Comorbidity-Driven Inflammation in HFpEF: Immune Profiling and Therapeutic Targets

Chronic low-grade inflammation underlies the heterogenous pathophysiology of heart failure with preserved ejection fraction (HFpEF) influenced by patient comorbidities. This review summarizes circulating inflammatory mediators in HFpEF, explores how comorbidities shape distinct immune signatures, and discusses current and emerging treatment strategies. Comorbidities, including hypertension, obesity, type 2 diabetes, and chronic kidney disease, drive distinct immune profiles in HFpEF through dysregulated cytokine signaling. Circulating mediators, including IL-6, IL-1β, TNF-α, soluble ST2, and CRP, reflect this comorbidity-driven immune activation and predict adverse outcomes. Current therapies, e.g. SGLT2 inhibitors, mineralocorticoid receptor antagonists, and angiotensin receptor-neprilysin inhibitors, display anti-inflammatory effects but benefit only specific subgroups. Emerging inflammation-targeted strategies, including anti-IL-6 or anti-IL-1β, NLRP3 inflammasome modulation and myeloperoxidase inhibition, are under clinical investigation. Linking immune profiles to HFpEF phenogroups may enable precision medicine by refining risk stratification and tailoring therapies, moving beyond the current one-size-fits-all approach.