Increased skeletal muscle expression of the p53 signalling community was significantly associated with worse prognosis and all-cause mortality in patients with severe heart failure (P=8.39x10-4).
Cohort (n=78)
No
Does skeletal muscle transcriptional dysregulation correlate with clinical status and prognosis in patients with severe heart failure?
Skeletal muscle transcriptional dysregulation, particularly increased p53 signaling and cellular senescence, is associated with worse prognosis in severe heart failure.
p-value: p=8.39 x 10-4
Abstract Background The skeletal muscle hypothesis refers to a vicious cycle of successive deterioration of left ventricular function, skeletal muscle remodeling, and functional capacity in patients with heart failure. Despite extensive research, the regulatory mechanisms and their associations with clinical status and prognosis are still largely unclear. Methods To identify mechanisms and characterize underlying processes involved in the disease pathophysiology, we performed RNA sequencing and network analysis using human skeletal muscle samples from 58 patients with severe symptomatic heart failure. A co-expression network with communities involved in established biological processes within human skeletal muscle was identified and validated in two independent cohorts. Results Here, we show network communities associated with mitochondrial beta-oxidation, extracellular matrix remodeling, oxidative phosphorylation, and contractile elements with lower expression in heart failure patients than in age-matched controls. Based on the strong correlation with clinical features and prognosis, extracellular matrix remodeling, mitochondrial beta-oxidation, and p53 signalling communities are identified as key underlying processes. The former two communities are highly enriched with genes regulated by physical (in)activity, i.e., bed rest and exercise, and associated weakly with prognosis. Community related to p53 signalling, with CDKN1A as a key regulator, is increased in heart failure patients relative to age-matched controls and associated with worse prognosis. Conclusion The current work differentiates previously proposed factors underlying heart failure-induced skeletal muscle dysfunction, emphasizing the p53 signalling community and importance of biological age in this process. The distinct association with clinical status and prognosis furthermore supports pathophysiological significance and clinical potential of this community.
Rullman et al. (Fri,) conducted a cohort in Severe heart failure with reduced ejection fraction (HFrEF) (n=78). Increased skeletal muscle expression of the p53 signalling community was significantly associated with worse prognosis and all-cause mortality in patients with severe heart failure (P=8.39x10-4).