apoB/apoA-I Ratio and Lp(a) Associations With Aortic Valve Stenosis Incidence: Insights From the EPIC-Norfolk Prospective Population Study.

Background Apolipoprotein B/apolipoprotein A-I (apoB/apoA-I) ratio and lipoprotein(a) (Lp[a]) are associated with aortic valve stenosis (AVS) disease progression. Clinical characteristics such as age, sex, and presence of concomitant coronary artery disease may strongly modify these associations; however, these effects have not been well defined in longitudinal studies. We set out to assess these associations between apoB/apoA-I ratio, Lp(a), and AVS incidence in a large population study. Methods and Results We analyzed data from 17 745 participants (mean age, 59.2±9.1 years; men, 44.9%) in the EPIC-Norfolk (European Prospective Investigation Into Cancer in Norfolk Prospective Population Study) population study in whom apoB/apoA-I and Lp(a) levels were measured. Participants were identified as having incident AVS if they were hospitalized or died with AVS as an underlying cause. After a median follow-up of 19.8 years (17.9-21.0 years) there were 403 (2.2%) incident cases of AVS. The hazard ratio for AVS risk was 1.30 (95% CI, 1.19-1.41; P50 mg/dL) remained an independent risk factor for AVS after adjustment for age, sex, low-density lipoprotein cholesterol, and concomitant coronary artery disease (hazard ratio, 1.70; 95% CI, 1.33-2.19 [P<0.001]). Conclusions In this population study, apoB/apoA-I ratio was associated with risk of AVS incidence, especially in younger and female participants and those without concomitant coronary artery disease. Lp(a) was an independent risk factor for AVS incidence. Interventional trials are needed to investigate whether modulating apoB/apoA-I or lowering Lp(a) can prevent or slow down AVS

C-Reactive Protein Identifies Low-Risk Metabolically Healthy Obese Persons: The European Prospective Investigation of Cancer-Norfolk Prospective Population Study.

BACKGROUND: Conflicting data exist about the cardiovascular risk of metabolically healthy obese persons. The prognostic value of C-reactive protein (CRP) in this intriguing group is unknown. We assessed the association between CRP levels and the risk of coronary heart disease (CHD) in metabolically healthy persons with abdominal obesity. METHODS AND RESULTS: In the European Prospective Investigation of Cancer-Norfolk prospective cohort, CRP levels and information on metabolic syndrome criteria were available for 7279 participants, of whom 825 (11%) developed CHD during a follow-up period of 10.9±1.8 years. There was a trend toward a higher multivariable-adjusted hazard ratio for CHD in metabolically healthy obese participants with CRP levels >2 mg/L compared with <2 mg/L (hazard ratio 1.59, 95% CI 0.97-2.62, P=0.066). Metabolically unhealthy obese participants had significantly higher CHD risk compared with metabolically healthy obese participants with CRP levels <2 mg/L (hazard ratio 1.88, 95% CI 1.20-2.94, P=0.006). Most important, we found that the risk of CHD among metabolically healthy obese persons with CRP levels <2 mg/L was comparable to that of metabolically healthy nonobese persons (hazard ratio 0.91, 95% CI 0.60-1.39, P=0.674). CONCLUSIONS: Among metabolically healthy obese persons, low CRP levels were associated with a CHD risk comparable to that of metabolically healthy nonobese persons. CRP appears to be an easy and widely available method for identifying a low-risk subpopulation among metabolically healthy obese persons.EPIC‐Norfolk is supported by program grants from the Medical Research Council UK and Cancer Research UK. The CRP measurements in the full cohort were supported by a grant from the Medical Research Council to the Medical Research Council Epidemiology Unit, Cambridge, United Kingdom (MRC G0701863). The funding sources had no role in the study design, the conduct of the analysis, or the decision to submit the manuscript for publication

A 3-SNP gene risk score and a metabolic risk score both predict hypertriglyceridemia and cardiovascular disease risk.

