Abstract
Heart failure with preserved ejection fraction (HFpEF) is characterized by complex metabolic derangements, yet considerable controversy exists regarding the role, and specifically the direction, of fatty acid oxidation (FAO) in disease progression. Through a systematic review with narrative synthesis of 44 studies identified from MEDLINE, Embase, and Web of Science databases, we critically examine the seemingly contradictory evidence regarding cardiac FAO in HFpEF. Our systematic analysis of experimental approaches reveals that many apparent contradictions can be resolved by considering differences in methodological approaches, interpretation of indirect metabolic markers, and the dynamic nature of metabolic adaptation in disease progression. Direct measurements consistently demonstrate that FAO remains active or increased in HFpEF hearts, whereas glucose oxidation becomes impaired, challenging previous assumptions based on indirect metabolic assessments. Methodological differences, particularly between studies using isolated mitochondria versus intact hearts and indirect versus direct substrate utilization measurements, can explain many apparent contradictions in the literature. Clinical and experimental evidence supports that FAO is maintained or elevated in HFpEF, with primary defects occurring in glucose oxidation and mitochondrial quality control. These findings suggest that successful therapeutic strategies for HFpEF should prioritize restoring metabolic flexibility and optimizing substrate utilization patterns rather than simply modulating FAO pathways. Our synthesis of the literature provides a comprehensive framework for understanding cardiac energy metabolism in HFpEF and identifies critical areas for future investigation.NEW & NOTEWORTHY Direct measurements reveal fatty acid oxidation remains active or increased in HFpEF hearts, whereas glucose oxidation becomes impaired, challenging previous assumptions. Apparent contradictions in HFpEF metabolism literature arise from methodological differences-studies using isolated mitochondria versus intact hearts. Evidence demonstrates fatty acid oxidation is maintained in HFpEF, with defects primarily in glucose oxidation. Successful therapeutic strategies should prioritize restoring metabolic flexibility rather than simply modulating fatty acid oxidation pathways.