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

DeepSRE: Identification of sterol responsive elements and nuclear transcription factors Y proximity in human DNA by Convolutional Neural Network analysis

SREBP1 and 2, are cholesterol sensors able to modulate cholesterol-related gene expression responses. SREBPs binding sites are characterized by the presence of multiple target sequences as SRE, NFY and SP1, that can be arranged differently in different genes, so that it is not easy to identify the binding site on the basis of direct DNA sequence analysis. This paper presents a complete workflow based on a one-dimensional Convolutional Neural Network (CNN) model able to detect putative SREBPs binding sites irrespective of target elements arrangements. The strategy is based on the recognition of SRE linked (less than 250 bp) to NFY sequences according to chromosomal localization derived from TF Immunoprecipitation (TF ChIP) experiments. The CNN is trained with several 100 bp sequences containing both SRE and NF-Y. Once trained, the model is used to predict the presence of SRE-NFY in the first 500 bp of all the known gene promoters. Finally, genes are grouped according to biological process and the processes enriched in genes containing SRE-NFY in their promoters are analyzed in details. This workflow allowed to identify biological processes enriched in SRE containing genes not directly linked to cholesterol metabolism and possible novel DNA patterns able to fill in for missing classical SRE sequences

Phosphorylation of rat brain calpastatins by protein kinase C

AbstractCalpastatin, the natural inhibitor of calpain, is present in rat brain in multiple forms, having different molecular masses, due to the presence of one (low Mr form) or four (high Mr form) repetitive inhibitory domains. Recombinant and native calpastatin forms are substrates of protein kinase C, which phosphorylates a single serine residue at their N-terminus. Furthermore, both low and high Mr calpastatins are phosphorylated by protein kinase C at the same site. These calpastatin forms are phosphorylated also by protein kinase A, although with a lower efficiency. The incorporation of a phosphate group determines an increase in the concentration of Ca2+ required to induce the formation of the calpain-calpastatin complex. This effect results in a large decrease of the inhibitory efficiency of calpastatins. We suggest that phosphorylation of calpastatin represents a mechanism capable to balance the actual amount of active calpastatin to the level of calpain to be activated

Formation of Hydrogen, Oxygen, and Hydrogen Peroxide in Electron Irradiated Crystalline Water Ice

Water ice is abundant both astrophysically, for example in molecular clouds, and in planetary systems. The Kuiper belt objects, many satellites of the outer solar system, the nuclei of comets and some planetary rings are all known to be water-rich. Processing of water ice by energetic particles and ultraviolet photons plays an important role in astrochemistry. To explore the detailed nature of this processing, we have conducted a systematic laboratory study of the irradiation of crystalline water ice in an ultrahigh vacuum setup by energetic electrons holding a linear energy transfer of 4.3 +/- 0.1 keV mm-1. The irradiated samples were monitored during the experiment both on line and in situ via mass spectrometry (gas phase) and Fourier transform infrared spectroscopy (solid state). We observed the production of hydrogen and oxygen, both molecular and atomic, and of hydrogen peroxide. The likely reaction mechanisms responsible for these species are discussed. Additional formation routes were derived from the sublimation profiles of molecular hydrogen (90-140 K), molecular oxygen (147 -151 K) and hydrogen peroxide (170 K). We also present evidence on the involvement of hydroxyl radicals and possibly oxygen atoms as building blocks to yield hydrogen peroxide at low temperatures (12 K) and via a diffusion-controlled mechanism in the warming up phase of the irradiated sample.Comment: ApJ, March 2006, v639 issue, 43 pages, 7 figure

Identification of a novel mutation of MTP gene in a patient with abetalipoproteinemia

