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Lipoprotein(a) and Oxidized Phospholipids Promote Valve Calcification in Patients With Aortic Stenosis.
J Am Coll Cardiol. 2019 05 07; 73(17):2150-2162.JACC

Abstract

BACKGROUND

Lipoprotein(a) [Lp(a)], a major carrier of oxidized phospholipids (OxPL), is associated with an increased incidence of aortic stenosis (AS). However, it remains unclear whether elevated Lp(a) and OxPL drive disease progression and are therefore targets for therapeutic intervention.

OBJECTIVES

This study investigated whether Lp(a) and OxPL on apolipoprotein B-100 (OxPL-apoB) levels are associated with disease activity, disease progression, and clinical events in AS patients, along with the mechanisms underlying any associations.

METHODS

This study combined 2 prospective cohorts and measured Lp(a) and OxPL-apoB levels in patients with AS (Vmax >2.0 m/s), who underwent baseline 18F-sodium fluoride (18F-NaF) positron emission tomography (PET), repeat computed tomography calcium scoring, and repeat echocardiography. In vitro studies investigated the effects of Lp(a) and OxPL on valvular interstitial cells.

RESULTS

Overall, 145 patients were studied (68% men; age 70.3 ± 9.9 years). On baseline positron emission tomography, patients in the top Lp(a) tertile had increased valve calcification activity compared with those in lower tertiles (n = 79; 18F-NaF tissue-to-background ratio of the most diseased segment: 2.16 vs. 1.97; p = 0.043). During follow-up, patients in the top Lp(a) tertile had increased progression of valvular computed tomography calcium score (n = 51; 309 AU/year [interquartile range: 142 to 483 AU/year] vs. 93 AU/year [interquartile range: 56 to 296 AU/year; p = 0.015), faster hemodynamic progression on echocardiography (n = 129; 0.23 ± 0.20 m/s/year vs. 0.14 ± 0.20 m/s/year] p = 0.019), and increased risk for aortic valve replacement and death (n = 145; hazard ratio: 1.87; 95% CI: 1.13 to 3.08; p = 0.014), compared with lower tertiles. Similar results were noted with OxPL-apoB. In vitro, Lp(a) induced osteogenic differentiation of valvular interstitial cells, mediated by OxPL and inhibited with the E06 monoclonal antibody against OxPL.

CONCLUSIONS

In patients with AS, Lp(a) and OxPL drive valve calcification and disease progression. These findings suggest lowering Lp(a) or inactivating OxPL may slow AS progression and provide a rationale for clinical trials to test this hypothesis.

Authors+Show Affiliations

Department of Vascular Medicine, Academic Medical Center, Amsterdam UMC, Amsterdam, the Netherlands. Electronic address: https://twitter.com/Zheng_KH.Division of Cardiovascular Medicine, Sulpizio Cardiovascular Center, University of California, San Diego, La Jolla, California.British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.Department of Vascular Medicine, Academic Medical Center, Amsterdam UMC, Amsterdam, the Netherlands.British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.Department of Vascular Medicine, Academic Medical Center, Amsterdam UMC, Amsterdam, the Netherlands.Department of Cardiothoracic Surgery, UMC Utrecht, Utrecht, the Netherlands.Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.Centre de recherche de l'Institut Universitaire de cardiologie et de pneumologie de Québec-Université Laval, Québec City, Québec, Canada.Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California.British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York.Department of Vascular Medicine, Academic Medical Center, Amsterdam UMC, Amsterdam, the Netherlands.Department of Cardiology, Academic Medical Center, Amsterdam UMC, Amsterdam, the Netherlands.British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom. Electronic address: marc.dweck@ed.ac.uk.

