Author + information
- Received December 21, 2016
- Revision received February 1, 2017
- Accepted February 1, 2017
- Published online June 26, 2017.
- Michael Torzewski, MDa,
- Amir Ravandi, MD, PhDb,
- Calvin Yeang, MD, PhDc,
- Andrea Edel, PhDb,
- Rahul Bhindi, MDb,
- Stefan Kath, MDa,
- Laura Twardowski, MDa,
- Jens Schmid, PhDc,
- Xiaohong Yang, BSd,
- Ulrich F.W. Franke, MDe,
- Joseph L. Witztum, MDf and
- Sotirios Tsimikas, MDd,∗ ()
- aDepartment of Laboratory Medicine, Robert-Bosch-Hospital, Stuttgart, Germany
- bCardiac Sciences Program, University of Manitoba and Institute of Cardiovascular Sciences, St. Boniface Hospital, Winnipeg, Canada
- cDr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany
- dDivision of Cardiovascular Medicine, Sulpizio Cardiovascular Center, University of California San Diego, La Jolla, California
- eDepartment of Cardiovascular Surgery, Robert-Bosch-Hospital, Stuttgart, Germany
- fDivision of Endocrinology and Metabolism, University of California San Diego, La Jolla, California
- ↵∗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.
• The LPA gene is the only monogenetic risk factor for CAVS, and OxPL and lysophosphatidic acid, generated by autotaxin from OxPL, are pro-inflammatory.
• Both autotaxin–apolipoprotein B and autotaxin–apo(a) were measureable in plasma.
• Immunohistochemistry revealed a strong presence of apo(a), OxPL, malondialdehyde-lysine, autotaxin, and macrophages, particularly in advanced lesions rich in cholesterol crystals and calcification.
• Six species of OxPL and lysophosphatidic acid, with aldehyde-containing phosphocholine-based OxPL most abundant, were identified and quantified after extraction from valve leaflets.
• 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.
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.
This work was supported by the innovation fund of the Robert-Bosch-Hospital and the Robert Bosch Foundation. Drs. Tsimikas and Witztum are supported by grants from the National Institutes of Health (R01 grants HL119828, P01-HL088093, P01 HL055798, R01-HL106579, R01-HL078610, and R01-HL124174). Drs. Tsimikas and Witztum are co-inventors of and receive royalties from patents or patent applications owned by the University of California San Diego on antibodies used in biotheranostic applications. Dr. Tsimikas has a dual appointment at the University of California San Diego and Ionis Pharmaceuticals, Inc. Dr. Witztum has received honoraria for consulting for Ionis, CymaBay, and Prometheus Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received December 21, 2016.
- Revision received February 1, 2017.
- Accepted February 1, 2017.
- 2017 The Authors