Peripheral atherosclerosis in familial hypercholesterolaemia

Unlike coronary artery disease, peripheral atherosclerosis is considered to be infrequent in heterozygous familial hypercholesterolaemia. The authors studied 20 consecutive asymptomatic familial hypercholesterolaemic patients and an age- and sex-matched control group of consecutive normolipidaemic and asymptomatic patients admitted to the hospital for elective non-vascular surgery. The patients and the controls were studied non-invasively by measuring the ankle-arm systolic blood pressure ratio at rest. Peripheral atherosclerosis was common in this study population in contrast to the control group: an abnormal (less than 0.97) pressure ratio was found in 13 patients (65%) in the study group but in only one person in the control group. Eight out of 20 patients had coronary artery disease, and seven of them had an asymptomatic concomitant peripheral artery disease. Neither the classical risk factors, i.e. age, smoking, obesity, hypertension and glucose intolerance, nor serum lipid or lipoprotein status or the parameters of cholesterol metabolism correlated with peripheral atherosclerosis. It is concluded that atherosclerosis in familial hypercholesterolaemia is a multilevel disease that frequently affects also the peripheral arteries.     

Omacor in familial combined hyperlipidemia: effects on lipids and low density lipoprotein subclasses

Elevations of plasma cholesterol and/or triglycerides, and the prevalence of small, dense LDL particles remarkably increase coronary risk in patients with familial combined hyperlipidemia (FCHL). A total of 14 FCHL patients were studied, to investigate the ability of Omacor, a drug containing the n-3 fatty acids eicosapentaenoic and docosahexaenoic acid (EPA and DHA), to favorably correct plasma lipid/lipoprotein levels and LDL particle distribution. The patients received four capsules daily of Omacor (providing 3.4 g EPA+DHA per day) or placebo for 8 weeks in a randomized, double-blind, cross-over study. Omacor significantly lowered plasma triglycerides and VLDL-cholesterol levels, by 27 and 18%, respectively. Total cholesterol did not change but LDL-cholesterol and apolipoprotein B (apoB) concentrations increased by 21 and 6%. As expected, LDL particles were small (diameter=24.9+/-0.3 nm) and apoB-rich (LDL-cholesterol/apoB ratio=1.27+/-0.26) in the selected subjects. After Omacor treatment LDL became enriched in cholesterol (LDL-cholesterol/apoB ratio=1.40+/-0.17), mainly cholesteryl esters, indicating accumulation in plasma of more buoyant and core enriched LDL particles. Indeed, the separation of LDL subclasses by rate zonal ultracentrifugation showed an increase of the plasma concentration of IDL and of the more buoyant, fast floating LDL-1 and LDL-2 subclasses after Omacor, with a parallel decrease in the concentration of the denser, slow floating LDL-3 subclass. However, the average LDL size did not change after Omacor (25.0+/-0.3 nm). The resistance of the small LDL pattern to drug-induced modifications implies that a maximal lipid-lowering effect must be achieved to reduce coronary risk in FCHL patients.     

Effects of pioglitazone in familial combined hyperlipidaemia

OBJECTIVES: Familial combined hyperlipidaemia (FCH) is associated with insulin resistance. We hypothesized that pioglitazone treatment of FCH patients might increase insulin sensitivity, but may also improve serum lipid levels, body fat distribution, intramyocellular lipids (IMCL) and endothelial function. DESIGN: Double blind, randomized, cross-over study. SUBJECTS: Seventeen FCH patients. INTERVENTIONS: Sixteen weeks of pioglitazone treatment (30 mg) compared with 16 weeks of placebo. MAIN OUTCOME MEASUREMENTS: Insulin sensitivity was measured using the hyperinsulinaemic euglycaemic clamp procedure, body fat distribution and IMCL using magnetic resonance techniques and endothelial function using flow-mediated vasodilatation. RESULTS: Pioglitazone improved insulin sensitivity (M value 37.7 +/- 3.6 micromol min(-1) kg(-1) vs. 33.0 +/- 3.3 micromol min(-1) kg(-1) during placebo, P < 0.05) and LDL composition by increasing the K value (-0.11 +/- 0.06 vs. -0.20 +/- 0.06 during placebo, P < 0.05). However, pioglitazone did not affect other serum lipid levels. Endothelial function, body fat distribution and IMCL were also not affected. In addition, pioglitazone was associated with a decrease in liver enzymes (alkaline phosphatase). CONCLUSION: Pioglitazone treatment of FCH patients without type 2 diabetes mellitus increases insulin sensitivity, decreases liver enzymes and improves LDL composition but has a neutral effect on total serum lipid levels. The change in insulin sensitivity might be too small to induce changes in endothelial function, body fat distribution and IMCL.     

Carotid intima-media thickness in young patients with familial hypercholesterolaemia.

