Welcome to the EAS 2021 Interactive Program
The congress will officially run on EEST time zone (Eastern European Summer Time, Helsinki, CET+1)
Introduction (ID 1505)
O017 - Elevated remnant cholesterol and 3-fold increased risk of peripheral artery disease: two population-based cohorts (ID 1016)
Abstract
Background and Aims
Remnant cholesterol is observationally and causally associated with ischemic heart disease and ischemic stroke. Whether this is also true for Peripheral Artery Disease (PAD) is not known. We tested the hypothesis that elevated remnant cholesterol is associated with increased risk of PAD.
Methods
A total of 107,169 individuals from the Copenhagen General Population Study examined in 2003–2015 were included in a prospective, observational association study. During 15 years of follow-up, 1,587 individuals were diagnosed with PAD. Hazard ratios were estimated using Cox regression models. Results were independently confirmed in 13,972 individuals from the Copenhagen City Heart Study examined in 1976-78, with 1,033 cases of PAD diagnosed during 43 years of follow-up.
Results
Higher levels of remnant cholesterol were associated with a stepwise increase in the risk of PAD up to a multivariable adjusted hazard ratio of 3.1 (95% confidence interval: 2.2-4.2) for individuals with remnant cholesterol concentrations ≥1.5 mmol/l compared to individuals with remnant cholesterol <0.5 mmol/l. Corresponding results for myocardial infarction and ischemic stroke were 2.6 (2.0-3.4) and 1.6 (1.3-2.0). Cumulative incidence of PAD at age 80 ranged from 2.9% in individuals with remnant cholesterol <0.5 mmol/l to 8.9% in individuals with remnant cholesterol ≥1.5 mmol/l (Figure). Results in the Copenhagen City Heart Study were similar.
Conclusions
Elevated remnant cholesterol is associated with a 3-fold increased risk of PAD, higher than for myocardial infarction or ischemic stroke. Clinical trials should evaluate the effect of remnant cholesterol lowering therapy in the context of PAD.
O018 - Interstitial postprandial hyperlipidemia and remnant lipoproteins in type 2 diabetes mellitus (ID 768)
Abstract
Background and Aims
Diabetic dyslipidemia is characterized by elevated fasting serum TG and VLDL and low HDL-c. Postprandial hypertriglyceridemia and changes in remnant-like lipoprotein particles are well recognized in T2D, but the metabolism and /or clearance of these triglyceride-rich lipoproteins (TGRL) is less clear. The interstitial fluid (IF) represents the immediate environment of most cells in the body and studying postprandial changes in this compartment should provide novel insights into the increased cardiovascular risk observed in T2D.
Methods
Five T2D patients with adequate control of diabetes and matched healthy controls were given a standardized meal (1270 kcal; 70/31g fat/saturated fat; 96/60g carbohydrates/sugar, 64g protein) after fasting overnight. Serum was collected hourly for 9h following meal, and IF was harvested through skin blisters at 3 timepoints (TP1=0-3h, TP2=3-6h, TP3=6-9h). Analyses of serum and IF TG, TGRL and lipoprotein lipids were determined by FPLC and ELISA.
Results
T2D patients exhibited typical serum dyslipidemia patterns, with elevated fasting TG followed by delayed and prolonged postprandial response. In IF, significant accumulation of TGs was observed postprandially for both T2D and controls. T2D displayed increased interstitial TGRL and lower HDL in all TPs which became even more pronounced in the later collections (p<0.05). Reduced IF-to-serum ratio of TG was seen at all TPs (p<0.05), VLDL-TG TP3 (p<0.05) and HDL-TG TP1+3 (p<0.05) in T2D.
Conclusions
By exploring the postprandial response in the interstitial compartment, we have identified a dysregulated and protracted metabolism of TGRL in T2D. We are currently exploring whether this is accompanied by an abnormal clearance of these pro-atherogenic particles.
O019 - miRNA target-binding sites as regulators of genes involved in the lipid metabolism might explain the hypercholesterolaemia in FH patients (ID 903)
Abstract
Background and Aims
Familial hypercholesterolemia (FH) is due to mutations in LDLR, APOB and PCSK9, however, about 50% of clinical FH patients do not have an identifiable genetic cause. MicroRNAs (small non-coding RNAs) are negative regulators of gene expression and creation of new biding sites can be the cause of hypercholesterolaemia in mutation-negative families. The present work aims to analyse miRNAs targets as regulators of genes involved in lipid metabolism in FH patients.
Methods
A sample of 180 mutation-negative individuals (FH negative) was re-sequenced using NGS and the 3’UTR regions of LDLR, APOB and PCSK9 were analysed. miRNA-SNP database was used to predict target gain or loss of miRNA:mRNA binding sites disturbed by SNPs in the 3'UTR. Two groups of samples were additionally sequenced, 174 FH mutation-positive individuals and 143 normolipidemic individuals.
Results
Preliminary results show that 99% of the FH negative individuals present 2 SNPs predicted to gain 2 miRNA targets in the LDLR 3’UTR. Gain of these miRNA target-binding sites might negatively regulate LDLR gene expression in the liver. We have also identified 1 SNP (1 individual) predicted to lose a miRNA target in the APOB 3’UTR and 4 SNPs (14 individuals) predicted to lose miRNAs targets in the PCSK9 3’UTR. Loss of miRNA target-binding sites in APOB and PCSK9 3’UTRs can contribute to a higher expression of these genes in the liver. FH positive and normolipidemic cohorts are being analysed.
