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Journal of the American College of... May 2023Lipoprotein(a) (Lp[a]) and oxidized phospholipids (OxPLs) are each independent risk factors for atherosclerotic cardiovascular disease. The extent to which Lp(a) and...
BACKGROUND
Lipoprotein(a) (Lp[a]) and oxidized phospholipids (OxPLs) are each independent risk factors for atherosclerotic cardiovascular disease. The extent to which Lp(a) and OxPLs predict coronary artery disease (CAD) severity and outcomes in a contemporary, statin-treated cohort is not well established.
OBJECTIVES
This study sought to evaluate the relationships between Lp(a) particle concentration and OxPLs associated with apolipoprotein B (OxPL-apoB) or apolipoprotein(a) (OxPL-apo[a]) with angiographic CAD and cardiovascular outcomes.
METHODS
Among 1,098 participants referred for coronary angiography in the CASABLANCA (Catheter Sampled Blood Archive in Cardiovascular Diseases) study, Lp(a), OxPL-apoB, and OxPL-apo(a) were measured. Logistic regression estimated the risk of multivessel coronary stenoses by Lp(a)-related biomarker level. Cox proportional hazards regression estimated the risk of major adverse cardiovascular events (MACEs) (coronary revascularization, nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) in follow-up.
RESULTS
Median Lp(a) was 26.45 nmol/L (IQR: 11.39-89.49 nmol/L). Lp(a), OxPL-apoB, and OxPL-apo(a) were highly correlated (Spearman R ≥0.91 for all pairwise combinations). Lp(a) and OxPL-apoB were associated with multivessel CAD. Odds of multivessel CAD per doubling of Lp(a), OxPL-apoB, and OxPL-apo(a) were 1.10 (95% CI: 1.03-1.18; P = 0.006), 1.18 (95% CI: 1.03-1.34; P = 0.01), and 1.07 (95% CI: 0.99-1.16; P = 0.07), respectively. All biomarkers were associated with cardiovascular events. HRs for MACE per doubling of Lp(a), OxPL-apoB, and OxPL-apo(a) were 1.08 (95% CI: 1.03-1.14; P = 0.001), 1.15 (95% CI: 1.05-1.26; P = 0.004), and 1.07 (95% CI: 1.01-1.14; P = 0.02), respectively.
CONCLUSIONS
In patients undergoing coronary angiography, Lp(a) and OxPL-apoB are associated with multivessel CAD. Lp(a), OxPL-apoB, and OxPL-apo(a) are associated with incident cardiovascular events. (Catheter Sampled Blood Archive in Cardiovascular Diseases [CASABLANCA]; NCT00842868).
Topics: Humans; Coronary Artery Disease; Lipoprotein(a); Cardiovascular Diseases; Phospholipids; Apolipoproteins B; Apolipoproteins A; Biomarkers; Apoprotein(a); Oxidation-Reduction
PubMed: 37137588
DOI: 10.1016/j.jacc.2023.02.050 -
Cell Cycle (Georgetown, Tex.) Jun 2022The maintenance of cellular cholesterol homeostasis is essential for normal cell function and viability. Excessive cholesterol accumulation is detrimental to cells and... (Review)
Review
The maintenance of cellular cholesterol homeostasis is essential for normal cell function and viability. Excessive cholesterol accumulation is detrimental to cells and serves as the molecular basis of many diseases, such as atherosclerosis, Alzheimer's disease, and diabetes mellitus. The peripheral cells do not have the ability to degrade cholesterol. Cholesterol efflux is therefore the only pathway to eliminate excessive cholesterol from these cells. This process is predominantly mediated by ATP-binding cassette transporter A1 (ABCA1), an integral membrane protein. ABCA1 is known to transfer intracellular free cholesterol and phospholipids to apolipoprotein A-I (apoA-I) for generating nascent high-density lipoprotein (nHDL) particles. nHDL can accept more free cholesterol from peripheral cells. Free cholesterol is then converted to cholesteryl ester by lecithin:cholesterol acyltransferase to form mature HDL. HDL-bound cholesterol enters the liver for biliary secretion and fecal excretion. Although how cholesterol is transported by ABCA1 to apoA-I remains incompletely understood, nine models have been proposed to explain this effect. In this review, we focus on the current view of the mechanisms underlying ABCA1-mediated cholesterol efflux to provide an important framework for future investigation and lipid-lowering therapy.
