Candidate Residual Inflammatory Risk in HFpEF: A Multiorgan Framework for Longitudinal Phenotyping, Trial Enrichment,...

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome in which ejection fraction, natriuretic peptides, and resting diastolic indices do not fully explain disease initiation, progression, or treatment response. The dominant contemporary phenotype is frequently cardiorenal-metabolic, characterized by obesity, visceral and epicardial adiposity, insulin resistance, diabetes, hypertension, kidney dysfunction, endothelial dysfunction, and chronic low-grade inflammation. In this setting, candidate residual inflammatory risk (RIR) is best conceptualized not as an isolated elevation of C-reactive protein or interleukin-6, but as a persistent multiorgan immunometabolic state that may continue to drive symptoms, organ remodeling, and clinical events despite control of congestion and indication-appropriate management of comorbidities. Adipose-tissue expansion, immune-cell activation, endothelial adhesion and oxidative stress, impaired nitric oxide-cyclic guanosine monophosphate-protein kinase G signaling, cardiomyocyte stiffening, extracellular-matrix remodeling, renal amplification, skeletal-muscle bioenergetic failure, and gut-liver metabolic inputs form a self-reinforcing disease network. Biomarker, proteomic, imaging, and phenomapping studies indicate that inflammatory burden in HFpEF is layered rather than binary, ranging from obesity-linked high-CRP states to pan-inflammatory phenotypes with cardiorenal dysfunction, fibrosis signals, and worse outcomes. This framework may explain why broad anti-inflammatory therapy has produced limited benefit, whereas upstream phenotype-matched therapies, including sodium-glucose cotransporter-2 inhibitors, nonsteroidal mineralocorticoid receptor antagonism, obesity-directed incretin therapy, and structured lifestyle interventions, appear more effective in selected populations. Candidate RIR remains a research construct without a validated diagnostic cutoff or treatment-predictive biomarker. Framing cardiometabolic and cardiorenal HFpEF through candidate RIR may improve mechanistic stratification, longitudinal phenotyping, trial enrichment, and mechanism-matched therapy.