Familial Hypercholesterolemia: The Most Frequent Cholesterol Metabolism Disorder Caused Disease.

Cholesterol is an essential component of cell barrier formation and signaling transduction involved in many essential physiologic processes. For this reason, cholesterol metabolism must be tightly controlled. Cell cholesterol is mainly acquired from two sources: Dietary cholesterol, which is absorbed in the intestine and, intracellularly synthesized cholesterol that is mainly synthesized in the liver. Once acquired, both are delivered to peripheral tissues in a lipoprotein dependent mechanism. Malfunctioning of cholesterol metabolism is caused by multiple hereditary diseases, including Familial Hypercholesterolemia, Sitosterolemia Type C and Niemann-Pick Type C1. Of these, familial hypercholesterolemia (FH) is a common inherited autosomal co-dominant disorder characterized by high plasma cholesterol levels. Its frequency is estimated to be 1:200 and, if untreated, increases the risk of premature cardiovascular disease. This review aims to summarize the current knowledge on cholesterol metabolism and the relation of FH to cholesterol homeostasis with special focus on the genetics, diagnosis and treatment.

Intracellular cholesterol accumulation and coenzyme Q10 deficiency in Familial Hypercholesterolemia.

Familial Hypercholesterolemia (FH) is an autosomal co-dominant genetic disorder characterized by elevated low-density lipoprotein (LDL) cholesterol levels and increased risk for premature cardiovascular disease. Here, we examined FH pathophysiology in skin fibroblasts derived from FH patients harboring heterozygous mutations in the LDL-receptor. Fibroblasts from FH patients showed a reduced LDL-uptake associated with increased intracellular cholesterol levels and coenzyme Q10 (CoQ10) deficiency, suggesting dysregulation of the mevalonate pathway. Secondary CoQ10 deficiency was associated with mitochondrial depolarization and mitophagy activation in FH fibroblasts. Persistent mitophagy altered autophagy flux and induced inflammasome activation accompanied by increased production of cytokines by mutant cells. All the pathological alterations in FH fibroblasts were also reproduced in a human endothelial cell line by LDL-receptor gene silencing. Both increased intracellular cholesterol and mitochondrial dysfunction in FH fibroblasts were partially restored by CoQ10 supplementation. Dysregulated mevalonate pathway in FH, including increased expression of cholesterogenic enzymes and decreased expression of CoQ10 biosynthetic enzymes, was also corrected by CoQ10 treatment. Reduced CoQ10 content and mitochondrial dysfunction may play an important role in the pathophysiology of early atherosclerosis in FH. The diagnosis of CoQ10 deficiency and mitochondrial impairment in FH patients may also be important to establish early treatment with CoQ10.

Treating homozygous familial hypercholesterolemia in a real-world setting: Experiences with lomitapide.

Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disease characterised by markedly elevated plasma levels of low-density lipoprotein-cholesterol (LDL-C). Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor approved as an adjunct to other lipid-lowering therapies (LLTs), with or without lipoprotein apheresis (LA), for the treatment of adult HoFH. Diet with <20% calories from fat is required. Due to a varying genetic and phenotypic profile of patients with HoFH, individual patients may respond to therapy differently; therefore examining individual cases in a 'real-world' setting provides valuable information on the effective day-to-day management of HoFH cases. Four HoFH cases were selected for analysis and discussion: a 20-year-old female compound heterozygote; a 62-year old female homozygote; a 42-year-old female compound heterozygote; and a 36-year-old male homozygote. Each patient was commenced on lomitapide according to the prescribed protocol and subjected to routine follow-up. All four patients experienced clinically meaningful reductions in LDL-C levels of 35-73%. Three of the patients had evidence of steatosis or mildly elevated liver function tests) before lomitapide was started, but effects of lomitapide on hepatic function were not universal. Three of the patients experienced gastrointestinal adverse events, but were managed with appropriate dietary control. Lomitapide is an effective adjunct LLT in the management of patients with HoFH, with or without LA. Real-world use of lomitapide has a side-effect profile consistent with clinical trials and one that can be managed by adherence to recommendations on dose escalation, dietary modification and dietary supplements.

Effects of vitamin E on peroxisome proliferator-activated receptor γ and nuclear factor-erythroid 2-related factor 2 in hypercholesterolemia-induced atherosclerosis.

