Usefulness of temporal changes in neurohormones as markers of ventricular remodeling and prognosis in patients with left ventricular systolic dysfunction and heart failure receiving either candesartan or enalapril or both

Am J Cardiol. 2005 Sep 1;96(5):698-704. doi: 10.1016/j.amjcard.2005.04.048.


Although various neurohormones at initial measurement confer prognostic value in heart failure and correlate with the left ventricular ejection fraction (EF) and cardiac volumes, the significance of their temporal changes (Delta) remains undetermined. This study examined temporal changes in neurohormones related to cardiac remodeling and prognosis in patients with systolic dysfunction and heart failure receiving therapeutic inhibition of the renin-angiotensin-aldosterone system. Temporal changes in plasma renin, angiotensin-II, aldosterone, epinephrine, norepinephrine, B-type natriuretic peptide (BNP), and N-terminal atrial natriuretic peptide (NT-ANP) in 768 treated patients with heart failure measured at baseline and 17 and 43 weeks after randomization were examined for their relations with concurrent changes in the EF, cardiac volumes, and risk for subsequent adverse clinical outcomes. Increasing BNP (p < 0.0001) and NT-ANP (p = 0.01) over time were associated with a concurrent decreasing EF, increasing end-diastolic volume (EDV), and increasing end-systolic volume (ESV; all p < 0.0001). In multivariable analysis, DeltaBNP and DeltaNT-ANP were independent predictors of DeltaESV and DeltaEDV, whereas DeltaBNP also predicted DeltaEF (all p < 0.0001). Patients who died or experienced heart failure hospitalization had larger antecedent increases in NT-ANP (+293.7 vs -21.5 pmol/ml, p = 0.006) and lesser decreases in norepinephrine (-22.3 vs -48.5 pg/ml, p = 0.04). Increasing NT-ANP (hazard ratio [HR] 3.45, p = 0.009) and norepinephrine (HR 2.04, p = 0.02) over time independently predicted increased risk for subsequent death or heart failure hospitalization. In conclusion, in treated patients with heart failure, increasing NT-ANP and BNP over time predict a decreasing EF and ventricular dilatation, while increasing NT-ANP and norepinephrine independently predict greater mortality and morbidity. Serial measurements of these neurohormones may serve as useful surrogate markers of ventricular remodeling and prognosticators for clinical risk stratification.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / therapeutic use
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Benzimidazoles / therapeutic use*
  • Biomarkers / blood
  • Biphenyl Compounds
  • Cardiac Output
  • Chromatography, High Pressure Liquid
  • Double-Blind Method
  • Drug Therapy, Combination
  • Enalapril / therapeutic use*
  • Female
  • Heart Failure* / blood
  • Heart Failure* / drug therapy
  • Heart Failure* / physiopathology
  • Humans
  • Male
  • Middle Aged
  • Neurotransmitter Agents / blood*
  • Prognosis
  • Systole
  • Tetrazoles / therapeutic use*
  • Treatment Outcome
  • Ventricular Dysfunction, Left* / blood
  • Ventricular Dysfunction, Left* / drug therapy
  • Ventricular Dysfunction, Left* / physiopathology
  • Ventricular Remodeling / physiology*


  • Angiotensin II Type 1 Receptor Blockers
  • Angiotensin-Converting Enzyme Inhibitors
  • Benzimidazoles
  • Biomarkers
  • Biphenyl Compounds
  • Neurotransmitter Agents
  • Tetrazoles
  • Enalapril
  • candesartan