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Sex Differences in Skeletal Muscle Pathology in Patients With Heart Failure and Reduced Ejection Fraction
Nathanael Wood1, Annabel Critchlow1, Chew W Cheng2
1Faculty of Biological Sciences, School of Biomedical Sciences (N.W., A.C., M.G.P., S.E., T.S.B.), University of Leeds, United Kingdom.
Circulation. Heart Failure
|October 9, 2024
Summary
Men with heart failure with reduced ejection fraction (HFrEF) exhibit more severe skeletal muscle abnormalities than women. These findings suggest muscle pathology may not be the primary driver of greater symptoms in women with HFrEF.
Area of Science:
- Cardiology
- Muscle Physiology
- Genomics
Background:
- Women with heart failure with reduced ejection fraction (HFrEF) experience more severe symptoms and reduced quality of life than men.
- The underlying noncardiac mechanisms, particularly skeletal muscle pathology, contributing to this clinical heterogeneity remain unclear.
Purpose of the Study:
- To investigate sex-based differences in skeletal muscle pathology in patients with HFrEF.
- To explore whether these differences explain the observed clinical heterogeneity between men and women with HFrEF.
Main Methods:
- Muscle biopsies from men and women with HFrEF and controls underwent transcriptomics (RNA-sequencing), histology, and molecular signaling analysis.
- Serum inflammatory profiles were analyzed using enzyme-linked immunosorbent assay.
- Statistical analysis included two-way ANOVA to assess interactions between sex and condition.
Main Results:
- RNA-sequencing revealed significant sex differences in gene expression, with men showing upregulated catabolism and downregulated mitochondrial terms, while women with HFrEF had higher proanabolic IGF1 expression.
- Men with HFrEF exhibited higher expression of proatrophic genes (ubiquitin proteasome, autophagy, myostatin systems) compared to women.
- Women displayed a pro-oxidative muscle phenotype with higher capillarity and type I fiber characteristics, alongside differences in key regulatory gene and circulating factor expression (e.g., VEGF, IL-6, IL-8).
Conclusions:
- Significant sex differences in skeletal muscle pathology exist in HFrEF, with men demonstrating greater abnormalities across transcriptome, fiber phenotype, capillarity, and circulating factors.
- These findings challenge the notion that muscle pathology is a primary contributor to the heightened symptoms observed in women with HFrEF.
- Further research is warranted to elucidate the precise mechanisms underlying sex-specific clinical manifestations in HFrEF.
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