BACKGROUND: Evidence on the causal link between plasma triglyceride (TG) levels and risk for cardiovascular disease (CVD) has recently emerged. Individuals with the metabolic syndrome have an increased risk for acquiring elevated TG levels later in life. Moreover, common DNA sequence variations in genes affecting TG levels identify individuals at risk for elevated plasma TG levels. OBJECTIVE: We evaluated whether a 3-single nucleotide polymorphism (SNP) TG gene risk score (GRS) and a metabolic risk score (MetRS) both improved CVD risk prediction. METHODS: A 3-SNP GRS and MetRS were generated in the EPIC-Norfolk cohort (n = 20,074) based on 3 SNPs in LPL and APOA5 or the number of Metabolic Syndrome criteria present (maximum 5), respectively. The associations between the 3-SNP GRS, MetRS, TG levels, and CVD risk were evaluated. RESULTS: The 3-SNP GRS and MetRS were both linearly associated with plasma TG levels, that is, +0.25 mmol/L [95% CI 0.22-0.27] per allele change (P < .001) and +0.72 mmol/L [95% CI 0.70-0.73] per increase of number of metabolic syndrome risk score points (P < .001), respectively. We observed a positive association between the 3-SNP GRS and the risk of CVD with an adjusted hazard ratio (HR) of 1.35 [95% CI 1.04-1.74] for the highest versus the lowest GRS, which was independent of the MetRS. For the MetRS, the adjusted HR was 2.03 [95% CI 1.73-2.40] for the highest versus the lowest MetRS. CONCLUSION: Both the 3-SNP GRS and the MetRS are associated with increased plasma TG levels and increased risk for CVD

High-density lipoprotein proteome dynamics in human endotoxemia

BACKGROUND: A large variety of proteins involved in inflammation, coagulation, lipid-oxidation and lipid metabolism have been associated with high-density lipoprotein (HDL) and it is anticipated that changes in the HDL proteome have implications for the multiple functions of HDL. Here, SELDI-TOF mass spectrometry (MS) was used to study the dynamic changes of HDL protein composition in a human experimental low-dose endotoxemia model. Ten healthy men with low HDL cholesterol (0.7+/-0.1 mmol/L) and 10 men with high HDL cholesterol levels (1.9+/-0.4 mmol/L) were challenged with endotoxin (LPS) intravenously (1 ng/kg bodyweight). We previously showed that subjects with low HDL cholesterol are more susceptible to an inflammatory challenge. The current study tested the hypothesis that this discrepancy may be related to differences in the HDL proteome. RESULTS: Plasma drawn at 7 time-points over a 24 hour time period after LPS challenge was used for direct capture of HDL using antibodies against apolipoprotein A-I followed by subsequent SELDI-TOF MS profiling. Upon LPS administration, profound changes in 21 markers (adjusted p-value < 0.05) were observed in the proteome in both study groups. These changes were observed 1 hour after LPS infusion and sustained up to 24 hours, but unexpectedly were not different between the 2 study groups. Hierarchical clustering of the protein spectra at all time points of all individuals revealed 3 distinct clusters, which were largely independent of baseline HDL cholesterol levels but correlated with paraoxonase 1 activity. The acute phase protein serum amyloid A-1/2 (SAA-1/2) was clearly upregulated after LPS infusion in both groups and comprised both native and N-terminal truncated variants that were identified by two-dimensional gel electrophoresis and mass spectrometry. Individuals of one of the clusters were distinguished by a lower SAA-1/2 response after LPS challenge and a delayed time-response of the truncated variants. CONCLUSIONS: This study shows that the semi-quantitative differences in the HDL proteome as assessed by SELDI-TOF MS cannot explain why subjects with low HDL cholesterol are more susceptible to a challenge with LPS than those with high HDL cholesterol. Instead the results indicate that hierarchical clustering could be useful to predict HDL functionality in acute phase responses towards LPS

Association of Long-term Exposure to Elevated Lipoprotein(a) Levels With Parental Life Span, Chronic Disease-Free Survival, and Mortality Risk: A Mendelian Randomization Analysis.

