Plasma Lp Concentrations Research Articles

A Polynesian-specific SLC22A3 variant associates with low plasma lipoprotein(a) concentrations independent of apo(a) isoform size in males.

Lipoprotein(a) (Lp(a)) is a low-density lipoprotein (LDL)-like particle in which the apolipoprotein B component is covalently linked to apolipoprotein(a) (apo(a)). Lp(a) is a well-established independent risk factor for cardiovascular diseases. Plasma Lp(a) concentrations vary enormously between individuals and ethnic groups. Several nucleotide polymorphisms in the SLC22A3 gene associate with Lp(a) concentration in people of different ethnicities. We investigated the association of a Polynesian-specific (Māori and Pacific peoples) SLC22A3 gene coding variant p.Thr44Met) with the plasma concentration of Lp(a) in a cohort of 302 healthy Polynesian males. An apo(a)-size independent assay assessed plasma Lp(a) concentrations; all other lipid and apolipoprotein concentrations were measured using standard laboratory techniques. Quantitative real-time polymerase chain reaction was used to determine apo(a) isoforms. The range of metabolic (HbA1c, blood pressure, and blood lipids) and blood lipid variables were similar between the non-carriers and carriers in age, ethnicity and BMI adjusted models. However, rs8187715 SLC22A3 variant was significantly associated with lower Lp(a) concentrations. Median Lp(a) concentration was 10.60 nmol/L (IQR: 5.40-41.00) in non-carrier group, and was 7.60 nmol/L (IQR: 5.50-12.10) in variant carrier group (P<0.05). Lp(a) concentration inversely correlated with apo(a) isoform size. After correction for apo(a) isoform size, metabolic parameters and ethnicity, the association between the SLC22A3 variant and plasma Lp(a) concentration remained. The present study is the first to identify the association of this gene variant and low plasma Lp(a) concentrations. This provides evidence for better guidance on ethnic specific cut-offs when defining 'elevated' and 'normal' plasma Lp(a) concentrations in clinical applications.

Changes in Lipoprotein(a) Levels in People after ST Elevation Myocardial Infarction-The STEMI-Lipids Study.

Lipoprotein(a) (Lp(a)) is considered an independent risk factor for cardiovascular diseases. The plasma concentration of Lp(a) is largely genetically determined but varies over a wide range within the population. This study investigated changes in Lp(a) levels after an acute myocardial infarction. Patients who underwent coronary angiography due to an ST elevation myocardial infarction were enrolled (n = 86), and Lp(a) levels were measured immediately after the intervention, one day, two days, and at a post-discharge follow-up visit at 3 to 6 months after the acute myocardial infarction. Median Lp(a) levels increased from a median of 7.9 mg/dL (3.8-37.1) at hospital admission to 8.4 mg/dL (3.9-35.4) on the following day, then to 9.3 mg/dL (3.7-39.1) on day two (p < 0.001), and to 11.2 mg/dL (4.4-59.6) at the post-discharge follow-up (p < 0.001). Lp(a) levels were the lowest during the acute myocardial infarction and started to increase significantly immediately thereafter, with the highest levels at the post-discharge follow-up. The moderate but significant increase in Lp(a) in people with acute myocardial infarction appears to be clinically relevant on an individual basis, especially when specific Lp(a) cut-off levels are supposed to determine the initiation of future treatment. Hence, a repeated measurement of Lp(a) after myocardial infarction should be performed.