Topics: ATP Binding Cassette Transporter 1; Apolipoprotein A-I; Biological Transport; Cholesterol; Cholesterol, HDL; Lipoproteins, HDL; Phosphatidylcholine-Sterol O-Acyltransferase
PubMed: 35192423
DOI: 10.1080/15384101.2022.2042777 -
Journal of the American College of... Mar 2022Laboratory methods that report low-density lipoprotein cholesterol (LDL-C) include both LDL-C and lipoprotein(a) cholesterol [Lp(a)-C] content. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Laboratory methods that report low-density lipoprotein cholesterol (LDL-C) include both LDL-C and lipoprotein(a) cholesterol [Lp(a)-C] content.
OBJECTIVES
The purpose of this study was to assess the effect of pelacarsen on directly measured Lp(a)-C and LDL-C corrected for its Lp(a)-C content.
METHODS
The authors evaluated subjects with a history of cardiovascular disease and elevated Lp(a) randomized to 5 groups of cumulative monthly doses of 20-80 mg pelacarsen vs placebo. Direct Lp(a)-C was measured on isolated Lp(a) using LPA4-magnetic beads directed to apolipoprotein(a). LDL-C was reported as: 1) LDL-C as reported by the clinical laboratory; 2) LDL-C = laboratory-reported LDL-C - direct Lp(a)-C; and 3) LDL-C = laboratory LDL-C - [Lp(a) mass × 0.30] estimated by the Dahlén formula.
RESULTS
The baseline median Lp(a)-C values in the groups ranged from 11.9 to 15.6 mg/dL. Compared with placebo, pelacarsen resulted in dose-dependent decreases in Lp(a)-C (2% vs -29% to -67%; P = 0.001-<0.0001). Baseline laboratory-reported mean LDL-C ranged from 68.5 to 89.5 mg/dL, whereas LDL-C ranged from 55 to 74 mg/dL. Pelacarsen resulted in mean percent/absolute changes of -2% to -19%/-0.7 to -8.0 mg/dL (P = 0.95-0.05) in LDL-C, -7% to -26%/-5.4 to -9.4 mg/dL (P = 0.44-<0.0001) in laboratory-reported LDL-C, and 3.1% to 28.3%/0.1 to 9.5 mg/dL (P = 0.006-0.50) increases in LDL-C. Total apoB declined by 3%-16% (P = 0.40-<0.0001), but non-Lp(a) apoB was not significantly changed.
CONCLUSIONS
Pelacarsen significantly lowers direct Lp(a)-C and has neutral to mild lowering of LDL-C. In patients with elevated Lp(a), LDL-C provides a more accurate reflection of changes in LDL-C than either laboratory-reported LDL-C or the Dahlén formula.
Topics: Apolipoproteins A; Cholesterol; Cholesterol, LDL; Humans; Lipoprotein(a); Oligonucleotides, Antisense
PubMed: 35300814
DOI: 10.1016/j.jacc.2021.12.032 -
JAMA Dec 2023Epidemiological and genetic data have implicated lipoprotein(a) as a potentially modifiable risk factor for atherosclerotic disease and aortic stenosis, but there are no... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Epidemiological and genetic data have implicated lipoprotein(a) as a potentially modifiable risk factor for atherosclerotic disease and aortic stenosis, but there are no approved pharmacological treatments.
OBJECTIVES
To assess the safety, tolerability, pharmacokinetics, and effects of lepodisiran on lipoprotein(a) concentrations after single doses of the drug; lepodisiran is a short interfering RNA directed at hepatic synthesis of apolipoprotein(a), an essential component necessary for assembly of lipoprotein(a) particles.
DESIGN, SETTING, AND PARTICIPANTS
A single ascending-dose trial conducted at 5 clinical research sites in the US and Singapore that enrolled 48 adults without cardiovascular disease and with lipoprotein(a) serum concentrations of 75 nmol/L or greater (or ≥30 mg/dL) between November 18, 2020, and December 7, 2021; the last follow-up visit occurred on November 9, 2022.
INTERVENTIONS
Participants were randomized to receive placebo or a single dose of lepodisiran (4 mg, 12 mg, 32 mg, 96 mg, 304 mg, or 608 mg) administered subcutaneously.
