Lipoprotein(a)-Associated Molecules Are Prominent Components in Plasma and Valve Leaflets in Calcific Aortic Valve Stenosis

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The LPA gene is the only monogenetic risk factor for CAVS, and OxPL and lysophosphatidic acid, generated by autotaxin from OxPL, are pro-inflammatory.
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Both autotaxin–apolipoprotein B and autotaxin–apo(a) were measureable in plasma.
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Immunohistochemistry revealed a strong presence of apo(a), OxPL, malondialdehyde-lysine, autotaxin, and macrophages, particularly in advanced lesions rich in cholesterol crystals and calcification.
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Six species of OxPL and lysophosphatidic acid, with aldehyde-containing phosphocholine-based OxPL most abundant, were identified and quantified after extraction from valve leaflets.
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We demonstrate the presence of a constellation of pathologically linked, Lp(a)-associated molecules in plasma and in aortic valve leaflets of patients with CAVS. These data are consistent with the hypothesis that Lp(a) is a key etiologic factor in patients with CAVS.

Summary

The LPA gene is the only monogenetic risk factor for calcific aortic valve stenosis (CAVS). Oxidized phospholipids (OxPL) and lysophosphatidic acid generated by autotaxin (ATX) from OxPL are pro-inflammatory. Aortic valve leaflets categorized pathologically from both ATX–apolipoprotein B and ATX–apolipoprotein(a) were measureable in plasma. Lipoprotein(a) (Lp[a]), ATX, OxPL, and malondialdehyde epitopes progressively increased in immunostaining (p < 0.001 for all). Six species of OxPL and lysophosphatidic acid were identified after extraction from valve leaflets. The presence of a constellation of pathologically linked, Lp(a)-associated molecules in plasma and in aortic valve leaflets of patients with CAVS suggest that Lp(a) is a key etiologic factor in CAVS.

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Most cited references 31

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Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis.

Anne Rossebø, Terje R Pedersen, Kurt Boman … (2008)

Hyperlipidemia has been suggested as a risk factor for stenosis of the aortic valve, but lipid-lowering studies have had conflicting results. We conducted a randomized, double-blind trial involving 1873 patients with mild-to-moderate, asymptomatic aortic stenosis. The patients received either 40 mg of simvastatin plus 10 mg of ezetimibe or placebo daily. The primary outcome was a composite of major cardiovascular events, including death from cardiovascular causes, aortic-valve replacement, nonfatal myocardial infarction, hospitalization for unstable angina pectoris, heart failure, coronary-artery bypass grafting, percutaneous coronary intervention, and nonhemorrhagic stroke. Secondary outcomes were events related to aortic-valve stenosis and ischemic cardiovascular events. During a median follow-up of 52.2 months, the primary outcome occurred in 333 patients (35.3%) in the simvastatin-ezetimibe group and in 355 patients (38.2%) in the placebo group (hazard ratio in the simvastatin-ezetimibe group, 0.96; 95% confidence interval [CI], 0.83 to 1.12; P=0.59). Aortic-valve replacement was performed in 267 patients (28.3%) in the simvastatin-ezetimibe group and in 278 patients (29.9%) in the placebo group (hazard ratio, 1.00; 95% CI, 0.84 to 1.18; P=0.97). Fewer patients had ischemic cardiovascular events in the simvastatin-ezetimibe group (148 patients) than in the placebo group (187 patients) (hazard ratio, 0.78; 95% CI, 0.63 to 0.97; P=0.02), mainly because of the smaller number of patients who underwent coronary-artery bypass grafting. Cancer occurred more frequently in the simvastatin-ezetimibe group (105 vs. 70, P=0.01). Simvastatin and ezetimibe did not reduce the composite outcome of combined aortic-valve events and ischemic events in patients with aortic stenosis. Such therapy reduced the incidence of ischemic cardiovascular events but not events related to aortic-valve stenosis. (ClinicalTrials.gov number, NCT00092677.) 2008 Massachusetts Medical Society

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Genetic associations with valvular calcification and aortic stenosis.

