Cholesterol efflux capacity is increased in subjects with familial hypercholesterolemia in a retrospective case-control study.

Familial Hypercholesterolemia (FH) is characterized by an increase in Low-Density Lipoprotein Cholesterol (LDL-C) and by premature Cardiovascular Disease (CVD). However, it remains to be fully elucidated if FH impairs cholesterol efflux capacity (CEC), and whether CEC is related to lipoprotein subfraction distribution. This study aimed at comparing FH patients and age, sex and BMI matched controls in terms of LDL and HDL subfraction distribution as well as CEC. Forty FH patients and 80 controls, matched for age, sex and BMI, were enrolled in this case-control study. LDL and HDL subfractions were analyzed using the Quantimetrix Lipoprint System. CEC was evaluated as aq-CEC and ABCA1-CEC. FH subjects showed a significantly higher concentration of all LDL subfractions, and a shift from large to small HDL subfraction pattern relative to controls. FH subjects with previous CVD event had smaller LDL lipoproteins than controls and FH subjects without previous CVD event. Both aq-CEC and ABCA1-CEC were increased in FH patients with respect to controls. To conclude, FH subjects had a metabolic profile characterized not only by higher LDL-C but also by shift from large to small HDL subfraction phenotype. However, FH subjects showed an increase CEC than controls.

Long-term efficacy of lipoprotein apheresis and lomitapide in the treatment of homozygous familial hypercholesterolemia (HoFH): a cross-national retrospective survey.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare life-threatening condition that represents a therapeutic challenge. The vast majority of HoFH patients fail to achieve LDL-C targets when treated with the standard protocol, which associates maximally tolerated dose of lipid-lowering medications with lipoprotein apheresis (LA). Lomitapide is an emerging therapy in HoFH, but its place in the treatment algorithm is disputed because a comparison of its long-term efficacy versus LA in reducing LDL-C burden is not available. We assessed changes in long-term LDL-C burden and goals achievement in two independent HoFH patients' cohorts, one treated with lomitapide in Italy (n = 30) and the other with LA in France (n = 29). RESULTS: The two cohorts differed significantly for genotype (p = 0.004), baseline lipid profile (p < 0.001), age of treatment initiation (p < 0.001), occurrence of cardiovascular disease (p = 0.003) as well as follow-up duration (p < 0.001). The adjunct of lomitapide to conventional lipid-lowering therapies determined an additional 58.0% reduction of last visit LDL-C levels, compared to 37.1% when LA was added (padj = 0.004). Yearly on-treatment LDL-C < 70 mg/dl and < 55 mg/dl goals were only achieved in 45.5% and 13.5% of HoFH patients treated with lomitapide. The long-term exposure to LDL-C burden was found to be higher in LA than in Lomitapide cohort (13,236.1 ± 5492.1 vs. 11,656.6 ± 4730.9 mg/dL-year respectively, padj = 0.002). A trend towards fewer total cardiovascular events was observed in the Lomitapide than in the LA cohort. CONCLUSIONS: In comparison with LA, lomitapide appears to provide a better control of LDL-C in HoFH. Further studies are needed to confirm this data and establish whether this translates into a reduction of cardiovascular risk.

Successful fenofibrate therapy for severe and persistent hypertriglyceridemia in a boy with cirrhosis and glycerol-3-phosphate dehydrogenase 1 deficiency.

Glycerol-3-phosphate dehydrogenase 1 deficiency is a rare autosomal recessive disorder caused by mutations in the GPD1 gene (GPD1; OMIM*138420). Very few cases are reported in literature. It usually manifests in early infancy with transient hypertriglyceridemia, hepatomegaly, steatosis, and fibrosis. We report the case of a 16-year-old boy followed since the age of 1 year for hepatomegaly, elevated liver enzymes, and persistent hypertriglyceridemia. Abdominal ultrasound showed diffuse liver echogenicity and liver biopsy disclosed cirrhosis with micro and macrovesicular steatosis. Next-generation sequencing for metabolic and genetic liver diseases was conducted with the identification of the homozygous mutation c.895G>A in GPD1 gene resulting in the aminocidic substitution p.G299R. Considering the persistent and progressive increase of plasma triglycerides, fenofibrate treatment was started at 15 years of age allowing triglyceride level reduction in the following 1-year follow-up.

