Modern Approaches to Lower Lipoprotein(a) Concentrations and Consequences for Cardiovascular Diseases.
Ontology highlight
ABSTRACT:
SUBMITTER: Korneva VA
PROVIDER: S-EPMC8469722 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Several epidemiological studies have clearly shown that low plasma levels of high density lipoprotein cholesterol (HDL-C) represent a cardiovascular disease (CVD) risk factor. However, it is unclear if there is a causal association between HDL-C concentration and CVD. A recent study published in the Lancet, which performed two Mendelian randomization analyses, showed that increased HDL-C levels were not associated with a decreased risk of myocardial infarction. These findings, together with the termination of the niacin-based AIM-HIGH trial and the discontinuation of cholesteryl ester transfer protein inhibitor dalcetrapib, challenge the concept that raising of plasma HDL-C will uniformly translate into reductions in CVD risk. HDL particles exhibit several anti-atherosclerotic properties, such as anti-inflammatory and anti-oxidative activities and cellular cholesterol efflux activity. Furthermore, HDL particles are very heterogeneous in terms of size, structure, composition and metabolism. HDL functionality may be associated more strongly with CVD risk than the traditional HDL-C levels. More research is needed to assess the association of the structure of HDL particle with its functionality and metabolism.
| S-EPMC3722418 | biostudies-other
Project description:Despite the advances in treatment options, cardiovascular disease (CVDs) remains the leading cause of death over the world. Chronic inflammatory response and irreversible fibrosis are the main underlying pathophysiological causes of progression of CVDs. In recent decades, cardiac macrophages have been recognized as main regulatory players in the development of these complex pathophysiological conditions. Numerous approaches aimed at macrophages have been devised, leading to novel prospects for therapeutic interventions. Our review covers the advancements in macrophage-centric treatment plans for various pathologic conditions and examines the potential consequences and obstacles of employing macrophage-targeted techniques in cardiac diseases.
| S-EPMC10837257 | biostudies-literature
Project description:DNA sequence variants are major components of the "causal field" for virtually all medical phenotypes, whether single gene familial disorders or complex traits without a clear familial aggregation. The causal variants in single gene disorders are necessary and sufficient to impart large effects. In contrast, complex traits are attributable to a much more complicated network of contributory components that in aggregate increase the probability of disease. The conventional approach to identification of the causal variants for single gene disorders is genetic linkage. However, it does not offer sufficient resolution to map the causal genes in small families or sporadic cases. The approach to genetic studies of complex traits entails candidate gene or genome-wide association studies. Genome-wide association studies provide an unbiased survey of the effects of common genetic variants (common disease-common variant hypothesis). Genome-wide association studies have led to identification of a large number of alleles for various cardiovascular diseases. However, common alleles account for a relatively small fraction of the total heritability of the traits. Accordingly, the focus has shifted toward identification of rare variants that might impart larger effect sizes (rare variant-common disease hypothesis). This shift is made feasible by recent advances in massively parallel DNA sequencing platforms, which afford the opportunity to identify virtually all common as well as rare alleles in individuals. In this review, we discuss various strategies that are used to delineate the genetic contribution to medically important cardiovascular phenotypes, emphasizing the utility of the new deep sequencing approaches.
| S-EPMC3115927 | biostudies-literature
Project description:Disorders of lipoprotein metabolism have been linked with an increased risk of cardiovascular diseases (CVDs) but the causal association is unclear. In this study, we investigated the causal association between disorders of lipoprotein metabolism and CVDs using two-sample Mendelian randomization (MR). The exposure was obtained from Finn genome-wide association studies (14,010 cases, 197,259 controls), and the corresponding CVDs were extracted from the largest published genome-wide association studies. A random-effects inverse-variance weighted method was used for the main analyses with a complementary analysis using the weighted median and MR-Egger approaches. Multiple sensitivity analyses were performed to assess horizontal pleiotropy. The MR analysis indicated positive associations of disorders of lipoprotein metabolism with coronary artery disease (odds ratio [OR] 1.670, 95% confidence interval [CI] 1.373-2.031; p < 0.001), aortic aneurysm (OR 1.394, 95% CI 1.199-1.619; p < 0.001), heart failure (OR 1.20, 95% CI 1.115-1.294; p < 0.001), hypertension (OR 1.011, 95% CI 1.006-1.091; p < 0.001), old myocardial infarction (OR 1.004, 95% CI 1.002-1.007; p = 0.001), and stroke (OR 1.002, 95% CI 1.001-1.003; p = 0.002). There is a suggestive causal relationship between disorders of lipoprotein metabolism and atrial fibrillation (OR 1.047, 95% CI 1.006-1.091; p = 0.026) and acute myocardial infarction (OR 1.003, 95% CI 1.001-1.005; p = 0.012). There was limited evidence of a causal association between disorders of lipoprotein metabolism and peripheral vascular disease and venous thromboembolism. Our findings indicate a significant causal association between disorders of lipoprotein metabolism and many CVDs, including coronary artery disease, aortic aneurysm, heart failure, hypertension, old myocardial infarction, and stroke. These associations may be useful for development of treatment strategies that regulate lipoprotein metabolism in patients with CVD.
