G. R. Thompson

Relation of serum lipoprotein(a) concentration and apolipoprotein(a) phenotype to coronary heart disease in patients with familial hypercholesterolemia

Familial hypercholesterolemia carries a marked increase in the risk of coronary heart disease (CHD), but there is considerable variation between individuals in susceptibility to CHD. To investigate the possible role of lipoprotein(a) as a risk factor for CHD, we studied the association between serum lipoprotein(a) levels, genetic types of apolipoprotein(a) (which influence lipoprotein(a) levels), and CHD in 115 patients with heterozygous familial hypercholesterolemia. The median lipoprotein(a) level in the 54 patients with CHD was 57 mg per deciliter, which is significantly higher than the corresponding value of 18 mg per deciliter in the 61 patients without CHD. According to discriminant-function analysis, the lipoprotein(a) level was the best discriminator between the two groups (as compared with all other lipid and lipoprotein levels, age, sex, and smoking status). Phenotyping for apolipoprotein(a) was performed in 109 patients. The frequencies of the apolipoprotein(a) phenotypes and alleles differed significantly between the patients with and those without CHD. The allele LpS2, which is associated with high lipoprotein(a) levels, was found more frequently among the patients with CHD (0.33 vs. 0.12). In contrast, the LpS4 allele, which is associated with low lipoprotein(a) levels, was more frequent among those without CHD (0.27 vs. 0.15). We conclude that an elevated level of lipoprotein(a) is a strong risk factor for CHD in patients with familial hypercholesterolemia, and the increase in risk is independent of age, sex, smoking status, and serum levels of total cholesterol, triglyceride, or high-density lipoprotein cholesterol. The higher level of lipoprotein(a) observed in the patients with CHD is the result of genetic influence.

Metabolic basis of hyperapobetalipoproteinemia. Turnover of apolipoprotein B in low density lipoprotein and its precursors and subfractions compared with normal and familial hypercholesterolemia.

The turnover of apolipoprotein B (apo B) in very low density, intermediate density, and low density lipoproteins (VLDL, IDL, and LDL) and in the light and heavy fractions of LDL was determined in seven patients with hyperapobetalipoproteinemia (hyperapo B), six normolipidemic subjects, and five patients with heterozygous familial hypercholesterolemia (FH). After receiving an injection of 125I-VLDL, hyperapo B patients were found to have a higher rate of synthesis of VLDL-apo B than controls (40.1 vs. 21.5 mg/kg per d, P less than 0.05) but a reduced fractional catabolic rate (FCR) (0.230 vs. 0.366/h, P less than 0.01). After receiving an injection of 131I-LDL, hyperapo B patients had higher rates of LDL-apo B synthesis than controls (23.1 vs. 13.0 mg/kg per d, P less than 0.001), as did FH patients (22.7 mg/kg per d). The FCR of LDL was similar in hyperapo B patients and controls (0.386 vs. 0.366/d) but was markedly decreased in FH patients (0.192/d). Most subjects exhibited precursor-product relationships between VLDL and IDL, and all did between IDL and light LDL; an analogous relationship between light and heavy LDL was evident in most hyperapo B patients and controls but not in FH patients. Simultaneous injection of differentially labeled LDL fractions and deconvolution analysis showed increased light LDL synthesis with normal conversion into heavy LDL in hyperapo B, whereas in FH conversion of light LDL was reduced and there was independent synthesis of heavy LDL. These data show that the increased concentration of LDL-apo B in hyperapo B is solely due to increased LDL synthesis, which is secondary to increased VLDL synthesis; in contrast, in FH there is both an increase in synthesis of LDL (which is partly VLDL-independent) and reduced catabolism.

Familial Hypercholesterolaemia Regression Study: a randomised trial of low-density-lipoprotein apheresis

Low-density-lipoprotein (LDL) apheresis has the theoretical advantage over anion-exchange resins and hydroxymethylglutaryl coenzyme A inhibitors of decreasing lipoprotein(a) as well as LDL. To confirm this advantage, patients with heterozygous familial hypercholesterolaemia and coronary artery disease were randomised to receive LDL apheresis fortnightly (with disposable dextran sulphate/cellulose columns) plus simvastatin 40 mg daily, or colestipol 20 g plus simvastatin 40 mg daily. Quantitative coronary angiography was repeated after a mean of 2.1 years in 20 patients undergoing apheresis and in 19 on combination drug therapy. Changes in serum lipoproteins were similar in both groups apart from greater lowering by apheresis of LDL cholesterol (3.2 vs 3.4 mmol/L in drug group, p = 0.03) and lipoprotein(a) (geometric means 14 vs 21 mg/dL, p = 0.03). There were no significant differences in primary angiographic endpoints per patient but lesion-based and segment-based secondary endpoints were biased in favour of the drug group (change in minimum lumen diameter of lesions 0.07 vs -0.004 mm, p = 0.046; change in mean lumen diameter of segments 0.02 vs -0.06 mm, p = 0.01). None of the angiographic changes correlated with lipoprotein(a) concentrations. Per patient changes in % diameter stenosis and minimum lumen diameter in the two groups were as or more favourable than those observed in five published trials that assessed lipid-lowering drug therapy by quantitative coronary angiography. Although LDL apheresis combined with simvastatin was more effective than colestipol plus simvastatin in reducing LDL cholesterol and lipoprotein(a), it was less beneficial in influencing coronary atherosclerosis and should be reserved for patients unresponsive to drugs. Decreasing lipoprotein(a) seems to be unnecessary if LDL cholesterol is reduced to 3.4 mmol/L or less.