Distribution of Paraoxonase-1 (PON-1) and Lipoprotein Phospholipase A2 (Lp-PLA2) across Lipoprotein Subclasses in Subjects with Type 2 Diabetes.

Paraoxonase-1 (PON1) and lipoprotein phospholipase A2 (Lp-PLA2) may exert an important protective role by preventing the oxidative transformation of high- and low-density lipoproteins (HDL and LDL, respectively). The activity of both enzymes is influenced by lipidome and proteome of the lipoprotein carriers. T2DM typically presents significant changes in the molecular composition of the lipoprotein subclasses. Thus, it becomes relevant to understand the interaction of PON1 and Lp-PLA2 with the subspecies of HDL, LDL, and other lipoproteins in T2DM. Serum levels of PON1-arylesterase and PON1-lactonase and Lp-PLA2 activities and lipoprotein subclasses were measured in 202 nondiabetic subjects (controls) and 92 T2DM outpatients. Arylesterase, but not lactonase or Lp-PLA2 activities, was inversely associated with TD2M after adjusting for potential confounding factors such as age, sex, smoking, body mass index, hypertension, and lipoprotein subclasses (odds ratio = 3.389, 95% confidence interval 1.069-14.756). Marked difference between controls and T2DM subjects emerged from the analyses of the associations of the three enzyme activities and lipoprotein subclasses. Arylesterase was independently related with large HDL-C and small intermediate-density lipoprotein cholesterol (IDL-C) in controls while, along with lactonase, it was related with small low-density lipoprotein cholesterol LDL-C, all IDL-C subspecies, and very low-density lipoprotein cholesterol (VLDL-C) in T2DM (p < 0.05 for all). Concerning Lp-PLA2, there were significant relationships with small LDL-C, large IDL-C, and VLDL-C only among T2DM subjects. Our study showed that T2DM subjects have lower levels of PON1-arylesterase compared to controls and that T2DM occurrence may coincide with a shift of PON1 and Lp-PLA2 towards the more proatherogenic lipoprotein subclasses. The possibility of a link between the two observed phenomena requires further investigations.

Combining LDL-C and HDL-C to predict survival in late life: The InChianti study.

BACKGROUND: While the relationship between total cholesterol (TC) and cardiovascular disease (CVD) progressively weakens with aging, several studies have shown that low TC is associated with increased mortality in older individuals. However, the possible additive/synergic contribution of the two most important cholesterol rich fractions (LDL-C and HDL-C) to mortality risk has not been previously investigated. Our study aimed to investigate the relationship between baseline LDL-C and HDL-C, both separately and combined, and 9-years mortality in a sample of community dwelling older individuals from the InCHIANTI study. METHODS AND FINDINGS: 1044 individuals over 64 years were included. CVD and cancer mortality were defined by ICD-9 codes 390-459 and 140-239, respectively. LDL-C <130 mg/dL (3.36 mmol/L) was defined as "optimal/near optimal". Low HDL-C was defined as <40/50 mg/dL (1.03/1.29 mmol/L) in males/females, respectively. Nine-years mortality risk was calculated by multivariate Cox proportional hazards model. We found that, compared to subjects with high LDL-C and normal HDL-C (reference group), total mortality was significantly increased in subjects with optimal/near optimal LDL-C and low HDL-C (H.R.:1.58; 95%CI:1.11-2.25). As regards the specific cause of death, CVD mortality was not affected by LDL-C/HDL-C levels, while cancer mortality was significantly increased in all subjects with optimal/near optimal LDL-C (with normal HDL-C: H.R.: 2.49; with low HDL-C: H.R.: 4.52). Results were unchanged after exclusion of the first three years of follow-up, and of subjects with low TC (<160 g/dL-4.13 mmol/L). CONCLUSIONS: Our findings suggest that, in community dwelling older individuals, the combined presence of optimal/near optimal LDL-C and low HDL-C represents a marker of increased future mortality.

Efficacy of Lomitapide in the Treatment of Familial Homozygous Hypercholesterolemia: Results of a Real-World Clinical Experience in Italy.

