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Introduction: Familial combined hyperlipidemia (FCH) is characterized by several phenotypes, including an atherogenic lipoprotein profile, low grade inflammation, visceral obesity, insulin resistance, and hypertension. In this study, we investigated which of the clinical and biochemical characteristics of FCH patients contributes most to their increased risk of cardiovascular disease, by determining the association of a broad variety cardiovascular risk factors with the intima media thickness (IMT) of the common carotid artery (CCA) in 94 FCH patients and 216 non-affected relatives., Methods: All subjects filled out a questionnaire about their smoking and drinking habits, medical history and medication use, and venous blood was drawn in the fasting state after discontinuation of lipid lowering medication (if used). IMT of the far wall and near wall of both CCAs was measured by high-resolution B-mode ultrasonography., Results: The mean IMT in FCH patients (adjusted for age and gender) was 33 microm thicker when compared to their non-affected relatives (p=0.006). In multivariate analysis, the waist-to-hip ratio, the apoB concentration and the pulse pressure were significant and independent predictors of IMT in both FCH patients and their normolipidemic relatives. The most important independent predictor of IMT in FCH patients however, was the VLDL-c/TG ratio, explaining 32.8% of the variation in age- and gender-adjusted IMT, whereas this ratio was not an independent predictor of IMT at all in their unaffected relatives., Conclusion: Abdominal obesity, a higher blood pressure and dyslipidemia characterised by both an increased number of atherogenic particles and the presence of highly atherogenic remnant lipoproteins play an important role in the development of cardiovascular disease in FCH-patients.

We compared in 506 members of families with familial combined hyperlipidaemia (FCH), two approaches to selecting subjects with an apparent increased risk for coronary heart disease: assay of apolipoprotein (apo) B only versus measurement of plasma lipids and lipoproteins. When comparing both criteria, there was an overlap of 81.2% at apo B levels < or = 1250 mg/l and of 86.9% at apo B levels > 1250 mg/l. At apo B < or = 1250 mg/l all subjects were normolipidemic. However, 18.8% of these subjects had sub-normal HDL-cholesterol concentrations (< 0.9 mmol/l) but were not considered to have an increased risk because of very low LDL-cholesterol levels (< 2.5 mmol/l). At apo B concentrations > 1250 mg/l we observed a group with normal plasma lipid levels (13.1%). In this group, defined as normolipidemic hyperapobetalipoproteinemia, and considered to have an increased risk for coronary heart disease, apo B determination was thus most informative. The selection of the subgroup with 'normolipidemic hyperapobetalipoproteinemia' on the basis of the conventional approach could be refined using a cut off limit for plasma triglycerides < 1.5 mmol/l. This limit distinguished optimally between an atherogenic very dense LDL pattern versus a dense and buoyant pattern. Thus, based on the results of our study, the determination of apo B appeared to be, if not superior, at least as effective as the conventional lipid and lipoprotein parameters in classifying subjects at increased risk for coronary heart disease.

We evaluated in a double-blind randomized trial with a double-dummy design in 28 patients with primary hypertriglyceridemia, the effect of gemfibrozil (1200 mg/day) versus Omacor (4 g/day), a drug containing the n-3 fatty acids eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), on lipid and lipoprotein levels, low density lipoprotein (LDL) subfraction profile and LDL oxidizability. Both Omacor and gemfibrozil therapy resulted in a similar significant decrease in serum triglyceride (TG), very low density lipoprotein (VLDL) triglyceride and VLDL cholesterol concentrations and an increase in high density lipoprotein (HDL) and LDL cholesterol concentrations. The increase in LDL cholesterol was due to a significant increase in cholesterol content of the relatively buoyant LDL subfractions LDL1, LDL2 and LDL3, whereas the relative contribution of the dense LDL subfractions LDL4 and LDL5 to total LDL tended to decrease. So, both therapies resulted in a more buoyant LDL subfraction profile, reflected by a significant increase of the value of parameter K (+10.3% on Omacor vs. +26.5% on gemfibrozil therapy, gemfibrozil vs Omacor P>0.05). Cu(2+)-induced oxidation of LDL was measured by continuous monitoring of conjugated dienes. After 12 weeks of Omacor treatment LDL appeared more prone to oxidative modification in vitro than LDL after gemfibrozil treatment, as measured by the significantly decreased lag time, preceding the onset of the lipid peroxidation. In both groups the rate of oxidation did not change with therapy. The amount of dienes formed during oxidation increased significantly on Omacor treatment, but not on gemfibrozil treatment. Plasma thiobarbituric acid reactive substances were higher after Omacor and lower after gemfibrozil treatment, although not significantly. We conclude that both Omacor and gemfibrozil have favorable effects on lipid and lipoprotein concentrations and the LDL subfraction profile. However, Omacor increased the susceptibility of LDL to oxidation, whereas gemfibrozil did not affect the resistance of LDL to oxidative modification in vitro. The clinical relevance of these changes remains to be established in the light of other postulated favorable effects of n-3 fatty acids on the course of cardiovascular disease.

