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Clinical Pharmacokinetics Apr 2023Cardiovascular diseases are the leading cause of death worldwide. Although there have been substantial advances over the last decades, recurrent adverse cardiovascular... (Review)
Review
Cardiovascular diseases are the leading cause of death worldwide. Although there have been substantial advances over the last decades, recurrent adverse cardiovascular events after myocardial infarction are still frequent, particularly during the first year of the index event. For decades, high-density lipoprotein (HDL) has been among the therapeutic targets for long-term prevention after an ischemic event. However, early trials focusing on increasing HDL circulating levels showed no improvement in clinical outcomes. Recently, the paradigm has shifted to increasing the functionality of HDL rather than its circulating plasma levels. For this purpose, apolipoprotein-AI-based infusion therapies have been developed, including reconstituted HDL, such as CSL112. During the last decade, CSL112 has been extensively studied in Phase 1 and 2 trials and has shown promising results. In particular, CSL112 has been studied in the Phase 2b AEGIS trial exhibiting good safety and tolerability profiles, which has led to the ongoing large-scale Phase 3 AEGIS-II trial. This systematic overview will provide a comprehensive summary of the CSL112 drug development program focusing on its pharmacodynamic, pharmacokinetic, and safety profiles.
Topics: Humans; Lipoproteins, HDL; Myocardial Infarction; Apolipoprotein A-I; Drug Development
PubMed: 36928983
DOI: 10.1007/s40262-023-01224-8 -
International Journal of Molecular... Aug 2022In vivo, apolipoprotein A-I (ApoA-I) is commonly found together with lipids in so-called lipoprotein particles. The protein has also been associated with several...
In vivo, apolipoprotein A-I (ApoA-I) is commonly found together with lipids in so-called lipoprotein particles. The protein has also been associated with several diseases-such as atherosclerosis and amyloidosis-where insoluble aggregates containing ApoA-I are deposited in various organs or arteries. The deposited ApoA-I has been found in the form of amyloid fibrils, suggesting that amyloid formation may be involved in the development of these diseases. In the present study we investigated ApoA-I aggregation into amyloid fibrils and other aggregate morphologies. We studied the aggregation of wildtype ApoA-I as well as a disease-associated mutant, ApoA-I K107Δ, under different solution conditions. The aggregation was followed using thioflavin T fluorescence intensity. For selected samples the aggregates formed were characterized in terms of size, secondary structure content, and morphology using circular dichroism spectroscopy, dynamic light scattering, atomic force microscopy and transmission electron microscopy. We find that ApoA-I may form globular protein-only condensates, in which the α-helical conformation of the protein is retained. The protein in its unmodified form appears resistant to amyloid formation; however, the conversion into amyloid fibrils rich in β-sheet is facilitated by oxidation or mutation. In particular, the K107Δ mutant shows higher amyloid formation propensity, and the end state appears to be a co-existence of β-sheet rich amyloid fibrils and α-helix-rich condensates.
Topics: Amyloid; Amyloidogenic Proteins; Apolipoprotein A-I; Circular Dichroism; Protein Conformation, beta-Strand; Protein Structure, Secondary
PubMed: 35955915
DOI: 10.3390/ijms23158780 -
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 -
Journal of Healthcare Engineering 2022To analyze apolipoprotein-A for its predictive value for long-term death in individuals suffering from acute ST-segment elevation myocardial infarction following...
OBJECTIVE
To analyze apolipoprotein-A for its predictive value for long-term death in individuals suffering from acute ST-segment elevation myocardial infarction following percutaneous coronary intervention.
METHODS
We selected patients suffering from acute ST-segment elevation myocardial infarction who underwent emergency PCI at the Affiliated Hospital of Putian University from January 2017 to August 2019. The patients were divided into a high-Apo-A group and low-Apo-A group, and we observed all-cause deaths of patients in the 2 groups within 2 years.
RESULTS
The ROC curve analysis indicated the best critical value for predicting 2-year mortality as 0.8150 (area under the curve was 0.626, sensitivity 75.1%, and specificity 51.9%). There was no statistical difference among the two groups in gender, age, lesion vessel, and comorbidities. The two groups had statistically significant differences in apolipoprotein-B/A, high-density lipoprotein, apolipoprotein-A, and hypersensitivity C-reactive protein. Correlation analysis showed a significant negative correlation between apolipoprotein-A and hypersensitive C-reactive protein. The results of the 24-month analysis indicated the incidence of all-cause mortality as higher in the low-Apo-A group, and Kaplan-Meier survival analysis showed the same trend.
CONCLUSION
Apolipoprotein-A can predict the potential for long-term mortality among individuals having acute ST-segment elevation myocardial infarction.
