Cargando…
Lipoprotein(a) and Oxidized Phospholipids Promote Valve Calcification in Patients With Aortic Stenosis
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. OBJEC...
Autores principales: | , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier Biomedical
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494952/ https://www.ncbi.nlm.nih.gov/pubmed/31047003 http://dx.doi.org/10.1016/j.jacc.2019.01.070 |
_version_ | 1783415309097500672 |
---|---|
author | Zheng, Kang H. Tsimikas, Sotirios Pawade, Tania Kroon, Jeffrey Jenkins, William S.A. Doris, Mhairi K. White, Audrey C. Timmers, Nyanza K.L.M. Hjortnaes, Jesper Rogers, Maximillian A. Aikawa, Elena Arsenault, Benoit J. Witztum, Joseph L. Newby, David E. Koschinsky, Marlys L. Fayad, Zahi A. Stroes, Erik S.G. Boekholdt, S. Matthijs Dweck, Marc R. |
author_facet | Zheng, Kang H. Tsimikas, Sotirios Pawade, Tania Kroon, Jeffrey Jenkins, William S.A. Doris, Mhairi K. White, Audrey C. Timmers, Nyanza K.L.M. Hjortnaes, Jesper Rogers, Maximillian A. Aikawa, Elena Arsenault, Benoit J. Witztum, Joseph L. Newby, David E. Koschinsky, Marlys L. Fayad, Zahi A. Stroes, Erik S.G. Boekholdt, S. Matthijs Dweck, Marc R. |
author_sort | Zheng, Kang H. |
collection | PubMed |
description | 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 (V(max) >2.0 m/s), who underwent baseline (18)F-sodium fluoride ((18)F-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; (18)F-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. |
format | Online Article Text |
id | pubmed-6494952 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Elsevier Biomedical |
record_format | MEDLINE/PubMed |
spelling | pubmed-64949522019-05-07 Lipoprotein(a) and Oxidized Phospholipids Promote Valve Calcification in Patients With Aortic Stenosis Zheng, Kang H. Tsimikas, Sotirios Pawade, Tania Kroon, Jeffrey Jenkins, William S.A. Doris, Mhairi K. White, Audrey C. Timmers, Nyanza K.L.M. Hjortnaes, Jesper Rogers, Maximillian A. Aikawa, Elena Arsenault, Benoit J. Witztum, Joseph L. Newby, David E. Koschinsky, Marlys L. Fayad, Zahi A. Stroes, Erik S.G. Boekholdt, S. Matthijs Dweck, Marc R. J Am Coll Cardiol Article 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 (V(max) >2.0 m/s), who underwent baseline (18)F-sodium fluoride ((18)F-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; (18)F-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. Elsevier Biomedical 2019-05-07 /pmc/articles/PMC6494952/ /pubmed/31047003 http://dx.doi.org/10.1016/j.jacc.2019.01.070 Text en © 2019 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Zheng, Kang H. Tsimikas, Sotirios Pawade, Tania Kroon, Jeffrey Jenkins, William S.A. Doris, Mhairi K. White, Audrey C. Timmers, Nyanza K.L.M. Hjortnaes, Jesper Rogers, Maximillian A. Aikawa, Elena Arsenault, Benoit J. Witztum, Joseph L. Newby, David E. Koschinsky, Marlys L. Fayad, Zahi A. Stroes, Erik S.G. Boekholdt, S. Matthijs Dweck, Marc R. Lipoprotein(a) and Oxidized Phospholipids Promote Valve Calcification in Patients With Aortic Stenosis |
title | Lipoprotein(a) and Oxidized Phospholipids Promote Valve Calcification in Patients With Aortic Stenosis |
title_full | Lipoprotein(a) and Oxidized Phospholipids Promote Valve Calcification in Patients With Aortic Stenosis |
title_fullStr | Lipoprotein(a) and Oxidized Phospholipids Promote Valve Calcification in Patients With Aortic Stenosis |
title_full_unstemmed | Lipoprotein(a) and Oxidized Phospholipids Promote Valve Calcification in Patients With Aortic Stenosis |
title_short | Lipoprotein(a) and Oxidized Phospholipids Promote Valve Calcification in Patients With Aortic Stenosis |
title_sort | lipoprotein(a) and oxidized phospholipids promote valve calcification in patients with aortic stenosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494952/ https://www.ncbi.nlm.nih.gov/pubmed/31047003 http://dx.doi.org/10.1016/j.jacc.2019.01.070 |
work_keys_str_mv | AT zhengkangh lipoproteinaandoxidizedphospholipidspromotevalvecalcificationinpatientswithaorticstenosis AT tsimikassotirios lipoproteinaandoxidizedphospholipidspromotevalvecalcificationinpatientswithaorticstenosis AT pawadetania lipoproteinaandoxidizedphospholipidspromotevalvecalcificationinpatientswithaorticstenosis AT kroonjeffrey lipoproteinaandoxidizedphospholipidspromotevalvecalcificationinpatientswithaorticstenosis AT jenkinswilliamsa lipoproteinaandoxidizedphospholipidspromotevalvecalcificationinpatientswithaorticstenosis AT dorismhairik lipoproteinaandoxidizedphospholipidspromotevalvecalcificationinpatientswithaorticstenosis AT whiteaudreyc lipoproteinaandoxidizedphospholipidspromotevalvecalcificationinpatientswithaorticstenosis AT timmersnyanzaklm lipoproteinaandoxidizedphospholipidspromotevalvecalcificationinpatientswithaorticstenosis AT hjortnaesjesper lipoproteinaandoxidizedphospholipidspromotevalvecalcificationinpatientswithaorticstenosis AT rogersmaximilliana lipoproteinaandoxidizedphospholipidspromotevalvecalcificationinpatientswithaorticstenosis AT aikawaelena lipoproteinaandoxidizedphospholipidspromotevalvecalcificationinpatientswithaorticstenosis AT arsenaultbenoitj lipoproteinaandoxidizedphospholipidspromotevalvecalcificationinpatientswithaorticstenosis AT witztumjosephl lipoproteinaandoxidizedphospholipidspromotevalvecalcificationinpatientswithaorticstenosis AT newbydavide lipoproteinaandoxidizedphospholipidspromotevalvecalcificationinpatientswithaorticstenosis AT koschinskymarlysl lipoproteinaandoxidizedphospholipidspromotevalvecalcificationinpatientswithaorticstenosis AT fayadzahia lipoproteinaandoxidizedphospholipidspromotevalvecalcificationinpatientswithaorticstenosis AT stroeseriksg lipoproteinaandoxidizedphospholipidspromotevalvecalcificationinpatientswithaorticstenosis AT boekholdtsmatthijs lipoproteinaandoxidizedphospholipidspromotevalvecalcificationinpatientswithaorticstenosis AT dweckmarcr lipoproteinaandoxidizedphospholipidspromotevalvecalcificationinpatientswithaorticstenosis |