George Thanassoulis, Catherine Y Campbell, David S Owens … (2013)

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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A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis.

S Cowell, David Newby, Robin Prescott … (2005)

Calcific aortic stenosis has many characteristics in common with atherosclerosis, including hypercholesterolemia. We hypothesized that intensive lipid-lowering therapy would halt the progression of calcific aortic stenosis or induce its regression. In this double-blind, placebo-controlled trial, patients with calcific aortic stenosis were randomly assigned to receive either 80 mg of atorvastatin daily or a matched placebo. Aortic-valve stenosis and calcification were assessed with the use of Doppler echocardiography and helical computed tomography, respectively. The primary end points were change in aortic-jet velocity and aortic-valve calcium score. Seventy-seven patients were assigned to atorvastatin and 78 to placebo, with a median follow-up of 25 months (range, 7 to 36). Serum low-density lipoprotein cholesterol concentrations remained at 130+/-30 mg per deciliter in the placebo group and fell to 63+/-23 mg per deciliter in the atorvastatin group (P<0.001). Increases in aortic-jet velocity were 0.199+/-0.210 m per second per year in the atorvastatin group and 0.203+/-0.208 m per second per year in the placebo group (P=0.95; adjusted mean difference, 0.002; 95 percent confidence interval, -0.066 to 0.070 m per second per year). Progression in valvular calcification was 22.3+/-21.0 percent per year in the atorvastatin group, and 21.7+/-19.8 percent per year in the placebo group (P=0.93; ratio of post-treatment aortic-valve calcium score, 0.998; 95 percent confidence interval, 0.947 to 1.050). Intensive lipid-lowering therapy does not halt the progression of calcific aortic stenosis or induce its regression. This study cannot exclude a small reduction in the rate of disease progression or a significant reduction in major clinical end points. Long-term, large-scale, randomized, controlled trials are needed to establish the role of statin therapy in patients with calcific aortic stenosis. Copyright 2005 Massachusetts Medical Society.

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Author and article information

Contributors

Sotirios Tsimikas

Journal

Journal ID (nlm-ta): JACC Basic Transl Sci

Journal ID (iso-abbrev): JACC Basic Transl Sci

Title: JACC: Basic to Translational Science

Publisher: Elsevier

ISSN (Electronic): 2452-302X

Publication date PMC-release: 26 June 2017

Publication date Collection: June 2017

Publication date (Electronic): 26 June 2017

Volume: 2

Issue: 3

Pages: 229-240

Affiliations

[a ]Department of Laboratory Medicine, Robert-Bosch-Hospital, Stuttgart, Germany

[b ]Cardiac Sciences Program, University of Manitoba and Institute of Cardiovascular Sciences, St. Boniface Hospital, Winnipeg, Canada

[c ]Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany

[d ]Division of Cardiovascular Medicine, Sulpizio Cardiovascular Center, University of California San Diego, La Jolla, California

[e ]Department of Cardiovascular Surgery, Robert-Bosch-Hospital, Stuttgart, Germany

[f ]Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, California

Author notes

[∗ ] Address for correspondence: Dr. Sotirios Tsimikas, Vascular Medicine Program, Department of Medicine, Sulpizio Cardiovascular Center, University of California San Diego, 9500 Gilman Drive, BSB 1080, La Jolla, California 92093-0682. stsimikas@ 123456ucsd.edu

Article

Publisher ID: S2452-302X(17)30094-3

DOI: 10.1016/j.jacbts.2017.02.004

PMC ID: 5685511

PubMed ID: 29147686

SO-VID: 5cec9676-6244-4039-9034-5f668af3402e

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 21 December 2016

Date revision received : 1 February 2017

Date accepted : 1 February 2017

Lipoprotein(a)-Associated Molecules Are Prominent Components in Plasma and Valve Leaflets in Calcific Aortic Valve Stenosis

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Most cited references 31

Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis.

Genetic associations with valvular calcification and aortic stenosis.

A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis.

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