Mitochondrial DNA efflux as a potential amplifier of systemic inflammatory network rewiring in heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) is a systemic inflammatory disease that affects multiple organs. However, the integration of different comorbid stress factors into a persistent and organ-specific inflammatory network remains unclear.

Under the background of HFpEF, mitochondrial DNA (mtDNA) may not only play a role as a damage-associated molecular pattern (DAMP), but also act as a cross-organ inflammatory signal, linking the comorbid-driven mitochondrial stress with endothelial dysfunction, myocardial remodeling, and extracardiac organ involvement. Under the influence of HFpEF-related stress factors, including aging, obesity, diabetes, hypertension, and renal dysfunction, mtDNA may undergo oxidation and structural remodeling and be released in the form of free DNA, extracellular vesicle (EV)-related DNA, or neutrophil extracellular trap-related DNA.

These mtDNA signals may activate the nucleic acid sensing pathways mediated by TLR9 and cGAS-STING, and promote the activation of downstream NLRP3 inflammasomes in endothelial cells, cardiomyocytes, fibroblasts, immune cells, and extracardiac tissues, thereby promoting IL-6/TNF production, type I interferon signaling, inflammasome activation, and self-amplifying inflammatory circuits related to the progression of HFpEF.