-
PloS One 2024Early life factors may predict cardiovascular disease (CVD), but the pathways are still unclear. There is emerging evidence of an association of early life factors with...
BACKGROUND
Early life factors may predict cardiovascular disease (CVD), but the pathways are still unclear. There is emerging evidence of an association of early life factors with apolipoproteins, which are linked to CVD. The study objective was to assess the associations between birth variables and adult apolipoproteins (apoA1 and apoB, and their ratio) in a population-based cohort.
METHODS
The LifeGene Study is a prospective cohort comprising index participants randomly sampled from the general population. Blood samples were collected between 2009 and 2016. In this sub-study, we used birth variables, obtained from a national registry for all participants born 1973 or later, including birth weight and gestational age, while adult CVD risk factors included age, sex, body mass index (BMI), lipids, and smoking history. We employed univariate and multivariate general linear regression to explore associations between birth variables, lipid levels and other adult CVD risk factors. The outcomes included non-fasting apoA1 and apoB and their ratio, as well as total cholesterol and triglycerides. A total of 10,093 participants with both birth information and lipoprotein levels at screening were included. Of these, nearly 42.5% were men (n = 4292) and 57.5% were women (n = 5801).
RESULTS
The mean (standard deviation) age of men was 30.2 (5.7) years, and for women 28.9 (5.8) years. There was an increase of 0.022 g/L in apoA1 levels per 1 kg increase in birth weight (p = 0.005) after adjusting for age, sex, BMI, gestational age, and smoking history. Similarly, there was a decrease of 0.023 g/L in apoB levels per 1 kg increase in birth weight (p<0.001) after adjusting for the same variables. There were inverse associations of birth weight with the apoB/apoA1 ratio. No independent association was found with total cholesterol, but with triglyceride levels (ẞ-coefficient (95% Confidence Interval); -0.067 (-0.114, -0.021); p-value 0.005).
CONCLUSIONS
Lower birth weight was associated with an adverse adult apolipoprotein pattern, i.e., a higher apoB/apoA1 ratio, indicating increased risk of future CVD manifestations. The study highlights the need of preconception care and pregnancy interventions that aim at improving maternal and child outcomes with long-term impacts for prevention of cardiovascular disease by influencing lipid levels.
Topics: Male; Adult; Pregnancy; Child; Humans; Female; Birth Weight; Prospective Studies; Cardiovascular Diseases; Apolipoproteins B; Apolipoproteins; Triglycerides; Cholesterol; Apolipoprotein A-I
PubMed: 38427666
DOI: 10.1371/journal.pone.0299725 -
Nature May 2024Lipoprotein(a) (Lp(a)), an independent, causal cardiovascular risk factor, is a lipoprotein particle that is formed by the interaction of a low-density lipoprotein (LDL)...
Lipoprotein(a) (Lp(a)), an independent, causal cardiovascular risk factor, is a lipoprotein particle that is formed by the interaction of a low-density lipoprotein (LDL) particle and apolipoprotein(a) (apo(a)). Apo(a) first binds to lysine residues of apolipoprotein B-100 (apoB-100) on LDL through the Kringle IV (K) 7 and 8 domains, before a disulfide bond forms between apo(a) and apoB-100 to create Lp(a) (refs. ). Here we show that the first step of Lp(a) formation can be inhibited through small-molecule interactions with apo(a) K7-8. We identify compounds that bind to apo(a) K7-8, and, through chemical optimization and further application of multivalency, we create compounds with subnanomolar potency that inhibit the formation of Lp(a). Oral doses of prototype compounds and a potent, multivalent disruptor, LY3473329 (muvalaplin), reduced the levels of Lp(a) in transgenic mice and in cynomolgus monkeys. Although multivalent molecules bind to the Kringle domains of rat plasminogen and reduce plasmin activity, species-selective differences in plasminogen sequences suggest that inhibitor molecules will reduce the levels of Lp(a), but not those of plasminogen, in humans. These data support the clinical development of LY3473329-which is already in phase 2 studies-as a potent and specific orally administered agent for reducing the levels of Lp(a).