Atherogenic Lipoproteins for the Statin Residual Cardiovascular Disease Risk

Randomized controlled trials (RCTs) show that decreases in low-density lipoprotein cholesterol (LDL-C) by the use of statins cause a significant reduction in the development of cardiovascular disease (CVD). However, one of our previous studies showed that, among eight RCTs that investigated the effect of statins vs. a placebo on CVD development, 56-79% of patients had residual CVD risk after the trials. In three RCTs that investigated the effect of a high dose vs. a usual dose of statins on CVD development, 78-87% of patients in the high-dose statin arms still had residual CVD risk. The risk of CVD development remains even when statins are used to strongly reduce LDL-C, and this type of risk is now regarded as statin residual CVD risk. Our study shows that elevated triglyceride (TG) levels, reduced high-density lipoprotein cholesterol (HDL-C), and the existence of obesity/insulin resistance and diabetes may be important metabolic factors that determine statin residual CVD risk. Here, we discuss atherogenic lipoproteins that were not investigated in such RCTs, such as lipoprotein (a) (Lp(a)), remnant lipoproteins, malondialdehyde-modified LDL (MDA-LDL), and small-dense LDL (Sd-LDL). Lp(a) is under strong genetic control by apolipoprotein (a), which is an LPA gene locus. Variations in the LPA gene account for 91% of the variability in the plasma concentration of Lp(a). A meta-analysis showed that genetic variations at the LPA locus are associated with CVD events during statin therapy, independent of the extent of LDL lowering, providing support for exploring strategies targeting circulating concentrations of Lp(a) to reduce CVD events in patients receiving statins. Remnant lipoproteins and small-dense LDL are highly associated with high TG levels, low HDL-C, and obesity/insulin resistance. MDA-LDL is a representative form of oxidized LDL and plays important roles in the formation and development of the primary lesions of atherosclerosis. MDA-LDL levels were higher in CVD patients and diabetic patients than in the control subjects. Furthermore, we demonstrated the atherogenic properties of such lipoproteins and their association with CVD as well as therapeutic approaches.

New Horizons: Revival of Lipoprotein (a) as a Risk Factor for Cardiovascular Disease.

The status of lipoprotein (a) [Lp(a)] as a cardiovascular risk factor has been resurrected by advances in genetics. Mendelian randomization studies show a causal link of Lp(a) with coronary artery disease (CAD), peripheral artery disease (PAD), and calcific aortic valve stenosis (CAVS). The genetics of Lp(a) is complex and extends beyond the kringle-IV type 2, as it is also dependent on ancestry. The plasma concentration of Lp(a) is determined by the hepatic production of apolipoprotein(a) [apo(a)] component of Lp(a), supporting the use of nucleic acids that inhibit the messenger RNA (mRNA) gene transcript for apo(a). Analytical barriers to measurement of Lp(a) are being addressed using isoform independent assays and a traceable standard. The association of Lp(a) and atherosclerotic cardiovascular disease is higher for myocardial infarction than PAD and CAVS. Increased risk of type 2 diabetes mellitus associated with low Lp(a) levels is perplexing and requires further investigation. The greatest advancement in Lp(a)-lowering therapies is based on using RNA therapeutics that are now being investigated in clinical trials. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition lowers Lp(a) modestly, but whether cardiovascular benefit is independent of low-density lipoprotein lowering remains unclear. Opportunistic and selective testing for Lp(a) is supported by moderate evidence, with the case for universal screening premature. Modification of behavioral and clinical risk factors may be targeted to mitigate Lp(a)-mediated risk of cardiovascular disease. Clinical practice guidelines have been developed to address gaps in care of high Lp(a), but full implementation awaits the findings of clinical outcome trials using RNA-directed therapies currently underway.

Lipoprotéine(a) et risque cardiovasculaire

AbstractDiscovered 60 years ago, lipoprotein (a) was very quickly recognized as an independent cardiovascular risk factor when its genetically determined concentration was high. Lp(a) is a lipoprotein containing apolipoprotein B100 like LDL but distinguished by the presence of an apolipoprotein (a) molecule. This apo(a) exhibits a very great structural heterogeneity as a function of the number of copies of the “kringle IV2” motif, making it possible to distinguish between small isoforms and large isoforms. The plasma concentration of Lp(a) is inversely proportional to the size of the apo(a) present in the Lp(a). The atherogenic properties of Lp(a) are linked to the LDL fraction, its thrombogenic properties are due to the anti- fibrinolytic action of apo(a) due to its partial homology with plasminogen. More recently a role in vascular calcification has also been demonstrated. During the 2000s, interest in Lp(a) declined considerably. Lp(a) is now back in the spotlight because its dosage makes it possible to improve the identification and management of subjects at high cardiovascular risk and because new therapies to reduce the synthesis of apo(a) look promising.