INTRODUCTION: Homozygous familial hypercholesterolaemia (HoFH) is a rare form of inherited dyslipidemia resistant to conventional cholesterol-lowering medications so that lipoprotein apheresis (LA) is usually required. Lomitapide has been approved for the treatment of HoFH. The aim of this study was to evaluate the benefits of lomitapide in HoFH patients followed with the usual clinical care. METHODS: Clinical and biochemical data were retrospectively collected in 15 HoFH patients (10 with mutations in the LDLR gene and 5 in the LDLRAP1 gene) treated for at least 6 months with lomitapide in addition to lipid-lowering therapies (LLT) in different Lipid Clinics across Italy. RESULTS: The mean follow-up period was 32.3 ± 29.7 months. During background therapies, HoFH patients showed a mean LDL-C level of 426.0 ± 204.0 mg/dl. The addition of lomitapide at the average dosage of 19 mg/day lowered LDL-C levels by 68.2 ± 24.8%. At their last visit, 60% of patients showed LDL-C <100 mg/dl and 46.6% <70 mg/dl. During follow-up, 8 of 10 patients receiving LA (80%) stopped this treatment due to marked LDL-C reduction. A wide range (13-95%) of individual LDL-C reduction was observed, but this was not related to genotype. During follow-up, 53.3% of patients reported at least one episode of diarrhea, but none was referred as severe; none had liver transaminase >5× ULN or had to stop treatment due to side effects. A subset of patients was evaluated by liver ultrasound and fibroscan (n = 5) or nuclear magnetic resonance with spectroscopy (MRS) (n = 1) not showing clinical evidence of liver damage. CONCLUSION: In this real-world experience, lomitapide was confirmed to be a very powerful cholesterol-lowering agent in HoFH showing a good safety profile.

Bilateral strio-pallido-dentate calcinosis (Fahr's disease): report of seven cases and revision of literature.

BACKGROUND: Fahr's disease is rare a neurodegenerative idiopathic condition characterized by symmetric and bilateral calcifications of basal ganglia, usually associated with progressive neuropsychiatric dysfunctions and movement disorders. The term "Fahr's syndrome" is used in presence of calcifications secondary to a specific cause, but the variability of etiology, pathogenesis, and clinical picture underlying this condition have raised the question of the real existence of a syndrome. Several classifications based on the etiology, the location of brain calcifications and the clinical presentation have been proposed. Here we describe seven clinical cases of basal ganglia calcifications, in order to search for pathognomonic features and correlations between clinical picture and imaging findings. CASES PRESENTATION: The patients came to our attention for different reasons (most of them for memory/behavior disturbances); all underwent neuro-psychologic evaluation and neuro-imaging. All patients showed variable degrees of deterioration in cognitive function; anxiety and depression were frequent too, and resistant to treatment in all cases. Less frequent, but severe if present, were psychotic symptoms, with different grade of structure and emotional involvement, and always resistant to treatment. We observed only few cases of extrapyramidal disorders related to the disease itself; anyway, mild extrapyramidal syndrome occurred quite frequently after treatment with antipsychotics. CONCLUSION: Based on these findings we discourage the use of the term "Fahr's syndrome", and suggest to refer to Idiopathic or Secondary basal ganglia calcification. Unlike early onset forms (idiopathic or inherited), the clinical presentation of late onset form and Secondary basal ganglia calcification seems to be really heterogeneous. Case-control studies are necessary to determine the actual significance of basal ganglia calcification in the adult population and in the elderly, in cognitive, physical and emotional terms.

Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study.

BACKGROUND: Patients with homozygous familial hypercholesterolaemia respond inadequately to existing drugs. We aimed to assess the efficacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in adults with this disease. METHODS: We did a single-arm, open-label, phase 3 study of lomitapide for treatment of patients with homozygous familial hypercholesterolemia. Current lipid lowering therapy was maintained from 6 weeks before baseline through to at least week 26. Lomitapide dose was escalated on the basis of safety and tolerability from 5 mg to a maximum of 60 mg a day. The primary endpoint was mean percent change in levels of LDL cholesterol from baseline to week 26, after which patients remained on lomitapide through to week 78 for safety assessment. Percent change from baseline to week 26 was assessed with a mixed linear model. FINDINGS: 29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the efficacy phase (26 weeks) and the full study (78 weeks). The median dose of lomitapide was 40 mg a day. LDL cholesterol was reduced by 50% (95% CI -62 to -39) from baseline (mean 8·7 mmol/L [SD 2·9]) to week 26 (4·3 mmol/L [2·5]; p<0·0001). Levels of LDL cholesterol were lower than 2·6 mmol/L in eight patients at 26 weeks. Concentrations of LDL cholesterol remained reduced by 44% (95% CI -57 to -31; p<0·0001) at week 56 and 38% (-52 to -24; p<0·0001) at week 78. Gastrointestinal symptoms were the most common adverse event. Four patients had aminotransaminase levels of more than five times the upper limit of normal, which resolved after dose reduction or temporary interruption of lomitapide. No patient permanently discontinued treatment because of liver abnormalities. INTERPRETATION: Our study suggests that treatment with lomitapide could be a valuable drug in the management of homozygous familial hypercholesterolaemia. FUNDING: FDA Office of the Orphan Product Development, Aegerion Pharmaceuticals.