IMPORTANCE: Elevated lipoprotein(a) (Lp[a]) levels are associated with atherosclerotic cardiovascular diseases. The association between high Lp(a) levels and human longevity phenotypes is, however, controversial. OBJECTIVE: To examine whether genetically determined Lp(a) levels are associated with parental life span and chronic disease-free survival (health span) and the association between Lp(a) levels and long-term, all-cause mortality risk. DESIGN, SETTING, AND PARTICIPANTS: In this genetic association study, cross-sectional mendelian randomization (UK Biobank [2006-2010] and LifeGen Consortium) and prospective analyses (European Prospective Investigation Into Cancer and Nutrition (EPIC)-Norfolk [1993-1997, with patients followed up to 2016]) were conducted using individual-level data on 139 362 participants. The association between a weighted genetic risk score of 26 independent single-nucleotide polymorphisms at the LPA locus on parental life span using individual participant data from the UK Biobank, as well as with summary statistics of a genome-wide association study of more than 1 million life spans (UK Biobank and LifeGen), were examined. The association between these single-nucleotide polymorphisms and the age at the end of the health span was tested using summary statistics of a previous genome-wide association study in the UK Biobank. The association between Lp(a) levels and all-cause mortality in the EPIC-Norfolk study was also investigated. Data were analyzed from December 2018 to December 2019. EXPOSURES: Genetically determined and measured Lp(a) levels. MAIN OUTCOMES AND MEASURES: Parental life span, health span, and all-cause mortality. RESULTS: In 139 362 white British participants (mean [SD] age, 62.8 [3.9] years; 52% women) from the UK Biobank, increases in the genetic risk score (weighted for a 50-mg/dL increase in Lp[a] levels) were inversely associated with a high parental life span (odds ratio, 0.92; 95% CI, 0.89-0.94; P = 2.7 × 10-8). Using the Egger-mendelian randomization method, a negative association between LPA single-nucleotide polymorphisms and parental life span (mean [SD] Egger-mendelian randomization slope, -0.0019 [0.0002]; P = 2.22 × 10-18) and health span (-0.0019 [0.0003]; P = 3.00 × 10-13) was noted. In 18 720 participants from EPIC-Norfolk (5686 cases), the mortality risk for those with Lp(a) levels equal to or above the 95th percentile was equivalent to being 1.5 years older in chronologic age (β coefficient [SE], 0.194 [0.064]). CONCLUSIONS AND RELEVANCE: The results of this study suggest a potential causal effect of absolute Lp(a) levels on human longevity as defined by parental life span, health span, and all-cause mortality. The results also provide a rationale for trials of Lp(a)-lowering therapy in individuals with high Lp(a) levels

Impact of cholesterol on proinflammatory monocyte production by the bone marrow.

AIM: Preclinical work indicates that low-density lipoprotein cholesterol (LDL-C) not only drives atherosclerosis by directing the innate immune response at plaque level but also augments proinflammatory monocyte production in the bone marrow (BM) compartment. In this study, we aim to unravel the impact of LDL-C on monocyte production in the BM compartment in human subjects. METHODS AND RESULTS: A multivariable linear regression analysis in 12 304 individuals of the EPIC-Norfolk prospective population study showed that LDL-C is associated with monocyte percentage (β = 0.131 [95% CI: 0.036-0.225]; P = 0.007), at the expense of granulocytes (β = -0.876 [95% CI: -1.046 to -0.705]; P < 0.001). Next, we investigated whether altered haematopoiesis could explain this monocytic skewing by characterizing CD34+ BM haematopoietic stem and progenitor cells (HSPCs) of patients with familial hypercholesterolaemia (FH) and healthy normocholesterolaemic controls. The HSPC transcriptomic profile of untreated FH patients showed increased gene expression in pathways involved in HSPC migration and, in agreement with our epidemiological findings, myelomonocytic skewing. Twelve weeks of cholesterol-lowering treatment reverted the myelomonocytic skewing, but transcriptomic enrichment of monocyte-associated inflammatory and migratory pathways persisted in HSPCs post-treatment. Lastly, we link hypercholesterolaemia to perturbed lipid homeostasis in HSPCs, characterized by lipid droplet formation and transcriptomic changes compatible with increased intracellular cholesterol availability. CONCLUSIONS: Collectively, these data highlight that LDL-C impacts haematopoiesis, promoting both the number and the proinflammatory activation of circulating monocytes. Furthermore, this study reveals a potential contributory role of HSPC transcriptomic reprogramming to residual inflammatory risk in FH patients despite cholesterol-lowering therapy

Sex-Specific Associations of Genetically Predicted Circulating Lp(a) (Lipoprotein(a)) and Hepatic LPA Gene Expression Levels With Cardiovascular Outcomes: Mendelian Randomization and Observational Analyses.

BACKGROUND: Elevated Lp(a) (Lipoprotein(a)) levels are associated with coronary artery disease (CAD), ischemic stroke (IS), and calcific aortic valve stenosis (CAVS). Studies investigating the association between Lp(a) levels and these diseases in women have yielded inconsistent results. METHODS: To investigate the association of Lp(a) with sex-specific cardiovascular outcomes, we determined the association between genetically predicted Lp(a) levels (using 27 single nucleotide polymorphisms at the LPA locus) and hepatic LPA expression (using 80 single nucleotide polymorphisms at the LPA locus associated with LPA mRNA expression in liver samples from the Genotype-Tissue Expression dataset) on CAD, IS, and CAVS using individual participant data from the UK Biobank: 408 403 participants of European ancestry (37 102, 4283, and 2574 with prevalent CAD, IS, and CAVS, respectively). The long-term association between Lp(a) levels and incident CAD, IS, and CAVS was also investigated in European Prospective Investigation into Cancer and Nutrition-Norfolk: 18 721 participants (3964, 846, and 424 with incident CAD, IS, and CAVS, respectively). RESULTS: Genetically predicted plasma Lp(a) levels were positively and similarly associated with prevalent and incident CAD and CAVS in men and women. Genetically predicted plasma Lp(a) levels were associated with prevalent and incident IS when we studied men and women pooled together, and in men only. Genetically predicted LPA expression levels were associated with prevalent CAD and CAVS in men and women but not with IS. CONCLUSIONS: Genetically predicted blood Lp(a) and hepatic LPA gene expression as well as serum Lp(a) levels predict the risk of CAD and CAVS in men and in women. Whether RNA interference therapies aiming at lowering Lp(a) levels could be useful in reducing cardiovascular disease risk in both men and women with high Lp(a) levels needs to be determined in large-scale cardiovascular outcomes trials

