Skeletal muscle transcriptomic analysis in chronic heart failure and their association with clinical phenotypes. An exploratory analysis
N Almulhim, C W Cheng, F Bartoli, N Makava, S Straw, S Kamalathasan, R M Cubbon, K K Witte, M T Kearney, D J Beech, J GierulaAbstract
Background
Skeletal muscle (SKM) remodelling is recognised as a contributor to exercise intolerance in chronic heart failure (CHF). Although studies have highlighted SKM transcriptomic changes in CHF, it remains unclear whether CHF associated transcriptomes reflect coherent structural and physiological alterations, and whether transcriptomic patterns are consistent with clinical phenotypes
Purpose
To explore the relationship between differentially expressed SKM transcriptomes identified in CHF and the clinical indicators of cardiovascular reserve.
Methods
Pectoralis SKM biopsies obtained from individuals undergoing cardiac implantable electronic device implantation. RNA sequencing was performed and differential expression analysis using DESeq2 encountered the main confounders and identified nine differently expressed gens (DEGs) that associated with HFrEF at FDR <0.05. Spearman correlation analysis was performed to examine the association between DEGs and key demographics, comorbidities, blood biomarkers, echocardiographic parameters and cardiopulmonary exercise testing indices.
Results
Biopsies were obtained from 30 individuals HFrEF n= 16 (53%) non-HF n=14 (47%). Several HFrEF associated DEGs exhibited divergent associations, including positive correlation with left ventricular internal diastolic diameter (r= 0.40 to 0.44, p <0.05), and negative correlation with left ventricular ejection fraction (r= -0.38 to -0.56, p < 0.05). Identified DEGs shows positive association with NYHA class. Limited negative association were observed between individual DEGs and exercise capacity measures. Stronger transcriptomic correlations were observed between DEGs (r= 0.39 to 0.91, p < 0.05).
Conclusion
Identified SKM transcriptomics alterations in HFrEFclosely reflect the clinical indicators of disease severity and cardiovascular reserve. We suggest that peripheral molecular alterations reflect the systemic physiological stress in HFrEF, these findings warrant further validation in larger, independent cohorts.