Familial combined hyperlipidemia (FCHL) is a heritable lipid disorder characterized by multiple lipoprotein phenotypes within a single family. Previously, we have shown an increased incidence of mutations in the LPL gene which was associated with elevated levels of very low density lipoprotein (VLDL) and decreased levels of high density lipoprotein among the families studied. Now, we report the results of our study on the hepatic lipase gene. We found the HL V73M variant to be present in four FCHL families. By means of a pedigree-based maximum log-likelihood method we analyzed the effect of this variant on the lipid levels in these families. Carriers of the HL V73M variant revealed significantly higher levels of total cholesterol (P < 0.01) and apoB (P <0.01). These findings show that the HL V73M mutant explains another part of the variability in the phenotype observed among FCHL family members, compared with mutations in the LPL gene. Family analysis shows that in these FCHL families, carriers of mutations in the LPL or HL genes have an increased risk for FCHL compared with their non-carrier relatives.

Vitamins A and E differ in hydrophobicity. When added to a fat load more or less specific labeling of chylomicrons and their remnants can be expected and this allows to approach the mechanism of postprandial lipemia from a new sight of view. Applied in a study in which 20 patients participated (eight patients with familial dysbetalipoproteinemia (FD), six patients with familial combined hyperlipidemia (FCH) and six controls) we found that vitamin A, no longer paralleled the apo B-48 concentrations from 9 h after a fat load, especially in the remnant fraction with Sf 15-100. Qualitatively, the distribution of vitamin A to the more dense fractions mirrored that of vitamin E, but the latter was more rapid. Both vitamins at the maximum of remnant-accumulation, at 14 h after the fat load, correlated with the cholesterol content of the remnant fraction. For vitamin E there was a similar concentration dependent distribution to all other lipoprotein fractions. The results confirm our view that the lipoprotein mechanism can be regarded as a dynamic system. During regular episodes following the meals, exogenous fat is, like the vitamins, distributed over all endogenously formed lipoproteins. This transfer process results in the formation of beta-VLDL and contributes to the pathogenesis of FCH and FD.

To gain more insight into the accumulation of beta-very low density lipoprotein (beta-VLDL) in familial dysbetalipoproteinemia (FD), we followed the courses of the levels of retinyl palmitate (rp), alpha-tocopherol (alpha-T) and apolipoprotein (apo) B-48 in various lipoprotein fractions for up to 48 h in eight patients with FD and six normolipidemic control subjects after an oral fat load (50 g fat/m2 containing 150000 IU of rp and 5000 IU of alpha-T). Alpha-T was added because of its rapid transfer to other lipoproteins. Fasting apo B-48 concentration in FD was normal to strongly elevated, dependent on the fasting lipid concentrations. 3 h after fat loading, total apo B-48 content did not abnormally increase; while the apo B-100 content in the triglyceride-rich lipoprotein fraction remained stable. The levels of both vitamins increased considerably, especially in the remnant fraction (Sf 15-100), which in due course exclusively contained apo B-100 in most hyperlipidemic patients. This, together with the observation that peaks for rp and alpha-T were observed 3-6 h later than for apo B-48 strongly suggests that both vitamins transfer or diffuse rapidly towards the apo B-100 containing VLDL. RP is thus more a marker for this process, which also comprises chylomicron lipids, than a specific marker for chylomicrons. This process, first described here, appears decisive in the pathogenesis of FD.

