Integrated miRNA-cytokine profiling reveals a molecular signature of cachexia in patients with chronic heart failure

Introduction: Cardiac cachexia (CC) complicates chronic heart failure (CHF). Circulating microRNAs (miRNAs) and cytokines, such as growth differentiation factor-15 (GDF-15) and fibroblast growth factor-21 (FGF-21), may reflect the catabolic-anabolic imbalance and structural remodelling associated with this syndrome. To define the circulating signature of CHF by profiling muscle and remodelling-related miRNAs alongside GDF-15 and FGF-21, and to assess their associations with cardiac function and clinical phenotypes. Methods: Twenty-five CHF patients (median age 78.0 years, 40% male) and 10 controls (median age 56.8 years, 60% male) were studied. CC was defined as unintentional, non-oedematous weight loss ≥6% within 6 months. Circulating miRNAs were quantified by RT-qPCR, GDF-15 and FGF-21 by ELISA. CHF patients were classified as having reduced (HFrEF) or preserved ejection fraction (HFpEF). Associations with CC and clinical CHF phenotypes were evaluated. Results: Compared with controls, CHF patients showed lower levels of miR-15b, miR-29b, miR-133a, and miR-486 (all P < .01) and elevated GDF-15 levels (P < .001). FGF-21 was higher in patients with CC (P = .012), in HFrEF vs HFpEF (P = .039), and in NYHA III-IV vs I-II (P = .05). miR-29b levels were lower in CC (P = .019) and in HFrEF + CC vs HFpEF + nCC (P = .019). In CC, FGF-21 inversely correlated with miR-486 (ρ = -.69, P = .035), whereas GDF-15 inversely correlated with miR-21 (ρ = -.81, P = .007). Conclusions: CHF is associated with miRNA suppression and elevated stress cytokine levels, amplified in CC. miR-29b and FGF-21 showed associations with CC, functional impairment, and structural remodelling, warranting validation in larger longitudinal cohorts.