Ceramide-Mediated Lipotoxicity: A Metabolic Driver of Myocardial Dysfunction in Heart Failure with Preserved Ejection Fraction

INTRODUCTION/OBJECTIVE: Heart Failure with Preserved Ejection Fraction (HFpEF) is increasingly recognized as a metabolic disorder. This review investigates the role of ceramidemediated lipotoxicity in its pathogenesis, focusing on how aberrant ceramide accumulation drives myocardial dysfunction. METHODS: We synthesized and critically evaluated current preclinical and clinical literature from major electronic databases (PubMed/MEDLINE, Embase, Web of Science) up to March 2026. Using a hierarchical evidence classification framework (Level 1: human HFpEF myocardium; Level 2: HFpEF-specific animal models; Level 3: related disease models; Level 4: in vitro studies), we analyzed evidence across calcium handling, apoptosis, autophagy, inflammation, and fibrosis pathways. RESULTS: Ceramide lipotoxicity represents an important pathological nexus. It directly impairs cardiomyocyte function by disrupting calcium homeostasis and ion channels (SERCA2a, RyR2, Kv4.3). Concurrently, it triggers mitochondrial and death receptor-mediated apoptosis, inhibits autophagic flux via AMPK/mTORC1 dysregulation, and activates pro-inflammatory (NF-κB, IL-6, TNF-α) and pro-fibrotic (TGF-β/Smad3) signaling pathways. These mechanisms collectively lead to diastolic dysfunction and disease progression. Interventions targeting ceramide synthesis (SPT inhibitors) or downstream effects show therapeutic promise in experimental models. DISCUSSION: The available evidence is derived predominantly from Level 3 models (diabetic cardiomyopathy, obesity-induced dysfunction) and Level 4 in vitro studies. Direct validation in human HFpEF myocardium (Level 1) and HFpEF-specific animal models (Level 2) remains a critical unmet need. The ceramide-centered hypothesis is most directly applicable to the metabolic/obesity-related phenotype of HFpEF, given the phenotypic heterogeneity of the syndrome. Therapeutic translation faces hurdles, including a lack of tissue selectivity, ceramide species complexity, and unknown long-term safety of inhibiting essential sphingolipid functions. CONCLUSION: Ceramide-mediated lipotoxicity constitutes a significant pathogenic mechanism in the metabolic phenotype of HFpEF. However, this conclusion is largely inferred from preclinical models recapitulating metabolic stress. Direct validation in human HFpEF myocardium is urgently needed. Future research must prioritize human tissue lipidomics, development of multifactorial animal models, and targeted clinical trials to translate these findings into effective therapies.