistance was first recognized as a major contributing factor to Type 2 diabetes. However, in 1998, Dr. Gerald Reaven presented the hypothesis that insulin resistance also can be a cause of risk factors of metabolic origin. Among these risk factors he first identified were hypertension,  low high-density lipoproteins levels,  and hypertriglyceridemia.

Although Dr. Reaven called the clustering of risk factors with insulin resistance and hyperinsulinemia tighten by the name syndrome X, others shortly thereafter changed the name to insulin resistance syndrome. Several different names have been used as alternatives for the metabolic syndrome.  Besides metabolic syndrome X, and insulin resistance syndrome, there are the dysmetabolic syndrome, metabolic syndrome X,  the deadly quartet,  CHAOS,  and the cardiometabolic syndrome. Often the name chosen is meant to highlight one or another feature of the syndrome. Recently some investigators have raised the question of whether a clustering of metabolic risk factors should be called a “syndrome” at all. This is a semantic issue,  but most researchers believe that the term “syndrome”  is appropriate for a clustering of risk factors of metabolic origin.  For another decade, the metabolic syndrome/insulin resistance syndrome remained a topic of research interest, but did not become an entity for clinical identification. But in 1998, the World Health Organization Working Group on Definition of Diabetes attempted to formulate criteria for the diagnosis of the metabolic syndrome.

These criteria were based on the assumption that insulin resistance is the major cause of the syndrome. Subsequently, other organizations have made an effort to reformulate diagnostic criteria both to add simplicity and to include the key features of the syndrome. Over the next eight years, diagnostic criteria have been suggested by the European Group for Study of Insulin Resistance, the United States National Cholesterol Education Program Adult Treatment Panel III, the American Association of Clinical Endocrinology,  the International Diabetes Federation,  and the American Heart Association/National Heart,  Lung,  and Blood Institute.  The World Health Organization definition was influential in concept but lacking in clinical utilization. The simplicity of the Adult Treatment Panel III definition, however, was attractive to many researchers and clinicians and has sparked great interest.  Subsequently,  the International Diabetes Federation and American Heart Association/National Heart,  Lung,  and Blood Institute made minor modifications to the Adult Treatment Panel III criteria. The two are very similar, and use the same risk factors and cut points for diagnosis.

This similarity provides enough harmonization to make the two essentially interchangeable for diagnosis.

The metabolic syndrome has been strongly associated with risk for atherosclerotic cardiovascular disease. When Gerald Reaven introduced syndrome X, it identified a clustering of factors related to insulin resistance and predicting risk for atherosclerotic cardiovascular disease.  Currently accepted metabolic risk factors for atherosclerotic cardiovascular disease are

•     Atherogenic dyslipidemia
•     Vascular dysfunction
•     Dysglycemia
•     A prothrombotic state
•     A proinflammatory state

Atherogenic dyslipidemia consists of

•     Elevated apolipoprotein B including elevated levels of triglyceride and small low-density lipoprotein particles
•     Reduced levels of high-density lipoproteins

There is general agreement that most apolipoprotein B-containing lipoproteins are atherogenic, whether contained in the low-density lipoprotein or very low-density lipoprotein fractions. The relationship between low levels of high-density lipoprotein and atherogenesis is less well understood. Several causative mechanisms have been proposed,  e.g.,  reduced reverse cholesterol transport,  loss of protection against low-density lipoprotein oxidation within the arterial wall, and reduction of anti-inflammatory properties. The extent to which a low high-density lipoprotein level contributes to atherogenesis must await controlled clinical trials with high-density lipoprotein-raising drugs. Such trials are currently underway.

Vascular dysfunction is manifest by elevations in blood pressure and by endothelial dysfunction. The former is known to be atherogenic, whereas the latter may be. The role of endothelial dysfunction in the development of atherosclerosis is still under investigation. Finally, some investigators believe that vascular dysfunction may play a direct role in the development of insulin resistance and other metabolic risk factors.

Dysglycemia can take several forms:  high–normal plasma glucose, impaired glucose tolerance, impaired fasting glucose, and clinical hyperglycemia (Type 2 diabetes). A variety of mechanisms have been proposed whereby elevations in plasma glucose can directly promote atherogenesis. In addition, higher glucose levels cause microvascular disease.  There is growing evidence that microvascular disease may secondarily cause macrovascular disease. Some investigators question whether the metabolic syndrome and Type 2 diabetes can coexist.  According to these investigators,  Type 2 diabetes subsumes the metabolic syndrome. Without question, most patients with Type 2 diabetes exhibit current diagnostic criteria for the metabolic syndrome. It must be pointed out, however, that current criterion for the diagnosis of Type 2 diabetes is based entirely on plasma glucose cut points. Further, an alternate view is that Type 2 diabetes is essentially a severe form of the metabolic syndrome.  This view is justified by those to point out that it is characterized by multiple metabolic risk factors.
Clearly the two conditions have many common pathogenic features.

A prothrombotic state is characterized mainly by elevations of plasminogen activator inhibitor-1. Nevertheless, several other coagulation abnormalities have been reported in patients with the metabolic syndrome. Some of these include

•     Platelet dysfunction
•     Elevated fibrinogen
•     Elevated von Willebrand factor
•     Elevated factor VII
•     Elevated tissue plasminogen activator antigen
•     Elevated factor V Leiden
•     Elevated protein C
•     Elevated antithrombin II

Abnormalities in coagulation and thrombolysis have been implicated both in atherogenesis itself and in propagation of thrombi following disruption of atherosclerotic plaques.

The proinflammatory state associated with the metabolic syndrome appears to have several features. First, circulating levels of inflammatory cytokines are raised. These high levels appear to be derived largely from adipose-tissue beds.

Second, in muscle and liver, an excessive influx of fatty acids can elicit the formation of intracellular inflammatory pathways that can induce insulin resistance.

###

Scott M. Grundy, MD, PhD
Professor of Internal Medicine
Distinguished Chair in Human Nutrition
Director, Center for Human Nutrition
University of Texas, Southwestern Medical Center
Dallas, Texas, U.S.A.