Oxidized Phospholipids, Lipoprotein(a), and Cardiovascular Outcomes After Acute Coronary Syndrome
Abstract
BACKGROUND: Oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) reflect pro-inflammatory properties of Lp(a) (lipoprotein(a)). The effect of OxPL-apoB on major adverse cardiovascular events (MACE) in patients with acute coronary syndrome in recent the era is not known. METHODS: OxPL-apoB levels and Lp(a) were measured in 11 630 participants before and 5185 participants 4 months after randomization to alirocumab or placebo in the ODYSSEY OUTCOMES trial. Proportional hazards models adjusted for baseline covariates evaluated associations between log 2 -transformed OxPL-apoB and Lp(a) with MACEs. Interactions between the 2 biomarkers and treatment were also evaluated. RESULTS: Participants were followed for a median 2.9 years; the median age was 58 years, and 23.9% were female. Alirocumab reduced median placebo-adjusted OxPL-apoB by 13.0% and Lp(a) by 26.2% (both P <0.0001). In the placebo group, a doubling of baseline OxPL-apoB was associated with a hazard ratio (HR) of 1.081 (95% CI, 1.026–1.139; P =0.0034) for MACEs. Addition of Lp(a) to the model relegated the relationship of OxPL-apoB insignificant. In the alirocumab group, neither OxPL-apoB nor Lp(a) remained significantly associated with MACEs. A significant 3-way interaction was present among continuous log 2 OxPL-apoB, Lp(a) stratified at the median, and treatment group on MACEs ( P interaction =0.0023) so that, in the placebo group, increasing OxPL-apoB was associated with higher risk of MACEs when Lp(a) was below the median concentration but not above. In the alirocumab group, OxPL-apoB was not related to MACE risk irrespective of Lp(a) concentration. CONCLUSIONS: In patients with recent acute coronary syndrome receiving optimized statin treatment, elevated OxPL-apoB levels predicted MACEs, a relationship abrogated by alirocumab. The interaction of OxPL-apoB and Lp(a) in the placebo group indicates that OxPL-apoB independently predicts MACEs when Lp(a) levels are relatively low. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT001747 and NCT01663402.
Article Details
Authors (17)
Sotirios Tsimikas
Michael Szarek
CPC Clinical Research, Aurora, CO (M.S.).
Christa M. Cobbaert
Departments of Clinical Chemistry and Laboratory Medicine (C.C., F. R.), Leiden University Medical Center, the Netherlands.
Fred Romijn
Departments of Clinical Chemistry and Laboratory Medicine (C.C., F. R.), Leiden University Medical Center, the Netherlands.
J. Wouter Jukema
Department of Cardiology, Leiden University Medical Center, The Netherlands (J.W.J.).
Deepak L. Bhatt
Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York
Vera A. Bittner
Rafael Diaz
Estudios Clinicos Latinoamerica, Rosario, Argentina (R.D.).
Sergio Fazio
Regeneron Pharmaceuticals Inc, Tarrytown, NY (S.F.).
Genevieve Garon
Division of Cardiology, University of Colorado School of Medicine, Aurora, CO (M.S., G.G.S.).
Chong Yuan
State Key Laboratory for Innovation and Transformation of Luobing Theory; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China (Q.W., J.T., D.L., T.Z., X.L., Y.Z., X.L. H.Z., J.P., C.Y., W.Z., M.Z., C.Z., M.Z.).
Xiao-Min Gong
Sanofi, ON, Canada (G.G.). Diazyme Laboratories, Poway, CA (C.Y., X.-M.G.).
Shaun G. Goodman
St. Michael’s Hospital, Unity Health Toronto, Peter Munk Cardiac Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada (S.G.G.).
Harvey D. White
Green Lane Clinical Coordinating Centre, Auckland, New Zealand (J.R.B., H.D.W.).
Joseph L. Witztum
Endocrinology and Metabolism (J.L.W.), University of California San Diego, La Jolla, CA.
P. Gabriel Steg
Université Paris-Cité, Paris, France (P.G.S.).
Gregory G. Schwartz
Cardiology Section, Rocky Mountain Regional VA Medical Center and University of Colorado School of Medicine, Aurora, CO (G.G.S.).