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Travel Medicine and Infectious Disease 2021Apolipoproteins are predictive biomarkers for cardiovascular, neoplasms and cerebrovascular diseases and are postulated as prognostic biomarkers in infectious diseases,... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Apolipoproteins are predictive biomarkers for cardiovascular, neoplasms and cerebrovascular diseases and are postulated as prognostic biomarkers in infectious diseases, as COVID-19. Thus, we assessed the prognosis value of apolipoproteins for COVID-19 severity and mortality.
METHODS
We conducted a systematic review and meta-analysis using observational studies that reported the association between apolipoproteins and severity or mortality in COVID-19 patients. Newcastle-Ottawa was used for the quality assessment of included studies. Effects measurements were shown as odds ratios (ORs) with 95% confidence intervals (CIs), and Egger-test was developed for assessing the risk of bias publication.
RESULTS
We analyzed 12 cohort studies (n = 3580). Patients with low ApoliproteinA1 (ApoA1) (OR 0.35; 95%CI 0.24 to 0.49; P < 0.001) and ApoliproteinB (ApoB) (OR = 0.78; 95%CI 0.69 to 0.87; P < 0.001) values had a higher risk of developing severe disease. ApoB/ApoA1 ratio showed no statistically significant association with higher odds of severity. Low ApoA1 levels were associated with higher odds of all-cause mortality (OR = 0.34; 95%CI 0.20 to 0.57; P < 0.001). ApoB values showed no statistically significant association with a high risk of all-cause mortality.
CONCLUSION
We suggest that adequate levels of ApoA1 and ApoB can be a protective factor for severity in COVID-19, and ApoB/ApoA1 ratio did not show predictive utility for severity.
Topics: Apolipoprotein A-I; Apolipoproteins; COVID-19; Humans; Prognosis; Risk Factors; SARS-CoV-2
PubMed: 34752921
DOI: 10.1016/j.tmaid.2021.102200 -
Current Opinion in Lipidology Jun 2022This review summarizes our current understanding of the processes of apolipoprotein(a) secretion, assembly of the Lp(a) particle and removal of Lp(a) from the... (Review)
Review
PURPOSE OF REVIEW
This review summarizes our current understanding of the processes of apolipoprotein(a) secretion, assembly of the Lp(a) particle and removal of Lp(a) from the circulation. We also identify existing knowledge gaps that need to be addressed in future studies.
RECENT FINDINGS
The Lp(a) particle is assembled in two steps: a noncovalent, lysine-dependent interaction of apo(a) with apoB-100 inside hepatocytes, followed by extracellular covalent association between these two molecules to form circulating apo(a).The production rate of Lp(a) is primarily responsible for the observed inverse correlation between apo(a) isoform size and Lp(a) levels, with a contribution of catabolism restricted to larger Lp(a) isoforms.Factors that affect apoB-100 secretion from hepatocytes also affect apo(a) secretion.The identification of key hepatic receptors involved in Lp(a) clearance in vivo remains unclear, with a role for the LDL receptor seemingly restricted to conditions wherein LDL concentrations are low, Lp(a) is highly elevated and LDL receptor number is maximally upregulated.
SUMMARY
The key role for production rate of Lp(a) [including secretion and assembly of the Lp(a) particle] rather than its catabolic rate suggests that the most fruitful therapies for Lp(a) reduction should focus on approaches that inhibit production of the particle rather than its removal from circulation.
