Atherosclerosis is a complex process involving the build-up of arterial plaque incorporating low-density lipoprotein cholesterol (LDL-C) and an inflammatory response. Lowering plasma LDL-C confers ...cardiovascular benefit for patients with hypercholesterolemia resulting from genetic and/or lifestyle factors. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of LDL-C metabolism. Secreted from liver cells, circulating PCSK9 binds to the LDL receptor and is subsequently internalized with the receptor, thereby promoting its cellular degradation. As a result, PCSK9 gain-of-function mutations are causatively associated with familial hypercholesterolemia, whereas PCSK9 loss-of-function mutations are associated with very low LDL-C levels and a reduced cardiovascular risk. Preventing PCSK9-mediated LDL receptor degradation with monoclonal antibodies is a novel strategy to further lower LDL-C, especially in patients with severe forms of hypercholesterolemia with elevated LDL-C despite maximal conventional treatment and/or in those intolerant to conventional therapies. Here, the safety and efficacy of these novel therapeutic agents targeting PCSK9 will be discussed with respect to recent clinical trials targeting this molecule, as well as inherited hypolipidemias and animal models that confer very low LDL-C because of PCSK9 deficiency.
The aim of this review is to place a historical perspective on linking dyslipidaemia with atherosclerosis and emphasises previous knowledge about the impact on the lipoprotein profile and health in ...persons with mild dyslipidaemia and in those with defined genetic disorders. CVD is becoming the leading cause of death and disability in developed and developing countries and is strongly related to lifestyle factors that influence plasma lipoprotein concentrations. It is established that risk of complications from atherosclerosis increases with increasing LDL and decreasing HDL and that there is potentiation of risk when these and other risk factors co-exist. High-fat diets used for losing body mass may increase risk through dyslipidaemia. Pharmaceutical modulation of the lipoproteins has lowered risk powerfully but residual risk persists, possibly relating to existing disease as well as progression relating in many instances to dietary lipids. The impact of various dietary lipids is reviewed as they relate to the conventional lipoprotein profile in persons who do not have significant metabolic defects, as well as the impact on inherited metabolic disease such as familial hypercholesterolaemia, hypertriglyceridaemia and phytosterolaemia. For most persons with dyslipidaemias a significant benefit will be seen on the lipid profile by adopting a low saturated fat diet with less cholesterol intake.
Homozygous familial hypercholesterolemia is an inherited disorder caused by mutations in both low-density lipoprotein receptor alleles, which results in extremely elevated plasma low-density ...lipoprotein cholesterol concentrations and very early morbidity and mortality due to cardiovascular disease.
To evaluate the impact of advances in lipid-lowering (predominantly statin) therapy on cardiovascular disease morbidity and mortality in a large cohort of patients with homozygous familial hypercholesterolemia, the records of 149 patients (81 females, 68 males) from 2 specialized lipid clinics in South Africa were evaluated retrospectively. Homozygous familial hypercholesterolemia was diagnosed by confirmation of mutations in genes affecting low-density lipoprotein cholesterol or by clinical criteria. A Cox proportional hazard model with time-varying exposure was used to estimate the risk of death and major adverse cardiovascular events among statin-treated patients compared with statin-naive patients. The hazard ratio for benefit from lipid therapy, calculated with the Cox proportional hazards model for the end point of death, was 0.34 (95% confidence interval 0.14-0.86; P=0.02), and for the end point of major adverse cardiovascular events, it was 0.49 (95% confidence interval 0.22-1.07; P=0.07). This occurred despite a mean reduction in low-density lipoprotein cholesterol of only 26.4% (from 15.9±3.9 to 11.7±3.4 mmol/L; P<0.0001) with lipid-lowering therapy.
Lipid-lowering therapy is associated with delayed cardiovascular events and prolonged survival in patients with homozygous familial hypercholesterolemia.
