The link between elevated plasma total cholesterol levels, high LDLc, and increased CHD risk has been known from epidemiological studies since the early 1980s. The Framingham Study followed over 5000 males and females, monitoring plasma lipid levels and the incidence of MI. In this cohort, subjects with elevated serum cholesterol ( >275 mgdL_ 1) had more adverse events whether they were healthy or already had CHD. The prevalence of plasma cholesterol levels above 240 mgdL_ 1 in subjects who experienced an MI was 35-52% in males and 66% in females.24 LDLc levels in this CHD subpopulation were well above 100mgdL_ 1 and were most prevalent at 160mgdL_ 1 Subjects who experienced an MI and had high plasma cholesterol levels were at increased risk for another MI or death from either CHD or other causes.
Similarly, the Multiple Risk Factor Intervention Trial (MRFIT) monitored 300000 middle-aged males. Using a comparative baseline plasma cholesterol of 200 mgdL_ 1, subjects in this study having total cholesterol of 250 mgdL_ 1 had a twofold increased risk of death from CHD, while those with values of 300 mgdL_ 1 had a threefold higher risk. The Atherosclerosis Risk in Communities (ARIC) Study followed over 12 000 males and females who were free of CHD and monitored their incidence of coronary events over a 10-year period. The lowest incidence of events occurred in those subjects with the lowest LDLc levels (<100mgdL_ 1) in both males and females. An associated 40% increased CHD risk occurred in both males and females for every ~40mgdL_ 1 increase in LDLc. Based upon these and other studies, it appeared that cardiovascular risk increased significantly above a certain threshold value of total plasma cholesterol and LDLc.4
Total cholesterol levels in FH patients exceed twice the normal range, and can reach higher than 500mgdL_ 1 in homozygous populations. LDL catabolism is dramatically lowered in these FH subjects due to functional impairment in their LDLr.14 Mutations in the LDLr of FH patients impedes LDL uptake by the liver, and excess LDL accumulates. While only one in a 1 million homozygous FH subjects occur in the general population, they develop severe atherosclerosis in early childhood and have one of the highest incidences of childhood CHD mortality.4
Based upon these and other studies, cholesterol reduction treatment strategies were initiated that sought to lower total plasma cholesterol below the threshold values of 200mgdL_ 1 and LDLc below 130 mgdL_ 1, particularly in patients having other risk factors. Recently, a more aggressive approach has been recommended by the National
Cholesterol Education Program Adult Treatment Panel following multiple successful outcome trials with lipid-lowering therapies.25,26
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