Topics: Apolipoprotein B-100; Apolipoproteins A; Apoprotein(a); Humans; Lipoprotein(a); Receptors, LDL
PubMed: 35695615
DOI: 10.1097/MOL.0000000000000823 -
Current Opinion in Lipidology Jun 2021Lipoprotein(a) [Lp(a)] is a plasma circulating apoB100 (apoB) containing lipoprotein. It has a unique glycoprotein bound to the apoB100, apolipoprotein(a) [apo(a)]. The... (Review)
Review
PURPOSE OF REVIEW
Lipoprotein(a) [Lp(a)] is a plasma circulating apoB100 (apoB) containing lipoprotein. It has a unique glycoprotein bound to the apoB100, apolipoprotein(a) [apo(a)]. The majority of the population expresses two apo(a) isoforms, when bound to apoB100 they create two circulating Lp(a) particles. Lp(a) levels are genetically determined and epidemiological studies have established elevated levels of Lp(a) to be a causal risk factor of cardiovascular disease (CVD). Lp(a) levels differ across racial groups and Blacks of Sub-Saharan decent have higher levels when compared to white. In comparison to white populations, studies in minorities are less represented in the published literature. Additionally, there is a lack of standardization in the commercial assays used to measured Lp(a) levels, and hence it is difficult to assess risk based on individual Lp(a) levels, but risk seems to occur in the upper percentiles of the population.
RECENT FINDINGS
A recent study using data from the UK biobank highlights the racial differences in Lp(a) levels and the increase risk in CVD amongst all races.
SUMMARY
This review will highlight Lp(a) biology and physiology with a focus on available data from racially diverse cohorts. There is a need to perform studies in diverse populations to understand if they are at higher risk than whites are.
Topics: Apolipoproteins A; Cardiovascular Diseases; Ethnicity; Heart Disease Risk Factors; Humans; Lipoprotein(a); Risk Factors
PubMed: 33900275
DOI: 10.1097/MOL.0000000000000753 -
Journal of the American Heart... Aug 2023Concern continues about whether the measurement of apolipoprotein B (apoB) is adequately standardized, and therefore, whether apoB should be applied widely in clinical... (Review)
Review
Concern continues about whether the measurement of apolipoprotein B (apoB) is adequately standardized, and therefore, whether apoB should be applied widely in clinical care. This concern is misplaced. Our objective is to explain why and what the term "standardization" means. To produce clinically valid results, a test must accurately, precisely, and selectively measure the marker of interest. That is, it must be standardized. Accuracy refers to how closely the result obtained with 1 method corresponds to the result obtained with the standard method, precision to how reproducible the result is on repeated testing, and selectivity to how susceptible the method is to error by inclusion of other classes of lipoprotein particles. Multiple expert groups have determined that the measurement of apoB is adequately standardized for clinical care, and that apoB can be measured inexpensively, using widely available automated methods, more accurately, precisely, and selectively than low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol. ApoB is a standard superior to low-density lipoprotein cholesterol and high-density lipoprotein cholesterol because it is a defined molecule, whereas the cholesterol markers are the mass of cholesterol within lipoprotein particles defined by their density, not by their molecular structure. Nevertheless, the standardization of apoB is being further improved by the application of mass spectrophotometric methods, whereas the limitations in the standardization and, therefore, the accurate, precise, and selective measurement of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol are unlikely to be overcome. We submit that greater accuracy, precision, and selectivity in measurement is a decisive advantage for apoB in the modern era of intensive lipid-lowering therapies.
Topics: Cholesterol, LDL; Cholesterol; Apolipoproteins B; Apolipoprotein B-100; Cholesterol, HDL; Lipoproteins; Apolipoprotein A-I
PubMed: 37489721
DOI: 10.1161/JAHA.123.030405 -
Journal of Diabetes Research 2019Nontraditional cardiovascular risk factors as apolipoprotein A (ApoA), apolipoprotein B (ApoB), and the proprotein convertase subtilisin/kexin type 9 (PCSK9) increase... (Review)
Review
PURPOSE
Nontraditional cardiovascular risk factors as apolipoprotein A (ApoA), apolipoprotein B (ApoB), and the proprotein convertase subtilisin/kexin type 9 (PCSK9) increase the prevalence of cardiovascular mortality in chronic kidney disease (CKD) or in end-stage renal disease (ESRD) through quantitative alterations. This review is aimed at establishing the biomarker (ApoA, ApoB, and PCSK9) level variations in uremic patients, to identify the studies showing the association between these biomarkers and the development of cardiovascular events and to depict the therapeutic options to reduce cardiovascular risk in CKD and ESRD patients.
