Maladaptive lipid partitioning in obesity-related heart failure with preserved ejection fraction: From depot dysfunction to metabolic phenotyping

Heart failure with preserved ejection fraction is a heterogeneous syndrome, with obesity defining an increasingly treatable cardiometabolic phenotype. Building on recent work identifying dysfunctional adiposity as an upstream contributor, this minireview focuses on the complementary question of how failure of safe lipid storage redirects substrate across visceral, hepatic, skeletal muscle, epicardial, perivascular, and myocardial compartments, and how this depot-specific routing intersects with myocardial metabolic inflexibility. Human imaging, invasive physiology, myocardial metabolomics, and recent clinical trials support associations between ectopic adiposity, insulin resistance, inflammation, impaired vascular and atrial reserve, congestion, and exercise intolerance, although causal pathways remain incompletely established in humans. We therefore propose an adiposity-aware, hypothesis-generating framework integrating body composition, regional adipose depots, metabolic-inflammatory biomarkers, atrial and right-sided function, and exercise assessment for phenotype-enriched research and future trial design. This framework is not intended to guide current treatment selection. Established treatment should remain evidence based, including exercise, sodium-glucose cotransporter 2 inhibition, mineralocorticoid receptor antagonism, decongestion, and obesity-directed incretin therapy, with attention to lean-mass preservation. Future prospective studies should investigate whether depot quality, metabolic flexibility, sex and ethnic heterogeneity, and body composition provide additional information for phenotypic characterization and risk stratification beyond conventional measures.