MAIN OUTCOMES AND MEASURES
The primary outcome was the safety and tolerability of the single ascending doses of lepodisiran. The secondary outcomes included plasma levels of lepodisiran for 168 days after dose administration and changes in fasting lipoprotein(a) serum concentrations through a maximum follow-up of 336 days (48 weeks).
RESULTS
Of the 48 participants enrolled (mean age, 46.8 [SD, 11.6] years; 35% were women), 1 serious adverse event occurred. The plasma concentrations of lepodisiran reached peak levels within 10.5 hours and were undetectable by 48 hours. The median baseline lipoprotein(a) concentration was 111 nmol/L (IQR, 78 to 134 nmol/L) in the placebo group, 78 nmol/L (IQR, 50 to 152 nmol/L) in the 4 mg of lepodisiran group, 97 nmol/L (IQR, 86 to 107 nmol/L) in the 12-mg dose group, 120 nmol/L (IQR, 110 to 188 nmol/L) in the 32-mg dose group, 167 nmol/L (IQR, 124 to 189 nmol/L) in the 96-mg dose group, 96 nmol/L (IQR, 72 to 132 nmol/L) in the 304-mg dose group, and 130 nmol/L (IQR, 87 to 151 nmol/L) in the 608-mg dose group. The maximal median change in lipoprotein(a) concentration was -5% (IQR, -16% to 11%) in the placebo group, -41% (IQR, -47% to -20%) in the 4 mg of lepodisiran group, -59% (IQR, -66% to -53%) in the 12-mg dose group, -76% (IQR, -76% to -75%) in the 32-mg dose group, -90% (IQR, -94% to -85%) in the 96-mg dose group, -96% (IQR, -98% to -95%) in the 304-mg dose group, and -97% (IQR, -98% to -96%) in the 608-mg dose group. At day 337, the median change in lipoprotein(a) concentration was -94% (IQR, -94% to -85%) in the 608 mg of lepodisiran group.
CONCLUSIONS AND RELEVANCE
In this phase 1 study of 48 participants with elevated lipoprotein(a) levels, lepodisiran was well tolerated and produced dose-dependent, long-duration reductions in serum lipoprotein(a) concentrations. The findings support further study of lepodisiran.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04914546.
Topics: Adult; Female; Humans; Male; Middle Aged; Double-Blind Method; Lipoprotein(a); Risk Factors; RNA, Small Interfering; Singapore; Apolipoproteins A; Liver; Administration, Cutaneous; United States
PubMed: 37952254
DOI: 10.1001/jama.2023.21835 -
Current Atherosclerosis Reports Feb 2021Apolipoprotein (APO) A1, the main apolipoprotein of plasma high-density lipoproteins (HDLs), has several well documented cardioprotective functions. A number of... (Review)
Review
PURPOSE OF THE REVIEW
Apolipoprotein (APO) A1, the main apolipoprotein of plasma high-density lipoproteins (HDLs), has several well documented cardioprotective functions. A number of additional potentially beneficial functions of APOA1 have recently been identified. This review is concerned with the therapeutic potential of all of these functions in multiple disease states.
RECENT FINDINGS
Knowledge of the beneficial functions of APOA1 in atherosclerosis, thrombosis, diabetes, cancer, and neurological disorders is increasing exponentially. These insights have led to the development of clinically relevant peptides and APOA1-containing, synthetic reconstituted HDL (rHDL) preparations that mimic the functions of full-length APOA1. APOA1 is a multifunctional apolipoprotein that has therapeutic potential in several diseases. Translation of this knowledge into the clinic is likely to be dependent on the efficacy and bioavailability of small peptides and synthetic rHDL preparations that are currently under investigation, or in development.
