Research Article| Volume 143, 155535, June 2023

The association of circulating fibroblast growth factor 21 levels with incident heart failure: The Multi-Ethnic Study of Atherosclerosis


      • FGF21 is involved in HF pathophysiology and is a potential biomarker candidate.
      • FGF21 levels are associated with incident HF among participants with elevated FGF21 only.
      • Among participants with elevated FGF21 levels, FGF21 levels were associated with HFpEF not HFrEF.
      • Findings suggest FGF21 has novel ability to distinguish between HF subtypes.
      • FGF21 may be included in a multi-marker panel to improve specificity of natriuretic peptides.



      Fibroblast growth factor 21 (FGF21) levels are often elevated in heart failure (HF), although this has not been assessed using a longitudinal study design. Therefore, we investigated the association between baseline plasma FGF21 levels and incident HF in the Multi-Ethnic Study of Atherosclerosis (MESA).


      A total of 5408 participants, free of clinically apparent cardiovascular disease, were included in the analysis, of which 342 developed HF over a median follow-up period of 16.7 years. Multivariable Cox regression analysis was performed and the additive value of FGF21 in the performance of risk prediction over other well-established cardiovascular biomarkers was assessed.


      The mean age of the participants was 62.6 years with 47.6 % male. Regression spline analysis demonstrated a significant association of FGF21 levels with incident HF among participants with FGF21 levels ≥239.0 pg/mL (hazard ratio = 1.84 [95 % confidence interval 1.21, 2.80] per SD increase in ln-transformed levels) after adjustment for traditional cardiovascular risk factors and biomarkers, but not in participants with FGF21 levels <239.0 pg/mL (p for heterogeneity = 0.004). Among participants with FGF21 levels ≥239.0 pg/mL, FGF21 levels were associated with HF with preserved ejection fraction (HR [95 % CI] = 2.57 [1.51, 4.37]), but not HF with reduced ejection fraction.


      The present study suggests baseline FGF21 levels could predict the development of incident HF with preserved ejection fraction, among participants with elevated FGF21 levels at baseline. This study may suggest a pathophysiological role of FGF21 resistance in HF with preserved ejection fraction.


      BMI (body mass index), BNP (brain natriuretic peptide), BP (blood pressure), CAC (coronary artery calcium), CHD (coronary heart disease), CI (confidence interval), CRP (C-reactive protein), CVD (cardiovascular disease), eGFR (estimated glomerular filtration rate), FGF21 (fibroblast growth factor 21), FGFR (fibroblast growth factor receptor), GGT (serum γ-glutamyl transferase), HDL (high density lipoprotein), HF (heart failure), HFpEF (heart failure with preserved ejection fraction), HFrEF (heart failure with reduced ejection fraction), HOMA2-IR (homeostasis model assessment of insulin resistance index), HR (hazards ratio), IL-6 (interleukin 6), LDL (low density lipoprotein), LV (left ventricular), LVEF (left ventricular ejection fraction), MESA (Multi-Ethnic Study of Atherosclerosis), MRI (magnetic resonance imaging), NRI (net reclassification improvement), NT-proBNP (N-terminal pro-brain natriuretic peptide), ln (natural logarithm), SD (standard deviation)


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