OBJECTIVE: To assess the extent of early atherosclerotic changes of the carotid arteries in young patients with familial hypercholesterolaemia (FH) detected as increased intima-media thickness (IMT), and to determine the relations between IMT and some clinical and blood variables such as lipid and lipoprotein(a) (Lp(a)) concentration and haemostatic factors. DESIGN: The IMT of the carotid bifurcation, the proximal 1 cm of the internal carotid artery, and the distal 1 cm of the common carotid artery was determined in all subjects using B mode ultrasonography. Blood lipids, fasting glucose, and several haemostatic variables were also analysed. SUBJECTS: 28 patients with FH (12 males and 16 females aged 11 to 27 years, one homozygote, 27 heterozygotes) and 28 sex and age matched normolipidaemic healthy subjects. RESULTS: The mean carotid IMT (the average of six measurements of the maximum far wall IMT in the three carotid segments on each side) was significantly greater in patients with FH than in controls (mean (SD) 0.71 (0.15) v 0.49 (0.08) mm, P < 0.001). In all subjects, the mean IMT was significantly correlated with total cholesterol (r = 0.59), low density lipoprotein (LDL) cholesterol (r = 0.60), triglycerides (r = 0.27), and systolic blood pressure (r = 0.47). No correlation was found between the mean IMT and Lp(a), fibrinogen, tissue plasminogen activator, and plasminogen activator inhibitor 1. CONCLUSIONS: The majority of young patients with FH have a greater intima-media thickness of the carotid arteries than healthy subjects. Since the individual susceptibility of patients with FH to increased LDL cholesterol is different, B mode ultrasonography could provide a useful tool to identify those who are more likely to develop premature atherosclerotic disease.     

高密度脂蛋白亚型与动脉粥样硬化相关性的研究进展

动脉粥样硬化（AS）是一种与脂质代谢障碍有关的病理改变。我国动脉粥样硬化性疾病的发生呈上升态势,危害人类健康。近年发现,高密度脂蛋白（HDL）水平与心血管急性事件和风险成反比,提高HDL水平,改善HDL功能以促进胆固醇逆转运（RCT）及防止血栓形成是当前防治AS和稳定斑块最新的防治策略。     

The effect of lovastatin on very low-density lipoprotein apolipoprotein B production by the liver in familial combined hyperlipidaemia

Summary Overproduction of very low-density lipoprotein apolipoprotein B by the liver is a metabolic marker for familial combined hyperlipidaemia, a common inherited disorder of lipoprotein metabolism. Four subjects with familial combined hyperlipidaemia had rates of apolipoprotein B production which were 2–7 times normal, using a protocol in which [¹⁵N]nglycine was used to label newly synthesized hepatic proteins. Following 4–6 months of therapy with lovastatin, very low-density lipoprotein apolipoprotein B production in all four subjects had returned to the normal range. This demonstrates that lovastatin, an inhibitor of cholesterol biosynthesis, acts also to reduce the apparent production rate of apolipoprotein B by the liver.     

High-density lipoprotein metabolism in familial hypercholesterolaemia: significance,mechanisms, therapy

AIM: To assess the significance, mechanisms and therapy of impaired high-density lipoprotein (HDL) metabolism in patients with heterozygous familial hypercholesterolaemia (FH). METHODS: Review of epidemiological, metabolic and clinical literature with synthetic analysis of data referring to HDL. PRINCIPAL FINDINGS AND SYNTHESIS: Low HDL is a powerful risk factor for coronary artery disease (CAD) in FH. Low HDL in FH is a metabolic sequel of insulin resistance, which is the central feature of the visceral accumulation of adipose tissue acquired in later life. Insulin resistance increases hepatic secretion of triglycerides that subsequently results in remodelling of holo-HDL particles and enhanced catabolism of apolipoprotein A-I. Gene-gene and gene-environment interactions may contribute to the pathogenesis of low HDL in FH. Low HDL may also point to other cardiovascular risk factors, such as hyper-remnantaemia, increased small dense low-density lipoproteins (LDL), procoagulopathy and vascular insulin resistance. Visceral obesity should be vigorously identified and treated in FH. Judicious addition of fish oils, niacin and fibrates to a statin may be required to optimise HDL metabolism. Extracorporeal removal of LDL cholesterol should aim not to extract HDL from plasma. CONCLUSIONS: With the increasing incidence of obesity in the community, the metabolic syndrome will overmanifest in patients with FH. Impaired HDL metabolism is an important consequence of this syndrome for FH patients, because it will per se or in collusion with other associated risk factors accelerate the progression of atherosclerosis and CAD. Dysregulation of HDL metabolism principally results from hepatic insulin resistance and remodelling of HDL particles. Obesity should be prevented and aggressively treated in FH and use of a safe combination drug regimen considered to correct the dysmetabolism of HDL in these patients.     