Familial combined hyperlipidemia (FCHL) is a frequent cause of premature coronary artery disease. Affected family members are characterized by different combinations of elevated cholesterol and/or triglyceride levels. A reduction in lipoprotein lipase (LPL) activity has been observed in a subgroup of FCHL patients. Recently, we have demonstrated an increased frequency of mutations in the LPL gene in Dutch FCHL patients compared to normolipidemic controls. In the present study, we have applied a pedigree-based maximum likelihood method to study the effect of LPL mutations on the phenotypic expression of FCHL in families. In 40 FCHL probandi, three different previously reported mutations in the LPL gene were identified resulting in amino acid changes, D9N, N291S, and S447X. The D9N mutation in exon 2 appeared to be in strong linkage disequilibrium with a T-->G substitution at position -93 in the promoter region of the LPL gene. We present data that the -93T-->G/D9N haplotype is associated with significantly higher levels of LDL and VLDL cholesterol, and VLDL triglycerides. Interestingly, the effect was only observed in male carriers. In line with our previous observations, these results further sustain that the LPL gene is a susceptibility gene for dyslipidemia which explains part of the variability in the phenotype observed among FCHL family members.

The impact of apo E polymorphism on interindividual variation in plasma lipid, lipoprotein concentrations, and LDL subfraction profiles was studied in 201 well-defined patients (88 men and 103 women) with familial combined hyperlipidemia (FCH). When corrected for the concomitant influences of age, gender and obesity, the allelic variation in the apo E gene was shown to explain a statistically significant portion of the variability in lipid and (apo)lipoprotein concentrations. Carriers of the apo epsilon 2 allele exhibited a substantially higher plasma triglyceride concentration and a lower low density lipoprotein (LDL) cholesterol level, while subjects with the apo epsilon 4 allele had significant higher total plasma cholesterol and LDL cholesterol levels. In line with this observation, our FCH population was characterized by an over-representation of the apo E4 allele as compared with a Dutch standard population (chi 2 = 55.2, P < 0.0001). The contribution of apo E polymorphism to trait variability was different between sexes for plasma triglyceride, VLDL cholesterol, VLDL triglycerides, and high density lipoprotein (HDL) cholesterol levels. Apo E polymorphism had no impact on chemical composition of VLDL; for LDL particles the apo epsilon 2 allele was associated with a lower cholesterol to protein (C/P) ratio, whereas the opposite was true for the apo epsilon 4 allele. Despite the demonstrated impact of apo E polymorphism on plasma lipids and LDL chemical composition, in all phenotypic groups a dense LDL subfraction profile predominated. Thus, apo E polymorphism contributes to the lipid phenotypic expression in FCH, whereas further evidence was obtained that a dense LDL subfraction profile is an integral feature of FCH.

Familial combined hyperlipidaemia (FCHL) is one of the major genetic causes of coronary heart disease (CHD) and is characterised by elevated levels of plasma cholesterol and/or triglycerides in individuals within a single family. Decreased lipoprotein lipase (LPL) activity has been found in some cases of FCHL. A recent study revealed a common mutation in the LPL gene, LPL(Asn291-->Ser), with a frequency of 9.3% in Dutch FCHL patients (Reymer et al,. Circulation, 90 (1994) I-998). This mutation was found in 3 out of 17 FCHL families. Extensive family studies were subsequently performed to determine the effect of this mutation on the phenotypic expression of FCHL. Using a pedigree-based maximum likelihood estimate, we demonstrated that the LPL(Asn291-->Ser) mutation significantly affects the levels of plasma and very low density lipoprotein (VLDL) triglycerides (2.03 +/- 0.21 vs. 1.14 +/- 0.13 and 1.21 +/- 0.16 vs. 0.62 +/- 0.09 mmol/l, carriers and non-carriers, respectively) and VLDL- and high density lipoprotein (HDL) cholesterol (0.83 +/- 0.10 vs. 0.38 +/- 0.06 and 1.02 +/- 0.08 vs. 1.29 +/- 0.05 mmol l, carriers and non-carriers, respectively), but not those of plasma and low density lipoprotein (LDL) cholesterol. These findings indicate that the LPL(Asn291-->Ser) mutation is associated with elevated lipid levels, indicating it may be one of the genetic factors predisposing to FCHL in the families studied.