George Markousis-Mavrogenis1, Jasper Tromp1,2,3, Wouter Ouwerkerk2,4, João Pedro Ferreira5,6, Stefan D Anker7,8,9, John G Cleland10,11, Kenneth Dickstein12, Gerasimos Filippatos13, Chim C Lang14, Marco Metra15, Nilesh J Samani14, Rudolf A de Boer1, Dirk J van Veldhuisen1, Adriaan A Voors1, Peter van der Meer1. 1. Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, TheNetherlands. 2. Saw Swee Hock School of Public Health, National University of Singapore, 12 Science Drive 2, #10-01, Singapore 117549, Singapore. 3. Duke-NUS Medical School Singapore, 8 College Road, Singapore 169857Singapore. 4. Department of Dermatology, Amsterdam UMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, De Boelelaan 1117, 1118, 1081 HV Amsterdam, The Netherlands. 5. Université de Lorraine, Inserm, Centre d'Investigations Cliniques, - PlurithÕmatique 14-33, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France. 6. Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal. 7. Division of Cardiology and Metabolism - Heart Failure, Cachexia & Sarcopenia, Department of Cardiology (CVK), Berlin-Brandenburg Center for Regenerative Therapies (BCRT), at Charité University Medicine, Charitépl. 1, 10117 Berlin, Germany. 8. Department of Cardiology and Pneumology, University Medicine Göttingen (UMG), Robert-Koch-Straße 40, 37075 Göttingen, Germany. 9. DZHK (German Center for Cardiovascular Research), Potsdamer Str. 58 10785 Berlin, Germany. 10. Robertson Centre for Biostatistics, Institute of Health and Wellbeing, University of Glasgow, Glasgow G12 8QQ, UK. 11. National Heart & Lung Institute, Imperial College, Guy Scadding Building, Dovehouse St, London SW3 6LY, UK. 12. University of Bergen, Stavanger University Hospital, Gerd-Ragna Bloch Thorsens gate 8, 4011 Stavanger, Norway. 13. Heart Failure Unit, Department of Cardiology, National and Kapodistrian University of Athens, School of Medicine, Athens University Hospital Attikon, Rimini 1, Chaidari 124 62, Athens, Greece. 14. Division of Molecular & Clinical Medicine, University of Dundee, Dundee DD1 9SY, UK. 15. Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Institute of Cardiology, University of Brescia, Piazza del Mercato, 15, 25121 Brescia BS, Italy.
Abstract
AIMS: The exploration of novel immunomodulatory interventions to improve outcome in heart failure (HF) is hampered by the complexity/redundancies of inflammatory pathways, which remain poorly understood. We thus aimed to investigate the associations between the activation of diverse immune processes and outcomes in patients with HF. METHODS AND RESULTS: We measured 355 biomarkers in 2022 patients with worsening HF and an independent validation cohort (n = 1691) (BIOSTAT-CHF index and validation cohorts), and classified them according to their functions into biological processes based on the gene ontology classification. Principal component analyses were used to extract weighted scores per process. We investigated the association of these processes with all-cause mortality at 2-year follow-up. The contribution of each biomarker to the weighted score(s) of the processes was used to identify potential therapeutic targets. Mean age was 69 (±12.0) years and 537 (27%) patients were women. We identified 64 unique overrepresented immune-related processes representing 188 of 355 biomarkers. Of these processes, 19 were associated with all-cause mortality (10 positively and 9 negatively). Increased activation of 'T-cell costimulation' and 'response to interferon-gamma/positive regulation of interferon-gamma production' showed the most consistent positive and negative associations with all-cause mortality, respectively, after external validation. Within T-cell costimulation, inducible costimulator ligand, CD28, CD70, and tumour necrosis factor superfamily member-14 were identified as potential therapeutic targets. CONCLUSIONS: We demonstrate the divergent protective and harmful effects of different immune processes in HF and suggest novel therapeutic targets. These findings constitute a rich knowledge base for informing future studies of inflammation in HF.
AIMS: The exploration of novel immunomodulatory interventions to improve outcome in heart failure (HF) is hampered by the complexity/redundancies of inflammatory pathways, which remain poorly understood. We thus aimed to investigate the associations between the activation of diverse immune processes and outcomes in patients with HF. METHODS AND RESULTS: We measured 355 biomarkers in 2022 patients with worsening HF and an independent validation cohort (n = 1691) (BIOSTAT-CHF index and validation cohorts), and classified them according to their functions into biological processes based on the gene ontology classification. Principal component analyses were used to extract weighted scores per process. We investigated the association of these processes with all-cause mortality at 2-year follow-up. The contribution of each biomarker to the weighted score(s) of the processes was used to identify potential therapeutic targets. Mean age was 69 (±12.0) years and 537 (27%) patients were women. We identified 64 unique overrepresented immune-related processes representing 188 of 355 biomarkers. Of these processes, 19 were associated with all-cause mortality (10 positively and 9 negatively). Increased activation of 'T-cell costimulation' and 'response to interferon-gamma/positive regulation of interferon-gamma production' showed the most consistent positive and negative associations with all-cause mortality, respectively, after external validation. Within T-cell costimulation, inducible costimulator ligand, CD28, CD70, and tumour necrosis factor superfamily member-14 were identified as potential therapeutic targets. CONCLUSIONS: We demonstrate the divergent protective and harmful effects of different immune processes in HF and suggest novel therapeutic targets. These findings constitute a rich knowledge base for informing future studies of inflammation in HF.
Authors: Anthony G Garcia; Richard M Wilson; Joline Heo; Namita R Murthy; Simoni Baid; Noriyuki Ouchi; Flora Sam Journal: Am J Physiol Heart Circ Physiol Date: 2012-06-22 Impact factor: 4.733
Authors: Roland Klingenberg; Frank Autschbach; Christian Gleissner; Thomas Giese; Nadine Wambsganss; Natascha Sommer; Guenther Richter; Hugo A Katus; Thomas J Dengler Journal: Eur J Immunol Date: 2005-06 Impact factor: 5.532