Abstract
This 2022 European Atherosclerosis Society lipoprotein(a) Lp(a) consensus statement updates evidence for the role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic valve ...stenosis, provides clinical guidance for testing and treating elevated Lp(a) levels, and considers its inclusion in global risk estimation. Epidemiologic and genetic studies involving hundreds of thousands of individuals strongly support a causal and continuous association between Lp(a) concentration and cardiovascular outcomes in different ethnicities; elevated Lp(a) is a risk factor even at very low levels of low-density lipoprotein cholesterol. High Lp(a) is associated with both microcalcification and macrocalcification of the aortic valve. Current findings do not support Lp(a) as a risk factor for venous thrombotic events and impaired fibrinolysis. Very low Lp(a) levels may associate with increased risk of diabetes mellitus meriting further study. Lp(a) has pro-inflammatory and pro-atherosclerotic properties, which may partly relate to the oxidized phospholipids carried by Lp(a). This panel recommends testing Lp(a) concentration at least once in adults; cascade testing has potential value in familial hypercholesterolaemia, or with family or personal history of (very) high Lp(a) or premature ASCVD. Without specific Lp(a)-lowering therapies, early intensive risk factor management is recommended, targeted according to global cardiovascular risk and Lp(a) level. Lipoprotein apheresis is an option for very high Lp(a) with progressive cardiovascular disease despite optimal management of risk factors. In conclusion, this statement reinforces evidence for Lp(a) as a causal risk factor for cardiovascular outcomes. Trials of specific Lp(a)-lowering treatments are critical to confirm clinical benefit for cardiovascular disease and aortic valve stenosis.
The PCSK9 decade Lambert, Gilles; Sjouke, Barbara; Choque, Benjamin ...
Journal of lipid research,
December 2012, 2012-Dec, 2012-12-00, 20121201, 2012-12-01, Letnik:
53, Številka:
12
Journal Article
Recenzirano
Odprti dostop
PCSK9 proprotein convertase subtilisin/kexin type (PCSK9) is a crucial protein in LDL cholesterol (LDL-C) metabolism by virtue of its pivotal role in the degradation of the LDL receptor. In recent ...years, both in vitro and in vivo studies have greatly supplemented our understanding of the (patho)physiological role of PCSK9 in human biology. In the current review, we summarize studies published or in print before May 2012 concerning the physiological role of PCSK9 in cholesterol metabolism. Moreover, we briefly describe the clinical phenotypes encountered in carriers of mutations in the gene encoding PCSK9. As PCSK9 has emerged as a novel target for LDL-C lowering therapy, methods to inhibit PCSK9 will also be reviewed. Initial data from investigations of PCSK9 inhibition in humans are promising and indicate that PCSK9 inhibition may be a viable new therapeutic option for the treatment of dyslipidemia and associated cardiovascular diseases.
Familial hypercholesterolemia (FH) is one of the most common genetic disorders in humans. It is an extremely atherogenic metabolic disorder characterized by lifelong elevations of circulating LDL-C ...levels often leading to premature cardiovascular events. In this review, we discuss the clinical phenotypes of heterozygous and homozygous FH, the genetic variants in four genes (LDLR/APOB/PCSK9/LDLRAP1) underpinning the FH phenotype as well as the most recent in vitro experimental approaches used to investigate molecular defects affecting the LDL receptor pathway. In addition, we review perturbations in the metabolism of lipoproteins other than LDL in FH, with a major focus on lipoprotein (a). Finally, we discuss the mode of action and efficacy of many of the currently approved hypocholesterolemic agents used to treat patients with FH, with a special emphasis on the treatment of phenotypically more severe forms of FH.
PCSK9 and the nervous system: a no-brainer? Jaafar, Ali K.; Techer, Romuald; Chemello, Kévin ...
Journal of lipid research,
09/2023, Letnik:
64, Številka:
9
Journal Article
Recenzirano
Odprti dostop
In the past 20 years, PCSK9 has been shown to play a pivotal role in LDL cholesterol metabolism and cardiovascular health by inducing the lysosomal degradation of the LDL receptor. PCSK9 was ...discovered by the cloning of genes up-regulated after apoptosis induced by serum deprivation in primary cerebellar neurons, but despite its initial identification in the brain, the precise role of PCSK9 in the nervous system remains to be clearly established. The present article is a comprehensive review of studies published or in print before July 2023 that have investigated the expression pattern of PCSK9, its effects on lipid metabolism as well as its putative roles specifically in the central and peripheral nervous systems, with a special focus on cerebrovascular and neurodegenerative diseases.
Population studies have shown that plasma HDL levels correlate inversely with cardiovascular disease risk. In recent years there has been intense interest in developing strategies for exploiting ...these cardioprotective properties by increasing HDL levels. While this approach has considerable merit, it is important to recognize that HDL are structurally and functionally diverse and consist of numerous, highly dynamic subpopulations of particles that do not all inhibit atherosclerosis to the same extent. For this reason it is essential to assess HDL subpopulation distribution and functionality when considering therapeutic interventions that raise HDL levels. This review documents what is known about the relationship between the metabolism and function of HDL subpopulations and how this affects their cardioprotective properties.