Atherosclerosis and associated cardiovascular complications such as stroke and myocardial infarction are major causes of morbidity and mortality. We have previously reported a significant increase in mRNA levels of the scavenger receptor CD36 in aortae of cholesterol-fed rabbits and shown that vitamin E treatment attenuated increased CD36 mRNA expression. In the present study, we further investigated the redox signaling pathways associated with protection against atherogenesis induced by high dietary cholesterol and correlated these with CD36 expression and the effects of vitamin E supplementation in a rabbit model. Male albino rabbits were assigned to either a control group fed with a low vitamin E diet alone or a test group fed with a low vitamin E diet containing 2% cholesterol in the absence or presence of daily intramuscular injections of vitamin E (50mg/kg). To elucidate the mechanisms by which vitamin E supplementation alters the effects of hypercholesterolemia in rabbit aortae, we measured peroxisome proliferator-activated receptor γ (PPARγ), ATP-binding cassette transporter A1 (ABCA1), and matrix metalloproteinase-1 (MMP-1) mRNA levels by quantitative RT-PCR and the expression of MMP-1, nuclear factor-erythroid 2-related factor 2 (Nrf2), and glutathione S-transferase α (GSTα) protein by immunoblotting. The increased MMP-1 and decreased GSTα expression observed suggests that a cholesterol-rich diet contributes to the development of atherosclerosis, whereas vitamin E supplementation affords protection by decreasing MMP-1 and increasing PPARγ, GSTα, and ABCA1 levels in aortae of rabbits fed a cholesterol-rich diet. Notably, protein expression of Nrf2, the antioxidant transcription factor, was increased in both the cholesterol-fed and the vitamin E-supplemented groups. Although Nrf2 activation can promote CD36-mediated cholesterol uptake by macrophages, the increased induction of Nrf2-mediated antioxidant genes is likely to contribute to decreased lesion progression. Thus, our study demonstrates that Nrf2 can mediate both pro- and antiatherosclerotic effects.

Effect of n-3 fatty acids on carotid atherosclerosis and haemostasis in patients with combined hyperlipoproteinemia: a double-blind pilot study in primary prevention.

BACKGROUND: Intake of n-3 polyunsaturated fatty acids (n-3 PUFA) either from natural sources or dietary supplementation is inversely associated with atherothrombosis. AIM: A double-blind pilot study was designed to address the impact of n-3 PUFA on atherosclerosis, haemostasis and vascular status in patients with combined hyperlipoproteinemia. METHODS: Carotid intima-media thickness (C-IMT), texture of intima-media complex (T-IMC), lipids and platelet function were evaluated in 64 patients with combined hyperlipoproteinemia who received placebo or n-3 PUFA (6 g/day) for 2 years. C-IMT and T-IMC were assessed by B-mode ultrasound. Lipids and platelet function were determined by validated methods. RESULTS: C-IMT increased in placebo, but not in n-3 PUFA group with respect to baseline. In contrast T-IMC decreased in n-3 PUFA, but not in placebo; in both cases, however, treatment effect did not reach statistical significance. A fall of triglycerides, concomitant to a rise of high- and low-density lipoprotein cholesterol (HDL and LDL), was observed in the active treated group. Platelet function was significantly reduced by n-3 PUFA. CONCLUSIONS: Results show a favourable effectiveness of n-3 PUFA on IMT progression and T-IMC that deserves to be confirmed in larger studies. Despite the small sample size, the beneficial effect of n-3 PUFA on platelet function, triglycerides and HDL-C is clearly highlighted.

[The pathological changes of abdominal and peripheral arteries in familial hypercholesterolemia--the result of high-resolution color Doppler ultrasonography].

OBJECTIVE: To explore changes of abdominal and peripheral arteries in familial hypercholesterolemia (FH) patients with definite etiopathogenesis by high-resolution color Doppler ultrasound; to identify the arteriosclerotic progression of FH patients and offer the valuable foundation for clinic treatment. METHODS: Observe the interior-media thickness (IMT), stenotic degree and hemodynamics change of arteries by ultrasonography in six children in five family constellations (index case) and six normal controls. RESULTS: There was significant difference between FH and control group in IMT of the posterior wall in left external carotid artery (origination), right common carotid artery (approaching piece) and IMT of the anterior and posterior wall right common carotid artery (intermediate piece) (P = 0.015). Significant thickening of IMT was not observed in vertebral arteries, subclavicular arteries, abdominal aorta, renal arteries, iliac arteries and popliteal arteries both in FH and control group. CONCLUSION: The arteriosclerotic aggravation of FH patients could not be revealed by the level of the blood fat, but could be revealed correctly by ultrasonography. It is possible to provide significant foundation for individualized treatment of FH patients by regular non-invasive ultrasonography.

Long-term safety and efficacy of high-dose atorvastatin treatment in patients with familial hypercholesterolemia.

