Smoldering inflammation: The silent flame driving heart failure

In recent years, significant advancements in the understanding of the processes underlying heart failure (HF) have been made, particularly regarding the role of chronic low-intensity inflammation or smoldering inflammation (SI). This review consolidates findings from the available literature and illustrates the relationships between inflammation, neurohormonal activation, metabolic derangements, and comorbidities in HF, with a focus on heart failure with preserved ejection fraction (HFpEF).A comprehensive literature search was conducted using PubMed®, Wiley Online Library, Scopus, and Web of Science (limited to 2025). The search terms included "heart failure", "HFpEF", "inflammation", "smoldering inflammation", "biomarkers", "cytokines", "fibrosis", and "comorbidities". Peer-reviewed articles, reviews, as well as clinical and observational studies describing the mechanistic, prognostic and therapeutic aspects of SI in HF were included. Studies limited to acute coronary syndrome (ACS) were excluded.Structural changes leading to hemodynamic perturbations in HFpEF are correlated with processes mediated by SI. Several biomarkers measure inflammation and provide diagnostic and prognostic value, including C-reactive protein (CRP), interleukin-6 (IL-6), soluble suppression of tumorigenicity 2 (sST2), galectin-3 (Gal-3), and iron homeostasis. Clinical trials demonstrate the efficacy of sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and other targeted interventions in the modulation of SI.Smoldering inflammation is a key mechanism in the pathogenesis of HFpEF and the progression of comorbidities. Understanding SI may improve risk stratification and management strategies. Both established and emerging anti-inflammatory therapies, when administered alone or in combination, may target SI in order to enhance HF management.