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

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          Abstract

          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; P<0.001) per SD increase in apoB/apoA‐I. Adjusting for age, sex, and coronary artery disease, there was no significant association between apoB/apoA‐I and AVS incidence (hazard ratio, 1.06; 95% CI, 0.97–1.17 [ P=0.215]). Elevated Lp(a) (>50 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.

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          Most cited references14

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          Genetic associations with valvular calcification and aortic stenosis.

          Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P=9.0×10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P=1.5×10(-8) and P=1.8×10(-8), respectively), but the findings were not replicated consistently. Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.).
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            Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials.

            Elevated lipoprotein(a) (Lp[a]) is a highly prevalent (around 20% of people) genetic risk factor for cardiovascular disease and calcific aortic valve stenosis, but no approved specific therapy exists to substantially lower Lp(a) concentrations. We aimed to assess the efficacy, safety, and tolerability of two unique antisense oligonucleotides designed to lower Lp(a) concentrations.
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              The apoB/apoA-I ratio: a strong, new risk factor for cardiovascular disease and a target for lipid-lowering therapy--a review of the evidence.

              During the last several years interest has focused on the importance of the lipid-transporting apolipoproteins--apoB transports all potentially atherogenic very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and LDL particles, and apoA-I transports and acts as the major antiatherogenic protein in the HDL particles. The evidence for the apoB/apoA-I ratio being a strong, new risk factor for cardiovascular (CV) disease and a target for lipid-lowering therapy is reviewed. Results from clinical prospective studies and lipid-lowering trials in healthy subjects and in patients with different clinical manifestations of atherosclerosis are reported. Risk of nonfatal and fatal myocardial infarction and stroke, and manifestations of atherosclerosis documented by angiographic, ultrasound and other techniques has been related to conventional lipids and apolipoproteins (apo). The cholesterol balance determined as the apoB/apoA-I ratio has repeatedly been shown to be a better marker than lipids, lipoproteins and lipid ratios. The results indicate that the apoB/apoA-I ratio is a simple, accurate and new risk factor for CV disease--the lower the apoB/apoA-I ratio, the lower is the risk. Guidelines should be developed in order to recognize the important clinical risk information embedded in the apoB/apoA-I ratio.
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                Author and article information

                Contributors
                k.h.zheng@amsterdamumc.nl
                Journal
                J Am Heart Assoc
                J Am Heart Assoc
                10.1002/(ISSN)2047-9980
                JAH3
                ahaoa
                Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
                John Wiley and Sons Inc. (Hoboken )
                2047-9980
                13 August 2019
                20 August 2019
                : 8
                : 16 ( doiID: 10.1002/jah3.2019.8.issue-16 )
                : e013020
                Affiliations
                [ 1 ] Department of Vascular Medicine Amsterdam Cardiovascular Sciences Amsterdam UMC University of Amsterdam Amsterdam The Netherlands
                [ 2 ] Department of Cardiology Amsterdam Cardiovascular Sciences Amsterdam UMC University of Amsterdam Amsterdam The Netherlands
                [ 3 ] Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec ‐ Université Laval Québec Canada
                [ 4 ] Department of Public Health and Primary Care University of Cambridge United Kingdom
                [ 5 ] Medical Research Council Epidemiology Unit University of Cambridge Cambridge United Kingdom
                Author notes
                [*] [* ] Correspondence to: Kang H. Zheng, MD, Department of Vascular Medicine, Amsterdam UMC, AMC, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E‐mail: k.h.zheng@ 123456amsterdamumc.nl
                Article
                JAH34363
                10.1161/JAHA.119.013020
                6759902
                31407609
                25651cf5-910a-47ff-94bc-95932f09046e
                © 2019 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 20 April 2019
                : 22 July 2019
                Page count
                Figures: 1, Tables: 1, Pages: 6, Words: 3751
                Categories
                Brief Communication
                Brief Communication
                Custom metadata
                2.0
                jah34363
                20 August 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.7 mode:remove_FC converted:20.08.2019

                Cardiovascular Medicine
                aortic valve stenosis,apob/apoa‐i ratio,lipids and lipoproteins,lipoprotein(a),low‐density lipoprotein cholesterol,cardiovascular disease,epidemiology,risk factors

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