Cholesterol levels increase with age. Total cholesterol increases, on the average, more than 2 mg/dL per year during early adulthood and continues increasing but at a lesser rate until age 65 years, after which it declines slightly. Men 45 years or older and women aged 55 years or older are considered to have age as a risk factor for CHD.

Men have higher total cholesterol levels than women until age 50 years and an approximately twofold higher risk of developing CHD. Women carry a higher proportion of cholesterol in the form of HDL cholesterol (primarily HDL₂). At the onset of menopause, women exhibit an increase in cholesterol and an increased risk of CHD. Hormone replacement is no longer believed to be protective for CHD. As women move into their mid-60s and beyond, their risk of developing CHD approaches that of men of the same age.

Primary lipid disorders arising from a monogenic (single gene) abnormality account for only a small fraction of patients with hyperlipidemia. These relatively uncommon genetic disorders are, however, frequently responsible for the most severe hyperlipidemias. These are, in turn, associated with the most aggressive forms of coronary artery disease. Because these disorders are more likely to affect the immediate relatives of an affected patient than are complex polygenic conditions, family screening should be performed in the relatives of patients suspected of harboring these genetic mutations.

Polygenic states with multiple markers contributing to risk appear to be much more common. A genotype score of 9 single nucleotide polymorphisms that contribute to abnormalities in LDL or HDL cholesterol levels was found to be an independent risk factor for CHD events.

A diet high in saturated fatty acids raises total and LDL cholesterol. Total and LDL cholesterol are also increased by dietary cholesterol, but the effect is smaller than that of saturated fatty acids. Caloric excess resulting in obesity has more of an effect on triglycerides than on cholesterol and can contribute to insulin resistance, which is associated with CHD. Alcohol has little effect on total cholesterol levels, but it can cause an acute rise in triglycerides among people with hypertriglyceridemia. Moderate alcohol ingestion also causes a rise in HDL levels.

Antihypertensive agents that adversely affect lipid levels can compromise the effort to reduce CHD risk. Thiazides may increase LDL cholesterol, at least temporarily, when taken in full doses. The effect is hypothesized to account for the shortfall in reduction in mortality found among hypertensive patients treated with thiazides (see Chapter 26). Beta-blockers may cause modest reductions in HDL cholesterol and increase serum triglyceride levels. Exogenous estrogens increase HDL₂ and can cause extreme triglyceride increases in patients with preexisting, moderate hypertriglyceridemia. Corticosteroids and HIV protease inhibitors can also dramatically elevate serum lipids.

Activity, weight loss, and smoking cessation increase HDL cholesterol. Diabetics commonly have a lipid disorder characterized by high triglycerides and low HDL cholesterol levels. Hypothyroidism, nephrotic syndrome, and obstructive liver disease are important causes of secondary hypercholesterolemia, characterized by increases in total and LDL cholesterol levels and, not infrequently, increased triglycerides as well.

A family history of CHD is considered a risk factor when it occurs in a first-degree relative in men less than the age of 55 years and in women less than the age of 65 years.

Both epidemiologic and prospective studies have demonstrated that hypercholesterolemia is an independent risk factor for the development of CHD. Coronary risk increases curvilinearly with increasing total cholesterol levels, even within the “normal” range. Over the usually encountered range of total cholesterol values (180 to 300 mg/dL), risk increases by an average of four- to fivefold. Risk begins to accelerate more sharply when the total cholesterol level exceeds 240 mg/dL. LDL is, in the majority of cases, the underlying cause of elevated levels of total cholesterol and is most closely linked with the development of CHD.

The positive relationship between total cholesterol and CHD risk derives mainly from the atherogenic LDL cholesterol component. Because the LDL cholesterol accounts for about two thirds of the total cholesterol in the typical patient, the total cholesterol concentration is generally used as a proxy for LDL cholesterol. Current guidelines define LDL levels of less than 100 mg/dL as optimal. Treatment goals for LDL depend on the presence of coronary disease or other risk factors such as diabetes, smoking, hypertension, family history of coronary disease, peripheral vascular disease, active carotid disease, abdominal aortic aneurysm, low HDL levels, or increased age. LDL serum levels in excess of 160 mg/dL are associated with significant increases in CHD risk.

Small, dense LDL particles are considered to be more atherogenic that larger forms of LDL. Small, dense forms are associated with high triglyceride levels. From a clinical standpoint, routine screening for LDL size is not indicated.

Lp(a) is a modified form of LDL. It consists of an LDL particle attached to a protein of variable size, called “apoprotein little a.” It appears in most (but not all) studies to contribute independently to CHD risk. Serum levels are genetically determined. Lp(a) is believed to be thrombogenic by competing with the binding of plasminogen and promoting clot formation. The absence of any studies demonstrating that a reduction in Lp(a) levels results in improved clinical outcomes has kept this marker from being routinely assayed. Niacin has been shown to reduce Lp(a), and thus it may be useful to measure Lp(a) levels in patients with intermediate CHD risk if an elevated level would tip the scale in favor of using niacin to treat the patient’s other lipid abnormalities.

