Karin Lifshitz1, Yaara Ber2, Chen Shenhar2, Jan Nillson3, Avivit Peer4,5, Eli Rosenbaum6, Jack Baniel2,7, Daniel Kedar2, Osnat Itzhaki Ben Zadok7,8, David Margel2,6. 1. Israel Defense Forces Medical Corps, Ramat Gan, Israel. 2. Division of Urology, Rabin Medical Center, Petach Tikva, Israel. 3. Department of Medicine, Malmö University Hospital, Lund University, Malmö, Sweden. 4. Department of Oncology, Rambam Health Care Campus, Haifa, Israel. 5. Rappaport Faculty of Medicine, Technion, Haifa, Israel. 6. Davidoff Cancer Centre, Rabin Medical Center, Petach Tikva, Israel. 7. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 8. Division of Cardiology, Rabin Medical Center, Petach Tikva, Israel.
Abstract
PURPOSE: Recent studies demonstrated reduced cardiovascular (CV) risk with gonadotropin-releasing hormone (GnRH) antagonist, yet the underlying mechanism remains undetermined. The objective of this study was to examine longitudinal changes over time in established CV related proteins among men treated with GnRH agonists vs GnRH antagonist. MATERIALS AND METHODS: We performed a proteomics analysis of serum samples collected during a phase II randomized study among 80 men with advanced prostate cancer and preexisting CV disease who were randomized to receive a GnRH agonist (39) or GnRH antagonist (41) for 1 year. Serum samples were collected at baseline and at 3, 6 and 12 months following treatment, and analyzed levels of 188 proteins using the CV panel II and III of the Olink Multiplex platform (Olink Proteomics AB, Uppsala, Sweden). We fitted a linear mixed effects model to assess evidence of a treatment effect across CV related protein values. This included terms for treatment arm, protein levels and time-by-treatment interaction. Results were corrected for multiple testing using the Benjamini-Hochberg method. RESULTS: The CV proteomics analysis included 283 samples from 78 subjects. We identified 5 proteins with distinct patterns over time depending on study arm: human chitotriosidase, macrophage receptor with collagenous structure, cathepsin D, superoxide dismutase 2 and hydroxyacid oxidase 1. All 5 are associated with plaque stability and demonstrated an increased level among subjects in the GnRH antagonist arm compared to agonist. CONCLUSIONS: We compared longitudinal changes in CV proteins among men using androgen deprivation therapy. Our results support a direct protective effect of GnRH antagonist on plaque stability rather than a hazardous consequence of GnRH agonists on plaque rupture. This is a hypothesis generating study, and requires further confirmation.
RCT Entities:
PURPOSE: Recent studies demonstrated reduced cardiovascular (CV) risk with gonadotropin-releasing hormone (GnRH) antagonist, yet the underlying mechanism remains undetermined. The objective of this study was to examine longitudinal changes over time in established CV related proteins among men treated with GnRH agonists vs GnRH antagonist. MATERIALS AND METHODS: We performed a proteomics analysis of serum samples collected during a phase II randomized study among 80 men with advanced prostate cancer and preexisting CV disease who were randomized to receive a GnRH agonist (39) or GnRH antagonist (41) for 1 year. Serum samples were collected at baseline and at 3, 6 and 12 months following treatment, and analyzed levels of 188 proteins using the CV panel II and III of the Olink Multiplex platform (Olink Proteomics AB, Uppsala, Sweden). We fitted a linear mixed effects model to assess evidence of a treatment effect across CV related protein values. This included terms for treatment arm, protein levels and time-by-treatment interaction. Results were corrected for multiple testing using the Benjamini-Hochberg method. RESULTS: The CV proteomics analysis included 283 samples from 78 subjects. We identified 5 proteins with distinct patterns over time depending on study arm: human chitotriosidase, macrophage receptor with collagenous structure, cathepsin D, superoxide dismutase 2 and hydroxyacid oxidase 1. All 5 are associated with plaque stability and demonstrated an increased level among subjects in the GnRH antagonist arm compared to agonist. CONCLUSIONS: We compared longitudinal changes in CV proteins among men using androgen deprivation therapy. Our results support a direct protective effect of GnRH antagonist on plaque stability rather than a hazardous consequence of GnRH agonists on plaque rupture. This is a hypothesis generating study, and requires further confirmation.
Authors: Daniel H Katz; Jeremy M Robbins; Shuliang Deng; Usman A Tahir; Alexander G Bick; Akhil Pampana; Zhi Yu; Debby Ngo; Mark D Benson; Zsu-Zsu Chen; Daniel E Cruz; Dongxiao Shen; Yan Gao; Claude Bouchard; Mark A Sarzynski; Adolfo Correa; Pradeep Natarajan; James G Wilson; Robert E Gerszten Journal: Sci Adv Date: 2022-08-19 Impact factor: 14.957