Inhibition of cholesterol synthesis by atorvastatin in homozygous familial hypercholesterolaemia.

Patients with homozygous familial hypercholesterolaemia (HoFH) have markedly elevated low density lipoprotein (LDL) cholesterol levels that are refractory to standard doses of lipid-lowering drug therapy. In the present study we evaluated the effect of atorvastatin on steady state concentrations of plasma lipids and mevalonic acid (MVA), as well as on 24-h urinary excretion of MVA in patients with well characterized HoFH. Thirty-five HoFH patients (18 males; 17 females) received 40 mg and then 80 mg atorvastatin/day. The dose of atorvastatin was increased further to 120 mg/day in 20 subjects and to 160 mg/day in 13 subjects who had not achieved LDL cholesterol goal, or in whom the dose of atorvastatin had not exceeded 2.5 mg/kg body wt per day. LDL cholesterol levels were reduced by 17% at the 40 mg/day and by 28% at the 80 mg/day dosage (P<0.01). Reduction in LDL cholesterol in the five receptor negative patients was similar to that achieved in the 30 patients with residual LDL receptor activity. Plasma MVA and 24-h urinary excretion of MVA, as markers of in vivo cholesterol synthesis, were elevated at baseline and decreased markedly with treatment. Urinary MVA excretion decreased by 57% at the 40 mg/day dose and by 63% at the 80 mg/day dosage (P<0. 01). There was a correlation between reduction in LDL cholesterol and reduction in urinary MVA excretion; those patients with the highest basal levels of MVA excretion and thus the highest rates of cholesterol synthesis having the greatest reduction in LDL cholesterol (r=0.38; P=0.02). Increasing the dose of atorvastatin to 120 and 160 mg/day did not result in any further reduction in LDL cholesterol or urinary MVA excretion suggesting a plateau effect with no further inhibition of cholesterol synthesis at doses of atorvastatin greater than 80 mg/day.

Efficacy of vitamin E compared with either simvastatin or atorvastatin in preventing the progression of atherosclerosis in homozygous familial hypercholesterolemia.

Over a 4-year period, antioxidant therapy (vitamin E) was compared with high-dose statin therapy in 15 patients with homozygous familial hypercholesterolemia. Carotid intima-media thickness, used as an in vivo assessment of atherosclerosis, progressed rapidly during the period of vitamin E therapy but regressed on statin therapy.

Atherosclerosis seems not to be associated with hyperinsulinaemia in patients with familial hypercholesterolaemia.

OBJECTIVE: To study the relationship between hyperinsulinaemia, insulin resistance, leptin and atherosclerosis in subjects with familial hypercholesterolaemia (FH). DESIGN: Case-control cross-sectional study. SETTING: Lipid clinic, Johannesburg Hospital, South Africa. SUBJECTS AND METHODS: Fasting serum lipid, glucose, insulin and leptin levels were measured in 24 homozygous FH subjects; 20 FH heterozygotes without coronary artery disease (CAD); 22 heterozygotes with documented CAD; and 20 healthy normocholesterolaemic subjects. Insulin resistance was calculated using the homeostasis model assessment (HOMA) formula. RESULTS: Mean glucose and insulin levels were similar in all 4 groups. There was no significant difference in calculated insulin resistance between any of the groups. There was also no relationship between the degree of insulin resistance and total or LDL-cholesterol levels. Using Spearman's correlation coefficient (Rs) calculated insulin resistance correlated with triglyceride (Rs = 0.27; P<0.05) and inversely with HDL-cholesterol (Rs = -0.26; P<0.05). Fasting insulin concentrations and calculated insulin resistance were similar in FH subjects with overt CAD compared to those without. Leptin levels were higher in the FH subjects with CAD. However, these subjects were older and had a larger body mass index (BMI), and when adjusted for age and BMI, only BMI correlated with leptin levels (multiple r = 0.65; P<0.001). CONCLUSIONS: In the absence of other causes of insulin resistance, FH subjects have normal fasting insulin levels and, in general, they are not insulin resistant. Insulin resistance appears to play little role in the pathogenesis of accelerated atherosclerosis in FH.