Improved cardiovascular risk prediction using targeted plasma proteomics in primary prevention.

AIMS: In the era of personalized medicine, it is of utmost importance to be able to identify subjects at the highest cardiovascular (CV) risk. To date, single biomarkers have failed to markedly improve the estimation of CV risk. Using novel technology, simultaneous assessment of large numbers of biomarkers may hold promise to improve prediction. In the present study, we compared a protein-based risk model with a model using traditional risk factors in predicting CV events in the primary prevention setting of the European Prospective Investigation (EPIC)-Norfolk study, followed by validation in the Progressione della Lesione Intimale Carotidea (PLIC) cohort. METHODS AND RESULTS: Using the proximity extension assay, 368 proteins were measured in a nested case-control sample of 822 individuals from the EPIC-Norfolk prospective cohort study and 702 individuals from the PLIC cohort. Using tree-based ensemble and boosting methods, we constructed a protein-based prediction model, an optimized clinical risk model, and a model combining both. In the derivation cohort (EPIC-Norfolk), we defined a panel of 50 proteins, which outperformed the clinical risk model in the prediction of myocardial infarction [area under the curve (AUC) 0.754 vs. 0.730; P < 0.001] during a median follow-up of 20 years. The clinically more relevant prediction of events occurring within 3 years showed an AUC of 0.732 using the clinical risk model and an AUC of 0.803 for the protein model (P < 0.001). The predictive value of the protein panel was confirmed to be superior to the clinical risk model in the validation cohort (AUC 0.705 vs. 0.609; P < 0.001). CONCLUSION: In a primary prevention setting, a proteome-based model outperforms a model comprising clinical risk factors in predicting the risk of CV events. Validation in a large prospective primary prevention cohort is required to address the value for future clinical implementation in CV prevention

Apolipoprotein B synthesis inhibition: results from clinical trials

Purpose of review Mipomersen is a second-generation antisense oligonucleotide developed to inhibit the synthesis of apolipoprotein B-100 in the liver. In this review we will summarize the results of recent preclinical and clinical studies addressing safety and low-density lipoprotein-cholesterol (LDL-c) lowering efficacy of this new compound. Recent findings In phase 3 clinical trials, mipomersen has been shown to significantly reduce LDL-c in patients with homozygous and heterozygous familial hypercholesterolemia on maximally tolerated lipid-lowering therapy. Injection site reactions, flu-like symptoms and increases in liver transaminases were the main adverse events. A recent safety study, designed to investigate the effects of mipomersen on intrahepatic triglyceride content, failed to show evidence of clinically relevant hepatic steatosis after 13 weeks of treatment. Summary Mipomersen is a new agent to lower LDL-c in patients at increased risk of cardiovascular disease and/or intolerant to statins. Whereas safety concerns have focused on hepatic fat accumulation, to date no evidence of clinically relevant increases of intrahepatic triglyceride content are reported. Ongoing and future studies are eagerly awaited to assess the impact of mipomersen on hepatic triglyceride content after prolonged exposur

Endothelial progenitor cell-seeded grafts: Rash and risky

The patency of prosthetic vascular grafts is impaired by intimal hyperplasia (IH) near the anastomotic regions. The absence of a functional endothelial monolayer on the prosthetic grafts is an important stimulus for IH. To improve the outcome of synthetic vascular bypass surgery, cell seeding is a promising concept that has been extensively investigated and is still evolving. In the present paper, the concept of prosthetic graft cell seeding is discussed, with emphasis on its newest era: seeding with endothelial progenitor cells. Although experimental studies on prosthetic graft seeding using endothelial progenitor cells have shown excellent results on graft endothelialization, none of these studies reported favourable effects on the more clinically relevant end points such as IH or graft patency