METHODS
We searched the electronic database of PubMed, Scopus, EBSCO, and Cochrane CENTRAL for studies evaluating apolipoproteins and PCSK9 in CKD and ESRD. Randomized controlled trials, observational studies (including case-control, prospective or retrospective cohort), and reviews/meta-analysis were included if reference was made to those keys and cardiovascular outcomes in CKD/ESRD.
RESULTS
18 studies met inclusion criteria. Serum ApoA-I has been significantly associated with the development of new cardiovascular event and with cardiovascular mortality in ESRD patients. ApoA-IV level was independently associated with maximum carotid intima-media thickness (cIMT) and was a predictor for sudden cardiac death. The ApoB/ApoA-I ratio represents a strong predictor for coronary artery calcifications, cardiovascular mortality, and myocardial infarction in CKD/ESRD. Plasma levels of PCSK9 were not associated with cardiovascular events in CKD patients.
CONCLUSIONS
Although the "dyslipidemic status" in CKD/ESRD is not clearly depicted, due to different research findings, ApoA-I, ApoA-IV, and ApoB/ApoA-I ratio could be predictors of cardiovascular risk. Serum PCSK9 levels were not associated with the cardiovascular events in patients with CKD/ESRD. Probably in the future, the treatment of dyslipidemia in CKD/ESRD will be aimed at discovering new effective therapies on the action of these biomarkers.
Topics: Apolipoproteins A; Apolipoproteins B; Cardiovascular Diseases; Humans; Kidney Failure, Chronic; Proprotein Convertase 9; Renal Insufficiency, Chronic; Risk Factors
PubMed: 31915710
DOI: 10.1155/2019/6906278 -
Atherosclerosis May 2022Elevated plasma concentrations of lipoprotein(a) (Lp(a)) are a causal risk factor for the development of atherothrombotic disorders including coronary heart disease.... (Review)
Review
Elevated plasma concentrations of lipoprotein(a) (Lp(a)) are a causal risk factor for the development of atherothrombotic disorders including coronary heart disease. However, the pathological mechanisms underlying this causal relationship remain incompletely defined. Lp(a) consists of a lipoprotein particle in which apolipoproteinB100 is covalently linked to the unique glycoprotein apolipoprotein(a) (apo(a)). The remarkable homology between apo(a) and the fibrinolytic proenzyme plasminogen strongly suggests an antifibrinolytic role: apo(a) contains a strong lysine binding site and can block the sites on fibrin and cellular receptors required for plasminogen activation, but itself lacks proteolytic activity. While numerous in vitro and animal model studies indicate that apo(a) can inhibit plasminogen activation and fibrinolysis, this activity may not be preserved in Lp(a). Moreover, elevated Lp(a) does not reduce the efficacy of thrombolytic therapy and is not a risk factor for some non-atherosclerotic thrombotic disorders such as venous thromboembolism. Accordingly, different prothrombotic mechanisms for Lp(a) must be contemplated. Evidence exists that Lp(a) binds to and inactivates tissue factor pathway inhibitor and stimulates expression of tissue factor by monocytes. Moreover, some studies have shown that Lp(a) promotes platelet activation and aggregation, at least in response to some agonists. Lp(a) alters the structure of the fibrin network to make it less permeable and more resistant to lysis. Finally, Lp(a) may promote the development of a vulnerable plaque phenotype that is more prone to rupture and hence the precipitation of atherothrombotic events. Further study, especially in animal models of thrombosis, is required to clarify the prothrombotic effects of Lp(a).