| S-EPMC9593056 | biostudies-literature
Project description:OBJECTIVE:Lp(a) (lipoprotein(a)) concentrations are widely genetically determined by the LPA isoforms and show 5-fold interpopulation differences. Two- to 3-fold differences have been reported even within Europe. Finns represent a distinctive population isolate within Europe and have been repeatedly reported to present lower Lp(a) concentrations than Central Europeans. The significance of this finding was unclear for a long time because of the difficult comparability of Lp(a) assays. Recently, a large standardized study in >50?000 individuals from 7 European populations confirmed this observation but could not provide insights into the causes. APPROACH AND RESULTS:We investigated Lp(a) concentrations, LPA isoforms, and genotypes of established genetic variants affecting Lp(a) concentrations (LPA variants, APOE isoforms, and PCSK9 R46L) in the Finnish YFS (Cardiovascular Risk in Young Finns Study) population (n=2281) and 3 Non-Finnish Central European populations (n=10?003). We observed ?50% lower Lp(a) concentrations in Finns. The isoform distribution was shifted toward longer isoforms, and the percentage of low-molecular-weight isoform carriers was reduced. Most interestingly, however, Lp(a) was reduced in each single-isoform group. In contrast to the known inverse relationship between LPA isoforms and Lp(a) concentrations, especially very short isoforms presented unexpectedly low Lp(a) concentrations in Finns. The investigated genetic variants, as well as age, sex, and renal function, explained 71.8% of the observed population differences. CONCLUSIONS:The population differences in Lp(a) concentrations between Finnish and Central European populations originate not only from a different LPA isoform distribution but suggest the existence of novel functional variation in the small-isoform range.
| S-EPMC5943067 | biostudies-literature
Project description:Linking marine epizootics to a specific aetiology is notoriously difficult. Recent diagnostic successes show that marine disease diagnosis requires both modern, cutting-edge technology (e.g. metagenomics, quantitative real-time PCR) and more classic methods (e.g. transect surveys, histopathology and cell culture). Here, we discuss how this combination of traditional and modern approaches is necessary for rapid and accurate identification of marine diseases, and emphasize how sole reliance on any one technology or technique may lead disease investigations astray. We present diagnostic approaches at different scales, from the macro (environment, community, population and organismal scales) to the micro (tissue, organ, cell and genomic scales). We use disease case studies from a broad range of taxa to illustrate diagnostic successes from combining traditional and modern diagnostic methods. Finally, we recognize the need for increased capacity of centralized databases, networks, data repositories and contingency plans for diagnosis and management of marine disease.
| S-EPMC4760137 | biostudies-literature
Project description:Purpose of reviewThis article summarizes recent observations on the role of lipoprotein(a) [Lp(a)] as a risk factor mediating cardiovascular disease.Recent findingsLp(a) is a highly prevalent cardiovascular risk factor, with levels above 30 mg/dl affecting 20-30% of the global population. Up until now, no specific therapies have been developed to lower Lp(a) levels. Three major levels of evidence support the notion that elevated Lp(a) levels are a causal, independent, genetic risk factor for cardiovascular disease: epidemiologic studies and meta-analyses, genome-wide association studies and Mendelian randomization studies. Recent studies also have noted that individuals with low levels of Lp(a) are associated with a higher risk of incident type 2 diabetes mellitus, and conversely individuals with high levels have a lower risk, but this association does not appear to be causal. Novel therapies to lower Lp(a) include PCSK9 inhibitors and antisense oligonucleotides directly preventing translation of apolipoprotein(a) mRNA.SummaryWith this robust and expanding clinical database, a reawakening of interest in Lp(a) as clinical risk factor is taking place. Trials are underway with novel drugs that substantially lower Lp(a) and may reduce its contribution to cardiovascular disease.
