Yiyi Zhang1, Elena Blasco-Colmenares2, Amy C Harms3, Barry London4, Indrani Halder5, Madhurmeet Singh5, Samuel C Dudley6, Rebecca Gutmann4, Eliseo Guallar1, Thomas Hankemeier7, Gordon F Tomaselli2, Alan Cheng8. 1. Department of Epidemiology, Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA. 2. Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Halsted 565, Baltimore, MD 21287, USA. 3. Netherlands Metabolomics Centre, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands. 4. Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA. 5. Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. 6. Lifespan Cardiovascular Institute and the Warren Alpert School of Medicine, Brown University, Providence, RI, USA. 7. Netherlands Metabolomics Centre, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands. 8. Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Halsted 565, Baltimore, MD 21287, USA alcheng@jhmi.edu.
Abstract
AIMS: Heart failure patients are at increased risk of ventricular arrhythmias and all-cause mortality. However, existing clinical and serum markers only modestly predict these adverse events. We sought to use metabolic profiling to identify novel biomarkers in two independent prospective cohorts of patients with implantable cardioverter-defibrillators (ICDs) for primary prevention of sudden cardiac death (SCD). METHODS AND RESULTS: Baseline serum was quantitatively profiled for 42 known biologically relevant amine-based metabolites among 402 patients from the Prospective Observational Study of Implantable Cardioverter-Defibrillators (PROSE-ICD) Study (derivation group) and 240 patients from the Genetic Risk Assessment of Defibrillator Events (GRADE) Study (validation group) for ventricular arrhythmia-induced ICD shocks and all-cause mortality. Three amines, N-methyl-l-histidine, symmetric dimethylarginine (SDMA), and l-kynurenine, were derived and validated to be associated with all-cause mortality. The hazard ratios of mortality in PROSE-ICD and GRADE were 1.48 (95% confidence interval 1.14-1.92) and 1.67 (1.22-2.27) for N-methyl-l-histidine, 1.49 (1.17-1.91) and 1.77 (1.27-2.45) for SDMA, 1.31 (1.06-1.63) and 1.73 (1.32-2.27) for l-kynurenine, respectively. l-Histidine, SDMA, and l-kynurenine were associated with ventricular arrhythmia-induced ICD shocks in PROSE-ICD, but they did not reach statistical significance in the GRADE cohort. CONCLUSION: Utilizing metabolic profiling in two independent prospective cohorts of patients undergoing ICD implantation for primary prevention of SCD, we identified several novel amine markers that were associated with appropriate shock and mortality. These findings shed insight into the potential biologic pathways leading to adverse events in ICD patients. Further studies are needed to confirm the prognostic value of these findings. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Heart failurepatients are at increased risk of ventricular arrhythmias and all-cause mortality. However, existing clinical and serum markers only modestly predict these adverse events. We sought to use metabolic profiling to identify novel biomarkers in two independent prospective cohorts of patients with implantable cardioverter-defibrillators (ICDs) for primary prevention of sudden cardiac death (SCD). METHODS AND RESULTS: Baseline serum was quantitatively profiled for 42 known biologically relevant amine-based metabolites among 402 patients from the Prospective Observational Study of Implantable Cardioverter-Defibrillators (PROSE-ICD) Study (derivation group) and 240 patients from the Genetic Risk Assessment of Defibrillator Events (GRADE) Study (validation group) for ventricular arrhythmia-induced ICD shocks and all-cause mortality. Three amines, N-methyl-l-histidine, symmetric dimethylarginine (SDMA), and l-kynurenine, were derived and validated to be associated with all-cause mortality. The hazard ratios of mortality in PROSE-ICD and GRADE were 1.48 (95% confidence interval 1.14-1.92) and 1.67 (1.22-2.27) for N-methyl-l-histidine, 1.49 (1.17-1.91) and 1.77 (1.27-2.45) for SDMA, 1.31 (1.06-1.63) and 1.73 (1.32-2.27) for l-kynurenine, respectively. l-Histidine, SDMA, and l-kynurenine were associated with ventricular arrhythmia-induced ICD shocks in PROSE-ICD, but they did not reach statistical significance in the GRADE cohort. CONCLUSION: Utilizing metabolic profiling in two independent prospective cohorts of patients undergoing ICD implantation for primary prevention of SCD, we identified several novel amine markers that were associated with appropriate shock and mortality. These findings shed insight into the potential biologic pathways leading to adverse events in ICDpatients. Further studies are needed to confirm the prognostic value of these findings. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: H Immo Lehmann; Andreas Goette; Jens Martens-Lobenhoffer; Matthias Hammwöhner; Friedrich-Wilhelm Röhl; Alicja Bukowska; Ali Ghanem; Helmut U Klein; Stefanie M Bode-Böger Journal: Europace Date: 2011-07-13 Impact factor: 5.214
Authors: Eva Schepers; Daniela V Barreto; Sophie Liabeuf; Griet Glorieux; Sunny Eloot; Fellype C Barreto; Ziad Massy; Raymond Vanholder Journal: Clin J Am Soc Nephrol Date: 2011-08-04 Impact factor: 8.237
Authors: Bob Siegerink; Renke Maas; Carla Y Vossen; Edzard Schwedhelm; Wolfgang Koenig; Rainer Böger; Dietrich Rothenbacher; Hermann Brenner; Lutz P Breitling Journal: Clin Res Cardiol Date: 2012-10-17 Impact factor: 5.460
Authors: M Pertovaara; A Raitala; T Lehtimäki; P J Karhunen; S S Oja; M Jylhä; A Hervonen; M Hurme Journal: Mech Ageing Dev Date: 2006-02-28 Impact factor: 5.432
Authors: Alan Cheng; Darshan Dalal; Barbara Butcher; Sanaz Norgard; Yiyi Zhang; Timm Dickfeld; Zayd A Eldadah; Kenneth A Ellenbogen; Eliseo Guallar; Gordon F Tomaselli Journal: J Am Heart Assoc Date: 2013-02-22 Impact factor: 5.501
Authors: Sarah Gleeson; Yi-Wen Liao; Clementina Dugo; Andrew Cave; Lifeng Zhou; Zina Ayar; Jonathan Christiansen; Tony Scott; Liane Dawson; Andrew Gavin; Todd T Schlegel; Patrick Gladding Journal: PLoS One Date: 2017-03-30 Impact factor: 3.240
Authors: Yiyi Zhang; Eliseo Guallar; Elena Blasco-Colmenares; Amy C Harms; Rob J Vreeken; Thomas Hankemeier; Gordon F Tomaselli; Alan Cheng Journal: PLoS One Date: 2016-06-09 Impact factor: 3.240