Author + information
- Received December 10, 2019
- Revision received January 31, 2020
- Accepted February 19, 2020
- Published online April 27, 2020.
- Nasrien E. Ibrahim, MDa,b,
- Marc Afilalo, MDc,
- Annabel Chen-Tournoux, MDd,
- Robert H. Christenson, PhDe,
- Hanna K. Gaggin, MD, MPHa,b,
- Judd E. Hollander, MDf,
- Peter Kastner, PhDg,
- Phillip D. Levy, MD, MPHh,
- Anika Mang, MSg,
- Serge Masson, PhDi,
- John T. Nagurney, MDb,j,
- Richard M. Nowak, MD, MBAh,k,
- Peter S. Pang, MD, MSl,
- W. Frank Peacock, MDm,
- Vinzent Rolny Dipl-Statg,
- E. Lea Walters, MDn and
- James L. Januzzi Jr., MDa,b,o,∗ (, )@JJHeart_doc
- aCardiology Division, Massachusetts General Hospital, Boston, Massachusetts
- bHarvard Medical School, Boston, Massachusetts
- cDepartment of Emergency Medicine, McGill University and Emergency Department, Jewish General Hospital, Montreal, Quebec, Canada
- dCardiology Division, McGill University, Jewish General Hospital, Montreal, Canada
- eDepartment of Pathology, University of Maryland School of Medicine, Baltimore, Maryland
- fDepartment of Emergency Medicine, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania
- gRoche Diagnostics, Penzberg, Germany
- hDepartment of Emergency Medicine, Wayne State University, Detroit, Michigan
- iRoche Diagnostics, Rotkreuz, Switzerland
- jDepartment of Emergency Medicine, Massachusetts General Hospital, Boston, Massachusetts
- kDepartment of Emergency Medicine, University of Michigan, Ann Arbor, Michigan
- lDepartment of Emergency Medicine and Cardiology Division, Indiana University School of Medicine, Indianapolis, Indiana
- mDepartment of Emergency Medicine, Baylor College of Medicine, Houston, Texas
- nDepartment of Emergency Medicine, Loma Linda University School of Medicine, Loma Linda, California
- oBaim Institute for Clinical Research, Boston, Massachusetts
- ↵∗Address for correspondence:
Dr. James L. Januzzi Jr., Massachusetts General Hospital, 32 Fruit Street, Yawkey 5984, Boston, Massachusetts 02114.
Objectives This study examined whether insulin-like growth factor binding protein-7 (IGFBP7) would aid in the diagnosis and prognosis of acute heart failure (HF) beyond N-terminal pro–B-type natriuretic peptide (NT-proBNP) concentration.
Background IGFBP7 is associated with impaired ventricular relaxation and worse prognosis.
Methods The ICON-RELOADED (International Collaborative of NT-proBNP-Re-evaluation of Acute Diagnostic Cut-Offs in the Emergency Department) study was a prospective, multicenter clinical trial that enrolled subjects presenting with dyspnea. Six-month prognosis for death or repeat hospitalization was obtained.
Results Among 1,449 patients, 274 (18.9%) were diagnosed with acute HF. Those with IGFBP7 concentrations in the highest quartile were older, male, had hypertension and HF, had lower estimated glomerular filtration rate (eGFR) and lowest ejection fraction (41 ± 20%; all p < 0.001). Independent predictors of IGFBP7 were age, male sex, history of diabetes, history of HF, and eGFR. Median concentrations of NT-proBNP (2,844 ng/ml vs. 99 ng/ml) and IGFBP7 (146.1 ng/ml vs. 86.1 ng/ml) were higher in those with acute HF (both; p < 0.001). Addition of IGFBP7 to NT-proBNP concentrations improved discrimination, therefore increasing the area under the receiver operating curve for diagnosis of acute HF (from 0.91 to 0.94; p < 0.001 for differences). Addition of IGFBP7 to a complete model of independent predictors of acute HF improved model calibration. IGFBP7 significantly reclassified acute HF diagnosis beyond NT-proBNP (net reclassification index: +0.25). Higher log2-IGFBP7 concentrations in patients with acute HF predicted death or rehospitalization at 6 months (hazard ratio: 1.84 per log2-SD; 95% confidence interval: 1.30 to 2.61; p = 0.001). In Kaplan-Meier analyses, supramedian concentrations of IGFBP7 were associated with shorter event-free survival (log-rank: p < 0.001).
