Effect of Simvastatin on markers of triglyceride-rich lipoproteins in familial hypercholesterolaemia.
BACKGROUND
We have previously shown elevated fasting plasma concentrations of intestinal remnants, as reflected by apolipoprotein (apo) B-48 and remnant-like particle-cholesterol (RLP-C) in patients with heterozygous familial hypercholesterolaemia (FH). We now investigate the effect of an HMG-CoA reductase inhibitor (simvastatin) on chylomicron remnant metabolism using the measurement of fasting apoB-48 and RLP-C in FH patients after long- and short-term simvastatin therapy and after a wash-out period. We also piloted the response of a breath test, involving the measurement of the fractional catabolic rate (FCR) of an intravenously injected chylomicron remnant-like emulsion labeled with cholesteryl (13)C-oleate.


METHODS
Fifteen FH patients were studied after > 6 months 40 mg day(-1) simvastatin treatment (long-term), a wash-out period (4 weeks), and 4 weeks of simvastatin treatment (short-term). Apolipoprotein B-48 was determined by SDS-PAGE and Western blotting/enhanced chemiluminescence and RLP-C by an immunoseparation assay. The FCR of the chylomicron remnant-like emulsion was determined from the appearance of (13)CO(2) in the breath and by multicompartmental mathematical modelling.


RESULTS
Both long- and short-term treatment with simvastatin were associated with decreases in the plasma concentration of apoB-48 (P < 0.05) and RLP-C (P < 0.001), but there was no significant change in the FCR of the emulsion.


CONCLUSIONS
We suggest that long- and short-term treatments with simvastatin have comparable effects in decreasing the plasma concentration of triglyceride-rich remnants in heterozygous FH, as measured by fasting apoB-48 and RLP-C. The mechanisms for this may involve decreased production of hepatic and possibly intestinal lipoproteins, and/or up-regulation of hepatic receptor clearance pathways, but these changes are apparently not associated with a change in remnant clearance as measured kinetically by the (13)CO(2) breath test.
Dane-Stewart
C A
CA
University of Western Australia, Australia.
Watts
G F
GF
Mamo
J C L
JC
Barrett
P H R
PH
Martins
I J
IJ
Dimmitt
S B
SB
Redgrave
T G
TG
D053283:Apolipoprotein B-48; D001055:Apolipoproteins B / Q000032:analysis; D015415:Biomarkers / Q000097:blood; D001944:Breath Tests; D002247:Carbon Isotopes; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D002914:Chylomicrons / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D008074:Lipoproteins / Q000097:blood*; D008297:Male; D008875:Middle Aged; D019821:Simvastatin / Q000627:therapeutic use*; D014280:Triglycerides / Q000097:blood
D053283:Apolipoprotein B-48; D001055:Apolipoproteins B; D015415:Biomarkers; D002247:Carbon Isotopes; D008078:Cholesterol, LDL; D002914:Chylomicrons; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008074:Lipoproteins; D014280:Triglycerides; C112017:remnant-like particle cholesterol; D002784:Cholesterol; D019821:Simvastatin