The relation of the HDL cholesterol level to CHD risk is an inverse one. HDL cholesterol exerts a protective effect that is at least as strong as the atherogenic effect of LDL. For every 10-mg/dL increment in HDL cholesterol concentration, there is a 50% decrease in coronary risk. An HDL cholesterol level lower than 40 mg/dL has come to be recognized as a major independent risk factor for CHD. A level in excess of 60 mg/dL is considered a “negative” risk factor (see Chapter 27). A low HDL cholesterol increases CHD risk across the full range of total and LDL cholesterol concentrations, with recent data indicating that HDL is a significant inverse predictor of cardiovascular events even in patients with LDL values less than 70 mg/dL. Conversely, it is possible for a person with elevated total cholesterol to be at low risk for CHD by virtue of having a very high HDL cholesterol (60 to 100 mg/dL). The determination of a total-to-HDL cholesterol ratio helps to distinguish such low-risk individuals from others with elevated total cholesterol. The Framingham Study showed that the ratio was a strong predictor of risk. A ratio of 5 approximates the average or standard risk, with ratios of 10 and 20 denoting double and triple the risk. A ratio of 4.5 or less is considered desirable.

HDL particles are functionally heterogeneous and vary in size, density, and composition. Inflammation can reduce
protective effects by modifying the major apolipoprotein within HDL, apolipoprotein A-I, rendering it proinflammatory and atherogenic. In addition, apolipoprotein A-II, another component of HDL, has been shown to be proatherogenic in animal models. Subcomponents (e.g., apolipoprotein A-1) are more difficult and expensive to measure, and their added contribution to the estimation of CHD risk does not yet appear to warrant their additional cost.

The contribution of hypertriglyceridemia to cardiovascular risk was, for a long time, controversial. In univariate analysis, it is consistently associated with increased CHD risk, but in multivariate analysis, this association goes away when the contribution of HDL cholesterol is accounted for. Because high serum levels of triglycerides causally contribute to lowered HDL levels, however, one cannot conclude that hypertriglyceridemia is unimportant. The latest National Cholesterol Education Program (NCEP) guidelines place increased emphasis on measuring and treating hypertriglyceridemia. This emphasis may be particularly important when the hypertriglyceridemia is accompanied by a large waist circumference (>40 inches for men and >35 inches for women). This combination, often associated with the metabolic syndrome, may be a better marker of insulin resistance and the risk of coronary disease than the triglyceride level alone.

The metabolic syndrome increases the risk of coronary artery disease at any level of LDL. It is a metabolic disorder associated with obesity and insulin resistance. The diagnosis of metabolic syndrome is made when individuals have three or more of the following clinical characteristics: abdominal obesity (waist circumference in men of >40 inches and in women of >35 inches), triglycerides of greater than 150 mg/dL, low levels of HDL cholesterol (men <40 mg/dL, women <50 mg/dL), blood pressure of greater than 135/85 mm Hg, and a fasting glucose of greater than 110. This syndrome is associated with obesity and inactivity.

For young men (younger than age 35 years) and premenopausal women, elevated total and LDL cholesterol levels increase the long-term risk of developing CHD. However, short-term CHD risk among those with even moderately high LDL cholesterol levels (160 to 220 mg/dL) but no other CHD risk factors remains relatively low. On the other hand, the presence of additional CHD risk factors, particularly diabetes or family history of early CHD, appears to increase short-term risk, as does the development of a very high LDL cholesterol level (220 mg/dL).

CHD risk due to hypercholesterolemia in the elderly is also incompletely defined. The relative risk of CHD observed in men 60 to 79 years of age with marked hypercholesterolemia is about 1.5. This relative risk is lower than that in comparably hypercholesterolemic patients younger than 60 years of age. The difference is believed to be related to the high prevalence of already established CHD, hypertension, and diabetes in this age group. Among hyperlipidemic elderly patients with established CHD, the relative risk of a new coronary event is just as high as in younger patients. Because the elderly have the highest rates of coronary disease in the population (85% of individuals dying of CHD are 65 years or older), the aggressiveness with which to screen older individuals is a topic of debate in the prevention field.

Decreases in the intake of cholesterol and saturated fat in controlled settings can reduce total and LDL cholesterol levels by 30% or more, but this magnitude of reduction is rarely achieved in clinical practice. LDL cholesterol levels are lowered by an average of 10% when reasonably intensive diets are used in the outpatient setting. Dietary measures may also produce a small (˜5%) reduction in HDL cholesterol concentration, although the overall total-to-HDL ratio typically still improves. Weight loss (if the patient is obese), aerobic exercise, and smoking cessation can raise the HDL cholesterol level and facilitate the dietary lowering of LDL cholesterol. These measures also reduce CHD risk by decreasing blood pressure and glucose intolerance. Caloric and fat restrictions and control of diabetes lower triglyceride levels, an effect enhanced by the restriction or elimination of alcohol. In patients with moderate to severe hypertriglyceridemia, even modest alcohol intake can be a significant factor. The CHD risk tradeoff between alcohol’s HDLand triglyceride-raising properties has not been well-studied. Reductions in CHD risk follow from cholesterol lowering and amelioration of other risk factors.