Topics: Animals; Female; Humans; Male; Mice; Administration, Oral; Drug Discovery; Kringles; Lipoprotein(a); Macaca fascicularis; Mice, Transgenic; Small Molecule Libraries; Plasminogen; Species Specificity; Clinical Trials, Phase II as Topic; Apolipoproteins A
PubMed: 38720069
DOI: 10.1038/s41586-024-07387-z -
Lipids in Health and Disease Sep 2023Lipoprotein (a) [Lp(a)] is an apoB100-containing lipoprotein with high levels being positively associated with atherosclerotic cardiovascular disease. Lp(a) levels are...
BACKGROUND
Lipoprotein (a) [Lp(a)] is an apoB100-containing lipoprotein with high levels being positively associated with atherosclerotic cardiovascular disease. Lp(a) levels are genetically determined. However, previous studies report a negative association between Lp(a) and saturated fatty acid intake. Currently, apoB100 lowering therapies are used to lower Lp(a) levels, and apheresis therapy is FDA approved for patients with extreme elevations of Lp(a). The current study analyzed the association of free-living diet components with plasma Lp(a) levels.
METHODS
Dietary composition data was collected during screening visits for enrollment in previously completed lipid and lipoprotein metabolism studies at Columbia University Irving Medical Center via a standardized protocol by registered dietitians using 24 hour recalls. Data were analyzed with the Nutrition Data System for Research (Version 2018). Diet quality was calculated using the Healthy Eating Index (HEI) score. Fasting plasma Lp(a) levels were measured via an isoform-independent ELISA and apo(a) isoforms were measured using gel electrophoresis.
RESULTS
We enrolled 28 subjects [Black (n = 18); Hispanic (n = 7); White (n = 3)]. The mean age was 48.3 ± 12.5 years with 17 males. Median level of Lp(a) was 79.9 nmol/L (34.4-146.0) and it was negatively associated with absolute (grams/day) and relative (percent of total calories) intake of dietary saturated fatty acids (SFA) (R = -0.43, P = 0.02, SFA …(% CAL): R = -0.38, P = 0.04), palmitic acid intake (R = -0.38, P = 0.05), and stearic acid intake (R = -0.40, P = 0.03). Analyses of associations with HEI score when stratified based on Lp(a) levels > or ≤ 100 nmol/L revealed no significant associations with any of the constituent factors.
CONCLUSIONS
Using 24 hour recall, we confirm previous findings that Lp(a) levels are negatively associated with dietary saturated fatty acid intake. Additionally, Lp(a) levels are not related to diet quality, as assessed by the HEI score. The mechanisms underlying the relationship of SFA with Lp(a) require further investigation.
Topics: Male; Humans; Adult; Middle Aged; Diet; Lipoprotein(a); Apolipoproteins A; Fasting; Energy Intake
PubMed: 37670291
DOI: 10.1186/s12944-023-01884-2 -
Pediatric Research Aug 2023We assessed serum concentrations of pancreatic stone protein (PSP), copeptin, and apolipoprotein A-V (APOA5) biomarkers for the diagnosis and prognosis of pediatric...
BACKGROUND
We assessed serum concentrations of pancreatic stone protein (PSP), copeptin, and apolipoprotein A-V (APOA5) biomarkers for the diagnosis and prognosis of pediatric sepsis, a condition associated with high mortality.
METHODS
This prospective study included 180 children admitted to the Pediatric Intensive Care Unit and 100 healthy controls at Menoufia University Hospital. Pediatric Risk of Mortality (PRISM), Pediatric Index of Mortality-2 (PIM2), and Pediatric Sequential Organ Failure Assessment (pSOFA) scores were calculated. Serum PSP, copeptin and APOA5 were measured once within 24 h of admission.
RESULTS
PSP, copeptin, and APOA5 were significantly higher in the patients than in the controls (p < 0.001). PSP and copeptin were increased among children who required mechanical ventilation (MV), had multiple organ dysfunctions, and were non-survivors, but APOA5 was decreased in those children. Logistic regression analyses showed that high pSOFA, high PSP and copeptin, low APOA5, and use of MV were associated with mortality. The receiver operating characteristic revealed that the area under the curve (AUC) for APOA5, copeptin, and PSP (0.965, 0.960, and 0.868, respectively) demonstrated high sensitivity (96%, 94%, and 80%) for sepsis diagnosis. The AUC values for PSP, copeptin, and APOA5 were 0.709, 0.705, and 0.571, respectively, with sensitivities of 74%, 58%, and 58% for mortality prediction.