Low-density lipoprotein cholesterol bulk is the pivotal determinant of atherosclerosis in familial hypercholesterolemia.

This study's aim was to determine whether biochemical risk factors such as lipoprotein(a), fibrinogen, homocysteine, and insulin, as well as low-density lipoprotein (LDL) particle size, were predictive of carotid intimamedia thickness (IMT), an early marker of atherosclerosis, in subjects with familial hypercholesterolemia (FH). We also determined whether plasma 8-isoprostane, as a marker of in vivo lipid oxidation, correlated with carotid IMT. Twenty-two homozygous and 20 heterozygous subjects with FH were compared with 20 normocholesterolemic controls. On univariate analysis, plasma total and LDL cholesterol, the cholesterol-years score (CYS), lipoprotein(a), and fibrinogen, but not homocysteine or insulin, were positively related, and high-density lipoprotein (HDL) cholesterol was negatively related to carotid IMT. However, on multivariate analysis, only LDL cholesterol and the CYS predicted carotid IMT (multiple r = 0.82; r2 = 0.68; p <0.0001). The subjects with FH had large rather than small dense LDL particles, and plasma 8-isoprostane levels were not increased. LDL cholesterol and the CYS, or "cholesterol bulk" are the pivotal determinants of atherosclerosis and are the strongest predictors of carotid IMT in FH.

Expanded-dose simvastatin is effective in homozygous familial hypercholesterolaemia.

Patients with homozygous familial hypercholesterolaemia (HFH) have abnormalities in both low-density lipoprotein (LDL) receptor alleles, resulting in severe hypercholesterolaemia and premature coronary heart disease. Limited treatment options are available and the response to drug therapy has been poor. In the present paper, we have evaluated the efficacy and safety of simvastatin at doses beyond the current maximal dose of 40 mg/day in patients with HFH. After a 4 week placebo diet run-in period, 12 patients with well-characterized HFH were randomized to simvastatin 80 mg/day administered in three divided doses (n = 8; group 1) or 40 mg once daily (n = 4; group 2). After 9 weeks, the dose in group 1 was increased to 160 mg/day while the dose in group 2 was kept at 40 mg/day, but with the drug given in three divided doses and treatment continued for an additional 9 weeks. All 12 patients completed the study and there were no serious or unexpected adverse effects. LDL-cholesterol concentrations fell by 14% at the 40 mg/day dose, but were reduced further at the higher doses (25% at the 80 mg/day and by 31% at the 160 mg/day dosage, P < 0.0001). Excretion of urinary mevalonic acid, as an index of in vivo cholesterol biosynthesis, was reduced but did not correlate with reduction in LDL-cholesterol in the individual patients. The magnitude of response to therapy was not predicted by the LDL-receptor gene defect as patients with the same LDL-receptor mutations responded differently to the same dose of simvastatin therapy. The ability of expanded doses of simvastatin (80 or 160 mg/day) to reduce LDL-cholesterol levels in patients with HFH, even if receptor negative, suggests that at these doses, the drug reduces LDL production. Simvastatin therapy, at doses of 80 or 160 mg/day, should therefore be considered in all patients with HFH, either as an adjunct to apheresis, or as monotherapy for those patients who do not have access to apheresis or other such treatment modalities.

Lack of effect of high dose vitamin E on xanthoma regression in homozygous familial hypercholesterolaemia.