Topics: Apolipoproteins; Apolipoproteins A; C-Reactive Protein; Humans; Percutaneous Coronary Intervention; ST Elevation Myocardial Infarction; Treatment Outcome
PubMed: 35075388
DOI: 10.1155/2022/5941117 -
The American Journal of Clinical... Jul 2018
Topics: Apolipoprotein A-I; Apolipoprotein A-II; Epigenomics; Humans; Lipid Metabolism; Metabolomics; Obesity
PubMed: 29982311
DOI: 10.1093/ajcn/nqy136 -
International Journal of Molecular... Jul 2022Chronic obstructive pulmonary disease (COPD) is a widespread disease associated with high rates of disability and mortality. COPD is characterized by chronic... (Review)
Review
Chronic obstructive pulmonary disease (COPD) is a widespread disease associated with high rates of disability and mortality. COPD is characterized by chronic inflammation in the bronchi as well as systemic inflammation, which contributes significantly to the clinically heterogeneous course of the disease. Lipid metabolism disorders are common in COPD, being a part of its pathogenesis. High-density lipoproteins (HDLs) are not only involved in lipid metabolism, but are also part of the organism's immune and antioxidant defense. In addition, HDL is a versatile transport system for endogenous regulatory agents and is also involved in the removal of exogenous substances such as lipopolysaccharide. These functions, as well as information about lipoprotein metabolism disorders in COPD, allow a broader assessment of their role in the pathogenesis of heterogeneous and comorbid course of the disease.
Topics: Apolipoprotein A-I; Humans; Inflammation; Lipid Metabolism; Lipoproteins, HDL; Pulmonary Disease, Chronic Obstructive
PubMed: 35897703
DOI: 10.3390/ijms23158128 -
American Journal of Physiology. Cell... Feb 2023Apolipoprotein A-I (apoA-I) mediates reverse cholesterol transport (RCT) out of cells. In addition to its important role in the RTC, apoA-I also possesses... (Review)
Review
Apolipoprotein A-I (apoA-I) mediates reverse cholesterol transport (RCT) out of cells. In addition to its important role in the RTC, apoA-I also possesses anti-inflammatory and antioxidative functions including the ability to activate inflammasome and signal via toll-like receptors. Dysfunctional apoA-I or its low abundance may cause accumulation of cholesterol mass in alveolar macrophages, leading to the formation of foam cells. Increased numbers of foam cells have been noted in the lungs of mice after experimental exposure to cigarette smoke, silica, or bleomycin and in the lungs of patients suffering from different types of lung fibrosis, including idiopathic pulmonary fibrosis (IPF). This suggests that dysregulation of lipid metabolism may be a common event in the pathogenesis of interstitial lung diseases. Recognition of the emerging role of cholesterol in the regulation of lung inflammation and remodeling provides a challenging concept for understanding lung diseases and offers novel and exciting avenues for therapeutic development. Accordingly, a number of preclinical studies demonstrated decreased expression of inflammatory and profibrotic mediators and preserved lung tissue structure following the administration of the apoA-I or its mimetic peptides. This review highlights the role of apoA-I in lung fibrosis and provides evidence for its potential use in the treatment of this pathological condition.
Topics: Animals; Mice; Apolipoprotein A-I; Atherosclerosis; Cholesterol; Foam Cells; Idiopathic Pulmonary Fibrosis; Lung
PubMed: 36534503
DOI: 10.1152/ajpcell.00491.2022 -
MEDICC Review 2019INTRODUCTION Hypertension is one of the most studied risk factors for cardiovascular disease in adults; in children and adolescents, its global prevalence changes with...
INTRODUCTION Hypertension is one of the most studied risk factors for cardiovascular disease in adults; in children and adolescents, its global prevalence changes with age, from 1%-3% in children to 3.2% in adolescents. In adults, in addition to hypertension, several biochemical markers of cardiovascular risk have been identified. Confirming an association between these and hypertension in childhood and adolescence would allow for more timely diagnosis and monitoring of cardiovascular disease, since the presence of both the markers and hypertension would imply increased risk. OBJECTIVE Confirm an association between biochemical risk markers of cardiovascular disease and hypertension in children aged 8 to 11 years. METHODS A cross-sectional study of 373 children aged 8-11 years was conducted in 3 primary schools in the city of Santa Clara in central Cuba. The variables examined were age, sex, height, blood pressure, cholesterol, triglycerides, lipoproteins and apolipoproteins. The children were classified as normotensive, prehypertensive or hypertensive, based on blood pressure readings and percentiles for age, sex and height. Descriptive statistics were calculated for quantitative variables. A bivariate analysis, tests of independence for qualitative variables and a means comparison for quantitative variables (ANOVA and its nonparametric alternative, the Kruskal Wallis test) were performed. Fisher's F-test and its associated probability value were employed. RESULTS Some 32.2% of the children were prehypertensive and 5.1% hypertensive. Cholesterol and triglyceride values were significantly higher in hypertensive than in normotensive children (p = 0.028 and p = 0.047, respectively). HDL numbers were higher in normotensive children (p =0.001), and LDL numbers and the LDL/HDL ratio were higher in the hypertensive children, with differences between groups (p = 0.001 for both variables). There were differences between the three blood pressure categories for lipoprotein(a) and ApoA (p <0.001 and p = 0.001), for ApoB and for the ApoB/ApoA ratio (p <0.001 for both variables), with lower ApoA values and higher ApoB and ApoB/ApoA values in the hypertensive children. CONCLUSIONS The biochemical risk markers most strongly associated with hypertension in children are ApoB values, LDL, lipoprotein(a), and LDL/HDL and ApoB/ApoA ratios. KEYWORDS Adolescent, child, hypertension, apolipoproteins, cardiovascular diseases, risk factors, Cuba.