CONCLUSIONS
PSP, copeptin, and APOA5 are promising diagnostic biomarkers for pediatric sepsis but inadequate predictors of mortality.
IMPACT
Apolipoprotein A-V (APOA5), copeptin, and pancreatic stone protein (PSP) are acute-phase proteins with diagnostic value in evaluating critically ill pediatric patients with sepsis and detecting sepsis severity. PSP and copeptin had the power to discriminate non-survivors from survivors. APOA5 was less powerful than the other biomarkers in discriminating between survivors and non-survivors.
Topics: Humans; Child; Apolipoprotein A-V; Prospective Studies; Lithostathine; Prognosis; Biomarkers; Sepsis; ROC Curve
PubMed: 36755189
DOI: 10.1038/s41390-023-02499-0 -
Scientific Reports Apr 2024The current state of knowledge on the relationship between lifestyle factors, glycemic traits, lipoprotein traits with liver cancer risk is still uncertain despite some...
The current state of knowledge on the relationship between lifestyle factors, glycemic traits, lipoprotein traits with liver cancer risk is still uncertain despite some attempts made by observational studies. This study aims to investigate the causal genetic relationship between factors highly associated with liver cancer incidence by using Mendelian randomization (MR) analysis. Employing MR analysis, this study utilized previously published GWAS datasets to investigate whether lifestyle factors, glycemic traits, and lipoprotein traits would affect the risk of liver cancer. The study utilized three MR methods, including inverse variance-weighted model (IVW), MR Egger, and weighted median. Furthermore, MR-Egger analyses were performed to detect heterogeneity in the MR results. The study also conducted a leave-one-out analysis to assess the potential influence of individual SNPs on the MR analysis results. MR-PRESSO was used to identify and remove SNP outliers associated with liver cancer. MR analyses revealed that 2-h glucose (odds ratio, OR 2.33, 95% confidence interval, CI 1.28-4.21), type 2 diabetes mellitus (T2DM, OR 1.67, 95% CI 1.18-2.37), body mass index (BMI, OR 1.67, 95% CI 1.18-2.37), waist circumference (OR 1.78, 95% CI 1.18-2.37) were associated with increased risk of liver cancer. On the contrary, apolipoproteins B (APOB, OR 0.67, 95% CI 0.47-0.97), and low-density lipoprotein (LDL, OR 0.62, 95% CI 0.42-0.92) were negatively related to liver cancer risk. Additionally, after adjusting for BMI, apolipoproteins A-I (APOA-I, OR 0.56, 95% CI, 0.38-0.81), total cholesterol (TC, OR 0.72, 95% CI, 0.54-0.94), and total triglycerides (TG, OR 0.57, 95% CI, 0.40-0.78) exhibited a significant inverse correlation with the risk of liver cancer. This study supports a causal relationship between 2-h glucose, T2DM, BMI, and waist circumference with the increased risk of liver cancer. Conversely, the study reveals a cause-effect relationship between TC, TG, LDL, APOA-I, and APOB with a decreased risk of liver cancer.
Topics: Humans; Apolipoprotein A-I; Mendelian Randomization Analysis; Diabetes Mellitus, Type 2; Lipoproteins; Liver Neoplasms; Apolipoproteins B; Glucose; Genome-Wide Association Study; Risk Factors
PubMed: 38605235
DOI: 10.1038/s41598-024-59211-3 -
Arthritis Research & Therapy Jan 2024The etiology of giant cell arteritis (GCA) and its predictors are incompletely understood. Previous studies have indicated reduced risk of future development of GCA in...
BACKGROUND
The etiology of giant cell arteritis (GCA) and its predictors are incompletely understood. Previous studies have indicated reduced risk of future development of GCA in individuals with obesity and/or diabetes mellitus. There is limited information on blood lipids before the onset of GCA. The objective of the study was to investigate the relation between apolipoprotein levels and future diagnosis of GCA in a nested case-control analysis.