Topics: Animals; Apolipoproteins A; Apoprotein(a); Fibrin; Fibrinolysis; Lipoprotein(a); Plasminogen; Thrombosis
PubMed: 35606079
DOI: 10.1016/j.atherosclerosis.2022.04.009 -
International Journal of Molecular... Mar 2022Lipoprotein(a) (Lp(a)) is one of the strongest causal risk factors of atherosclerotic disease. It is rich in cholesteryl ester and composed of apolipoprotein B and... (Review)
Review
Lipoprotein(a) (Lp(a)) is one of the strongest causal risk factors of atherosclerotic disease. It is rich in cholesteryl ester and composed of apolipoprotein B and apo(a). Plasma Lp(a) levels are determined by apo(a) transcriptional activity driven by a direct repeat (DR) response element in the apo(a) promoter under the control of (HNF)4α Farnesoid-X receptor (FXR) ligands play a key role in the downregulation of expression. In vitro studies on the catabolism of Lp(a) have revealed that Lp(a) binds to several specific lipoprotein receptors; however, their in vivo role remains elusive. There are more than 1000 publications on the role of diabetes mellitus (DM) in Lp(a) metabolism; however, the data is often inconsistent and confusing. In patients suffering from Type-I diabetes mellitus (T1DM), provided they are metabolically well-controlled, Lp(a) plasma concentrations are directly comparable to healthy individuals. In contrast, there exists a paradox in T2DM patients, as many of these patients have reduced Lp(a) levels; however, they are still at an increased cardiovascular risk. The Lp(a) lowering mechanism observed in T2DM patients is most probably caused by mutations in the mature-onset diabetes of the young (MODY) gene and possibly other polymorphisms in key transcription factors of the apolipoprotein (a) gene (APOA).
Topics: Apolipoproteins A; Apoprotein(a); Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Lipoprotein(a)
PubMed: 35408941
DOI: 10.3390/ijms23073584 -
Respiratory Medicine 2022Asthma prevailed as a common inflammatory disease affecting mainly the lower respiratory tract, with notable inflammation in the upper airways leading to significant... (Review)
Review
Asthma prevailed as a common inflammatory disease affecting mainly the lower respiratory tract, with notable inflammation in the upper airways leading to significant morbidity and mortality. An extensive search for a new therapeutic target is continuously being carried out. Still, the majority have failed in the trials, and eventually, the drugs, including β-adrenergic agonists, muscarinic antagonists, and certain corticosteroids, remain the backbone for asthma control. Numerous endogenous factors aid in maintaining the normal homeostasis of the lungs and prevents disease progression. One among them is the apolipoproteins which are different sets of lipoprotein moieties that not only aid in the transport and metabolism of lipids but also impart immunomodulatory roles in various pathologies. Modern research joins the links between the immunomodulatory nature of apolipoproteins in chronic respiratory diseases like asthma and COPD, which can assist in ameliorating the disease progression. Recent studies have elucidated the protective roles of apoA-I and apoE in asthma. This has enabled the utilization of certain apolipoprotein-mimetic peptides to treat these severe pulmonary diseases in the long run. In this review, we have described the prominent and probable mechanistic roles of apolipoproteins like apoA-I, apoB, apoE, apoJ, and apoM in the pathogenesis and treatment of asthma along with the development of apoA-I and apoE-mimetics as a cardinal treatment strategy for eosinophilic as well as corticosteroid resistant neutrophilic asthma.
Topics: Humans; Apolipoprotein A-I; Apolipoproteins E; Apolipoproteins; Asthma; Peptides; Disease Progression
PubMed: 36265420
DOI: 10.1016/j.rmed.2022.107007 -
Atherosclerosis May 2022Epidemiological studies investigating the association between a biomarker and a disease have many limitations. The most prominent among these is that we cannot impute... (Review)
Review
Epidemiological studies investigating the association between a biomarker and a disease have many limitations. The most prominent among these is that we cannot impute causality purely from a statistical association. If we observe an association, the biomarker might really be causal for the development of the disease, the association might be caused by a confounding variable or by reverse causation. With Mendelian Randomization (MR) methods, we have a potent tool at hand to derive evidence for a direct causal relationship. One of the core assumptions of MR studies is that genetic variants can be identified, which are strongly associated with the biomarker of interest, and can serve as an instrument indicating lifetime exposure. Since Lp(a) is primarily genetically determined by KIV-2 repeats, that in turn determine apo(a) isoform size, and by numerous single nucleotide polymorphisms (SNPs) and SNP-scores, this assumption is definitely fulfilled and it is probably one of the best phenotypes to be studied with Mendelian Randomization methods. The first studies evaluating the causal role of Lp(a) for cardiovascular diseases were performed in the early 1990s and more recently gained interest after several Lp(a)-increasing SNPs were identified in genome wide association studies. In this review, the principles behind MR methods are explained, together with their important role for Lp(a) research, particularly reconsidered in their historic context. MR methods have also been used to estimate the extent of Lp(a) reduction that would be required to yield a clinically meaningful reduction in outcomes in clinical intervention trials.