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31047003

Citation

Zheng, Kang H., et al. "Lipoprotein(a) and Oxidized Phospholipids Promote Valve Calcification in Patients With Aortic Stenosis." Journal of the American College of Cardiology, vol. 73, no. 17, 2019, pp. 2150-2162.
Zheng KH, Tsimikas S, Pawade T, et al. Lipoprotein(a) and Oxidized Phospholipids Promote Valve Calcification in Patients With Aortic Stenosis. J Am Coll Cardiol. 2019;73(17):2150-2162.
Zheng, K. H., Tsimikas, S., Pawade, T., Kroon, J., Jenkins, W. S. A., Doris, M. K., White, A. C., Timmers, N. K. L. M., Hjortnaes, J., Rogers, M. A., Aikawa, E., Arsenault, B. J., Witztum, J. L., Newby, D. E., Koschinsky, M. L., Fayad, Z. A., Stroes, E. S. G., Boekholdt, S. M., & Dweck, M. R. (2019). Lipoprotein(a) and Oxidized Phospholipids Promote Valve Calcification in Patients With Aortic Stenosis. Journal of the American College of Cardiology, 73(17), 2150-2162. https://doi.org/10.1016/j.jacc.2019.01.070
Zheng KH, et al. Lipoprotein(a) and Oxidized Phospholipids Promote Valve Calcification in Patients With Aortic Stenosis. J Am Coll Cardiol. 2019 05 7;73(17):2150-2162. PubMed PMID: 31047003.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lipoprotein(a) and Oxidized Phospholipids Promote Valve Calcification in Patients With Aortic Stenosis. AU - Zheng,Kang H, AU - Tsimikas,Sotirios, AU - Pawade,Tania, AU - Kroon,Jeffrey, AU - Jenkins,William S A, AU - Doris,Mhairi K, AU - White,Audrey C, AU - Timmers,Nyanza K L M, AU - Hjortnaes,Jesper, AU - Rogers,Maximillian A, AU - Aikawa,Elena, AU - Arsenault,Benoit J, AU - Witztum,Joseph L, AU - Newby,David E, AU - Koschinsky,Marlys L, AU - Fayad,Zahi A, AU - Stroes,Erik S G, AU - Boekholdt,S Matthijs, AU - Dweck,Marc R, PY - 2018/09/17/received PY - 2019/01/28/revised PY - 2019/01/28/accepted PY - 2019/5/4/entrez PY - 2019/5/3/pubmed PY - 2020/3/4/medline KW - aortic valve stenosis KW - calcific aortic valve disease KW - lipoprotein(a) KW - oxidized phospholipids KW - valvular interstitial cells SP - 2150 EP - 2162 JF - Journal of the American College of Cardiology JO - J Am Coll Cardiol VL - 73 IS - 17 N2 - BACKGROUND: Lipoprotein(a) [Lp(a)], a major carrier of oxidized phospholipids (OxPL), is associated with an increased incidence of aortic stenosis (AS). However, it remains unclear whether elevated Lp(a) and OxPL drive disease progression and are therefore targets for therapeutic intervention. OBJECTIVES: This study investigated whether Lp(a) and OxPL on apolipoprotein B-100 (OxPL-apoB) levels are associated with disease activity, disease progression, and clinical events in AS patients, along with the mechanisms underlying any associations. METHODS: This study combined 2 prospective cohorts and measured Lp(a) and OxPL-apoB levels in patients with AS (Vmax >2.0 m/s), who underwent baseline 18F-sodium fluoride (18F-NaF) positron emission tomography (PET), repeat computed tomography calcium scoring, and repeat echocardiography. In vitro studies investigated the effects of Lp(a) and OxPL on valvular interstitial cells. RESULTS: Overall, 145 patients were studied (68% men; age 70.3 ± 9.9 years). On baseline positron emission tomography, patients in the top Lp(a) tertile had increased valve calcification activity compared with those in lower tertiles (n = 79; 18F-NaF tissue-to-background ratio of the most diseased segment: 2.16 vs. 1.97; p = 0.043). During follow-up, patients in the top Lp(a) tertile had increased progression of valvular computed tomography calcium score (n = 51; 309 AU/year [interquartile range: 142 to 483 AU/year] vs. 93 AU/year [interquartile range: 56 to 296 AU/year; p = 0.015), faster hemodynamic progression on echocardiography (n = 129; 0.23 ± 0.20 m/s/year vs. 0.14 ± 0.20 m/s/year] p = 0.019), and increased risk for aortic valve replacement and death (n = 145; hazard ratio: 1.87; 95% CI: 1.13 to 3.08; p = 0.014), compared with lower tertiles. Similar results were noted with OxPL-apoB. In vitro, Lp(a) induced osteogenic differentiation of valvular interstitial cells, mediated by OxPL and inhibited with the E06 monoclonal antibody against OxPL. CONCLUSIONS: In patients with AS, Lp(a) and OxPL drive valve calcification and disease progression. These findings suggest lowering Lp(a) or inactivating OxPL may slow AS progression and provide a rationale for clinical trials to test this hypothesis. SN - 1558-3597 UR - https://www.unboundmedicine.com/medline/citation/31047003/Lipoprotein_a__and_Oxidized_Phospholipids_Promote_Valve_Calcification_in_Patients_With_Aortic_Stenosis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0735-1097(19)33881-1 DB - PRIME DP - Unbound Medicine ER -