12. high triglycerides, low hdl and coronary risk

Atherosclerosis 146 Suppl. 1 (1999) S16

12. High triglycerides, low HDL and coronary risk

James ShepherdInstitute of Biochemistry, Royal Infirmary, Glasgow G4 OSF, UK

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The product of the lipolytic cascade, LDL, has beenrecognized for some years to be structurally heteroge-neous and more recently has been found to exist in theplasma of all individuals as a group of discrete, butoverlapping, particle populations or subfractions. Thesesubfractions have traditionally been separated on thebasis of hydrated density and particle size, using densitygradient ultrcentrifugation and gradient gel elec-trophoresis, respectively, and are defined as LDL-I–LDL-IIV. Gofman et al. in 1950 were the first todemonstrate that LDL is heterogeneous in the analyti-cal ultracentrifuge and to suggest that certain subfrac-tions may be more closely associated with CHD thanothers. These early observations have now been sub-stantiated in a series of cross-sectional studies that haverevealed a constellation of abnormalities in LDL struc-ture and concentration that lead to increased risk ofCHD. A predominance of small, dense LDL in combi-nation with a raised triglyceride level and low levels ofHDL has been associated with a threefold increase inrisk of myocardial infarction. These changes have beencollectively described as an atherogenic lipoprotein phe-notype (ALP). There is strong evidence to suggest thatALP, and more specifically the distribution of LDLsubfractions, is influenced by a major gene. However,

the profile is also subject to the environmental effects ofdiet and drugs. The effect of fibrate therapy in hyper-triglyceridaemia, described above, is to correct an ini-tially low plasma LDL level. This change in the totalLDL mass is accompanied by significant compositionalchanges. The particles become enriched in cholesterylester and relatively depleted in phospholipid andtriglyceride, thereby increasing the lipid core to coatratio. This change in lipid composition is consistentwith an increase in LDL particle size, away from thesmall, dense LDL characteristic of hypertri-glyceridaemia.

In patients who are normotriglyceridaemic, yet hy-percholesterolaemic, fibrate therapy lowers the totalLDL mass. This is predominantly due to a significantdecrease in LDL subfraction of mid-density (LDL-II).The changes in the LDL subfractions of lower density(LDL-I) and higher density (LDL-III) are inverselyrelated, the most consistent finding being an increase inLDL-I and a decrease in LDL-III.

Thus, in both hyperlipidaemic states fibrate therapyinduces a redistribution of LDL density and size to-wards lighter and larger particles: an LDL subfractionprofile that has been associated with reduced coronaryrisk.

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