Abetalipoproteinemia (ABL), or Bassen-Kornzweig syndrome, is a rare autosomal recessive disorder of lipoprotein metabolism, characterized by fat malabsorption, hypocholesterolemia retinitis pigmentosa, progressive neuropathy and acanthocytosis from early infancy. We describe the clinical and molecular characterization of a 6-month-old infant born of consanguineous, apparently healthy parents from Iran. The patient was hospitalized because of failure to thrive, greasy stool and vomiting. The patient's serum lipid profile, the clinical phenotype and the duodenal histology suggested the clinical diagnosis of ABL. The MTP gene analysis by direct sequencing revealed a novel homozygous mutation (c.1586 A > G-H529R). The parents were heterozygotes for the same mutation and interestingly the father showed a lipid profile characterized by a slight reduction of total and LDL-cholesterol plasma levels

LINEE GUIDA CLINICHE PER LA PREVENZIONE DELLA CARDIOPATIA ISCHEMICA NELLA IPERCOLESTEROLEMIA FAMILIARE Una patologia sotto-diagnosticata e sotto-trattata

AIMS. Familial hypercholesterolaemia (FH) is a common genetic cause of premature coronary heart disease (CHD) due to lifelong elevated plasma low-density lipoprotein (LDL) cholesterol levels. This paper aims to describe the problem of FH underdiagnosis and undertreatment and to promote CHD prevention providing recommendations for the screening and treatment of patients with FH. Methods and results. In many countries, less then 1% of FH patients are diagnosed, although the estimated prevalence of this condition is about 1/500 for heterozygous FH and the results of FH screening in a general population of Northern Europe suggest a prevalence of 1/200. Studies on FH patients agree on a widespread failure to achieve recommended target of LDL-cholesterol and on a 12-fold increased CHD risk. With a theoretical prevalence between 1/500 and 1/200, it is estimated that 14 to 34 million subjects worldwide have FH. With evidence of plasma cholesterol ≥8 mmol/L (≥310 mg/dL) in an adult or ≥6 mmol/L (≥230 mg/dL) in a child, premature CHD, tendon xanthomas, or sudden premature cardiac death, we recommend the screening for FH of this subject and of all first-degree relatives. The treatment of a patient with diagnosis of FH should have LDL targets of <3.5 mmol/L (<135 mg/ dL) for children, <2.5 mmol/L (<100 mg/dL) for adults, and <1.8 mmol/L (<70 mg/dL) for adults with known CHD or diabetes. Beside life-style and dietary modifications, first line therapies are statins, ezetimibe, and bile acid binding resins in children, and maximal potent statin dose, ezetimibe, bile acid binding resins, and fibrates in adults. Homozygotes FH and in treatment-resistant heterozygotes FH with CHD should be referred for LDL-apheresis. Conclusion. Familial hypercholesterolemia is a common condition that carries a high risk of CHD. The underdiagnosis and undertreatment of FH require a focused intervention that implements the screening and promote the early and aggressive treatment of these patients

Lipid Peroxidation, Nitric Oxide Metabolites, and Their Ratio in a Group of Subjects with Metabolic Syndrome

Our aim was to evaluate lipid peroxidation, expressed as thiobarbituric acid-reactive substances (TBARS), nitric oxide metabolites (nitrite + nitrate) expressed as NOx, and TBARS/NOx ratio in a group of subjects with metabolic syndrome (MS). In this regard we enrolled 106 subjects with MS defined according to the IDF criteria, subsequently subdivided into diabetic (DMS) and nondiabetic (NDMS) and also into subjects with a low triglycerides/HDL-cholesterol (TG/HDL-C) index or with a high TG/HDL-C index. In the entire group and in the four subgroups of MS subjects we found an increase in TBARS and NOx levels and a decrease in TBARS/NOx ratio in comparison with normal controls. Regarding all these parameters no statistical difference between DMS and NDMS was evident, but a significant increase in NOx was present in subjects with a high TG/HDL-C index in comparison with those with a low index. In MS subjects we also found a negative correlation between TBARS/NO x ratio and TG/HDL-C index. Considering the hyperactivity of the inducible NO synthase in MS, these data confirm the altered redox and inflammatory status that characterizes the MS and suggest a link between lipid peroxidation, inflammation, and insulin resistance, evaluated as TG/HDL-C index