Topics: Apolipoprotein A-I; Atherosclerosis; Humans; Lipoproteins, HDL; Neoplasms
PubMed: 33591433
DOI: 10.1007/s11883-021-00906-7 -
International Journal of Molecular... Sep 2023Lipoprotein(a) [Lp(a)] is a well-established risk factor for cardiovascular disease, predisposing to major cardiovascular events, including coronary heart disease,... (Review)
Review
Lipoprotein(a) [Lp(a)] is a well-established risk factor for cardiovascular disease, predisposing to major cardiovascular events, including coronary heart disease, stroke, aortic valve calcification and abdominal aortic aneurysm. Lp(a) is differentiated from other lipoprotein molecules through apolipoprotein(a), which possesses atherogenic and antithrombolytic properties attributed to its structure. Lp(a) levels are mostly genetically predetermined and influenced by the size of LPA gene variants, with smaller isoforms resulting in a greater synthesis rate of apo(a) and, ultimately, elevated Lp(a) levels. As a result, serum Lp(a) levels may highly vary from extremely low to extremely high. Hyperlipoproteinemia(a) is defined as Lp(a) levels > 30 mg/dL in the US and >50 mg/dL in Europe. Because of its association with CVD, Lp(a) levels should be measured at least once a lifetime in adults. The ultimate goal is to identify individuals with increased risk of CVD and intervene accordingly. Traditional pharmacological interventions like niacin, statins, ezetimibe, aspirin, PCSK-9 inhibitors, mipomersen, estrogens and CETP inhibitors have not yet yielded satisfactory results. The mean Lp(a) reduction, if any, is barely 50% for all agents, with statins increasing Lp(a) levels, whereas a reduction of 80-90% appears to be required to achieve a significant decrease in major cardiovascular events. Novel RNA-interfering agents that specifically target hepatocytes are aimed in this direction. Pelacarsen is an antisense oligonucleotide, while olpasiran, LY3819469 and SLN360 are small interfering RNAs, all conjugated with a N-acetylgalactosamine molecule. Their ultimate objective is to genetically silence LPA, reduce apo(a) production and lower serum Lp(a) levels. Evidence thus so far demonstrates that monthly subcutaneous administration of a single dose yields optimal results with persisting substantial reductions in Lp(a) levels, potentially enhancing CVD risk reduction. The Lp(a) reduction achieved with novel RNA agents may exceed 95%. The results of ongoing and future clinical trials are eagerly anticipated, and it is hoped that guidelines for the tailored management of Lp(a) levels with these novel agents may not be far off.
Topics: Adult; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Apoprotein(a); Lipoprotein(a); Apolipoproteins A; Hyperlipoproteinemias; Aortic Valve Stenosis
PubMed: 37686428
DOI: 10.3390/ijms241713622 -
Biomedicine & Pharmacotherapy =... Oct 2022Apolipoprotein A1 (ApoA1) is a member of the Apolipoprotein family of proteins. It's a vital protein that helps in the production of high-density lipoprotein (HDL)... (Review)
Review
Apolipoprotein A1 (ApoA1) is a member of the Apolipoprotein family of proteins. It's a vital protein that helps in the production of high-density lipoprotein (HDL) particles, which are crucial for reverse cholesterol transport (RCT). It also has anti-inflammatory, anti-atherogenic, anti-apoptotic, and anti-thrombotic properties. These functions interact to give HDL particles their cardioprotective characteristics. ApoA1 has recently been investigated for its potential role in atherosclerosis, diabetes, neurological diseases, cancer, and certain infectious diseases. Since ApoA1's discovery, numerous mutations have been reported that affect its structural integrity and alter its function. Hence these insights have led to the development of clinically relevant peptides and synthetic reconstituted HDL (rHDL) that mimics the function of ApoA1. As a result, this review has aimed to provide an organized explanation of our understanding of the ApoA1 protein structure and its role in various essential pathways. Furthermore, we have comprehensively reviewed the important ApoA1 mutations (24 mutations) that are reported to be involved in various diseases. Finally, we've focused on the therapeutic potentials of some of the beneficial mutations, small peptides, and synthetic rHDL that are currently being researched or developed, since these will aid in the development of novel therapeutics in the future.
