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

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.

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).

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.

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.