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

BACKGROUND: Women with heart failure with reduced ejection fraction (HFrEF) experience greater symptom burden than men, potentially due to skeletal muscle dysfunction. Skeletal muscle abnormalities are linked to systemic low-grade inflammation, a hallmark of HFrEF pathophysiology, and may be driven by altered inflammatory regulation of skeletal muscle homeostasis. In patients with HFrEF and age-matched controls, we investigated sex differences in skeletal muscle inflammation, muscle stem cells, fibro-adipogenic progenitor cells, and their associations with skeletal muscle mass and strength. METHODS: Participants underwent dual x-ray absorptiometry, cardiopulmonary exercise testing, and dynamometry. Vastus lateralis muscle biopsies were analyzed by flow cytometry to quantify immune cell populations, muscle stem cells, and fibro-adipogenic progenitor cells. Outcomes were log-transformed and analyzed using linear regression with sex-by-HFrEF interaction. Between-group differences were expressed as geometric mean ratios (GMRs). RESULTS: We included 86 patients with HFrEF and 41 age- and sex-matched healthy controls (mean age, 71±7 years; 32% women). Skeletal muscle immune cell composition differed by sex in HFrEF, with significant sex-by-HFrEF interactions for macrophage fraction ( P =0.006), lymphocyte content ( P =0.045), and lymphocyte fraction ( P =0.039). In HFrEF, women showed an increased lymphocyte fraction (GMR, 1.27 [1.06–1.53]; P =0.014), whereas men had an increased macrophage content (GMR, 1.75 [1.16–2.64]; P =0.009). Macrophage content was associated with greater muscle mass and strength in women (mass, R=0.42, P =0.014; strength, R=0.42, P =0.013), but with reduced mass and strength in men (mass, R=−0.25, P =0.017; strength, R=−0.21, P =0.046). Muscle stem cells (GMR, 1.92 [0.99–3.74]; P =0.054) and fibro-adipogenic progenitor cells (GMR, 1.72 [1.03–2.85]; P =0.038) were reduced in HFrEF. CONCLUSIONS: Skeletal muscle immune cell alterations, particularly macrophage and lymphocyte imbalances, are associated with muscle dysfunction in HFrEF, exhibiting distinct sex-specific patterns. These findings demonstrate sex-specific skeletal muscle inflammation and dysfunction in HFrEF.