Single Ascending Dose Study of a Short Interfering RNA Targeting Lipoprotein(a) Production in Individuals With Elevated Plasma Lipoprotein(a) Levels

ImportanceLipoprotein(a) (Lp[a]) is an important risk factor for atherothrombotic cardiovascular disease and aortic stenosis, for which there are no treatments approved by regulatory authorities.ObjectivesTo assess adverse events and tolerability of a short interfering RNA (siRNA) designed to reduce hepatic production of apolipoprotein(a) and to assess associated changes in plasma concentrations of Lp(a) at different doses.Design, Setting, and ParticipantsA single ascending dose study of SLN360, an siRNA targeting apolipoprotein(a) synthesis conducted at 5 clinical research unit sites located in the US, United Kingdom, and Australia. The study enrolled adults with Lp(a) plasma concentrations of 150 nmol/L or greater at screening and no known clinically overt cardiovascular disease. Participants were enrolled between November 18, 2020, and July 21, 2021, with last follow-up on December 29, 2021.InterventionsParticipants were randomized to receive placebo (n = 8) or single doses of SLN360 at 30 mg (n = 6), 100 mg (n = 6), 300 mg (n = 6), or 600 mg (n = 6), administered subcutaneously.Main Outcomes and MeasuresThe primary outcome was evaluation of safety and tolerability. Secondary outcomes included change in plasma concentrations of Lp(a) to a maximum follow-up of 150 days.ResultsAmong 32 participants who were randomized and received the study intervention (mean age, 50 [SD, 13.5] years; 17 women [53%]), 32 (100%) completed the trial. One participant experienced 2 serious adverse event episodes: admission to the hospital for headache following SARS-CoV-2 vaccination and later for complications of cholecystitis, both of which were judged to be unrelated to study drug. Median baseline Lp(a) concentrations were as follows: placebo, 238 (IQR, 203-308) nmol/L; 30-mg SLN360, 171 (IQR, 142-219) nmol/L; 100-mg SLN360, 217 (IQR, 202-274) nmol/L; 300-mg SLN360, 285 (IQR, 195-338) nmol/L; and 600-mg SLN360, 231 (IQR, 179-276) nmol/L. Maximal median changes in Lp(a) were −20 (IQR, −61 to 3) nmol/L, −89 (IQR, −119 to −61) nmol/L, −185 (IQR, −226 to −163) nmol/L, −268 (IQR, −292 to −189) nmol/L, and −227 (IQR, −270 to −174) nmol/L, with maximal median percentage changes of −10% (IQR, −16% to 1%), −46% (IQR, −64% to −40%), −86% (IQR, −92% to −82%), −96% (IQR, −98% to −89%), and −98% (IQR, −98% to −97%), for the placebo group and the 30-mg, 100-mg, 300-mg, and 600-mg SLN360 groups, respectively. The duration of Lp(a) lowering was dose dependent, persisting for at least 150 days after administration.Conclusions and RelevanceIn this phase 1 study of 32 participants with elevated Lp(a) levels and no known cardiovascular disease, the siRNA SLN360 was well tolerated, and a dose-dependent lowering of plasma Lp(a) concentrations was observed. The findings support further study to determine the safety and efficacy of this siRNA.Trial RegistrationClinicalTrials.gov Identifier: NCT04606602; EudraCT Identifier: 2020-002471-35

Lipoprotein(a) and kidney diseases

Lipoprotein(a) [Lp(a)] is a subclass of lipoproteins consisting of a cholesterol-rich low-density lipoprotein (LDL) particle with a single apolipoprotein B100 molecule covalently bound (via a disulfide bridge) to a unique hydrophilic high-glycosylated protein called apolipoprotein a [apo(a)]. To date, there is sufficient evidence to consider an increase Lp(a) level as a causal and independent risk factor for cardiovascular disease and calcifying aortic valve stenosis. Plasma concentration of Lp(a) can vary in a wide range, which is mainly determined by genetic factors. Up to 30 % of the world's population has an elevated Lp(a) level, but this category of lipid disorders has not been currently receiving adequate attention. Determining the Lp(a) plasma concentrations is not included in the standard lipid profile, so a significant number of individuals with hyperlipoproteinemia(a) who could potentially benefit from treatment remain undiagnosed. Certain significant obstacles are still associated with the lack of standardized assay for measuring Lp(a) concentrations and a consensus on its optimal levels in blood plasma. Although some limited but statistically significant data suggest a possible benefit of lipoprotein(a) lowering on cardiovascular outcomes, no specific recommendations were made for the management of that dyslipidemia in the latest guidelines. Plasma Lp(a) levels reflect a balance of Lp(a) synthesis, which occurs in the liver, and catabolism, which is thought to involve the kidney. Lp(a) concentration begins already to increase in the earliest stages of chronic kidney disease, and patients with nephrotic syndrome have a four-fold elevated Lp(a) in comparison to healthy individuals. However, it remains unclear if elevated Lp(a) levels affect cardiovascular risk in patients with kidney diseases. This article summarizes the main data regarding the relationship between Lp(a) content, impaired renal function, and an increased risk of adverse cardiovascular events.

