João Pedro Ferreira1, Job Verdonschot2, Ping Wang2, Anne Pizard3, Timothy Collier4, Fozia Z Ahmed5, Hans-Peter Brunner-La-Rocca2, Andrew L Clark6, Franco Cosmi7, Joe Cuthbert6, Javier Díez8, Frank Edelmann9, Nicolas Girerd10, Arantxa González8, Stéphanie Grojean3, Mark Hazebroek2, Javed Khan10, Roberto Latini11, Mamas A Mamas5, Beatrice Mariottoni7, Blerim Mujaj12, Pierpaolo Pellicori10, Johannes Petutschnigg9, Burkert Pieske9, Patrick Rossignol3, Philippe Rouet13, Jan A Staessen12, John G F Cleland10, Stephane Heymans2, Faiez Zannad14. 1. Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique 1433, CHRU de Nancy, F-CRIN INI-CRCT, Nancy, France. Electronic address: j.ferreira@chru-nancy.fr. 2. Department of Cardiology, Maastricht University Medical Center, the Netherlands. 3. Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique 1433, CHRU de Nancy, F-CRIN INI-CRCT, Nancy, France. 4. Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, United Kingdom. 5. Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom. 6. Department of Academic Cardiology, University of Hull, Castle Hill Hospital, Cottingham, United Kingdom. 7. Department of Cardiology, Cortona Hospital, Arezzo, Italy. 8. Program of Cardiovascular Diseases, CIMA Universidad de Navarra and IdiSNA, Pamplona, Spain; CIBERCV, Carlos III Institute of Health, Madrid, Spain. 9. Department of Internal Medicine/Cardiology, German Heart Center Berlin, Berlin, Germany. 10. Robertson Centre for Biostatistics, Institute of Health and Wellbeing, University of Glasgow, Glasgow Royal Infirmary, Glasgow, United Kingdom. 11. Mario Negri Institute of Pharmacological Research-IRCCS, Milan, Italy. 12. Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium. 13. UMR UT3 CNRS 5288, Obesity and Heart Failure, Toulouse, France. 14. Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique 1433, CHRU de Nancy, F-CRIN INI-CRCT, Nancy, France. Electronic address: f.zannad@chru-nancy.fr.
Abstract
OBJECTIVES: This study sought to further understand the mechanisms underlying effect of spironolactone and assessed its impact on multiple plasma protein biomarkers and their respective underlying biologic pathways. BACKGROUND: In addition to their beneficial effects in established heart failure (HF), mineralocorticoid receptor antagonists may act upstream on mechanisms, preventing incident HF. In people at risk for developing HF, the HOMAGE (Heart OMics in AGEing) trial showed that spironolactone treatment could provide antifibrotic and antiremodeling effects, potentially slowing the progression to HF. METHODS: Baseline, 1-month, and 9-month (or last visit) plasma samples of HOMAGE participants were measured for protein biomarkers (n = 276) by using Olink Proseek-Multiplex cardiovascular and inflammation panels (Olink, Uppsala, Sweden). The effect of spironolactone on biomarkers was assessed by analysis of covariance and explored by knowledge-based network analysis. RESULTS: A total of 527 participants were enrolled; 265 were randomized to spironolactone (25 to 50 mg/day) and 262 to standard care ("control"). The median (interquartile range) age was 73 years (69 to 79 years), and 26% were female. Spironolactone reduced biomarkers of collagen metabolism (e.g., COL1A1, MMP-2); brain natriuretic peptide; and biomarkers related to metabolic processes (e.g., PAPPA), inflammation, and thrombosis (e.g., IL17A, VEGF, and urokinase). Spironolactone increased biomarkers that reflect the blockade of the mineralocorticoid receptor (e.g., renin) and increased the levels of adipokines involved in the anti-inflammatory response (e.g., RARRES2) and biomarkers of hemostasis maintenance (e.g., tPA, UPAR), myelosuppressive activity (e.g., CCL16), insulin suppression (e.g., RETN), and inflammatory regulation (e.g., IL-12B). CONCLUSIONS: Proteomic analyses suggest that spironolactone exerts pleiotropic effects including reduction in fibrosis, inflammation, thrombosis, congestion, and vascular function improvement, all of which may mediate cardiovascular protective effects, potentially slowing progression toward heart failure. (HOMAGE [Bioprofiling Response to Mineralocorticoid Receptor Antagonists for the Prevention of Heart Failure]; NCT02556450).
