Background

Clustering of cardiovascular risk factors has been recognized for decades. In 1923, Kylin drew attention to clustering of hypertension, hyperglycemia, and gout. In the 1960s, the phenomenon became widely known in medical circles, and Gerald Reaven reintroduced the concept of syndrome X in 1988. Over the years, the condition has come to be known by a variety of terms, including Reaven syndrome, plurimetabolic syndrome, dysmetabolic syndrome, the deadly quartet, insulin resistance syndrome, 4H syndrome, and cardiometabolic syndrome.

In 1998, the World Health Organization (WHO) proposed to call the condition metabolic syndrome rather than insulin resistance syndrome, since insulin resistance alone could probably not be the sole explanation for all components of the syndrome (Alberti, 1998). In 2001, the National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP III) report identified metabolic syndrome as a risk factor for cardiovascular disease (CVD). Metabolic syndrome is a cluster of the following conditions: abdominal obesity, atherogenic dyslipidemia, hypertension, insulin resistance plus glucose intolerance, and a prothrombotic and proinflammatory state.

The currently accepted definitions of metabolic syndrome, provided by the NCEP/ATP III and the WHO, are listed in the table below.

National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP III) and World Health Organization (WHO) Definitions of Metabolic Syndrome

NCEP/ATP III Definition1	WHO Definition2
Three or more of the following:	Diabetes, IGT, IFG, or insulin resistance, plus 2 or more of the following:
Waist circumference 102 cm (>40 in) in men 88 cm (>35 in) in women	BMI >30 kg/m2 and/or WHR >0.9 in men >0.85 in women
Triglycerides ³ 150 mg/dL	Triglycerides ³150 mg/dL and/or HDL-C <35 mg/dL in men <39 mg/dL in women
HDL-C <40 mg/dL in men <50 mg/dL in women
Blood pressure ³130/85 mm Hg	Blood pressure ³140/90 mm Hg
FPG ³100 mg/dL	Microalbuminuria UAE ³20 mg/min or albumin: creatinine ³30 mg/g

Data from the Third National Health and Nutrition Examination Survey (NHANES III) using the NCEP/ATP III definition revealed a prevalence of 23.9% in participants older than age 20 years. The prevalence increased to greater than 40% in those older than age 60 years. Prevalence is also related to sex and ethnic background. Given that approximately 201 million Americans were older than age 20 years in 2000, and using the prevalence estimates of metabolic syndrome based on modification of glucose threshold, an estimated 50 million people in 1990 and 64 million in 2000 had metabolic syndrome (Ford, 2004).

Etiology of metabolic syndrome

The etiology(ies) of metabolic syndrome is not well understood, though it clearly involves many traits (eg, obesity/visceral adiposity, atherogenic dyslipidemia, dysglycemia/insulin resistance, hypertension). Whether the risk conferred is a sum of individual component-related risks or involves a totally different risk burden remains conjectural, although the presence of several coexistent risk factors obviously magnifies the threat. Clustering analysis seems to indicate that these traits occur simultaneously more frequently than could be explained by chance alone.

• Obesity and atherogenic dyslipidemia can explain much of the morbidity associated with metabolic syndrome. Both are associated with insulin resistance in a bidirectional cause-and-effect relationship. Factor analysis indicates that hypertension constitutes a separate factor independent of insulin resistance (Meigs, 1997; Hanley, 2002).
  
• Adipokines have been linked to obesity-associated hypertension (Engeli, 2002).
  
• A clustering of metabolic defects caused by a mutation in mitochondrial tRNA was recently reported in a kindred with hypomagnesemia associated with hypertension and hypercholesterolemia (Wilson, 2004).
  
• Interestingly, according to 2 reports, a relatively reduced risk of diabetes and myocardial infarction exists when alanine is substituted for proline at codon 12 in the peroxisome proliferator-activated receptor-gamma-2 gene (PPARG2) (Altshuler, 2000; Ridker, 2003).
  
• Psychological stress and attendant hormonal changes, such as hypotestosteronemia, have been implicated (Laaksonen, 2003).
  
• Polymorphisms in the beta2-adrenergic receptor gene have also been implicated in the pathogenesis of cardiovascular and metabolic phenotypes (Zee et al, 2004).

Cardiovascular disease risk and metabolic syndrome

The NCEP/ATP III panel identified metabolic syndrome as a multicomponent risk factor for CVD. The following recent studies confirm an increased risk for atherosclerotic CVD and type 2 diabetes mellitus:

• The Kuopio Ischemic Heart Disease Risk Factor Study (Lakka, 2002)
  
• The Second National Health and Nutrition Examination Survey (Malik, 2004)
  
• The San Antonio Heart and Framingham Offspring Studies (Meigs, 2003)
  
• The Third National Health and Nutrition Examination Survey (Ninomiya, 2004)
  
• The Botnia Study (Isomaa, 2001)
  
• The Atherosclerosis Risk in Communities Study (McNeill, 2004)
  
• The West of Scotland Coronary Prevention Study (Sattar, 2003)
  
• National Cholesterol Education Program (NCEP)/the San Antonio Heart Study (Hunt, 2004)

At least 3 studies cast doubt on an absolute relationship between CVD risk and metabolic syndrome: the Casale Monferrato Study (Bruno, 2004), the Strong Heart Study (Resnick, 2003), and the Atherosclerosis Risk in Communities (ARIC) Study (McNeill, 2005).

These studies were unable to show a relationship that could not be explained either by the individual components or the Framingham Risk Score. Cardiorespiratory fitness has been reported to have a major impact, largely explaining the all-cause and CVD mortality rates in metabolic syndrome and obesity (Katzmarzyk, 2005). Interestingly, cardiovascular risk factors emerge after artificial selection for low aerobic capacity. The decrease in aerobic capacity was associated with a decrease in the amounts of transcription factors required for mitochondrial biogenesis and the amounts of oxidative enzymes in the skeletal muscle (Wisloff, 2005).

Treatment of metabolic syndrome

No algorithms currently exist for treatment of metabolic syndrome. Current recommendations and guidelines emphasize treating individual abnormalities and stressing weight reduction in individuals who are overweight or obese (Hill, 2003; Sattar, 2003). In 2003, Zimmet, Shaw, and Alberti provided a realistic perspective on preventing diabetes and dysmetabolic syndrome, and Wong et al examined the potential effects of optimizing lipid (LDL, HDL) and blood pressure control and demonstrated a likelihood of preventing coronary events by 46.2% in men and 38.1% in women with metabolic syndrome. Currently available lipid-lowering statins appear to be very effective (Deedwania, 2004).

The targets should probably be no less than those recommended for patients with type 2 diabetes mellitus. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers should be used as first-line antihypertensive agents, and daily aspirin should be recommended unless clear contraindications exist. Diet and exercise remain the main cornerstones of treatment, along with smoking cessation. Although thiazolidinediones (insulin sensitizers) appear to be a logical and practical choice, no data on cardiovascular outcomes are currently available.

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