Hypercholesterolemia and Dyslipidemia

Disorders of cholesterol and lipoprotein metabolism are at the heart of atherosclerosis and coronary artery disease (CAD). CAD, however, is a metabolic disorder that involves a complex interaction between genetic susceptibility and environmental conditions. Despite considerable success in the treatment of hypercholesterolemia, atherosclerosis remains the leading cause of death in most Western countries. Although cholesterol-lowering trials have revealed a 25% to 30% reduction in clinical events, most patients continue to have events even when treated successfully with cholesterol-lowering medications (Fig. 1). This less-than-optimal result is partly because atherosclerosis is a multifactorial disease. Although disorders of lipoprotein metabolism are found in more than 80% of patients with CAD, these disorders are very heterogeneous, and single-drug therapy aimed at one disorder should not be expected to improve the disease status in most patients. Metabolic treatment still requires identification and treatment of patients with high cholesterol levels, but the focus has shifted to identifying high-risk patients in groups previously thought to be low risk, or to identifying disorders coexistent with high cholesterol levels that are not corrected by standard cholesterol-lowering medications (Table 1). The ability to detect high-risk CAD traits, which are often inherited, and to predict response to treatment has substantially improved in the past few years. These improvements allow identification of metabolic subgroups of patients, which can alter risk prediction and response to specific treatments. Sophisticated laboratory methods permit physicians to apply this knowledge to patient care and to enter a new era of CAD risk factor detection and treatment. These advances allow for a more scientific approach than did the previously standard epidemiologic risk factors and routine blood lipid profiles. The current state-of-the-art method of diagnosing and treating lipoprotein disorders has progressed beyond the standard "lipid profile," which includes total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol along with fasting triglyceride levels. Incorporating aspects of the atherogenic lipid profile (ALP), LDL subclass distribution, HDL subclass distribution, apo E isoforms, and lipoprotein (a) provides the interested clinician with the tools to create a more detailed and accurate diagnosis of lipoprotein disorders. Sophisticated laboratory tests are available to clinicians through technology transfer programs, as exemplified by the Lawrence Berkeley National Laboratory/Berkeley HeartLab collaboration, and allow clinicians access to research-quality laboratory tools. This has significant clinical relevance because the presence of these disorders guides treatment specific to the disorder(s). Appropriate treatment is more beneficial in subgroups exhibiting the disorder that the therapy is most likely to correct. A single drug or lifestyle therapy is no longer appropriate for all patients. The treatment must match the disorder.