Abstract 13951: Safety, Tolerability and Efficacy of Single-dose Amg 890, a Novel Sirna Targeting Lp(a), in Healthy Subjects and Subjects With Elevated Lp(a)

Introduction: Mendelian and epidemiological randomization studies have identified lipoprotein(a) [Lp(a)] as a risk factor for myocardial infarction and other atherosclerotic events. There are currently no approved medicines that selectively target Lp(a) and have demonstrated reduction in CV events. AMG 890 is a siRNA designed to reduce the production of Lp(a) by targeting mRNA transcribed from the LPA gene. Methods: This phase 1 study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of AMG 890. Adults with plasma concentrations of Lp(a) ≥ 70 to ≤ 199 nmol/L (cohorts 1-5), and ≥ 200 nmol/L (cohorts 6-7), were randomized 3:1 to receive a single subcutaneous dose of investigational product (IP; AMG 890 or placebo). The primary endpoints were treatment-emergent adverse events (TEAEs), safety laboratory analytes, vital signs and ECGs. Secondary endpoints included PK parameters and percent reduction from baseline in Lp(a). Results: 64 subjects were administered IP (cohorts 1-5: AMG 890, n=30, doses: 3 mg, 9 mg, 30 mg, 75 mg, 225 mg; placebo, n=10; cohorts 6-7: AMG 890, n=18, doses: 9 mg and 75 mg; placebo, n=6). The most common TEAEs were headache (10% AMG 890; 25% placebo) and upper respiratory tract infection (15% AMG 890; 13% placebo); no safety concerns were identified for AMG 890. In cohorts 1-5, single doses of AMG 890 effectively reduced mean Lp(a) levels from baseline by 71-96% (based on doses) at Day 43, and by 80-94% at Day 113 (cohorts 2-5). In cohorts 6 and 7, single doses of AMG 890 effectively reduced mean Lp(a) levels from baseline by 75% and 89% at Day 43, respectively, and by 61% and 80% at Day 113, respectively. Conclusions: In adults with elevated Lp(a), single-dose treatment of AMG 890 was well-tolerated and significantly reduced Lp(a) with observed maximal percent reductions of &gt; 90% and effects persisting for more than 6 months at doses of 9 mg or higher.

Coronary artery disease and the risk-associated LPA variants, rs3798220 and rs10455872, in patients with suspected familial hypercholesterolaemia

BackgroundThe rs3798220 and rs10455872 single nucleotide polymorphisms (SNPs) in LPA are associated with increased plasma concentrations of lipoprotein(a) [Lp(a)] and coronary artery disease (CAD). MethodsWe investigated the association between rs3798220 and rs10455872 and prevalent CAD in 763 patients with suspected familial hypercholesterolaemia (FH). The rs3798220 and rs10455872 SNPs in LPA were detected using a SEQUENOM platform. ResultsBoth LPA SNPs were significantly associated with CAD, but only rs3798220 after adjustment for other risk factors (odds ratio [OR] 2.05; 95% confidence interval [CI] 1.02–4.12; p = 0.045), and neither after adjustment for Lp(a) concentrations. Both SNPs were positively and independently associated with increased Lp(a) (rs3798220: OR 1.27; 95% CI 0.96–1.57; p < 0.001. rs10455872: OR 1.41; 95% CI 1.24–1.58; p < 0.001). Plasma concentrations of Lp(a) were independently associated with prevalent CAD (OR 1.28; 95% CI 1.08–1.52, p = 0.005) after adjustment for LPA SNPs and other cardiovascular risk factors. While both the rs3798220 and rs10455872 SNPs were associated with Lp(a) concentrations and prevalent CAD in patients with suspected FH, this was not independent of Lp(a) concentration. ConclusionsQuantification of Lp(a) is more likely to be useful than assessment of these Lp(a)-associated SNPs to augment CAD risk prediction.