Statins are well-known cholesterol lowering drugs targeting HMG-CoA-reductase, reducing the risk of coronary disorders and hypercholesterolemia. Statins are also involved in immunomodulation, which ...might influence the outcome of bacterial infection. Hence, a possible effect of statin treatment on Listeriosis was explored in mice. Statin treatment prior to subsequent L. monocytogenes infection strikingly reduced bacterial burden in liver and spleen (up to 100-fold) and reduced histopathological lesions. Statin-treatment in infected macrophages resulted in increased IL-12p40 and TNF-α and up to 4-fold reduced bacterial burden within 6 hours post infection, demonstrating a direct effect of statins on limiting bacterial growth in macrophages. Bacterial uptake was normal investigated in microbeads and GFP-expressing Listeria experiments by confocal microscopy. However, intracellular membrane-bound cholesterol level was decreased, as analyzed by cholesterol-dependent filipin staining and cellular lipid extraction. Mevalonate supplementation restored statin-inhibited cholesterol biosynthesis and reverted bacterial growth in Listeria monocytogenes but not in listeriolysin O (LLO)-deficient Listeria. Together, these results suggest that statin pretreatment increases protection against L. monocytogenes infection by reducing membrane cholesterol in macrophages and thereby preventing effectivity of the cholesterol-dependent LLO-mediated phagosomal escape of bacteria.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Glucocorticoids have multiple therapeutic uses, but their impact on lipid metabolism and cardiovascular disease risk is not always considered during long-term treatment. Genetic variations, ...environmental factors and the reasons for glucocorticoid treatment all influence the lipid profile and atherosclerosis. Responses to glucocorticoid treatment may therefore be variable and unpredictable. Despite the frequency with which pharmacological doses of glucocorticoids are used, surprisingly few publications examine their effects on lipid metabolism and atherosclerosis. Patients managed with glucocorticoids should have their cardiovascular risk assessed, especially if long-term treatment is planned. While some apparent favourable changes have been reported in high-density lipoprotein metabolism, very-low-density lipoprotein and low-density lipoprotein responses seem unfavourable. The impact of glucocorticoids on atherosclerosis, which is often viewed as an inflammatory process, is unclear. Glucocorticoid treatment should be undertaken for appropriate indications, but in some instances special attention should be given to management of dyslipidaemia, as long-term survivors of treatment are likely to encounter atherosclerosis.
Abstract
The optical radiation emitted by blazars contains contributions from synchrotron radiation by relativistic electrons in the jets, as well as thermal radiation emitted mainly by the accretion ...disk (AD), the broad-line region (BLR), and the host galaxy. The unpolarized radiation components from the AD, BLR, and host galaxy present themselves by decreasing the total polarization in the optical/ultraviolet (UV) spectrum. A combined model for the spectral energy distribution (SED) and degree of optical/UV polarization is constructed, enabling the disentanglement of the synchrotron and AD components. Our model is applied to the multiwavelength SED and spectropolarimetry observations of the flat-spectrum radio quasar 4C+01.02 (
z
= 2.1) in its 2016 July–August flaring state and 2017 July–August quiescent state, using data from the Fermi Large Area Telescope, the Southern African Large Telescope, and the Las Cumbres Observatory network of telescopes. By constraining the AD component, the mass of the supermassive black hole is obtained as ∼3 × 10
9
M
⊙
. Furthermore, the model retrieves the characteristics of the relativistic electron distribution in the jet and the degree of ordering of the magnetic field. Our results highlight the potential of spectropolarimetry observations for disentangling thermal from nonthermal (jet) emission components, thus revealing the physics of particle acceleration and high-energy emission in active galactic nucleus jets.
In a 2-year clinical trial, the addition of ezetimibe to simvastatin had no effect on the progression of atherosclerosis, as measured by carotid-artery intima–media thickness, despite the additional ...lowering of levels of low-density lipoprotein cholesterol and C-reactive protein by ezetimibe when added to simvastatin. However, the study was not powered to assess clinical end points.
The addition of ezetimibe to simvastatin had no effect on the progression of atherosclerosis, as measured by carotid-artery intima–media thickness, despite the additional lowering of levels of low-density lipoprotein cholesterol and C-reactive protein.
A reduction in levels of low-density lipoprotein (LDL) cholesterol constitutes one of the cornerstones in the prevention of cardiovascular disease. In recent trials comparing various statins or the same statin at various doses, aggressive therapy to lower LDL cholesterol levels was associated with a reduction in rates of cardiovascular events.
1
–
4
However, administration of the highest approved statin dose offers only limited additional lowering of LDL cholesterol at the expense of an increased incidence of side effects.
5
Therefore, novel compounds that further reduce LDL cholesterol levels when added to statin therapy are of interest. A recently introduced compound, ezetimibe, selectively . . .