Topics: Apolipoproteins A; Apoprotein(a); Biomarkers; Genome-Wide Association Study; Lipoprotein(a); Mendelian Randomization Analysis; Polymorphism, Single Nucleotide
PubMed: 35606074
DOI: 10.1016/j.atherosclerosis.2022.04.013 -
Atherosclerosis Nov 2023Despite increased clinical interest in lipoprotein(a) (Lp(a)), many questions remain about the molecular mechanisms by which it contributes to atherosclerotic...
BACKGROUND AND AIMS
Despite increased clinical interest in lipoprotein(a) (Lp(a)), many questions remain about the molecular mechanisms by which it contributes to atherosclerotic cardiovascular disease. Existing murine transgenic (Tg) Lp(a) models are limited by low plasma levels of Lp(a) and have not consistently shown a pro-atherosclerotic effect of Lp(a).
METHODS
We generated Tg mice expressing both human apolipoprotein(a) (apo(a)) and human apoB-100, with pathogenic levels of plasma Lp(a) (range 87-250 mg/dL). Female and male Lp(a) Tg mice (Tg(LPA;APOB)) and human apoB-100-only controls (Tg(APOB)) (n = 10-13/group) were fed a high-fat, high-cholesterol diet for 12 weeks, with Ldlr knocked down using an antisense oligonucleotide. FPLC was used to characterize plasma lipoprotein profiles. Plaque area and necrotic core size were quantified and immunohistochemical assessment of lesions using a variety of cellular and protein markers was performed.
RESULTS
Male and female Tg(LPA;APOB) and Tg(APOB) mice exhibited proatherogenic lipoprotein profiles with increased cholesterol-rich VLDL and LDL-sized particles and no difference in plasma total cholesterol between genotypes. Complex lesions developed in the aortic sinus of all mice. Plaque area (+22%), necrotic core size (+25%), and calcified area (+65%) were all significantly increased in female Tg(LPA;APOB) mice compared to female Tg(APOB) mice. Immunohistochemistry of lesions demonstrated that apo(a) deposited in a similar pattern as apoB-100 in Tg(LPA;APOB) mice. Furthermore, female Tg(LPA;APOB) mice exhibited less organized collagen deposition as well as 42% higher staining for oxidized phospholipids (OxPL) compared to female Tg(APOB) mice. Tg(LPA;APOB) mice had dramatically higher levels of plasma OxPL-apo(a) and OxPL-apoB compared to Tg(APOB) mice, and female Tg(LPA;APOB) mice had higher plasma levels of the proinflammatory cytokine MCP-1 (+3.1-fold) compared to female Tg(APOB) mice.
CONCLUSIONS
These data suggest a pro-inflammatory phenotype exhibited by female Tg mice expressing Lp(a) that appears to contribute to the development of more severe lesions with greater vulnerable features.
Topics: Male; Humans; Female; Mice; Animals; Lipoprotein(a); Apolipoprotein B-100; Mice, Transgenic; Atherosclerosis; Apolipoproteins B; Apolipoproteins A; Apoprotein(a); Cholesterol
PubMed: 37290980
DOI: 10.1016/j.atherosclerosis.2023.05.019