Recommendations for the use of LDL apheresis.

Plasma exchange has been shown to increase life-expectancy in homozygous familial hypercholesterolaemia (FH) but increasingly is being replaced by LDL apheresis. Several methods are now available for undertaking this procedure, which lowers LDL cholesterol and Lp(a) efficiently and safely when performed weekly or bi-weekly and causes only slight decreases in HDL cholesterol. Hitherto the main clinical indication has been homozygous FH, including children and pregnant women, but there are limited data showing that LDL apheresis has effects on the progression of cardiovascular disease in FH heterozygotes which are similar to those of maximal lipid-lowering drug therapy. Hence it has the potential to be beneficial in hypercholesterolaemic patients with overt coronary disease who are refractory to or intolerant of drugs. It is therefore recommended that LDL apheresis should be the treatment of choice for: (1) all FH homozygotes from the age of seven onwards unless their serum cholesterol can be reduced by >50% and/or decreased to <or=9mmol/l by drug therapy; (2) individual patients with either heterozygous FH or a bad family history of premature cardiac death whose coronary disease progresses and where LDL cholesterol remains >5.0mmol/l or is decreased by <40% with maximal drug therapy. Apheresis may also occasionally be indicated on a case-by-case basis for patients with lower levels of LDL. (3) LDL apheresis should also be considered for patients with aggressive progressing coronary disease and Lp(a)>60mg/l whose LDL cholesterol remains >3.2mmol/l despite maximal drug therapy.

Triglyceride-lowering effect of marine polyunsaturates in patients with hypertriglyceridemia.

Twenty male patients with primary hypertriglyceridemia were treated for 4 weeks with daily supplements (15 g) of oil, which provided approximately 6 g of polyunsaturated fatty acid (PUFA) either of fish or of vegetable origin. Total plasma cholesterol concentrations were unaffected, but both types of supplement increased high density lipoprotein-3 (HDL3) cholesterol concentrations. The fish, but not the vegetable, oil supplement led to a decrease in plasma triglyceride concentrations. Very low density lipoprotein (VLDL), fatty acid composition, and VLDL triglyceride kinetics were subsequently studied in five patients (four male, one female) before and after 4 weeks of therapy with 15 g of the same fish oil. The fish oil led to increases in the proportion of eicosapentaenoic acid in both the VLDL triglyceride and phospholipid fractions, but the increase was greater in the latter. In contrast, the proportion of docosahexanoic acid was increased only in the VLDL triglycerides. The decrease in plasma triglyceride concentrations that occurred with fish-oil therapy was accompanied by a reduction in the absolute catabolic rate of VLDL triglyceride, implying a concomitant change in synthetic rate; the fractional catabolic rate of VLDL triglyceride was unaltered. It is suggested that polyunsaturated fatty acids of marine origin may be therapeutically useful for hypertriglyceridemia.

Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk

Aims: To determine the relative frequency of mutations in three different genes (low-density lipoprotein receptor (LDLR), APOB, PCSK9), and to examine their effect in development of coronary heart disease (CHD) in patients with clinically defined definite familial hypercholesterolaemia in UK. Patients and methods: 409 patients with familial hypercholesterolaemia patients (158 with CHD) were studied. The LDLR was partially screened by single-strand conformational polymorphism (SSCP) (exons 3, 4, 6–10 and 14) and by using a commercial kit for gross deletions or rearrangements. APOB (p.R3500Q) and PCSK9 (p.D374Y) were detected by specific assays. Coding exons of PCSK9 were screened by SSCP. Results: Mutations were detected in 253 (61.9%) patients: 236 (57.7%) carried LDLR, 10 (2.4%) carried APOB p.Q3500 and 7 (1.7%) PCSK9 p.Y374. No additional mutations were identified in PCSK9. After adjusting for age, sex, smoking and systolic blood pressure, compared to those with no detectable mutation, the odds ratio of having CHD in those with an LDLR mutation was 1.84 (95% CI 1.10 to 3.06), for APOB 3.40 (0.71 to 16.36), and for PCSK9 19.96 (1.88 to 211.5; p = 0.001 overall). The high risk in patients carrying LDLR and PCSK9 p.Y374 was partly explained by their higher pretreatment cholesterol levels (LDLR, PCSK9 and no mutation, 10.29 (1.85), 13.12 and 9.85 (1.90) mmol/l, respectively, p = 0.001). The post-statin treatment lipid profile in PCSK9 p.Y374 carriers was worse than in patients with no identified mutation (LDL-C, 6.77 (1.82) mmol/l v 4.19 (1.26) mmol/l, p = 0.001, HDL-C 1.09 (0.27) mmol/l v 1.36 (0.36) mmol/l, p = 0.03). Conclusions: The higher CHD risk in patients carrying PCSK9 p.Y347 or a detected LDLR mutation supports the usefulness of DNA testing in the diagnosis and management of patients with familial hypercholesterolaemia. Mutations in PCSK9 appear uncommon in patients with familial hypercholesterolaemia in UK.