Topics: Apolipoprotein A-I; Atherosclerosis; Humans; Lipoproteins, HDL; Mutation; Peptides
PubMed: 36063649
DOI: 10.1016/j.biopha.2022.113634 -
Atherosclerosis May 2022Lp(a) and diabetes are both known and established risk factors for the development of cardiovascular disease. However, studies trying to link both risk factors find an... (Review)
Review
Lp(a) and diabetes are both known and established risk factors for the development of cardiovascular disease. However, studies trying to link both risk factors find an inverse association between Lp(a) and risk of prevalent and incident diabetes. It is not yet clear though whether this association is causal and whether this possible causal link is due to Lp(a) concentration itself, to length of the apo(a) isoforms, or both. The results of Mendelian Randomisation studies are highly heterogeneous. This review aims to shed light on the most recent findings of epidemiological and Mendelian Randomisation studies and disentangle the contradictory results. Only part of the observed association of Lp(a) with diabetes can likely be explained by causality and may also be driven by reverse causation, co-morbidities, or medications. Furthermore, this review also summarizes the role of Lp(a) within patients with diabetes. Several studies suggest that elevated Lp(a) is a causal independent risk factor for CVD in patients. Although therapies that specifically target and lower Lp(a) have not been evaluated in diabetic patients, analysis of the large PCSK9 clinical outcomes trials suggest they are beneficial on cardiovascular outcomes.
Topics: Apolipoproteins A; Apoprotein(a); Cardiovascular Diseases; Diabetes Mellitus; Humans; Lipoprotein(a); Proprotein Convertase 9; Risk Factors
PubMed: 35606077
DOI: 10.1016/j.atherosclerosis.2022.04.016 -
Advances in Experimental Medicine and... 2022A wealth of evidence indicates that high-density lipoprotein assumes the unique antiatherosclerosis and other cardioprotective properties. Based on that, HDL-C has been...
A wealth of evidence indicates that high-density lipoprotein assumes the unique antiatherosclerosis and other cardioprotective properties. Based on that, HDL-C has been considered as a promising therapy target to reduce the cardiovascular diseases. Recombinant HDL (rHDL) and apolipoprotein mimetic peptides emerge in recent years and have great potential in the future. Here we discussed the pleiotropic therapeutic effect of rHDL based on the effects of atherogenic, angiogenesis, platelet, vascular, and Alzheimer's disease. On the other hand, rHDL not only plays the key role as the major protein component of HDL, it is also used as a nanovector in antiatherosclerotic, antitumor, cardiovascular diagnosing and other therapeutic areas. Synthetic apolipoprotein mimetic peptides like apoA-I and and apoE mimetics have undergone clinical assessment, and we have also reviewed the advances of clinical trials and gave an outlook for the therapy of rHDL and mimetic peptides.
Topics: Apolipoprotein A-I; Apolipoproteins; Atherosclerosis; Cardiovascular Diseases; Humans; Lipoproteins, HDL; Peptides
PubMed: 35575930
DOI: 10.1007/978-981-19-1592-5_14 -
Atherosclerosis May 2022Lipoprotein(a) [Lp(a)] has been established as an independent and causal risk factor for cardiovascular disease. Individuals with elevated levels of Lp(a) (>125 nmol/L;... (Review)
Review
Lipoprotein(a) [Lp(a)] has been established as an independent and causal risk factor for cardiovascular disease. Individuals with elevated levels of Lp(a) (>125 nmol/L; >50 mg/dl) display increased arterial wall inflammation characterized by activation of the endothelium by Lp(a)-carried oxidized phospholipids and recruitment of circulating monocytes. This results in increased secretion of chemoattractants and cytokines, upregulation of adhesion molecules and increased migration of leukocytes through the vessel wall. In addition, Lp(a) is also pivotal in the initiation phase of aortic valve stenosis. The oxidized phospholipids associated, in part, with the apolipoprotein(a) [apo(a)] moiety of Lp(a) stimulate the aortic valve residential cell, the valve interstitial cells (VICs), to either induce osteoblastic differentiation or apoptosis, thereby initiating the process of aortic valve calcification. Lastly, Lp(a) has been linked to systemic inflammation, including the acute phase response. Specifically, the cytokine interleukin 6 (IL-6) has a unique relationship with Lp(a), since the LPA gene contains IL-6 response elements. In this review, we will discuss the pathways and cell types affected by Lp(a) in the context of atherosclerosis, aortic valve stenosis and the acute phase response, highlighting the role of Lp(a) as an inflammatory mastermind.
Topics: Acute-Phase Reaction; Aortic Valve Stenosis; Apolipoproteins A; Apoprotein(a); Humans; Inflammation; Interleukin-6; Lipoprotein(a); Phospholipids; Risk Factors
PubMed: 35606070
DOI: 10.1016/j.atherosclerosis.2022.04.004