Topics: Anthropometry; Apolipoprotein B-100; Apolipoproteins A; Biomarkers; Cardiovascular Diseases; Child; Cholesterol; Cross-Sectional Studies; Cuba; Female; Humans; Hypertension; Male
PubMed: 31373579
DOI: 10.37757/MR2019.V21.N2-3.4 -
Atherosclerosis May 2022High lipoprotein(a) [Lp(a)] concentrations are one of the most important genetically determined risk factors for cardiovascular disease. Lp(a) concentrations are an... (Review)
Review
High lipoprotein(a) [Lp(a)] concentrations are one of the most important genetically determined risk factors for cardiovascular disease. Lp(a) concentrations are an enigmatic trait largely controlled by one single gene (LPA) that contains a complex interplay of several genetic elements with many surprising effects discussed in this review. A hypervariable coding copy number variation (the kringle IV type-2 repeat, KIV-2) generates >40 apolipoprotein(a) protein isoforms and determines the median Lp(a) concentrations. Carriers of small isoforms with up to 22 kringle IV domains have median Lp(a) concentrations up to 5 times higher than those with large isoforms (>22 kringle IV domains). The effect of the apo(a) isoforms are, however, modified by many functional single nucleotide polymorphisms (SNPs) distributed over the complete range of allele frequencies (<0.1% to >20%) with very pronounced effects on Lp(a) concentrations. A complex interaction is present between the apo(a) isoforms and LPA SNPs, with isoforms partially masking the effect of functional SNPs and, vice versa, SNPs lowering the Lp(a) concentrations of affected isoforms. This picture is further complicated by SNP-SNP interactions, a poorly understood role of other polymorphisms such as short tandem repeats and linkage structures that are poorly captured by common R values. A further layer of complexity derives from recent findings that several functional SNPs are located in the KIV-2 repeat and are thus not accessible to conventional sequencing and genotyping technologies. A critical impact of the ancestry on correlation structures and baseline Lp(a) values becomes increasingly evident. This review provides a comprehensive overview on the complex genetic architecture of the Lp(a) concentrations in plasma, a field that has made tremendous progress with the introduction of new technologies. Understanding the genetics of Lp(a) might be a key to many mysteries of Lp(a) and booster new ideas on the metabolism of Lp(a) and possible interventional targets.
Topics: Apolipoproteins A; Apoprotein(a); DNA Copy Number Variations; Kringles; Lipoprotein(a); Polymorphism, Single Nucleotide; Protein Isoforms
PubMed: 35606073
DOI: 10.1016/j.atherosclerosis.2022.04.003 -
Metabolism: Clinical and Experimental Apr 2016Lipoprotein(a) [Lp(a)] is mainly similar in composition to LDL, but differs in having apolipoprotein (apo) (a) covalently linked to apoB-100. Our purpose was to examine...
OBJECTIVES
Lipoprotein(a) [Lp(a)] is mainly similar in composition to LDL, but differs in having apolipoprotein (apo) (a) covalently linked to apoB-100. Our purpose was to examine the individual metabolism of apo(a) and apoB-100 within plasma Lp(a).
MATERIALS AND METHODS
The kinetics of apo(a) and apoB-100 in plasma Lp(a) were assessed in four men with dyslipidemia [Lp(a) concentration: 8.9-124.7nmol/L]. All subjects received a primed constant infusion of [5,5,5-(2)H3] L-leucine while in the constantly fed state. Lp(a) was immunoprecipitated directly from whole plasma; apo(a) and apoB-100 were separated by gel electrophoresis; and isotopic enrichment was determined by gas chromatography/mass spectrometry.
RESULTS
Multicompartmental modeling analysis indicated that the median fractional catabolic rates of apo(a) and apoB-100 within Lp(a) were significantly different at 0.104 and 0.263 pools/day, respectively (P=0.04). The median Lp(a) apo(a) production rate at 0.248nmol/kg·day(-1) was significantly lower than that of Lp(a) apoB-100 at 0.514nmol/kg·day(-1) (P=0.03).
CONCLUSION
Our data indicate that apo(a) has a plasma residence time (11days) that is more than twice as long as that of apoB-100 (4days) within Lp(a), supporting the concept that apo(a) and apoB-100 within plasma Lp(a) are not catabolized from the bloodstream as a unit in humans in the fed state.
Topics: Apolipoprotein B-100; Apolipoproteins A; Dyslipidemias; Humans; Hypertriglyceridemia; Kinetics; Leucine; Lipids; Lipoprotein(a); Male; Middle Aged
PubMed: 26975530
DOI: 10.1016/j.metabol.2015.10.031