Paradoxical elevation of LDL apoprotein B levels in hypertriglyceridaemic patients and normal subjects ingesting fish oil

Twenty-three hypertriglyceridaemic patients treated with 15 g/day of a fish oil concentrate (Maxepa) showed the expected reduction in serum triglyceride concentration but levels of LDL apoprotein B (apoB), measured by radial immunodiffusion, increased significantly. Increases in LDL apoB did not correlate with lipoprotein phenotype or changes in serum triglyceride. Studies in eight normal volunteers demonstrated that the effect of fish oil on LDL apoB was not restricted to hypertriglyceridaemic subjects. In view of the evidence that LDL apoB may be a risk factor for coronary heart disease these findings raise questions regarding the use of fish oil in the treatment of hypertriglyceridaemia.

The effect of growth hormone replacement on serum lipids, lipoproteins, apolipoproteins and cholesterol precursors in adult growth hormone deficient patients

OBJECTIVE Adult patients with growth hormone deflciency are thought to be at higher risk of mortallty from cardiovascular disease. We therefore investlgated the effect of recombinant human growth hormone (rhGH) replacement therapy on fasting serum concentrations of IIplds, lipoproteins and cholesterol precursors in adult growth hormone deficient patients.

Assessment of long-term plasma exchange for familial hypercholesterolaemia.

The effectiveness of repeated plasma exchange with 2 to 4 litres of plasma protein fraction as long-term treatment for familial hypercholesterolaemia has been evaluated in six severely affected patients receiving conventional cholesterol lowering treatment. Cell-separator mediated exchange at monthly intervals for one to two years reduced mean serum cholesterol levels from 18.5 mmol/l (715 mg/dl) to 12.4 mmol/l (480 mg/dl) in two female homozygotes but failed to influence xanthomata or prevent a two- to threefold increase in their left ventricular aortic systolic pressure gradients. More effective reduction of mean serum cholesterol levels from 15.7 mmol/l (608 mg/dl) to 8.6 mmol/l (333 mg/dl) in two male homozygotes by plasma exchange at fortnightly intervals for two to three years was accompanied by resolution of xanthomata and by stabilisation of aortocoronary lesions. In two male heterozygotes with angina, coronary angiographic appearances were unaltered or improved after one to two years of thrice-monthly plasma exchange, which reduced mean serum cholesterol levels from 6.4 mmol/l (248 mg/dl) to 4.7 mmol/l (182 mg/dl). We conclude that plasma exchange every one to two weeks, combined with oral nicotinic acid and/or cholestyramine, retards the rate of progression of atheroma in homozygotes and possibly induces regression in heterozygotes.

Simultaneous measurement of apolipoprotein B turnover in very-low- and low-density lipoproteins in familial hypercholesterolaemia

Abstract The rates of synthesis of apolipoprotein B (apoB) in VLDL and LDL were measured simultaneously using [ 125 I]VLDL and [ 131 I]LDL in 5 patients with familial hypercholesterolaemia (FH). In 3 homozygotes the rate of synthesis of VLDL-apoB was in the normal range, whereas LDL-apoB synthesis was higher than normal and exceeded the rate of VLDL-apoB synthesis by 1.5–2-fold. In one Type IIb heterozygote, both VLDL-apoB synthesis and LDL-apoB synthesis were increased, but to an equal extent, whereas in one Type IIa heterozygote VLDL-apoB and LDL-apoB synthetic rates were both normal. These data suggest that an additional pathway for the synthesis of LDL exists in homozygous FH, involving direct secretion into the circulation of an apoB-containing lipoprotein of density >1.006 g/ml. Simultaneous measurements of VLDL-apoB and LDL-apoB turnover were carried out on one of the homozygotes before and after a portacaval shunt. Initially VLDL-apoB synthesis was normal, while LDL-apoB synthesis was elevated and exceeded VLDL-apoB synthesis. Two months after the operation, plasma cholesterol had decreased to 60% and plasma triglyceride to 45% of the pre-operative values. Although LDL-apoB synthesis decreased only slightly, it could now be accounted for entirely on the basis of VLDL-apoB synthesis. These data suggest that the liver may be the source of the VLDL-independent pathway of apoB synthesis in homozygous FH.