High Density Lipoprotein Cholesterol and Coronary Heart Disease Risk

In contrast to the elevated CHD risk associated with higher LDLc levels, several epidemiological studies have demonstrated an inverse relationship between serum HDLc levels and the incidence of ischemic heart disease in both middle-aged males and the elderly.16 In the Framingham cohort,24 a higher prevalence (19%) of heart disease occurred in subjects due solely to low (<35 mgdL_ 1) HDLc compared to the prevalence of disease (12%) in those who only had elevated (>130mgdL_ 1) LDLc. Thus, low levels of HDLc represent a significant independent risk factor in CHD irrespective of whether patients have elevated LDLc.26 A risk prediction model developed from the Framingham cohort showed that a nearly 50% higher cardiovascular risk was associated with male patients having HDLc levels below 35 mgdL_ 1 compared with those in the normal range (35-59 mgdL_ 1). An even higher (twofold) associated risk was observed in females with HDLc below 35 mgdL_ 1. In contrast, a significantly reduced risk (0.61 versus 1.00) was present in both males and females having HDLc levels above 60 mgdL_ 1.29 Elevated HDLc levels ( > 60 mgdL_ 1) in both males and females reduced plaque growth in patients with preexisting lesions, and were shown to be protective in atherosclerotic plaque progression.

These atheroprotective effects of HDL have been primarily attributed to apoA-I. Humans with genetic deficiencies in apoA-I have very low levels of plasma HDL and exhibit premature CHD.16 Infusion or overexpression of apoA-I in animals produced profound reductions in atherosclerotic lesions.16 Human subjects have been identified with hyperalphalipoproteinemia, i.e., markedly elevated HDLc, as much as three- to sixfold higher than normal. The elevated HDLc in these subjects has been attributed to CETP deficiency or genetic CETP defects that produce lower CETP plasma levels and/or impaired CETP activity.16 The Honolulu Heart Study followed more than 3000 elderly Japanese-American males with CETP deficiency arising from two different CETP gene mutations and found that the relationship between CETP deficiency and CHD risk was complex and possibly dependent upon the accompanying HDLc and TG levels. The prevalence of disease was higher in males with CETP gene mutations (21%) than in subjects without mutations (16%), even though subjects with mutations had reduced CETP levels and an overall higher average of HDLc. However, those subjects with HDLc levels greater than 60mgdL_ 1 had a significantly reduced and near-normal cardiovascular risk.30

HDLc is now recognized as one of the best predictors of cardiovascular risk in females of all ages and in males after middle age.31 The National Cholesterol Education Panel (NCEP) has recently raised the threshold for treatment intervention in those coronary artery disease patients at risk because of low HDLc levels to include subjects having HDLc below 40mgdL_ 1.26 In these patients, it is still uncertain to what extent HDLc must be raised to produce a cardiovascular benefit, but elevations of 50% or more may be required.

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