Fibroblast growth factor-23, cardiovascular prognosis, and benefit of angiotensin-converting enzyme inhibition in stable ischemic heart disease

J Am Coll Cardiol. 2014 Jun 10;63(22):2421-8. doi: 10.1016/j.jacc.2014.03.026. Epub 2014 Apr 9.

Abstract

Objectives: This study sought to test 2 hypotheses: 1) fibroblast growth factor (FGF)-23 identifies patients with stable ischemic heart disease (SIHD) at high risk of cardiovascular events independent of clinical factors, renal function, and established cardiovascular biomarkers; and 2) FGF-23 identifies patients who derive greater clinical benefit from angiotensin-converting enzyme inhibitor therapy.

Background: FGF-23 is an endocrine regulator of mineral metabolism and markedly elevated levels are associated with cardiovascular events in patients with chronic kidney disease. Data in patients with SIHD are more sparse.

Methods: FGF-23 levels were measured in 3,627 patients with SIHD randomly assigned to trandolapril or placebo within the PEACE (Prevention of Events With Angiotensin-Converting Enzyme) trial and followed up for a median of 5.1 years.

Results: After adjustment for clinical risk predictors, left ventricular ejection fraction, markers of renal function, and established cardiovascular biomarkers, FGF-23 concentration was independently associated with an increased risk of cardiovascular death or heart failure among patients allocated to placebo (quartile 4 hazard ratio: 1.73; 95% confidence interval, 1.09 to 2.74; p = 0.02) and significantly improved metrics of discrimination. Furthermore, among patients in the top quartile of FGF-23 levels, trandolapril significantly reduced cardiovascular death or incident heart failure (hazard ratio: 0.45; 95% confidence interval: 0.28 to 0.72), whereas there was no clinical benefit in the remaining patients (hazard ratio: 1.07; 95% confidence interval: 0.75 to 1.52; p interaction = 0.0039). This interaction was independent of and additive to stratification based on renal function.

Conclusions: Elevated levels of FGF-23 are associated with cardiovascular death and incident heart failure in patients with SIHD and identify patients who derive significant clinical benefit from angiotensin-converting enzyme inhibitor therapy regardless of renal function. (Prevention of Events With Angiotensin-Converting Enzyme Inhibitor Therapy [PEACE]: NCT00000558).

Keywords: angiotensin-converting enzyme inhibitors; biomarkers; coronary artery disease; fibroblast growth factor-23; kidney.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use*
  • Biomarkers / blood
  • Cardiovascular Diseases / etiology
  • Female
  • Fibroblast Growth Factors / blood*
  • Humans
  • Indoles / therapeutic use*
  • Male
  • Middle Aged
  • Myocardial Ischemia / blood*
  • Myocardial Ischemia / complications
  • Myocardial Ischemia / drug therapy*
  • Prognosis
  • Risk

Substances

  • Angiotensin-Converting Enzyme Inhibitors
  • Biomarkers
  • Indoles
  • trandolapril
  • Fibroblast Growth Factors
  • fibroblast growth factor 23

Associated data

  • ClinicalTrials.gov/NCT00000558