The benefit and risk of testosterone replacement therapy in older men: effects on lipid metabolism.

Over the last decades, testosterone replacement therapy for middle-aged and older men has been gaining increasing and widespread attention and popularity. Although several benefits of testosterone replacement therapy are well established, including but not limited to improvement in libido, body composition, and bone density, concerns for multiple potential adverse effects remain. In particular, concerns are frequently raised regarding the possibility that testosterone replacement therapy may increase the risks of prostate cancer and cardiovascular disease as consequence of a potential detrimental effect of testosterone on cardiovascular risk factors. This mini-review will present and discuss the current knowledge on the relationship between testosterone replacement therapy and change in lipid fractions in older men.

Effect of a standardized grape seed extract on low-density lipoprotein susceptibility to oxidation in heavy smokers.

The aim of our study was to evaluate the effect of a standardized formulation of a polyphenolic extract of grapes (Leucoselect-Phytosome [LP]) on low-density lipoprotein (LDL) susceptibility to oxidation in a group of heavy smokers. A randomized, double-blind, crossover study was undertaken in 24 healthy male heavy smokers, aged > or = 50 years. Enrolled subjects were given 2 capsules twice daily for 4 weeks (phase 1). Each capsule contained 75 mg of a grape procyanidin extracts and soy-phosphatidlcholine or placebo consisiting of 75 mg lactose and soy-phosphatidlcholine. A wash out period of 3 weeks was then followed by 4 weeks of the opposite treatment (phase 2). Blood samples were taken at baseline and at the end of each phase and assayed for plasma lipids and LDL susceptibility to oxidation. Compliance was good, and no adverse effects were recorded. Subjects did not show significant modification of total cholesterol (TC), triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C) and LDL-C during LP treatment. Among oxidative indices, thiobarbituric acid reactive substances (TBARS) concentration was significantly reduced in subjects taking LP (-14.7% +/- 21.1% v +5.0% +/- 18.1%, P <.01), and the lag phase prolonged (+15.4% +/- 24.4% v -0.1% +/- 16.0%, P <.05) compared with placebo and basal values. The antioxidant potential of grape seed extract polyphenols may prove effective in a model of oxidative stress (smoking); however more investigational data are needed before use in wider clinical settings.

[Dyslipidemia and global cardiovascular risk: treatment guidelines]. / Dislipidemie e rischio cardiovascolare globale: linee guida per il trattamento.

Epidemiological studies identified several risk factors as cardiovascular disease correlates, including smoking, obesity, hypertension, diabetes, and increased plasma lipids. High blood cholesterol, and in particular LDL cholesterol levels, represents a major determinant of coronary artery disease, in particular when included in the context of a comprehensive risk profile. The more recent guidelines (especially NCEP ATP III in the United States, and the European Joint Task Force) have suggested the opportunity to favor treatment of those subjects with higher global cardiovascular risk, first of all of those individuals with coronary artery disease or another cardiovascular manifestation or diabetes, then of subjects with clustered risk factors or with markedly raised levels of single risk factors, eventually of other subjects. In this perspective the treatment also of slight dyslipidemias has been shown capable of reducing cardiovascular event incidence and mortality. Recent investigations, aiming at evaluating the impact of these "clinical recommendations" in the treatment of dyslipidemias or other cardiovascular risk factors within a framework of high global cardiovascular risk (EURO-ASPIRE II, L-TAP, etc.), showed inadequate attention of community-based medicine, disclosed by the insufficient number of subjects investigated and by the large number of untreated or undertreated patients. Rosuvastatin, a recently marketed inhibitor of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, is an effective drug which may normalize high plasma cholesterol among high-risk subjects more often than other similar molecules, thus permitting to reach stringent guideline lipid targets. It is hoped that coronary risk charts based on Italian data will be implemented, with the purpose of better finding and treating those subjects who may benefit, at a suitable level of cardiovascular risk.