Atorvastatin versus four statin-fibrate combinations in patients with familial combined hyperlipidaemia

BACKGROUND: Statin-fibrate combinations are very effective in the treatment of familial combined hyperlipidaemia (FCHL). Nonetheless, they have not been extensively used because of the fear of side effects. Thus, a therapeutic alternative is required for this lipid disorder. OBJECTIVE: To compare the long-term (one-year) efficacy of atorvastatin monotherapy with those of four statin-fibrate combinations in 675 FCHL patients. METHODS: Patients were randomly assigned to atorvastatin monotherapy (A 20 mg/day) n = 134, or pravastatin (P 20 mg/day)+gemfibrozil (G 1200 mg/day) n = 135, simvastatin (S 20 mg/day)+G (1200 mg/day) n = 137, P (20 mg/day)+ciprofibrate (C 100 mg/day) n = 135, and S (20 mg/day)+C (100 mg/day) n = 134. RESULTS: Twelve patients on statin-fibrate combinations were withdrawn from the study because of side effects: three because of CK elevation, two because of myalgia and seven due to increase in serum transaminase levels. One patient on A was withdrawn because of persistent epigastric discomfort. Atorvastatin reduced low density lipoprotein cholesterol and apoprotein B more than all four combinations (-45% vs. maximum -40% of S+C, and -39% vs. maximum -32% of the same combination, respectively, P < 0.001 for both), but had a lesser effect on triglycerides (-38% vs. maximum -53% of S+C, P = 0.0002) and high density lipoprotein cholesterol (6% vs. maximum 21% of S+G, P = 0.0003). The effect of A on plasma fibrinogen was analogous to that of G combinations (-8% vs. -9% of P+G and -11% of S+G, P = NS vs. baseline and among each other) and inferior to that of the ciprofibrate combinations (-8% vs. -24% of P+C, P = 0.0002 and -26% S+C, P = 0.0001). A had a lower treatment cost and better patient compliance, P = 0.04 vs. C combinations and P = 0.02 vs. G combinations. CONCLUSIONS: The data suggest that statin-fibrate combinations have a beneficial effect on all lipid parameters. Atorvastatin monotherapy has a better effect on LDL-C and apoprotein B than statin-fibrate combinations, but a lesser effect on HDL-C, TG and in the case of ciprofibrate combinations, fibrinogen. The clinical significance of these findings should be tested in a large, long-term survival study.     

Gemfibrozil decreases autoantibodies against oxidized low-density lipoprotein in men with combined hyperlipidaemia

Hoogerbrugge N, Kerkhofs LGN, Jansen H (University Hospital Dijkzigt, Rotterdam, The Netherlands). Gemfibrozil decreases autoantibodies against oxidized low-density lipoprotein in men with combined hyperlipidaemia. J Intern Med 1998; 243 : 355–59.

Objectives

Gemfibrozil is the most widely used fibric acid for the management of combined hyperlipidaemia. It has beneficial effects in the prevention of coronary heart disease (CHD). The mechanisms by which it exerts this effect are not completely resolved. We studied whether gemfibrozil affects low-density lipoprotein (LDL) size and LDL oxidation parameters in males with a moderate combined hyperlipidaemia at high risk for progressive atherosclerosis.

Design

Open treatment with 2 × 600 mg gemfibrozil daily for 12 weeks.

Setting

Outpatient lipid clinic of a tertiary referral centre.

Subjects

Twenty-three patients with combined hyperlipidaemia and CHD or a positive family history for both CHD and hyperlipidaemia.

Main outcome measures

Effects on triglyceride (TG), autoantibodies to oxidized LDL, LDL pattern and resistance to oxidative modification.

Results

During treatment with gemfibrozil, plasma TG concentration decreased from 2.83 ± 0.85 to 2.02 ± 0.89 mmol L^?1 (P < 0.001). All but one patient were shown to have LDL pattern B. The LDL pattern did not change upon treatment with gemfibrozil. The resistance to oxidation, reflected in the lagtime during in-vitro oxidation slightly decreased from 105 ± 22 to 99 ± 18 min (P= 0.01). The concentration of autoantibodies against oxidized LDL indicates the rate of LDL oxidation in vivo. This concentration significantly decreased from 14.2 ± 9.9 to 13.1 ± 9.2 mg L^?1 (P < 0.01).

Conclusions

The beneficial effect of gemfibrozil in reducing CHD may at least in part depend on a decrease of the rate of LDL oxidation in vivo.

     

Characterization of atherosclerosis in a patient with familial high-density lipoprotein deficiency

We describe the cardiovascular state of a 60-year-old homozygous patient with familial HDL deficiency (Tangier disease). The patient was examined by coronary angiography and intravascular ultrasound because of chest pain at rest and on exertion. We found a normal left ventricular function, moderately diffuse coronary sclerosis without stenosis and no critical stenosis of peripheral arteries. Intravascular ultrasound revealed the three layer appearance of arterial intima, media and adventitia with normal thickness. No calcified plaques or intimal hyperplasia could be detected apart from a single, discrete atherosclerotic lesion in one iliac artery segment. Concentric non-occlusive atherosclerotic lesions which are readily detectable with intravascular ultrasound were not found. The lack of severe atherosclerosis was remarkable insofar as massive foam cell formation and the virtually complete absence of circulating HDL is characteristic of Tangier disease and has been previously demonstrated in this patient. Our findings suggest that HDL deficiency and foam cell formation in Tangier disease are not necessarily associated with accelerated development of atherosclerosis.