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Original research
ApoCIII-Lp(a) complexes in conjunction with Lp(a)-OxPL predict rapid progression of aortic stenosis
  1. Romain Capoulade1,2,
  2. Michael Torzewski3,
  3. Manuel Mayr4,
  4. Kwan-Leung Chan5,
  5. Patrick Mathieu1,
  6. Yohan Bossé1,
  7. Jean G Dumesnil1,
  8. James Tam6,
  9. Koon K Teo7,
  10. Sean A. Burnap4,
  11. Jens Schmid3,
  12. Nora Gobel3,
  13. Ulrich F W Franke3,
  14. Amber Sanchez8,
  15. Joseph L Witztum9,
  16. Xiaohong Yang10,
  17. Calvin Yeang10,
  18. Benoit Arsenault1,
  19. Jean-Pierre Després1,
  20. Philippe Pibarot1,
  21. Sotirios Tsimikas10
  1. 1 Centre de recherche de l‘Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec Heart and Lung Institut, Quebec city, Quebec, Canada
  2. 2 Université de Nantes, CHU Nantes, CNRS, INSERM, l’institut du thorax, F-44000, Nantes, France
  3. 3 Department of Cardiovascular Surgery, Robert Bosch Hospital, Stuttgart, Baden-Wurttemberg, Germany
  4. 4 King’s British Heart Foundation Centre, King's College London, London, UK
  5. 5 Department of Medicine, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
  6. 6 Department of Internal Medecine, St Boniface Hospital Research, Winnipeg, Manitoba, Canada
  7. 7 Department of Medicine, McMaster University, Hamilton, Ontario, Canada
  8. 8 Department of Nephrology, University of California San Diego, La Jolla, California, USA
  9. 9 Department of Endocrinology and Metabolism, University of California San Diego, La Jolla, California, USA
  10. 10 Department of cardiology, University of California San Diego, La Jolla, California, USA
  1. Correspondence to Dr Sotirios Tsimikas, Cardiology, University of California San Diego, La Jolla, CA 92093-0682, USA; stsimikas{at}ucsd.edu

Abstract

Objective This study assessed whether apolipoprotein CIII-lipoprotein(a) complexes (ApoCIII-Lp(a)) associate with progression of calcific aortic valve stenosis (AS).

Methods Immunostaining for ApoC-III was performed in explanted aortic valve leaflets in 68 patients with leaflet pathological grades of 1–4. Assays measuring circulating levels of ApoCIII-Lp(a) complexes were measured in 218 patients with mild–moderate AS from the AS Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) trial. The progression rate of AS, measured as annualised changes in peak aortic jet velocity (Vpeak), and combined rates of aortic valve replacement (AVR) and cardiac death were determined. For further confirmation of the assay data, a proteomic analysis of purified Lp(a) was performed to confirm the presence of apoC-III on Lp(a).

Results Immunohistochemically detected ApoC-III was prominent in all grades of leaflet lesion severity. Significant interactions were present between ApoCIII-Lp(a) and Lp(a), oxidised phospholipids on apolipoprotein B-100 (OxPL-apoB) or on apolipoprotein (a) (OxPL-apo(a)) with annualised Vpeak (all p<0.05). After multivariable adjustment, patients in the top tertile of both apoCIII-Lp(a) and Lp(a) had significantly higher annualised Vpeak (p<0.001) and risk of AVR/cardiac death (p=0.03). Similar results were noted with OxPL-apoB and OxPL-apo(a). There was no association between autotaxin (ATX) on ApoB and ATX on Lp(a) with faster progression of AS. Proteomic analysis of purified Lp(a) showed that apoC-III was prominently present on Lp(a).

Conclusion ApoC-III is present on Lp(a) and in aortic valve leaflets. Elevated levels of ApoCIII-Lp(a) complexes in conjunction with Lp(a), OxPL-apoB or OxPL-apo(a) identify patients with pre-existing mild–moderate AS who display rapid progression of AS and higher rates of AVR/cardiac death.

Trial registration NCT00800800.

  • echocardiography
  • aortic stenosis
  • lipoproteins and hyperlipidaemia
  • cardiac surgery
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Footnotes

  • Twitter @ArsenaultBenoit, @PPibarot

  • Contributors All authors have contributed to the manuscript either as substantial contributions to the conception or design of the work, or the acquisition, analysis or interpretation of data. Drafting the work or revising it critically for important intellectual content.Final approval of the version published. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

  • Funding The ASTRONOMER trial was funded by Astra-Zeneca and Canadian Institutes of Health Research (CIHR), Ottawa, Canada. The present substudy was supported in part by grants (FDN-143225 and MOP-114997 [PP] and MOP-245048 [PM]) from CIHR. RC is supported by a post-doctoral fellowship grant from Institut de France - Fondation Lefoulon-Delalande (Paris, France) and holds a “Connect Talent” research chair from Region Pays de la Loire and Nantes Metropole (France). PM holds the FRQS Research Chair on the Pathobiology of Calcific Aortic Valve Disease. YB holds a Canada Research Chair in Genomics of Heart and Lung Diseases. BA is a research scholar from the Fonds de recherche Québec – Santé (FRQS), Montreal, Québec, Canada. PP holds the Canada Research Chair in Valvular Heart Diseases, CIHR. ST and JLW are supported by NIH grants R01-HL119828, P01-HL088093, P01-HL055798, R01-HL106579, R01-HL078610, and R01-HL124174.

  • Competing interests J-PD has served as a speaker for Abbott Laboratories, AstraZeneca, Solvay Pharma, GlaxoSmithKline, and Pfizer Canada, Inc.; has received research funding from Eli Lilly Canada; and has served on the advisory boards of Novartis, Theratechnologies, Torrent Pharmaceuticals Ltd., and Sanofi-Aventis. PM has a patent application on the use of Lp-PLA2 inhibitors in the treatment of AS. BA has received research funding from Ionis Pharmaceuticals, Merck and Pfizer. ST and JLW are co-inventors and receive royalties from patents owned by UCSD on oxidation-specific antibodies and of biomarkers related to oxidised lipoproteins and are co-founders of Oxitope, Inc. ST is a consultant to Boston Heart Diagnostics, a co-founder of Oxitope, Inc. and has a dual appointment at UCSD and Ionis Pharmaceuticals. JLW is a consultant to Ionis Pharmaceuticals and a co-founder of Oxitope, Inc.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement No data are available.

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