Lipoprotein(a) - Link between Atherogenesis and Thrombosis.

Lipoprotein(a) - Lp(a) - is an independent risk factor for cardiovascular disease (CVD). Indeed, individuals with plasma concentrations of Lp(a) > 200 mg/l carry an increased risk of developing CVD. Circulating levels of Lp(a) are remarkably resistant to common lipid lowering therapies, currently available treatment for reduction of Lp(a) is plasma apheresis, which is costly and labour intensive. The Lp(a) molecule is composed of two parts: LDL/apoB-100 core and glycoprotein, apolipoprotein(a) - Apo(a), both of them can interact with components of the coagulation cascade, inflammatory pathways and blood vessel cells (smooth muscle cells and endothelial cells). Therefore, it is very important to determine the molecular pathways by which Lp(a) affect the vascular system in order to design therapeutics for targeting the Lp(a) cellular effects. This paper summarises the cellular effects and molecular mechanisms by which Lp(a) participate in atherogenesis, thrombogenesis, inflammation and development of cardiovascular diseases.

Core/shell PLGA microspheres with controllable in vivo release profile via rational core phase design

Highly soluble drugs tend to release from preparations at high speeds, which make them need to be taken at frequent intervals. Additionally, some drugs need to be controlled to release in vivo at certain periods, so as to achieve therapeutic effects. Thus, the objective of this study is to design injectable microparticulate systems with controllable in vivo release profile. Biodegradable PLGA was used as the matrix material to fabricate microspheres using the traditional double emulsification-solvent evaporation method as well as improved techniques, with gel (5% gelatine or 25% F127) or LP powders as the inner phases. Their physicochemical properties were systemically investigated. Microspheres prepared by modified methods had an increase in drug loading (15.50, 16.72, 15.66%, respectively) and encapsulation efficiencies (73.46, 79.42, 74.40%, respectively) when compared with traditional methods (12.01 and 57.06%). The morphology of the particles was characterized by optical microscope (OM) and scanning electron microscopy (SEM), and the amorphous nature of the encapsulated drug was confirmed by differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis. To evaluate their release behaviour, the in vitro degradation, in vitro release and in vivo pharmacodynamics were subsequently studied. Traditional microspheres prepared in this study with water as the inner phase had a relatively short release period within 16 d when compared with modified microspheres with 5% gelatine as the inner phase, which resulted in a smooth release profile and appropriate plasma LP concentrations over 21 d. Thus this type of modified microspheres can be better used in drugs requiring sustained release. The other two formulations containing 25% F127 and LP micropowders presented two-stage release profiles, resulting in fluctuant plasma LP concentrations which may be suitable for drugs requiring controlled release. All the results suggested that drug release rates from the microspheres prepared by various methods were mainly controlled by either the porosity inside the microspheres or the degradation of materials, which could, therefore, lead to different release behaviours. This results indicated great potential of the PLGA microsphere formulation as an injectable depot for controllable in vivo release profile via rational core phase design. Core/shell microspheres fabricated by modified double emulsification-solvent evaporation methods, with various inner phases, to obtain high loading drugs system, as well as appropriate release behaviours. Accordingly, control in vivo release profile via rational core phase design.

Raloxifene Lowers Plasma Lipoprotein(a) Concentrations: a Systematic Review and Meta-analysis of Randomized Placebo-Controlled Trials.

