Immunology of heart failure with preserved ejection fraction

INTRODUCTION: Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by diastolic dysfunction, systemic comorbidities, and chronic low-grade inflammation. Emerging evidence suggests that immune dysregulation plays a central role in its pathophysiology. Both innate and adaptive immune responses contribute to myocardial remodeling, endothelial dysfunction, and comorbidity-driven inflammation that are hallmarks of HFpEF. AREAS COVERED: In this systematic review, we summarize current evidence on the contribution of immunological pathways to HFpEF, including the role of proinflammatory cytokines, immune cell infiltration (particularly macrophages, mast cells, and T cells), and immune - endothelial interactions. We also highlight findings from experimental models linking systemic metabolic inflammation to myocardial fibrosis, coronary microvascular dysfunction, and cardiomyocyte stiffness in HFpEF. Finally, we explore potential immunomodulatory therapeutic approaches currently under investigation and discuss biomarkers of immune activation with potential clinical relevance. EXPERT OPINION: While no immunologically targeted therapy is yet approved for HFpEF, interventions that modulate inflammation - such as IL-1 blockade, mast cell stabilization, or myeloid-targeted therapies - offer promise. Future clinical trials should incorporate immune profiling to enable patient stratification and personalized treatment approaches. A deeper understanding of immune-mediated mechanisms in HFpEF will be essential to advance therapeutic innovation and improve outcomes in this challenging and growing patient population.