Apolipoproteins govern lipoprotein metabolism and are promising biomarkers of metabolic and cardiovascular diseases. Unlike immunoassays, MS enables the quantification and phenotyping of multiple ...apolipoproteins. Hence, here, we aimed to develop a LC-MS/MS assay that can simultaneously quantitate 18 human apolipoproteins A-I, A-II, A-IV, A-V, B48, B100, C-I, C-II, C-III, C-IV, D, E, F, H, J, L1, M, and (a) and determined apoE, apoL1, and apo(a) phenotypes in human plasma and serum samples. The plasma and serum apolipoproteins were trypsin digested through an optimized procedure and peptides were extracted and analyzed by LC-MS/MS. The method was validated according to standard guidelines in samples spiked with known peptide amounts. The LC-MS/MS results were compared with those obtained with other techniques, and reproducibility, dilution effects, and stabilities were also assessed. Peptide markers were successfully selected for targeted apolipoprotein quantification and phenotyping. After optimization, the assay was validated for linearity, lower limits of quantification, accuracy (biases: –14.8% to 12.1%), intra-assay variability coefficients of variation (CVs): 1.5–14.2%, and inter-assay repeatability (CVs: 4.1–14.3%). Bland-Altman plots indicated no major statistically significant differences between LC-MS/MS and other techniques. The LC-MS/MS results were reproducible over five repeated experiments (CVs: 1.8–13.7%), and we identified marked differences among the plasma and serum samples. The LC-MS/MS assay developed here is rapid, requires only small sampling volumes, and incurs reasonable costs, thus making it amenable for a wide range of studies of apolipoprotein metabolism. We also highlight how this assay can be implemented in laboratories.
Assessment criteria for septic transfusion reactions (STRs) are variable around the world. A scoping review will be carried out to find out, explore and map existing literature on STRs associated ...criteria.
This scoping review will include indexed and grey literatures available in English or French language from January 1, 2000, to December 31, 2021. Literature search will be conducted using four electronic databases (i.e., MEDLINE via PubMed, Web of Science, Science Direct, and Embase via Ovid), and grey literatures accompanying the research questions and objectives. Based on the inclusion criteria, studies will be independently screened by two reviewers for title, abstract, and full text. Extracted data will be presented in tabular form followed by a narrative description of inputs corresponding to research objectives and questions.
Summary Background The focus on prevention strategies aimed at curbing the HIV epidemic is growing, and therefore screening for HIV has again taken centre stage. Our aim was to establish whether a ...convenient, non-invasive, HIV test that uses oral fluid was accurate by comparison with the same test with blood-based specimens. Methods We did a systematic review and meta-analysis to compare the diagnostic accuracy of a rapid HIV-antibody-based point-of-care test (Oraquick advance rapid HIV-1/2, OraSure Technologies Inc, PA, USA) when used with oral versus blood-based specimens in adults. We searched five databases of published work and databases of five key HIV conferences. Studies we deemed eligible were those focused on adults at risk of HIV; we excluded studies in children, in co-infected populations, with self-reported inferior reference standards, and with incomplete reporting of key data items. We assessed the diagnostic accuracy of testing with oral and blood-based specimens with bivariate regression analysis. We computed positive predictive values (PPVs) in high-prevalence and low-prevalence settings with Bayesian methods. Findings In a direct head-to-head comparison of studies, we identified a pooled sensitivity about 2% lower in oral (98·03%, 95% CI 95·85–99·08) than in blood-based specimens (99·68%, 97·31–99·96), but similar specificity (oral 99·74%, 99·47–99·88; blood 99·91%, 99·84–99·95). Negative likelihood ratios were small and similar (oral 0·019, 0.009–0·040; blood 0·003, 0·001–0·034), but positive likelihood ratios differed (oral 383·37, 183·87–799·31; blood 1105·16, 633·14–2004·37). Although in high-prevalence settings PPVs were similar (oral 98·65%, 95% credible interval 85·71–99·94; blood 98·50, 93·10–99·79), in low-prevalence settings PPVs were lower for oral (88·55%, 77·31–95·87) than blood (97·65%, 95·48–99·09) specimens. Interpretation Although Oraquick had a high PPV in high-prevelence settings in oral specimens, the slightly lower sensitivity and PPV in low-prevalence settings in oral specimens should be carefully reviewed when planning worldwide expanded initiatives with this popular test. Funding Canadian Institutes for Health Research (CIHR KRS 102067).
Proprotein convertase subtilisin–kexin type 9 (PCSK9) is a key regulator of low density lipoprotein (LDL) receptor processing, but the PCSK9 pathway may also be implicated in the metabolism of ...triglyceride-rich lipoproteins. Here we determined the relationship of plasma PCSK9 with very low density lipoprotein (VLDL) and LDL subfractions.
The relationship of plasma PCSK9 (sandwich enzyme-linked immunosorbent assay) with 3 very low density lipoprotein (VLDL) and 3 low density lipoprotein (LDL) subfractions (nuclear magnetic resonance spectroscopy) was determined in 52 subjects (30 women).
In age- and sex-adjusted analysis plasma PCSK9 was correlated positively with total cholesterol, non-high density lipoprotein cholesterol and LDL cholesterol (r=0.516 to 0.547, all p<0.001), as well as with triglycerides (r=0.286, p=0.044). PCSK9 was correlated with the VLDL particle concentration (r=0.336, p=0.017) and with the LDL particle concentration (r=0.362, p=0.010), but only the relationship with the LDL particle concentration remained significant in multivariable linear regression analysis. In an analysis which included the 3 LDL subfractions, PCSK9 was independently related to intermediate density lipoproteins (IDL) (p<0.001), but not to other LDL subfractions.
This study suggests that plasma PCSK9 predominantly relates to IDL, a triglyceride-rich LDL subfraction. The PCSK9 pathway may affect plasma triglycerides via effects on the metabolism of triglyceride-rich LDL particles.
•The PCSK9 system regulates low density lipoprotein (LDL) receptor availability.•Plasma PCSK9 levels relate positively to LDL cholesterol as well as to triglycerides.•We determined relations of PCSK9 with lipoprotein subfractions (NMR spectroscopy).•In 52 subjects, plasma PCSK9 was related to intermediate density lipoproteins (IDL).•Plasma PCSK9 may influence triglyceride levels via effects on IDL metabolism.
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