Lipoprotein(a) (Lp(a)) is a proatherogenic plasma lipoprotein and an independent risk factor for atherosclerotic cardiovascular disease. We investigated the effects of raloxifene, selective estrogen receptor modulator, on circulating Lp(a) levels in postmenopausal women using a systematic review and meta-analysis of randomized controlled trials (RCTs). To identify relevant studies, electronic databases (PUBMED, Scopus, Web of Science, and Google Scholar) were searched by up to May 2015 to find controlled trials exploring the effects of oral raloxifene treatment on plasma Lp(a) levels in postmenopausal women. A random-effects model and generic inverse variance method were used for quantitative data synthesis. Overall, seven eligible RCTs with ten treatment arms were included in this meta-analysis. Meta-analysis suggested a significant reduction of Lp(a) levels after treatment with raloxifene (standardized mean difference (SMD) -0.42; 95% CI -0.65, -0.19; p < 0.001), which may be considered as a medium effect size. When the studies were categorized according to the administered dose, there was a significant effect in both subsets of studies with administered doses ≤60mg/day (SMD -0.43; 95% CI -0.73, -0.13; p = 0.004) and >60mg/day (SMD -0.36; 95% CI -0.68, -0.05; p = 0.025). No significant association between the changes in plasma concentrations of Lp(a) with dose and baseline Lp(a) levels was found in the random-effects meta-regression analysis. However, a significant inverse association was observed between the Lp(a)-lowering effect of raloxifene and duration of treatment (p = 0.001). Results of the present meta-analysis showed a reduction in plasma Lp(a) concentrations of postmenopausal women with oral raloxifene treatment.

Genetic Polymorphisms, Plasma Levels of Lipoprotein (A) and its Possible Links with Degenerative Aortic Stenosis

Summary Degenerative aortic stenosis is the second most common acquired valvular heart disease in adults (after mitral insufficiency) and the second most common cause for cardiac surgery (after coronary heart disease). The reasons for the occurrence of these diseases (congenital abnormality of the valve: bicuspid aortic valve disease, advanced renal failure, impaired calcium-phosphorus metabolism) have been established only in a small portion of these patients. The absence of a specific reason, causing calcification and narrowing of the aortic valve in recent years has challenged researchers to start investigating genetic factors that may correlate with the development of degenerative aortic stenosis. Regardless of the conducted studies, knowledge and identification of predictive genetic factors in the occurrence and progression of aortic stenosis are still insufficient. It is assumed that a specific genetic variant in the Lipoprotein (a) locus (LPA locus), reflected by the Lipoprotein (a) [Lp(a)] plasma levels, is connected to the pathology of aortic stenosis in multiethnic groups. The study of the genetic nature of aortic stenosis and significance of Lp( a) plasma levels and genetically determined variations of its structure associated with the manifestation and progression of valvular calcification in the future might provide predictive intervention. Similar studies relating to genetic polymorphisms in LPA locus, plasma concentrations of Lp(a) and their correlation with aortic stenosis have not beenconducted in Bulgaria so far.

Effect of extended-release niacin on plasma lipoprotein(a) levels: A systematic review and meta-analysis of randomized placebo-controlled trials

AimLipoprotein(a) (Lp(a)) is a proatherogenic and prothrombotic lipoprotein. Our aim was to quantify the extended-release nicotinic acid Lp(a) reducing effect with a meta-analysis of the available randomized clinical trials. MethodsA meta-analysis and random-effects meta-regression were performed on data pooled from 14 randomized placebo-controlled clinical trials published between 1998 and 2015, comprising 17 treatment arms, which included 9013 subjects, with 5362 in the niacin arm. ResultsThe impact of ER niacin on plasma Lp(a) concentrations was reported in 17 treatment arms. Meta-analysis suggested a significant reduction of Lp(a) levels following ER niacin treatment (weighted mean difference – WMD: −22.90%, 95% CI: −27.32, −18.48, p<0.001).Results also remained similar when the meta-analysis was repeated with standardized mean difference as summary statistic (WMD: −0.66, 95% CI: −0.82, −0.50, p<0.001). When the studies were categorized according to the administered dose, there was a comparable effect between the subsets of studies with administered doses of <2000mg/day (WMD: −21.85%, 95% CI: −30.61, −13.10, p<0.001) and ≥2000mg/day (WMD: −23.21%, 95% CI: −28.41, −18.01, p<0.001).The results of the random-effects meta-regression did not suggest any significant association between the changes in plasma concentrations of Lp(a) with dose (slope: −0.0001; 95% CI: −0.01, 0.01; p=0.983), treatment duration (slope: −0.40; 95% CI: −0.97, 0.17; p=0.166), and percentage change in plasma HDL-C concentrations (slope: 0.44; 95% CI: −0.48, 1.36; p=0.350). ConclusionIn this meta-analysis of randomized placebo-controlled clinical trials, treatment with nicotinic acid was associated with a significant reduction in Lp(a) levels.

