The cardiovascular dysmetabolic syndrome

Abstract

Aclustering of metabolic abnormalities associated with cardiovascular disease has been recognized since at least 1988. This clustering has been given many names including Syndrome X, The Deadly Quartet, and The Insulin Resistance Syndrome. For various reasons each of these names is unsatisfactory. The Western Working Group believes that cardiovascular dysmetabolic syndrome (CDS) is the name that best describes this group of abnormalities, because it emphasizes the cardiovascular consequences of these abnormalities, recognizes that they are distinguishable abnormalities, and indicates that any given patient may have some or all of the components of the syndrome. The CDS is summarized in Table 1. The mnemonic D-R-O-P stands for Dyslipidemia, insulin Resistance, Obesity, and high blood Pressure. Other abnormalities that may be associated include elevated serum uric acid and elevated plasminogen activator inhibitor-1 (PAI-1) levels. Insulin resistance is thought to be central to the metabolic abnormalities, but all of the mechanisms are not established and other etiologies are possible. A diagnosis of CDS requires the presence of criteria for at least 2 of the first 3 components (dyslipidemia, insulin resistance, and obesity). Any component is a risk factor for macrovascular (coronary, cerebral, or peripheral vascular) disease. Additional components confer additional risk, although some, such as diabetes mellitus, confer more risk than others. These risk factors are in addition to, but not necessarily completely independent of, other traditional risk factors, such as established vascular disease, smoking, age, gender, elevated LDL cholesterol, sedentary lifestyle, and positive family history of vascular disease. All risk factors do not convey equal risk of atherosclerotic cardiovascular disease. Existing vascular disease increases risk of a subsequent event 5-fold compared to a patient without pre-existing vascular disease. Diabetes mellitus increases the risk of macrovascular disease 2-fold in men and 4 –5-fold in women. Thus, women with diabetes lose the protective effect of their gender and are at equally high risk of coronary artery disease (CAD) as men of the same age with the same additional risk factors. Hyperinsulinemia has been shown to be associated with CAD in multiple studies in nondiabetic men, but most studies in women have not shown a significant relationship. Recently, the Atherosclerosis Risk in Communities study has shown a significant relationship between plasma insulin levels and CAD in women. The relationship between CAD risk and increased plasma insulin levels is stronger in younger compared to older individuals. Whether hyperinsulinemia is a marker for insulin resistance and/or causative of atherosclerosis is unclear. Insulin resistance (which is harder to document than frank diabetes mellitus) is more highly correlated with atherosclerotic cardiovascular disease than is elevated insulin, per se. This may be because insulin levels are affected by many factors and elevated plasma insulin is only a surrogate for insulin resistance, and/or because insulin resistance impairs insulin-dependent production of nitric oxide (NO), which is anti-atherogenic, without affecting insulin-dependent vascular smooth muscle cell growth and migration, which are pro-atherogenic. Insulin resistance, rather than hyperglycemia, appears to be the primary factor in endothelial dysfunction in type 2 diabetes. Furthermore, insulin potentiates angiotensin II–stimulated production of PAI-1, which may contribute to a prothrombotic effect. Adequate studies are lacking regarding whether different insulin regimens—and specifically the 4 classes of oral hypoglycemic agents— have different effects on morbidity and mortality due to cardiovascular disease. Insulin resistance is difficult to detect clinically, although the extreme of type 2 diabetes mellitus is well defined. Fasting plasma glucose $110 mg/dL identifies persons who have insulin resistance. Diabetes mellitus affects approximately 6% of the US population, yet only 50% of those individuals have been diagnosed. These patients have predominantly type 2 diabetes mellitus. Significant sequelae often develop prior to diagnosis; at the time of diagnosis of type 2 diabetes, 20% of patients have retinopathy, 8% have nephropathy, and 9% have neuropathy. In addition to these microvascular complications, the prevalence of macrovascular complications is similar to that in diagnosed type 2 diabetes. The new classification promulgated by the American Diabetes Association (ADA) divides diabetes mellitus into type 1 (absolute insulin deficiency) and type 2 (insulin resistance with inadequate compensatory insulin secretory response), as well as gestational diabetes and From the Departments of Medicine and Pharmacology, University of Arizona College of Medicine, Tucson, Arizona; Cardiology Division, Department of Medicine, University of California, San Francisco, San Francisco, California; Stanford University Medical Center, Palo Alto, California. Requests for reprints should be addressed to Timothy C. Fagan, MD, University Health Care at Ventana Vista, 5620 North Kolb Road, Suite 166, Tucson, Arizona 85750.