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

IF 7.8 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Circulation: Heart Failure Pub Date : 2024-10-01 Epub Date: 2024-10-09 DOI:10.1161/CIRCHEARTFAILURE.123.011471
Nathanael Wood, Annabel Critchlow, Chew W Cheng, Sam Straw, Paul W Hendrickse, Marcelo G Pereira, Stephen B Wheatcroft, Stuart Egginton, Klaus K Witte, Lee D Roberts, T Scott Bowen
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Abstract

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.

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心力衰竭和射血分数降低患者骨骼肌病理学的性别差异
背景:与男性相比,患有射血分数降低型心力衰竭(HFrEF)的女性症状更重,生活质量更低;然而,非心脏机制的作用仍未得到很好的解决。我们假设,患有 HFrEF 的男性和女性在骨骼肌病理学方面的差异可能是临床异质性的原因:中度 HFrEF(纽约心脏协会 I-III 级)男性(n=22)和女性(n=16)以及年龄和性别匹配的对照组(分别为 n=18 和 n=16)的肌肉活检组织接受了转录组学(RNA 序列)、肌纤维结构成像(组织学)和分子信号转导分析(基因/蛋白表达),并对血清炎症概况进行了分析(酶联免疫吸附试验)。进行了双向方差分析(性别和条件交互作用):mRNA表达证实了性别的影响(PIGF1表达较高(PPinteractionPinteractionHIF1α、ESR1、VEGF(血管内皮生长因子)和PGC1α表达较高(PPConclusions:与女性相比,男性在转录组、纤维表型、毛细血管和循环因子方面表现出更大的异常。这些初步数据质疑了肌肉病理学是否是导致女性高频心衰患者出现更多症状的主要机制,并强调了进一步研究的必要性。
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来源期刊
Circulation: Heart Failure
Circulation: Heart Failure 医学-心血管系统
CiteScore
12.90
自引率
3.10%
发文量
271
审稿时长
6-12 weeks
期刊介绍: Circulation: Heart Failure focuses on content related to heart failure, mechanical circulatory support, and heart transplant science and medicine. It considers studies conducted in humans or analyses of human data, as well as preclinical studies with direct clinical correlation or relevance. While primarily a clinical journal, it may publish novel basic and preclinical studies that significantly advance the field of heart failure.
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