Introduction: Metabolism changes leading to secondary sarcopenia is a hallmark of heart failure (HF). This study aimed to investigate how frailty and muscle weakness are associated with metabolic pathways in patients with HF using high-throughput plasma metabolomics.
Methods: Frailty was defined according to the European Working Group on Sarcopenia in Older People criteria as low physical activity combined with reduced handgrip strength and/or poor performance based on the 30-second chair stand test. Plasma metabolomic profiling was performed using gas chromatography-mass spectrometry to compare metabolic profiles among four groups: HF patients with frailty (HF-Frail), HF patients without frailty (HF-NonFrail), and non-HF controls with and without frailty (NonHF-Frail and NonHF-NonFrail). Circulating biomarkers including growth differentiation factor-15 (GDF-15), myostatin, activin A, follistatin-3, and TNF-α were quantified by enzyme-linked immunosorbent assay (ELISA). Statistical analyses were conducted using MetaboAnalyst and SPSS.
Results: Twenty-five outpatients with HF (mean age 67.9 ± 10.0 years; 19 males, 7 females) and 29 non-HF controls (mean age 67.8 ± 11.1 years; 14 males, 15 females) were included. Among HF patients, 18 were classified as frail (HF-Frail), while 8 of the 29 controls were frail (NonHF-Frail). Compared with NonHF-NonFrail individuals, HF-Frail patients exhibited lower appendicular lean soft tissue index relative to body mass index (p = 0.03), reduced functional performance (6-minute walk distance, timed-up-and-go, 30-second chair stand, and handgrip strength; all p < 0.05), and elevated GDF-15 levels (p < 0.01). Metabolomic analysis revealed that HF-Frail patients had higher levels of glucose, tumour necrosis factor-alpha (TNF-a), GDF-15, amino acids (e.g., alanine, isoleucine, glutamic acid), and carbohydrate metabolites (e.g., galactose, galacturonic acid-1-phosphate) compared with non-HF controls. In contrast, compared with HF-NonFrail patients, HF-Frail showed lower levels of galacturonic acid-1-phosphate, methionine, indole-3-acetamide, and energy-related metabolites (e.g., pyruvic acid, malic acid), but higher concentrations of 2-hydroxy-glutaric acid (p < 0.05), isoleucine (p = 0.02), and valine (p < 0.01).
Conclusions: Patients with HF and frailty display distinct alterations in amino acid and carbohydrate metabolism, accompanied by elevated inflammatory and catabolic markers (TNF-a and GDF-15) compared with both non-frail HF patients and non-HF controls. These findings suggest that metabolic profiling may aid in frailty screening and highlight the potential of targeting catabolic and inflammatory pathways as therapeutic strategies in patients with HF and frailty.