Plasma metabolomic and inflammatory profiles associated with low physical function in heart failure: an integrated cardiac-metabolic-muscular phenotype.

Dysregulated metabolomic profiles (dysmetabolism) have been observed in patients with heart failure (HF). In this study, we investigated metabolomic profiling differences in HF with reduced physical-functional capacity, hereafter termed reduced "muscle health" for brevity (HF-RM) compared to preserved muscle health (HF-PM) and healthy adults (NonHF). The HF-RM label denotes a screening-level functional phenotype consistent with EWGSOP2 "probable sarcopenia" and Fried physical-frailty constructs and is not intended to imply primary skeletal myopathy independent of cardiac limitation. Exploratory objectives included compared HFrEF and HFpEF subtypes to detangle muscle and metabolomic phenotype from cardiac markers. Twenty-five patients with HF (67.9 ± 10.0 years) and 29 NonHF (67.8 ± 11.1 years) underwent body composition, muscle strength, and lifestyle habits assessments. Reduced muscle health was defined based on low physical activity and sex-specific cut-offs for handgrip strength (HGS) and/or 30-s chair stand test (30CST). Energy and inflammatory metabolites were assessed via untargeted plasma metabolomic profiling. Statistical analyses were conducted using SPSS and MetaboAnalyst. Agnostic principal component analysis revealed elevated branched-chain amino acids (BCAA) and reduced glutamine, methionine and tryptophan in HF-RM vs. NonHF-PM controls (p < 0.05). Compared to HF-PM, HF-RM had lower galacturonic acid-1-phosphate, methionine, indole-3-propionic acid, and pyruvic and malic acid (p < 0.05). Significant negative correlations were found between N-terminal pro-B-type natriuretic peptide, tumour necrosis factor-alpha, GDF-15, HGS/BMI, appendicular lean soft tissue index (ALSTI)/BMI, and 30CST (p < 0.05). Among HF, higher HGS/body mass index (BMI) was linked to longer 6MWD (β = 0.677, p < 0.001) and shorter walking speed (β = -0.532, p = 0.006). HF-RM compared to NonHF-PM had significantly elevated growth differentiation factor-15 (GDF-15) levels (median 1202 vs. 344 pg/ml, p < 0.01). HF-RM is marked by impaired energy and fatty acid metabolism, and elevated BCAA catabolism, inflammation, and GDF-15. These biomarkers may represent candidate therapeutic targets to mitigate functional decline in HF, although the present cross-sectional design precludes causal inference. Also, HGS/BMI shows promise as a body-load-normalised functional indicator in HF; given the absence of group differences in absolute strength and the predominantly sarcopenic-obesity phenotype of this cohort, this exploratory finding requires confirmation in larger and HFrEF/HFpEF-balanced studies.