| S-EPMC5061509 | biostudies-literature
Project description:Cardiovascular disease (CVD) is still a leading cause of morbidity and mortality, despite all the progress achieved as regards to both prevention and treatment. Having high levels of lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular disease that operates independently. It can increase the risk of developing cardiovascular disease even when LDL cholesterol (LDL-C) levels are within the recommended range, which is referred to as residual cardiovascular risk. Lp(a) is an LDL-like particle present in human plasma, in which a large plasminogen-like glycoprotein, apolipoprotein(a) [Apo(a)], is covalently bound to Apo B100 via one disulfide bridge. Apo(a) contains one plasminogen-like kringle V structure, a variable number of plasminogen-like kringle IV structures (types 1-10), and one inactive protease region. There is a large inter-individual variation of plasma concentrations of Lp(a), mainly ascribable to genetic variants in the Lp(a) gene: in the general po-pulation, Lp(a) levels can range from <1 mg/dL to >1000 mg/dL. Concentrations also vary between different ethnicities. Lp(a) has been established as one of the risk factors that play an important role in the development of atherosclerotic plaque. Indeed, high concentrations of Lp(a) have been related to a greater risk of ischemic CVD, aortic valve stenosis, and heart failure. The threshold value has been set at 50 mg/dL, but the risk may increase already at levels above 30 mg/dL. Although there is a well-established and strong link between high Lp(a) levels and coronary as well as cerebrovascular disease, the evidence regarding incident peripheral arterial disease and carotid atherosclerosis is not as conclusive. Because lifestyle changes and standard lipid-lowering treatments, such as statins, niacin, and cholesteryl ester transfer protein inhibitors, are not highly effective in reducing Lp(a) levels, there is increased interest in developing new drugs that can address this issue. PCSK9 inhibitors seem to be capable of reducing Lp(a) levels by 25-30%. Mipomersen decreases Lp(a) levels by 25-40%, but its use is burdened with important side effects. At the current time, the most effective and tolerated treatment for patients with a high Lp(a) plasma level is apheresis, while antisense oligonucleotides, small interfering RNAs, and microRNAs, which reduce Lp(a) levels by targeting RNA molecules and regulating gene expression as well as protein production levels, are the most widely explored and promising perspectives. The aim of this review is to provide an update on the current state of the art with regard to Lp(a) pathophysiological mechanisms, focusing on the most effective strategies for lowering Lp(a), including new emerging alternative therapies. The purpose of this manuscript is to improve the management of hyperlipoproteinemia(a) in order to achieve better control of the residual cardiovascular risk, which remains unacceptably high.
| S-EPMC10531345 | biostudies-literature
Project description:Dyslipidemia, characterized by elevation of plasma low density lipoprotein cholesterol (LDL-C), triglyceride (TG) and reduction of plasma high density lipoprotein cholesterol (HDL-C), has been verified as a causal risk factor for cardiovascular diseases (CVD), leading to a high mortality rate in general population. It is important to understand the molecular metabolism underlying dyslipidemia in order to reduce the risk and to develop effective therapeutic approaches against CVD. ANGPTL3 (human) or Angptl3 (mouse), one member of the angiopoietin-like protein (ANGPTL) family, has been identified as an important regulator of lipid metabolism by inhibiting LPL and EL activity. Results have demonstrated that inactivation of Angptl3 in mice could obviously reduce the level of TG, LDL-C and the atherosclerotic lesion size, leading to a lower risk for dyslipidemia and CVD. Additionally, in humans, carriers with homozygous LOF mutations in ANGPTL3 have lower plasma LDL-C, TG levels and lower risk of atherosclerosis compared to the non-carriers. Here, we collect the latest data and results, giving a new insight into the important role of ANGPTL3 in controlling lipoprotein metabolism. Finally, we introduce two update reports on the antisense oligonucleotide and monoclonal antibody-based inactivation of ANGPTL3 in human clinical trials, to identify that ANGPTL3 could be a novel and effective target for the treatment of dyslipidemia and CVD.
| S-EPMC5769531 | biostudies-literature
Project description:Uncomplicated upper respiratory viral infections are the most common cause of days lost from work and school and exert a major economic burden. In susceptible individuals, however, common respiratory viruses, particularly human rhinoviruses, also can have a major impact on diseases that involve the lower airways, including asthma, chronic obstructive pulmonary diseases (COPD) and cystic fibrosis (CF). Respiratory virus-induced wheezing illnesses in early life are a significant risk factor for the subsequent development of asthma, and virus infections may also play a role in the development and progression of airway remodeling in asthma. It is clear that upper respiratory tract virus infections can spread to the lower airway and trigger acute attacks of asthma, COPD or CF. These exacerbations can be life-threatening, and exert an enormous burden on health care systems. In recent years we have gained new insights into the mechanisms by which respiratory viruses may induce acute exacerbations of lower airway diseases, as well as into host defense pathways that may regulate the outcomes to viral infections. In the current article we review the role of viruses in lower airway diseases, including our current understanding on pathways by which they may cause remodeling and trigger acute exacerbations. We also review the efficacy of current and emerging therapies used to treat these lower airway diseases on the outcomes due to viral infection, and discuss alternative therapeutic approaches for the management of virus-induced airway inflammation.
| S-EPMC7173263 | biostudies-literature