There is increasing evidence that oxidative modification of low-density lipoprotein (LDL) plays an important role in the pathogenesis of atherosclerosis. Homozygous familial hypercholesterolaemia (HFH) is characterized by premature, severe atherosclerosis. Drugs available at present are ineffective in lowering the markedly elevated LDL levels in this condition; antioxidant therapy to protect the LDL against oxidation may be of benefit. Probucol, the only drug shown to induce xanthoma regression in HFH, is a potent antioxidant, but it also lowers high-density lipoprotein cholesterol (HDL-C) levels, causing some concern. Vitamin E is a naturally occurring antioxidant that does not affect HDL-C levels. We have therefore evaluated the effect of long-term high dose vitamin E on xanthoma regression in HFH. Ten subjects with HFH, mean age 17 years (range 4-34), received vitamin E (400-1000 mg/dl alpha-tocopherol acetate/day) for a period of 23 months (range 12-27). There was a 4.2-fold increase in the mean serum vitamin E level (mean (S.D.) 49.7 (19.9) to 177.9 (45.6) mumol/l; P < 0.005), but no change in serum lipid or lipoprotein concentrations. Although there was an increase in the in vitro resistance of LDL to oxidation as determined by the duration of the lag phase during copper-mediated oxidation (116 (8.34) vs. 141.5 (9.23) min; P < 0.005) there was no xanthoma regression; in fact they progressed in 4 subjects. Unlike probucol, high dose long-term vitamin E has no demonstrable effect on xanthoma regression in HFH.

Prevalence of hypercholesterolaemia in young Afrikaners with myocardial infarction. Ischaemic heart disease risk factors.

Ischaemic heart disease (IHD) risk factors, with particular reference to familial hypercholesterolaemia (FH), were studied in 39 male and 12 female Afrikaners aged 55 years or under in an intensive care unit immediately after an acute myocardial infarction and in the survivors at about 3 months after the infarct. Two major risk factors were found. Firstly, about three-quarters of both male and female patients smoked more than 15 cigarettes daily. Secondly, 51% of males and 37% of females had serum cholesterol values of greater than or equal to 7.0 mmol/l and about 20% of both men and women had levels of greater than or equal to 8.5 mmol/l. Three male and 2 female patients--1:10 of the whole sample--had FH diagnosed by rigorous criteria, a prevalence similar to the figure of 1:8 predicted from the frequency of FH heterozygotes in the Afrikaans-speaking population. None of the other IHD risk factors such as hypertension, diabetes and hyperuricaemia appeared to be important. The role of obesity appeared to be indirect by virtue of its frequent association with and possible contribution to hypercholesterolaemia. Many of the patients had a history of previous IHD episodes.

Prevalence of hypercholesterolaemia in young Afrikaners undergoing coronary artery bypass surgery. Ischaemic heart disease risk factors.

Ischaemic heart disease risk factors, with particular reference to familial hypercholesterolaemia, were studied in 47 male and 6 female Afrikaners, aged 55 years and under, admitted to hospital for coronary bypass surgery. The outstanding feature in this group with severe coronary atherosclerosis demonstrated angiographically was that about half had severe hypercholesterolaemia (greater than or equal to 8.5 mmol/l), and that of the severely hypercholesterolaemic patients about half again had familial hypercholesterolaemia (FH). This yielded an overall prevalence of FH in the 53 cases of 1 in 4 (26.7%) and strongly supports the contention that FH is a major risk factor for severe coronary artery disease in young Afrikaners. The only other risk factor of importance was cigarette smoking, about 80% of the patients being current or ex-smokers.

Familial hypercholesterolaemia--the need for adequate counselling and family tracing.

A search for the founder member(s) responsible for the familial hypercholesterolaemia (FH) gene(s) in the RSA inadvertently revealed the existence of a marriage which links two pedigrees in which FH occurs. This marriage could result in the birth of an FH homozygote child. The couple concerned should have--but had not--been informed of the implications of their union before their marriage. The importance of identifying individuals at risk through extensive tracing of families in which FH occurs and the relevance of subsequent counselling are illustrated.

Association between familial hypercholesterolaemia and church affiliation. Is this the result of sociocultural isolation of migrant farmers in 19th-century South Africa?

The family trees of 57 Afrikaans -speaking familial hypercholesterolaemia (FH) index cases were traced to look for founder surnames, for an association between FH and affiliation to the Gereformeerde Kerk (GK), and for consanguinity. Two possible founder surnames were identified. Each occurred in more than 5% of individuals and both were well known among the founders of the GK. Affiliation to the GK was much more common in our sample (45% of 994 individuals) than in the general population (5%), an overall odds ratio of 7,38. This association was stronger in older generations. There were 21 consanguineous marriages, the two suspected founder surnames and affiliation to the GK featuring prominently among them.