METHODS
Individuals who developed GCA after inclusion in a population-based health survey (the Malmö Diet Cancer Study; N = 30,447) were identified by linking the health survey database to the local patient administrative register and the national patient register. A structured review of medical records was performed. Four controls for every validated case, matched for sex, year of birth, and year of screening, were selected from the database. Anthropometric measures, self-reported physical activity, based on a comprehensive, validated questionnaire, and non-fasting blood samples had been obtained at health survey screening. Concentrations of apolipoprotein A-I (ApoA-I) and apolipoprotein B (ApoB) in stored serum were measured using an immunonephelometric assay. Potential predictors of GCA were examined in conditional logistic regression models.
RESULTS
There were 100 cases with a confirmed clinical diagnosis of GCA (81% female; mean age at diagnosis 73.6 years). The median time from screening to diagnosis was 12 years (range 0.3-19.1). The cases had significantly higher ApoA-I at baseline screening compared to controls (mean 168.7 vs 160.9 mg/dL, odds ratio [OR] 1.57 per standard deviation (SD); 95% confidence interval [CI] 1.18-2.10) (SD 25.5 mg/dL). ApoB levels were similar between cases and controls (mean 109.3 vs 110.4 mg/dL, OR 0.99 per SD; 95% CI 0.74-1.32) (SD 27.1 mg/dL). The ApoB/ApoA1 ratio tended to be lower in cases than in controls, but the difference did not reach significance. The association between ApoA-I and GCA development remained significant in analysis adjusted for body mass index and physical activity (OR 1.48 per SD; 95% CI 1.09-1.99).
CONCLUSION
Subsequent development of GCA was associated with significantly higher levels of ApoA-I. These findings suggest that a metabolic profile associated with lower risk of cardiovascular disease may predispose to GCA.
Topics: Humans; Female; Aged; Male; Giant Cell Arteritis; Risk Factors; Apolipoprotein A-I; Case-Control Studies; Apolipoproteins; Apolipoproteins B
PubMed: 38281009
DOI: 10.1186/s13075-024-03273-1 -
Circulation. Cardiovascular Imaging Jul 2023Apo AI amyloidosis (AApoAI) and Apo AIV amyloidosis (AApoAIV) are rare but increasingly recognized causes of cardiac amyloidosis (CA). We sought to define the cardiac...
BACKGROUND
Apo AI amyloidosis (AApoAI) and Apo AIV amyloidosis (AApoAIV) are rare but increasingly recognized causes of cardiac amyloidosis (CA). We sought to define the cardiac phenotype in AApoAI and AApoAIV using multimodality imaging.
METHODS
We identified all patients with AApoAI and AApoAIV assessed at our center between 2000 and 2021, and 2 cohorts of patients with immunoglobulin light-chain amyloidosis (AL) and transthyretin amyloidosis matched for age, sex, and cardiac involvement.
RESULTS
Forty-five patients had AApoAI, 13 (29%) of whom had cardiac involvement, 32 (71%) renal involvement, 28 (62%) splenic involvement, 27 (60%) hepatic involvement, and 7 (16%) laryngeal involvement. AApoAI-CA commonly presented with heart failure (n=8, 62%) or dysphonia (n=7, 54%). The Arg173Pro variant universally caused cardiac and laryngeal involvement (n=7, 100%). AApoAI-CA was associated with right-sided involvement, with a thicker right ventricular free wall (8.6±1.9 versus 6.3±1.3 mm versus 7.7±1.2 mm, =0.004), greater incidence of tricuspid stenosis (4 [31%] versus 0 [0%] versus 0 [0%], =0.012) and tricuspid regurgitation (6 [46%] versus 1 [8%] versus 2 [15%], =0.048) than AL-CA and transthyretin CA. Twenty-one patients had AApoAIV, and cardiac involvement was more common than in AApoAI (15 [71%] versus 13 [29%], =0.001). AApoAIV-CA most commonly presented with heart failure (n=12, 80%), and a lower median estimated glomerular filtration rate than AL-CA and transthyretin CA (36 mL/[min·1.73 m²] versus 65 mL/[min·1.73 m²] versus 63 mL/[min·1.73 m²], <0.001). All AApoAIV-CA patients had classical CA features on echocardiography/cardiac magnetic resonance, including an apical-sparing strain pattern, which was less common in AApoAI-CA (15 [100%] versus 7 [54%], =0.003), whereas cardiac uptake on bone scintigraphy was less common in AApoAIV-CA than AApoAI-CA (all grade 1) (14% versus 82%, <0.001). Patients with AApoAI and AApoAIV had a good prognosis (median survival >172 and >30 months, respectively), and a lower risk of mortality than matched patients with AL-amyloidosis (AL versus AApoAI: hazard ratio, 4.54 [95% CI, 2.02-10.14]; <0.001; AL versus AApoAIV: hazard ratio, 3.07 [95% CI, 1.27-7.44]; =0.013).
