Sex Differences in Skeletal Muscle Pathology in Patients With Heart Failure and Reduced Ejection Fraction

BACKGROUND: Women with heart failure and reduced ejection fraction (HFrEF) have greater symptoms and a lower quality of life compared with men; however, the role of noncardiac mechanisms remains poorly resolved. We hypothesized that differences in skeletal muscle pathology between men and women with HFrEF may explain clinical heterogeneity. METHODS: Muscle biopsies from both men (n=22) and women (n=16) with moderate HFrEF (New York Heart Association classes I–III) and age- and sex-matched controls (n=18 and n=16, respectively) underwent transcriptomics (RNA-sequencing), myofiber structural imaging (histology), and molecular signaling analysis (gene/protein expression), with serum inflammatory profiles analyzed (enzyme-linked immunosorbent assay). Two-way ANOVA was conducted (interaction sex and condition). RESULTS: RNA-sequencing identified 5629 differentially expressed genes between men and women with HFrEF, with upregulated terms for catabolism and downregulated terms for mitochondria in men. mRNA expression confirmed an effect of sex (P<0.05) on proatrophic genes related to ubiquitin proteasome, autophagy, and myostatin systems (higher in all men versus all women), whereas proanabolic IGF1 expression was higher (P<0.05) in women with HFrEF only. Structurally, women compared with men with HFrEF showed a pro-oxidative phenotype, with smaller but higher numbers of type I fibers, alongside higher muscle capillarity (Pinteraction<0.05) and higher type I fiber areal density (Pinteraction<0.05). Differences in gene/protein expression of regulators of muscle phenotype were detected between sexes, including HIF1α, ESR1, VEGF (vascular endothelial growth factor), and PGC1α expression (P<0.05), and for upstream circulating factors, including VEGF, IL (interleukin)-6, and IL-8 (P<0.05). CONCLUSIONS: Sex differences in muscle pathology in HFrEF exist, with men showing greater abnormalities compared with women related to the transcriptome, fiber phenotype, capillarity, and circulating factors. These preliminary data question whether muscle pathology is a primary mechanism contributing to greater symptoms in women with HFrEF and highlight the need for further investigation.