OBJECTIVES: This study sought to further understand the mechanisms underlying effect of spironolactone and assessed its impact on multiple plasma protein biomarkers and their respective underlying biologic pathways. BACKGROUND: In addition to their beneficial effects in established heart failure (HF), mineralocorticoid receptor antagonists may act upstream on mechanisms, preventing incident HF. In people at risk for developing HF, the HOMAGE (Heart OMics in AGEing) trial showed that spironolactone treatment could provide antifibrotic and antiremodeling effects, potentially slowing the progression to HF. METHODS: Baseline, 1-month, and 9-month (or last visit) plasma samples of HOMAGE participants were measured for protein biomarkers (n = 276) by using Olink Proseek-Multiplex cardiovascular and inflammation panels (Olink, Uppsala, Sweden). The effect of spironolactone on biomarkers was assessed by analysis of covariance and explored by knowledge-based network analysis. RESULTS: A total of 527 participants were enrolled; 265 were randomized to spironolactone (25 to 50 mg/day) and 262 to standard care ("control"). The median (interquartile range) age was 73 years (69 to 79 years), and 26% were female. Spironolactone reduced biomarkers of collagen metabolism (e.g., COL1A1, MMP-2); brain natriuretic peptide; and biomarkers related to metabolic processes (e.g., PAPPA), inflammation, and thrombosis (e.g., IL17A, VEGF, and urokinase). Spironolactone increased biomarkers that reflect the blockade of the mineralocorticoid receptor (e.g., renin) and increased the levels of adipokines involved in the anti-inflammatory response (e.g., RARRES2) and biomarkers of hemostasis maintenance (e.g., tPA, UPAR), myelosuppressive activity (e.g., CCL16), insulin suppression (e.g., RETN), and inflammatory regulation (e.g., IL-12B). CONCLUSIONS: Proteomic analyses suggest that spironolactone exerts pleiotropic effects including reduction in fibrosis, inflammation, thrombosis, congestion, and vascular function improvement, all of which may mediate cardiovascular protective effects, potentially slowing progression toward heart failure. (HOMAGE [Bioprofiling Response to Mineralocorticoid Receptor Antagonists for the Prevention of Heart Failure]; NCT02556450).
Authors: Jay S Shavadia; Wendimagegn Alemayehu; Christopher deFilippi; Cynthia M Westerhout; Jasper Tromp; Christopher B Granger; Paul W Armstrong; Sean van Diepen Journal: J Thromb Thrombolysis Date: 2021-10-27 Impact factor: 2.300
Authors: Ali Javaheri; Ahmed Diab; Lei Zhao; Chenao Qian; Jordana B Cohen; Payman Zamani; Anupam Kumar; Zhaoqing Wang; Christina Ebert; Joseph Maranville; Erika Kvikstad; Michael Basso; Vanessa van Empel; A Mark Richards; Robert N Doughty; Ernst Rietzschel; Karl Kammerhoff; Joseph Gogain; Peter Schafer; Dietmar A Seiffert; David A Gordon; Francisco Ramirez-Valle; Douglas L Mann; Thomas P Cappola; Julio A Chirinos Journal: Circ Heart Fail Date: 2022-08-09 Impact factor: 10.447
Authors: Michiel T H M Henkens; Jerremy Weerts; Job A J Verdonschot; Anne G Raafs; Sophia Stroeks; Maurits A Sikking; Hesam Amin; Sanne G J Mourmans; Chrit B G Geraeds; Sandra Sanders-van Wijk; Arantxa Barandiarán Aizpurua; Nicole H M K Uszko-Lencer; Ingrid P C Krapels; Petra F G Wolffs; Han G Brunner; Rick E W van Leeuwen; Wouter Verhesen; Simon M Schalla; Antonius W M van Stipdonk; Christian Knackstedt; Xiaofei Li; Myrurgia A Abdul Hamid; Pieter van Paassen; Mark R Hazebroek; Kevin Vernooy; Hans-Peter Brunner-La Rocca; Vanessa P M van Empel; Stephane R B Heymans Journal: ESC Heart Fail Date: 2022-02-04
Authors: Job A J Verdonschot; João Pedro Ferreira; Faiez Zannad; Stephane R B Heymans; Pierpaolo Pellicori; Hans-Peter Brunner-La Rocca; Andrew L Clark; Franco Cosmi; Joe Cuthbert; Nicolas Girerd; Beatrice Mariottoni; Johannes Petutschnigg; Patrick Rossignol; John G F Cleland Journal: Cardiovasc Diabetol Date: 2021-08-09 Impact factor: 9.951