CONCLUSIONS
Dysphonia, multisystem involvement, or right-sided cardiac disease should raise suspicion of AApoAI-CA. AApoAIV-CA presents most commonly with heart failure and always displays classical CA imaging features, mimicking common forms of CA. Both AApoAI and AApoAIV are associated with a good prognosis and a lower risk of mortality than matched patients with AL-amyloidosis.
Topics: Humans; Apolipoprotein A-I; Dysphonia; Prealbumin; Amyloid Neuropathies, Familial; Immunoglobulin Light-chain Amyloidosis; Heart Failure; Echocardiography; Cardiomyopathies
PubMed: 37431665
DOI: 10.1161/CIRCIMAGING.123.015259 -
Circulation Mar 2024Cholesterol efflux capacity (CEC) predicts cardiovascular disease independently of high-density lipoprotein (HDL) cholesterol levels. Isolated small HDL particles are...
BACKGROUND
Cholesterol efflux capacity (CEC) predicts cardiovascular disease independently of high-density lipoprotein (HDL) cholesterol levels. Isolated small HDL particles are potent promoters of macrophage CEC by the ABCA1 (ATP-binding cassette transporter A1) pathway, but the underlying mechanisms are unclear.
METHODS
We used model system studies of reconstituted HDL and plasma from control and lecithin-cholesterol acyltransferase (LCAT)-deficient subjects to investigate the relationships among the sizes of HDL particles, the structure of APOA1 (apolipoprotein A1) in the different particles, and the CECs of plasma and isolated HDLs.
RESULTS
We quantified macrophage and ABCA1 CEC of 4 distinct sizes of reconstituted HDL. CEC increased as particle size decreased. Tandem mass spectrometric analysis of chemically cross-linked peptides and molecular dynamics simulations of APOA1, the major protein of HDL, indicated that the mobility of C-terminus of that protein was markedly higher and flipped off the surface in the smallest particles. To explore the physiological relevance of the model system studies, we isolated HDL from LCAT-deficient subjects, whose small HDLs (like reconstituted HDLs) are discoidal and composed of APOA1, cholesterol, and phospholipid. Despite their very low plasma levels of HDL particles, these subjects had normal CEC. In both the LCAT-deficient subjects and control subjects, the CEC of isolated extra-small HDL (a mixture of extra-small and small HDL by calibrated ion mobility analysis) was 3- to 5-fold greater than that of the larger sizes of isolated HDL. Incubating LCAT-deficient plasma and control plasma with human LCAT converted extra-small and small HDL particles into larger particles, and it markedly inhibited CEC.
CONCLUSIONS
We present a mechanism for the enhanced CEC of small HDLs. In smaller particles, the C-termini of the 2 antiparallel molecules of APOA1 are "flipped" off the lipid surface of HDL. This extended conformation allows them to engage with ABCA1. In contrast, the C-termini of larger HDLs are unable to interact productively with ABCA1 because they form a helical bundle that strongly adheres to the lipid on the particle. Enhanced CEC, as seen with the smaller particles, predicts decreased cardiovascular disease risk. Thus, extra-small and small HDLs may be key mediators and indicators of the cardioprotective effects of HDL.
Topics: Humans; Apolipoprotein A-I; Cardiovascular Diseases; Lipoproteins, HDL; Cholesterol; ATP Binding Cassette Transporter 1; Macrophages; Cholesterol, HDL
PubMed: 38018436
DOI: 10.1161/CIRCULATIONAHA.123.065959 -
European Review For Medical and... Dec 2023Patients with pancreatic diseases are at increased risk of cardiovascular events. Investigating various apolipoprotein forms as important atherogenesis components may...
