title: Biomarkers of myocardial stress and fibrosis as predictors of mode of death in patients with chronic heart failure.
abstract: OBJECTIVE
  The aim of this study was to determine whether biomarkers of myocardial stress and fibrosis improve prediction of the mode of death in patients with chronic heart failure.
  
  
  BACKGROUND
  The 2 most common modes of death in patients with chronic heart failure are pump failure and sudden cardiac death. Prediction of the mode of death may facilitate treatment decisions. The relationship between amino-terminal pro-brain natriuretic peptide (NT-proBNP), galectin-3, and ST2, biomarkers that reflect different pathogenic pathways in heart failure (myocardial stress and fibrosis), and mode of death is unknown.
  
  
  METHODS
  HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) was a randomized controlled trial of exercise training versus usual care in patients with chronic heart failure due to left ventricular systolic dysfunction (left ventricular ejection fraction ≤35%). An independent clinical events committee prospectively adjudicated mode of death. NT-proBNP, galectin-3, and ST2 levels were assessed at baseline in 813 subjects. Associations between biomarkers and mode of death were assessed using cause-specific Cox proportional hazards modeling, and interaction testing was used to measure differential associations between biomarkers and pump failure versus sudden cardiac death. Discrimination and risk reclassification metrics were used to assess the added value of galectin-3 and ST2 in predicting mode of death risk beyond a clinical model that included NT-proBNP.
  
  
  RESULTS
  After a median follow-up period of 2.5 years, there were 155 deaths: 49 from pump failure, 42 from sudden cardiac death, and 64 from other causes. Elevations in all biomarkers were associated with increased risk for both pump failure and sudden cardiac death in both adjusted and unadjusted analyses. In each case, increases in the biomarker had a stronger association with pump failure than sudden cardiac death, but this relationship was attenuated after adjustment for clinical risk factors. Clinical variables along with NT-proBNP levels were stronger predictors of pump failure (C statistic: 0.87) than sudden cardiac death (C statistic: 0.73). Addition of ST2 and galectin-3 led to improved net risk classification of 11% for sudden cardiac death, but not pump failure.
  
  
  CONCLUSIONS
  Clinical predictors along with NT-proBNP levels were strong predictors of pump failure risk, with insignificant incremental contributions of ST2 and galectin-3. Predictability of sudden cardiac death risk was less robust and enhanced by information provided by novel biomarkers.
authors: Division of Cardiology, Duke University Medical Center, Durham, North Carolina; Duke Clinical Research Institute, Durham, North Carolina.
authors: Tariq
authors: T
authors: Ahmad
authors: Division of Cardiology, Duke University Medical Center, Durham, North Carolina; Duke Clinical Research Institute, Durham, North Carolina.
authors: Mona
authors: M
authors: Fiuzat
authors: Duke Clinical Research Institute, Durham, North Carolina.
authors: Benjamin
authors: B
authors: Neely
authors: Duke Clinical Research Institute, Durham, North Carolina.
authors: Megan L
authors: ML
authors: Neely
authors: Duke Clinical Research Institute, Durham, North Carolina.
authors: Michael J
authors: MJ
authors: Pencina
authors: Division of Cardiology, Duke University Medical Center, Durham, North Carolina.
authors: William E
authors: WE
authors: Kraus
authors: Nancy University, Nancy, France.
authors: Faiez
authors: F
authors: Zannad
authors: Thomas Jefferson University, Philadelphia, Pennsylvania.
authors: David J
authors: DJ
authors: Whellan
authors: Division of Cardiology, Duke University Medical Center, Durham, North Carolina.
authors: Mark P
authors: MP
authors: Donahue
authors: Montefiore Medical Center, Bronx, New York.
authors: Ileana L
authors: IL
authors: Piña
authors: University of North Carolina, Chapel Hill, North Carolina.
authors: Kirkwood F
authors: KF
authors: Adams
authors: Wake Forest University, Winston-Salem, North Carolina.
authors: Dalane W
authors: DW
authors: Kitzman
authors: Division of Cardiology, Duke University Medical Center, Durham, North Carolina; Duke Clinical Research Institute, Durham, North Carolina.
authors: Christopher M
authors: CM
authors: O'Connor
authors: Division of Cardiology, Duke University Medical Center, Durham, North Carolina; Duke Clinical Research Institute, Durham, North Carolina. Electronic address: michael.felker@duke.edu.
authors: G Michael
authors: GM
authors: Felker
mesh_terms: D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015415:Biomarkers / Q000378:metabolism; D002423:Cause of Death; D002908:Chronic Disease; D016757:Death, Sudden, Cardiac / Q000209:etiology; D005355:Fibrosis / Q000401:mortality; D037502:Galectin 3 / Q000378:metabolism; D054143:Heart Failure, Systolic / Q000097:blood / Q000401:mortality; D000072179:Interleukin-1 Receptor-Like 1 Protein; D009206:Myocardium / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D011379:Prognosis; D011446:Prospective Studies; D011956:Receptors, Cell Surface / Q000378:metabolism; D012307:Risk Factors; D013312:Stress, Physiological / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000097:blood / Q000401:mortality
chemical_list: D015415:Biomarkers; D037502:Galectin 3; C079241:IL1RL1 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D020097:Natriuretic Peptide, Brain; D010446:Peptide Fragments; C109794:pro-brain natriuretic peptide (1-76); D011956:Receptors, Cell Surface
keywords: biomarker; heart failure; mode of death; prognosis