In the 2-year Atorvastatin versus Simvastatin on Atherosclerosis Progression extension study, patients with familial hypercholesterolemia who continued to take atorvastatin 80 mg for an additional 2 years had complete arrest of the progression of mean carotid intima-media thickness (0.89 mm at the start vs 0.90 mm at the end of the study, p = 0.58). In contrast, patients previously taking simvastatin 40 mg had significant regression of intima-media thickness (0.95 mm at the start vs 0.92 mm at the end of the study, p = 0.01). Therefore, both placebo- and statin-treated patients with familial hypercholesterolemia are best treated with high-dose atorvastatin, a therapeutic regimen that induces atherosclerosis regression and is safe and well tolerated over a 4-year period.

Inhibitory effects of Dai-saiko-to (Da-Chai-Hu-Tang) on the progression of atherosclerotic lesions in Kurosawa and Kusanagi-hypercholesterolemic rabbits.

The inhibitory effects of the traditional herbal medicine Dai-saiko-to (Da-Chai-Hu-Tang) on the progression of the atherosclerotic lesions were studied using the spontaneous familial hypercholesterolemia (FH) model, Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits. Changes in blood chemistry, pathology and low-density lipoprotein (LDL) oxidation were measured in a control group and a Dai-saiko-to-treated group. In the control group, the area of atheromatous plaques of the aorta progressed between week 12 (29.1%) and 26 (51.5%). This progression of atherosclerotic lesions did not happen in the Dai-saiko-to-treated group between week 12 (26%) and 26 (27.4%). Antioxidative effects on LDL were seen in the Dai-saiko-to-treated group in weeks 16 and 18. Dai-saiko-to did not improve the hypercholesterolemia in the KHC rabbits. These results suggest that Dai-saiko-to has inhibitory effects on the development of atheromatous plaque formation in spontaneous FH model rabbits. It is possible that the antioxidative effects of Dai-saiko-to on LDL led to the beneficial effects observed in this study.

Magnetic resonance imaging of Achilles tendon xanthomas in familial hypercholesterolemia.

The demonstration of tendon xanthomas is helpful in diagnosing heterozygous familial hypercholesterolemia, but in many patients lipid may accumulate without clinical abnormality being present. We investigated the possibility of detecting the lipid element with magnetic resonance (MR) imaging in seven patients with familial hypercholesterolemia and six controls. Although the mean relative signal intensities measured on long TR/TE spin echo sequences of the tendon were significantly higher in patients than in controls, the lack of such elevation does not rule out the presence of such lesions. In vitro measurements indicated that the signal intensity of triglycerides was quenched by cholesterolesters. The anatomic findings of MR imaging were compared with those of ultrasonography (US), showing excellent correlation in measurements between MR images and US [r(S) = 0.95 and 0.97 respectively]. MR imaging and US provide equal information on the anatomy of the Achilles tendon; as an abnormally increased signal intensity within the xanthoma on MRI was found in only a minority of our patients, the value of MRI in the demonstration of Achilles tendon xanthomas is limited when using conventional T1 and T2 spin echo sequences.

Pathobiology of human familial hypercholesterolaemia and a related animal model, the Watanabe heritable hyperlipidaemic rabbit.

Defective expression of low density lipoprotein (LDL) receptors is the basic genetic defect in human familial hypercholesterolaemia (FH) and its animal counterpart, the Watanabe heritable hyperlipidaemic (WHHL) rabbit. The pathologic manifestations of human FH were evaluated based on the study of material from six subjects with homozygous FH and a review of the literature. This analysis indicated that homozygous FH is characterized by accelerated atherosclerosis and prominent lipid accumulation in macrophages and other stromal cells of the aortic and mitral valves, skin, tendon, and, variably, in other extravascular sites. Disease progression was studied in the WHHL rabbit. From birth to 1 year, WHHL rabbits show evidence of progressive disease of the aorta with accumulation of birefringent lipid in intimal lesions, including fatty streaks, raised foam cell lesions, and plaques (atheromas), as well as in the media. At 1-2 years, WHHL rabbits develop coronary atherosclerosis and focal extravascular lipid deposits, including subcutaneous and tendinous xanthomas. Vascular lesion development is associated with adhesion of monocytes and other leucocytes to the endothelium. The cells of the intimal lesions are lipid-containing macrophages, smooth muscle cells and foam cells. Most of the intracellular lipid is in the form of non-membrane-bound neutral lipid droplets indicating that the cytoplasm is the major site of lipid storage. Similar ultrastructural features are shown by human FH lesions. Observations are reviewed regarding therapeutic approaches aimed at altering the pathologic expression of familial hypercholesterolaemia, including the negative results of treatment of WHHL rabbits with the calcium-channel antagonist, verapamil, and omega-3 fatty acids.