Effect of garlic on plasma lipoprotein(a) concentrations: A systematic review and meta-analysis of randomized controlled clinical trials

ObjectivesGarlic can play an essential role in the prevention of atherosclerosis, but the research addressing the effect of garlic on the concentration of lipoprotein(a) [Lp(a)] has not been fully demonstrated. The aim of this study was to assess the effect of garlic on plasma Lp(a) concentrations through systematic review of literature and meta-analysis of available randomized controlled trials. MethodsThe literature search included SCOPUS, PubMed-Medline, ISI Web of Science, and Google Scholar databases up to March 10, 2015 to identify randomized controlled trials investigating the effect of garlic on plasma Lp(a) concentrations. Two independent reviewers extracted data on study characteristics, methods, and outcomes. Overall, the effect of garlic on plasma Lp(a) levels was reported in six trials. ResultsMeta-analysis did not suggest a significant alteration in plasma Lp(a) levels after garlic consumption (weighted mean difference [WMD] = 16.86%; 95% confidence interval, −4.59 to 38.31; P = 0.124). This result was robust in the leave-one-out sensitivity analysis. When the studies were categorized according to the duration of supplementation, there was no effect in the subgroup of trials lasting ≤12 wk (WMD = 2.01%; 95% CI, −14.67 to 18.68; P = 0.813) but a significant elevation of plasma Lp(a) concentrations was found in trials lasting >12 wk (WMD = 54.59%; 95% CI, 30.47–78.71; P < 0.001). Random-effects meta-regression suggested an inverse association between the changes in plasma concentrations of Lp(a) and duration of supplementation (slope 1.71; 95% CI, 0.46–2.97; P = 0.007). ConclusionsThe present meta-analysis did not suggest a significant effect of garlic supplementation on the reduction of Lp(a) levels.

Lipoprotein(a) metabolism.

Lipoprotein(a) [Lp(a)] is an atherogenic lipoprotein. The metabolism of this lipoprotein is still not well understood. It has long been known that the plasma concentration of Lp(a) is highly heritable, with its genetic determinants located in the apo(a) locus and regulating the rate of hepatic apo(a) production. Recent human intervention trials have convincingly established that, in addition to apo(a) production, hepatic apoB100 production plays an important role in Lp(a) levels. Although the major site and mode of Lp(a) clearance remain unidentified, a recent cell and animal study points to the involvement of the hepatic scavenger receptor class B type I in the uptake of both the lipid and protein constituents of Lp(a) from plasma. Progress in the understanding of Lp(a) metabolism has the potential to lead to the development of novel and specific treatments for the reduction of Lp(a) levels and the associated risk of cardiovascular disease.

Scavenger receptor-BI is a receptor for lipoprotein(a)

Scavenger receptor class B type I (SR-BI) is a multi-ligand receptor that binds a variety of lipoproteins, including high density lipoprotein (HDL) and low density lipoprotein (LDL), but lipoprotein(a) [Lp(a)] has not been investigated as a possible ligand. Stable cell lines (HEK293 and HeLa) expressing human SR-BI were incubated with protein- or lipid-labeled Lp(a) to investigate SR-BI-dependent Lp(a) cell association. SR-BI expression enhanced the association of both (125)I- and Alexa Fluor-labeled protein from Lp(a). By confocal microscopy, SR-BI was also found to promote the internalization of fluorescent lipids (BODIPY-cholesteryl ester (CE)- and DiI-labeled) from Lp(a), and by immunocytochemistry the cellular internalization of apolipoprotein(a) and apolipoprotein B. When dual-labeled ((3)H-cholesteryl ether,(125)I-protein) Lp(a) was added to cells expressing SR-BI, there was a greater relative increase in lipid uptake over protein, indicating that SR-BI mediates selective lipid uptake from Lp(a). Compared with C57BL/6 control mice, transgenic mice overexpressing human SR-BI in liver were found to have increased plasma clearance of (3)H-CE-Lp(a), whereas mouse scavenger receptor class B type I knockout (Sr-b1-KO) mice had decreased plasma clearance (fractional catabolic rate: 0.63 ± 0.08/day, 1.64 ± 0.62/day, and 4.64 ± 0.40/day for Sr-b1-KO, C57BL/6, and human scavenger receptor class B type I transgenic mice, respectively). We conclude that Lp(a) is a novel ligand for SR-BI and that SR-BI mediates selective uptake of Lp(a)-associated lipids.

