Growth Differentiation Factor-15 as an Emerging Biomarker in Cardiology: Diagnostic and Prognostic Implications

Abstract

Growth Differentiation Factor-15 (GDF-15) is a stress-responsive cytokine belonging to the Transforming Growth Factor-beta (TGF-β) superfamily. Initially identified as macrophage inhibitory cytokine-1 (MIC-1), GDF-15 is expressed in various tissues and markedly upregulated under pathological conditions involving inflammation, oxidative stress, and tissue injury. Notably, GDF-15 upregulation has been associated with several cardiovascular events, such as heart failure, atrial fibrillation, atherosclerosis, coronary artery disease, and stroke. Furthermore, it has been observed that GDF-15, either alone or in combination with other cardiac biomarkers, can provide valuable complementary information enhancing risk assessment, early detection of cardiovascular events, and prediction of adverse outcomes. GDF-15 can be measured in various body fluids, using different methods. Immunoassays are widely employed and offer good sensitivity and reproducibility; however, variability between methods and potential interference from genetic variants highlight the need for standardization. This review summarizes current insights into GDF-15, with emphasis on its quantification methods, biological functions in cardiovascular diseases, and its emerging role as a diagnostic and prognostic biomarker.

Keywords: GDF-15; biomarker; cardiovascular disease; heart failure; risk stratification.

Figure 1

Schematic representation of GDF-15 biosynthesis, maturation, and secretion. (a) GDF-15 is synthesized as pre-pro-GDF-15, consisting of a signal peptide (blue), a pro-domain (yellow), and a mature C-terminal domain (red). Removal of the signal peptide generates pro-GDF-15, which rapidly dimerizes; (b) In the Golgi apparatus, pro-GDF-15 dimer is cleaved by PCSK3, PCSK5, and PCSK6 at the RXXR site, producing mature GDF-15; (c) Mature GDF-15 homodimers are secreted through the classical secretory pathway and released into circulation, while in specific cells pro-GDF-15 dimers may remain bound to the extracellular matrix until further cleavage by MMP26 or PCSKs. GDF-15: Growth Differentiation Factor-15; PCSK: proprotein convertase subtilisin–kexin; MMP26: matrix metalloproteinase 26.

Figure 2

Molecular regulation of GDF-15. Inflammatory and stress-related mediators (IL-1β, TNF-α, IL-2, M-CSF) regulate GDF-15 expression by activating key transcription factors such as ATF4, CHOP, p53, EGR-1, and NF-κB, emphasizing the complex and tissue-dependent nature of this regulatory network. IL-1ß: interleukin-1ß; TNF-α: tumor necrosis factor-α, IL-2: interleukin-2; MCSF-1: macrophage colony-stimulating factor-1; EGR-1: early growth response transcription factor 1; NF-Kb: Nuclear Factor kappa B; CHOP: C/EBP homologous protein; ATF4: activating transcription factor 4; GDF-15: Growth Differentiation Factor-15.

Figure 3

GDF-15–mediated mechanisms of cardiac protection. In cardiomyocytes, GDF-15 activates the Smad2/3 and Smad1/5/8 pathways to limit hypertrophy and apoptosis, enhances myocardial survival through the PI3K/PKB signaling cascade, and inhibits pro-apoptotic pathways involving JNK, Bad, and EGFR, thereby contributing to cardiac protection. GDF-15: Growth Differentiation Factor-15; EGFR: epidermal growth factor receptor; ERK: extracellular signal-regulated kinase; PKB: protein kinase B; NF-Kb: Nuclear Factor kappa B; JNK: c-Jun N-terminal kinase; CAS-3: Caspase-3; PI3K: phosphatidylinositol 3-kinase; BAD: Bcl-2-associated death promoter.