OBJECTIVE
Patients with pancreatic diseases are at increased risk of cardiovascular events. Investigating various apolipoprotein forms as important atherogenesis components may improve cardiovascular risk (CVR) prediction. This study aimed to investigate CVR factors in patients with chronic pancreatitis.
PATIENTS AND METHODS
The study enrolled 70 patients (40 males and 30 females, mean age 55.2 years) with chronic pancreatitis and treated pancreatic exocrine insufficiency. We assessed CVR by apolipoproteins A-I, A-II, B, and C-III, lipid profile; score systems [SCORE risk chart and Framingham Risk Score (FRS)], diabetes mellitus; chronic pancreatitis by M-ANNHEIM classification. Statistics were performed via SPSS v. 22.
RESULTS
Low apolipoprotein A-I and high apolipoprotein B levels with increased atherogenic potential were observed in 37 and 26 patients. 45.71% demonstrated a high risk of myocardial infarction with high apolipoprotein B/apolipoprotein A-I ratio. Men are at higher CVR risk. Apolipoproteins A-I and A-II correlated with the cardioprotective high-density lipoprotein (HDL) in contrast to apolipoproteins B and C-III, which correlated strongly with low-density lipoprotein (LDL), total cholesterol (TC), and triglycerides (TG). Increased CVR assessed by FRS correlated with significantly lower apolipoprotein A-I and higher apolipoprotein B and apolipoprotein B/apolipoprotein A-I ratio. With the increase in chronic pancreatitis severity, we observed decreased apolipoproteins and increased apolipoprotein B/apolipoprotein A-I ratio.
CONCLUSIONS
Apolipoproteins are valuable CVR indicators. Further studies are required to establish a CVR screening panel in this population.
Topics: Male; Female; Humans; Middle Aged; Apolipoprotein A-I; Cardiovascular Diseases; Risk Factors; Apolipoproteins; Apolipoproteins B; Triglycerides; Atherosclerosis; Heart Disease Risk Factors; Pancreatitis, Chronic; Cholesterol, HDL
PubMed: 38164866
DOI: 10.26355/eurrev_202312_34802 -
Journal of Lipid Research Apr 2024Dyslipidemia has long been implicated in elevating mortality risk; yet, the precise associations between lipid traits and mortality remained undisclosed. Our study aimed...
Dyslipidemia has long been implicated in elevating mortality risk; yet, the precise associations between lipid traits and mortality remained undisclosed. Our study aimed to explore the causal effects of lipid traits on both all-cause and cause-specific mortality. One-sample Mendelian randomization (MR) with linear and nonlinear assumptions was conducted in a cohort of 407,951 European participants from the UK Biobank. Six lipid traits, consisting of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), and lipoprotein(a), were included to investigate the causal associations with mortality. Two-sample MR was performed to replicate the association between each lipid trait and all-cause mortality. Univariable MR results showed that genetically predicted higher ApoA1 was significantly associated with a decreased all-cause mortality risk (HR[95% CI]:0.93 [0.89-0.97], P value = 0.001), which was validated by the two-sample MR analysis. Higher lipoprotein(a) was associated with an increased risk of all-cause mortality (1.03 [1.01-1.04], P value = 0.002). Multivariable MR confirmed the direct causal effects of ApoA1 and lipoprotein(a) on all-cause mortality. Meanwhile, nonlinear MR found no evidence for nonlinearity between lipids and all-cause mortality. Our examination into cause-specific mortality revealed a suggestive inverse association between ApoA1 and cancer mortality, a significant positive association between lipoprotein(a) and cardiovascular disease mortality, and a suggestive positive association between lipoprotein(a) and digestive disease mortality. High LDL-C was associated with an increased risk of cardiovascular disease mortality but a decreased risk of neurodegenerative disease mortality. The findings suggest that implementing interventions to raise ApoA1 and decrease lipoprotein(a) levels may improve overall health outcomes and mitigate cancer and digestive disease mortality.
Topics: Humans; Mendelian Randomization Analysis; Male; Female; Lipids; Middle Aged; Risk Factors; Apolipoprotein A-I; Lipoprotein(a); Cause of Death; Aged
PubMed: 38458338
DOI: 10.1016/j.jlr.2024.100528