Abstract Body: Background
Heart failure with preserved ejection fraction (HFpEF) is increasingly recognized as a systemic metabolic disorder characterized by diastolic dysfunction. Although lipid dysregulation contributes to HFpEF pathogenesis, the mechanisms linking adipose tissue lipid handling to cardiac remodeling remain poorly defined. Angiopoietin-like protein 4 (ANGPTL4) regulates lipoprotein lipase–dependent lipid partitioning; however, its role in HFpEF has not been established.

Methods
We investigated the role of adipocyte-derived ANGPTL4 in a two-hit murine HFpEF model using adipocyte-specific knockout mice. Cardiac and metabolic phenotyping included echocardiography, gene expression analysis, histological assessment, and untargeted LC–MS/MS–based serum lipidomics. Parallel lipidomic profiling was performed in the Berlin HFpEF cohort (n = 136). Functional relevance was assessed by mass spectrometry–based proteomics in primary human cardiac fibroblasts (HCFs).

Results
Adipocyte-specific ANGPTL4 deficiency improved diastolic function (E/e′: p = 0.0458), global longitudinal strain (GLS: p < 0.0001) and significantly reduced myocardial fibrosis (p = 0.0275) in HFpEF mice. Serum lipidomic profiling revealed a distinct circulating signature characterized by increased long-chain acylcarnitines (CAR16:0, CAR18:0, CAR18:1) in HFpEF, which were significantly attenuated upon ANGPTL4 deletion (p = 0.0435). Cell-based analysis in human cardiac fibrobloasts revealed that these acylcarnitines induce profibrotic remodeling, as evidenced by increased expression of Col1a1 (p = 0.035) and Postn (p = 0.04), and enrichment of profibrotic pathways by LC-MS/MS-based proteomic analysis (GSEA, p < 0.05). In the patient cohort, the identical CAR-species were markedly elevated (p < 0.0001) in individuals with high versus low–intermediate HFA-HFpEF scores and strongly correlated with disease severity.

Conclusions
Adipose-derived ANGPTL4 promotes HFpEF by regulating circulating acylcarnitines that drive fibroblast activation and myocardial fibrosis. These findings establish a mechanistic link between adipose lipid metabolism and cardiac remodeling and identify ANGPTL4 as a potential therapeutic target to disrupt the metabolic–fibrotic axis in HFpEF.