Conclusions
We have identified several SNPs that predict to gain/lose miRNAs target-binding sites that might explain the hypercholesterolaemia in FH mutation-negative.
O020 - Association of the apolipoprotein M and sphingosine-1-phosphate complex with brown adipose tissue after cold exposure in humans (ID 1184)
Abstract
Background and Aims
The HDL-associated apolipoprotein M (apoM) and its ligand sphingosine-1-phosphate (S1P) may control energy metabolism, as supported by apoM-deficient mice showing a favorable metabolic phenotype with increased triglyceride turnover and protection against obesity-induced insulin resistance. In addition, apoM deficiency is associated with increased vascular permeability and brown adipose tissue (BAT) mass and activity, and these effects are partly mediated by the S1P receptor 1.
Methods
In the current study, we explored the connection between plasma apoM/S1P levels and parameters of BAT as measured via 18F-FDG PET/CT after cold exposure using three different protocols in humans.
Results
Fixed (n=15) vs personalized (n=20) short-term cooling protocols decreased and increased apoM (-8.4%, p=0.032 vs 15.7%, p<0.0005) and S1P (-41.0%, p<0.0005 vs 19.1%, p<0.005) plasma levels, respectively. Long-term cooling (n=44) had no effect on plasma apoM or S1P levels. Plasma apoM and S1P did not correlate significantly to BAT volume and activity in the individual study using fixed or personalized cooling protocols. The short-term studies combined, showed that increased changes in plasma apoM correlated with BAT volume (β:0.39, 95% CI [-0.01-0.78], P=0.054) and metabolic activity (β:0.44, 95% CI [0.06-0.81], P=0.024) after adjusting for study design.
Conclusions
Plasma apoM and S1P levels are altered in response to cold exposure and may be linked to changes in BAT metabolic activity and volume. Our results highlight a possible role of the apoM/S1P complex on human BAT biology.
O021 - Genetic and Metabolic Determinants of Plasma Levels of ANGPTL8 (ID 202)
Abstract
Background and Aims
Angiopoietin-like protein (ANGPTL)8 (A8), together with A3 and A4, coordinate changes in triglyceride (TG) delivery to tissues in response to nutritional status. Plasma A8 levels are associated with indices of glucose and TG metabolism, but the causality of these relationships and the contribution of genetic variants to inter-individual differences in A8 levels has not been investigated.
Methods
To address these questions, we developed a sensitive and specific A8 ELISA and measured plasma A8 levels in the Dallas Heart Study (DHS), a large multiethnic population-based cohort.
Results
The distribution of fasting A8 levels was highly skewed to the right with a median (IQR) of 13.3 (6.8–23.1) ng/mL. A8 levels did not differ significantly across age groups or genders. Remarkable differences were found among racial/ethnic groups with Blacks having significantly higher A8 levels than either Hispanics or Whites. A8 levels correlated with BMI, fasting glucose, insulin and TG levels. Exome-wide association study revealed a strong association between the minor T-allele of the A8(R59W) variant with plasma A8 levels. After adjustment for age, sex, race/ethnicity and BMI, the A8(59W) variant explained ~17% of the inter-individual variation in A8 levels. This variant was not associated with any of the metabolic parameters correlated with plasma A8 concentrations despite resulting in a 4-fold increase in A8 levels.
Conclusions
A8 levels are a consequence, not the cause, of the associated metabolic phenotypes.
O022 - Elucidating the atherogenicity of Lp(a): an unbiased lipidomics approach (ID 472)
Abstract
Background and Aims
Mendelian randomisation as well as epidemiology studies have established an association between elevated lipoprotein(a) [Lp(a)] levels and increased cardiovascular risk. Besides the pro-atherogenic properties of the LDL- like moiety, Lp(a) further contributes to the disease pathology by carrying pro-inflammatory oxidized phospholipids (OxPLs). While blocking these OxPL epitopes profoundly reduces the monocytic inflammatory response, a residual inflammatory risk remains.
Methods
To determine the contributing factors resulting in this residual inflammation, we performed lipidomics on complete plasma from healthy individuals with either elevated [median 87 mg/dL (218 nmol/L); N=12]or low [median 7 mg/dL (18 nmol/L); N=13] levels of Lp(a).
Results
Using this unbiased lipidomics approach, we discovered a distinct “lipidome” in individuals with elevated Lp(a) levels as displayed by an upregulation of several diacylglycerol species (DAGs) and lysophosphatic acid (LPA). Further fractionation and purification of different lipoprotein fractions showed that these DAGs are preferentially carried by Lp(a). Next, we functionally assessed if these upregulated DAGs are able to elicit an inflammatory response in monocytes. Upon ex vivo DAG stimulation, monocytes elicited a dose dependent increase in IL-8, IL-6 and IL-1β secretion. Functionally, our preliminary data demonstrated this coincided with increased transendothelial migration.
Conclusions
By using transwell migration assays with fluorescently labelled monocytes, combined with sprouting assays and in-depth phosphorylation analysis, we aim to further characterise the pathways effected by DAGs and LPA to further unravel the atherogenicity of Lp(a) and will be available at the EAS 2021.