Lipoprotein abnormalities in chronic kidney disease and renal transplantation

Chronic kidney disease (CKD) is one of the most important risk factors for cardiovascular disease (CVD). Despite the kidney having no direct implications for lipoproteins metabolism, advanced CKD dyslipidemia is usually present in patients with CKD, and the frequent lipid and lipoprotein alterations occurring in these patients play a role of primary importance in the development of CVD. Although hypertriglyceridemia is the main disorder, a number of lipoprotein abnormalities occur in these patients. Different enzymes pathways and proteins involved in lipoprotein metabolism are impaired in CKD. In addition, treatment of uremia may modify the expression of lipoprotein pattern as well as determine acute changes. In renal transplantation recipients, the main lipid alteration is hypercholesterolemia, while hypertriglyceridemia is less pronounced. In this review we have analyzed lipid and lipoprotein disturbances in CKD and also their relationship with progression of renal disease. Hypolipidemic treatments may also change the natural history of CVD in CKD patients and may represent important strategies in the management of CKD patients

Efficacy and Safety of Ezetimibe Added to Atorvastatin Versus Atorvastatin Uptitration or Switching to Rosuvastatin in Patients With Primary Hypercholesterolemia

Hypercholesterolemic patients (n = 1,547) at high atherosclerotic cardiovascular disease risk with low-density lipoprotein cholesterol (LDL-C) levels 65100 and 64160 mg/dl while treated with atorvastatin 10 mg/day entered a multicenter, randomized, double-blind, active-controlled, clinical trial using two 6-week study periods. Period I compared the efficacy/safety of (1) adding ezetimibe 10 mg (ezetimibe) to stable atorvastatin 10 mg, (2) doubling atorvastatin to 20 mg, or (3) switching to rosuvastatin 10 mg. Subjects in the latter 2 groups who persisted with elevated LDL-C levels ( 65100 and 64160 mg/dl) after period I, entered period II; subjects on atorvastatin 20 mg had ezetimibe added to their atorvastatin 20 mg, or uptitrated their atorvastatin to 40 mg; subjects on rosuvastatin 10 mg switched to atorvastatin 20 mg plus ezetimibe or uptitrated their rosuvastatin to 20 mg. Some subjects on atorvastatin 10 mg plus ezetimibe continued the same treatment into period II. At the end of period I, ezetimibe plus atorvastatin 10 mg reduced LDL-C significantly more than atorvastatin 20 mg or rosuvastatin 10 mg (22.2% vs 9.5% or 13.0%, respectively, p <0.001). At the end of period II, ezetimibe plus atorvastatin 20 mg reduced LDL-C significantly more than atorvastatin 40 mg (17.4% vs 6.9%, p <0.001); switching from rosuvastatin 10 mg to ezetimibe plus atorvastatin 20 mg reduced LDL-C significantly more than uptitrating to rosuvastatin 20 mg (17.1% vs 7.5%, p <0.001). Relative to comparative treatments, ezetimibe added to atorvastatin 10 mg (period I) or atorvastatin 20 mg (period II) produced significantly greater percent attainment of LDL-C targets <100 or <70 mg/dl, and significantly greater percent reductions in total cholesterol, non-high-density lipoprotein cholesterol, most lipid and lipoprotein ratios, and apolipoprotein B (except ezetimibe plus atorvastatin 20 vs atorvastatin 40 mg). Reports of adverse experiences were generally similar among groups. In conclusion, treatment of hypercholesterolemic subjects at high cardiovascular risk with ezetimibe added to atorvastatin 10 or 20 mg produced significantly greater improvements in key lipid parameters and significantly greater attainment of LDL-C treatment targets than doubling atorvastatin or switching to (or doubling) rosuvastatin at the compared doses