Objectives Do elevated proprotein convertase subtilisin/kexin type 9 (PCSK9) levels constitute an even greater risk for patients who already have reduced low-density lipoprotein receptor (LDLR) ...levels, such as those with heterozygous familial hypercholesterolemia (HeFH)? Background As a circulating inhibitor of LDLR, PCSK9 is an attractive target for lowering LDL-cholesterol (LDL-C) levels. Methods Circulating PCSK9 levels were measured by enzyme-linked immunosorbent assay in nontreated patients with HeFH carrying a D206E (n = 237), V408M (n = 117), or D154N (n = 38) LDLR missense mutation and in normolipidemic controls (n = 152). Skin fibroblasts and lymphocytes were isolated from a subset of patients and grown in 0.5% serum and mevastatin with increasing amounts of recombinant PCSK9. LDLR abundance at the cell surface was determined by flow cytometry. Results PCSK9 reduced LDLR expression in a dose-dependent manner in control and FH fibroblasts to similar extents, by up to 77 ± 8% and 82 ± 7%, respectively. Likewise, PCSK9 reduced LDLR abundance by 39 ± 8% in nonfamilial hypercholesterolemia (non-FH) and by 45 ± 10% in HeFH lymphocytes, irrespective of their LDLR mutation status. We found positive correlations of the same magnitude between PCSK9 and LDL-C levels in controls (beta = 0.22; p = 0.0003), D206E (beta = 0.20; p = 0.0002), V408M (beta = 0.24; p = 0.0002), and D154N (beta = 0.25; p = 0.048) patients with HeFH. The strengths of these associations were all similar. Conclusions Elevated PCSK9 levels are equally detrimental for patients with HeFH or non-FH: a 100-ng/ml increase in PCSK9 will lead to an increase in LDL-C of 0.20 to 0.25 mmol/l in controls and HeFH alike, irrespective of their LDLR mutation. This explains why patients with non-FH or HeFH respond equally well to monoclonal antibodies targeting PCSK9.
Objective To determine the safety and efficacy of atorvastatin (10 to 20 mg) in children and adolescents with familial hypercholesterolemia or severe hypercholesterolemia.
Study design Subjects ...(n=187) were randomly assigned to 26 weeks of treatment with atorvastatin (10 mg) or placebo. Dosage was increased to 20 mg if LDL cholesterol (LDL-C) levels remained >3.4 mmol/L (130 mg/dL) at week 4. At week 26, subjects received 10 mg of atorvastatin for an additional 26 weeks. Efficacy variables included percent changes in LDL-C, total cholesterol, triglycerides, HDL cholesterol, and apolipoprotein B from baseline to week 26.
Results Atorvastatin caused a highly significant reduction in LDL-C compared with placebo (−40% vs −0.4%, respectively; P<.001). Percent changes at week 26 also significantly favored atorvastatin for total cholesterol (−32% vs −1.5%; P<.001), triglycerides (−12% vs +1.0%; P=0.03), and apolipoprotein B (−34% vs +0.7%; P<.001), with a significantly greater increase in HDL cholesterol with atorvastatin compared with placebo (+2.8% vs −1.8%; P=.02). Atorvastatin was as well-tolerated as placebo.
Conclusions Treatment with atorvastatin for 12 months was effective and safe for pediatric subjects with known familial hypercholesterolemia or severe hypercholesterolemia.
Loss-of-function mutations in
cause familial partial lipodystrophy type 3 (FPLD3) and severe metabolic disease in many patients. Missense mutations in
are present in ∼1 in 500 people. Although ...mutations are often binarily classified as benign or deleterious, prospective functional classification of all missense
variants suggests that their impact is graded. Furthermore, in testing novel mutations with both prototypic endogenous (e.g., prostaglandin J2 PGJ2) and synthetic ligands (thiazolidinediones, tyrosine agonists), we observed that synthetic agonists selectively rescue function of some peroxisome proliferator-activated receptor-γ (PPARγ) mutants. We report on patients with FPLD3 who harbor two such PPARγ mutations (R308P and A261E). Both PPARγ mutants exhibit negligible constitutive or PGJ2-induced transcriptional activity but respond readily to synthetic agonists in vitro, with structural modeling providing a basis for such differential ligand-dependent responsiveness. Concordant with this finding, dramatic clinical improvement was seen after pioglitazone treatment of a patient with R308P mutant PPARγ. A patient with A261E mutant PPARγ also responded beneficially to rosiglitazone, although cardiomyopathy precluded prolonged thiazolidinedione use. These observations indicate that detailed structural and functional classification can be used to inform therapeutic decisions in patients with
mutations.
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