Conclusions Among patients with acute dyspnea, concentrations of IGFBP7 add to NT-proBNP for diagnosis of acute HF and provide added prognostic utility for short-term risk.
Supported by Roche Diagnostics International. Dr. Ibrahim is supported in part by the Dennis and Marilyn Barry Fellowship in Cardiology. Dr. Afilalo is supported in part by the Canadian Institutes of Health Research and Fonds de recherche du Québec-Santé. Dr. Gaggin is supported in part by the Clark Fund for Cardiac Research Innovation. Dr. Januzzi is supported in part by the Hutter Family Professorship. Dr. Ibrahim has received honorarium from Roche Diagnostics. Dr. Christenson is a consultant for Siemens Healthcare, Roche Diagnostics, Becton Dickinson, Quidel, and Beckman Coulter. Dr. Gaggin has received research support from Roche Diagnostics, Jana Care, Ortho Clinical, and Novartis; and is a consultant for Merck and Roche Diagnostics; and serves on a clinical endpoint committee from Radiometer. Dr. Hollander has received research funding from Roche, Alere, Trinity, Siemens, and Portola. Dr. Kastner is an employee of Roche Diagnostics. Dr. Levy is a consultant for Apex Innovations, AstraZeneca, Mespere, Novartis, Ortho Clinical Diagnostics, Roche Diagnostics, Veravas, Shire, Siemens, and Hospital Quality Foundation; and has received research support from Amgen, Arterez, Beckman Coulter, Agency for Healthcare Research and Quality (AHRQ), Blue Cross Blue Shield Massachusetts Foundation, Emergency Medicine Foundation, Michigan Department of Health and Human Services, Patient Centered Outcome Research Institute, U.S. National Institutes of Health (NIH)/National Institute on Minority Health and Health Disparities, and NIH/National Heart Lung Blood Institute (NHLBI). Ms. Mang and Dr. Masson are employees of Roche Diagnostics. Dr. Nagurney has received research funding from Biosite/Alere, Quidel, Thermo-Fisher, Clindevor, and Roche. Dr. Nowak has received research grants from Abbott, Ortho Clinical Diagnostics, Roche, Beckman, and Siemens; and is a consultant for Abbott, Ortho Clinical Diagnostics, Roche, Beckman, and Siemens. Dr. Pang has received research support from Bristol-Myers Squibb, Roche, Novartis, Patient-Centered Outcomes Research Institute (PCORI), American Heart Association, NIH/NHLBI, AHRQ, Ortho Diagnostics, and Abbott; and is a consultant for Baxter, Bristol-Myers Squibb, and Novartis. Dr. Peacock has research grants from Abbott, Boehringer Ingelheim, Braincheck, CSL Behring, Daiichi-Sankyo, Immunarray, Janssen, Ortho Clinical Diagnostics, Portola, Relypsa, and Roche; is a consultant for Abbott, AstraZeneca, Bayer, Beckman, Boehrhinger-Ingelheim, Ischemia Care, Dx, Immunarray, Instrument Labs, Janssen, Nabriva, Ortho Clinical Diagnostics, Relypsa, Roche, Quidel, and Siemens; has provided expert testimony for Johnson and Johnson; and has stock/ownership interests in AseptiScope Inc., Brainbox Inc., Comprehensive Research Associates LLC, Emergencies in Medicine LLC, and Ischemia DX LLC. Mr. Rolny is an employee of Roche Diagnostics. Dr. Walters has received research funding from Roche. Dr. Januzzi has received grant support from Roche Diagnostics, Abbott, Singulex and Prevencio, consulting income from Roche Diagnostics, Critical Diagnostics, Janssen, and Novartis; and participates in clinical endpoint committees/data safety monitoring boards for Novartis, Amgen, Pfizer, Janssen, AbbVie, and Boehringer Ingelheim. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Heart Failure author instructions page.
- Received December 10, 2019.
- Revision received January 31, 2020.
- Accepted February 19, 2020.
- 2020 American College of Cardiology Foundation
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