Changes in lipoprotein(a), oxidized phospholipids, and LDL subclasses with a low-fat high-carbohydrate diet

Low-fat diets have been shown to increase plasma concentrations of lipoprotein(a) [Lp(a)], a preferential lipoprotein carrier of oxidized phospholipids (OxPLs) in plasma, as well as small dense LDL particles. We sought to determine whether increases in plasma Lp(a) induced by a low-fat high-carbohydrate (LFHC) diet are related to changes in OxPL and LDL subclasses. We studied 63 healthy subjects after 4 weeks of consuming, in random order, a high-fat low-carbohydrate (HFLC) diet and a LFHC diet. Plasma concentrations of Lp(a) (P < 0.01), OxPL/apolipoprotein (apo)B (P < 0.005), and OxPL-apo(a) (P < 0.05) were significantly higher on the LFHC diet compared with the HFLC diet whereas LDL peak particle size was significantly smaller (P < 0.0001). Diet-induced changes in Lp(a) were strongly correlated with changes in OxPL/apoB (P < 0.0001). The increases in plasma Lp(a) levels after the LFHC diet were also correlated with decreases in medium LDL particles (P < 0.01) and increases in very small LDL particles (P < 0.05). These results demonstrate that induction of increased levels of Lp(a) by an LFHC diet is associated with increases in OxPLs and with changes in LDL subclass distribution that may reflect altered metabolism of Lp(a) particles.

Variation of Lp(a) Plasma Concentrations in Health and Disease~!2009-11-03~!2010-02-06~!2010-09-08~!

Lipoprotein(a) (Lp(a)) is an established risk marker of cardiovascular diseases which is independent from other risk markers. The main difference of Lp(a) compared to low density lipoprotein (LDL) is the apo(a) residue which is covalently bound to apoB. Apo(a) is a glycoprotein which underlies a large genetic polymorphism. The latter is caused by a variation of the kringle-IV-type-2 repeats of the protein which is characterized by a large structural homology to plasminogen. The Lp(a) plasma concentration in the population is highly skewed and determined to more than 90 % by genetic factors. In healthy subjects the Lp(a)-concentration is correlated to its synthesis and not to its metabolism. However, plasma concentrations of Lp(a) are also affected by different diseases (e.g. diseases of liver and kidney), hormonal factors (e.g. sexual steroids, glucocorticoids, thyroid hormones), individual and environmental factors (e.g. age, cigarette smoking) as well as pharmaceuticals (e.g. derivatives of nicotinic acid) and therapeutic procedures (lipid apheresis). Aim of this review was to describe the physiological regulation of Lp(a) as well as factors influencing its plasma concentration.

Apo(a) phenotyping and long-term prognosis for coronary artery disease

Objectives Identify whether the plasma concentration of Lp(a), apo(a) size or a greater affinity for fibrin predict the likelihood of cardiac death, non-fatal myocardial infarction, unstable angina, the need for additional revascularization, and stroke (MACCE). Design and methods We analyzed the clinical prognosis of 68 patients with coronary artery disease included in a case-controlled study which evaluated Lp(a) concentration, apo(a) size, and Lp(a) fibrin-binding. Cohort was conducted over a median of 8 years. We used Kaplan–Meier survival tables to evaluate cardiovascular and cerebrovascular events in the follow-up period. Results Apo(a) isoforms of small size are predictors of MACCE. We find an association between Lp(a) concentration and apo(a) fibrin-binding with major adverse cardiovascular and cerebrovascular events, although without statistically significant results. Conclusions Small-sized apo(a) isoforms are an independent risk factor for MACCE in patients with coronary artery disease in follow-up. Lp(a) plasma concentration and apo(a) fibrin-binding were associated, although not significant.