Heart failure with physical frailty is associated with inflammation, insulin resistance, GDF-15 and impaired energy and amino acid metabolism

Abstract Aims While physical frailty is a common feature in heart failure (HF), less is known about how frailty is linked to impaired clinical biomarkers and metabolic dysregulation in HF. Methods We recruited 25 patients with HF (67.9 ± 10.0 years) and 29 adults without HF (NonHF) (67.8 ± 11.1 years). Physical frailty was assessed using low physical activity levels with low handgrip strength (HGS) and/or 30-second chair stand test (30CST). Untargeted plasma metabolomic profiling was performed via gas chromatography-mass spectrometry. Statistical analyses were conducted via SPSS and MetaboAnalyst. Results HF-Frail (n=25) compared to NonHF-NonFrail (n=18), had lower 6-minute walking distance (386.4 vs. 501.3 meters, P<0.01) and weaker HGS/body mass index (BMI) (1.05 vs. 1.41, P=0.04). HF-Frail compared to NonHF-NonFrail had significantly elevated plasma N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP) (241.2 vs. 117.1 pg/ml, P=0.007) and growth differentiation factor-15 (GDF-15) levels (1227.2 vs. 382.5 pg/ml, P<0.01). Agnostic principal component analysis revealed elevated plasma branched chain amino acids and reduced glutamine, methionine and tryptophan in HF-Frail vs. NonHF-NonFrail controls (P<0.05). Compared to HF-NonFrail (n=7), HF-Frail had lower galacturonic acid-1-phosphate, methionine, indole-3-acetamide, pyruvic and malic acid (P<0.05). Significant negative correlations were found between NT-proBNP, tumour necrosis factor-alpha (TNF-α), GDF-15, and frailty outcomes (HGS/BMI, 30CST; P<0.05). Conclusions In HF, physical frailty is linked to impaired energy and amino acid metabolism, along with elevated inflammation and GDF-15. These findings warrant for longitudinal studies to unravel clinical biomarkers that could serve as therapeutic agents, targeting frailty progression in HF. Lay Summary This study investigated the association between physical frailty, clinical biomarkers, and metabolic dysregulation in patients with heart failure (HF), revealing significant impairments in physical performance and metabolic profiles compared to non-frail HF and non-HF controls. Patients with HF and frailty exhibited reduced 6-minute walk distance and 30-second chair stand repetitions, had weaker handgrip strength, and elevated levels of N-terminal pro-B-type natriuretic peptide and growth differentiation factor-15 compared to non-frail controls (P<0.05). Metabolomic analysis showed increased plasma branched-chain amino acids, reduced glutamine and methionine, and altered energy metabolism intermediates (i.e., pyruvic acid) (P<0.05) in HF with frailty, indicating significant metabolic disruptions.