Galán-Arriola, CarlosPérez-Camargo, DanielFerrarini, AlessiaMastrangelo, AnnalauraHiguero-Verdejo, María IsabelLópez-Martín, Gonzalo JavierDevesa, AnaGutiérrez, Rocío VillenaFernández-Tocino, MiguelDíaz-Guerra, AnabelMontero-Cruces, LourdesCarnero, ManuelFernández-Jiménez, RodrigoFuster, ValentinSánchez-González, JavierIbáñez, Borja2026-04-272026-04-272026-03-27Basic Res Cardiol. 2026 Mar 27.https://hdl.handle.net/20.500.12105/27447Most forms of heart failure are characterized by a metabolic switch from the use of fatty acids to glucose as the main fuel source for ATP generation in the myocardium. Whether metabolic reprogramming is a therapeutic target remains controversial. In this study, heart failure with reduced ejection fraction (HFrEF) and metabolic switch (i.e., increased myocardial glucose uptake) was induced in pigs by generating viable dysfunctional myocardium secondary to progressive coronary artery stenosis. Pigs (n = 19) were then randomized to a high-fat diet (HFD, chow diet supplemented with 20% lard) or control diet (no supplementation) for two months. Pre- and post-nutritional treatment contrast-enhanced cardiac magnetic resonance (CMR) and FDG-PET/CT studies were performed. Hearts were then harvested for further analysis. LVEF significantly improved in pigs receiving the 2-month HFD (38% [33, 43] to 54% [47, 62], p = 0.036) but remained unchanged in control-diet pigs (36% [35, 45] to 41% [38, 43], p = 0.24). HFD-fed pigs had a smaller extent of fibrosis after the dietary intervention (late gadolinium enhancement 0.45% LV [0.17, 1.67] vs 6.23 [5.54, 9.57], p = 0.0047). On FDG-PET, a reversion of the metabolic reprogramming in the LAD-dysfunctional myocardium was observed only in HFD-fed pigs (0.46 counts [0.21, 0.65] vs 1.80 [1.53, 2.83], p = 0.016). Transmission electron microscopy of explanted hearts revealed less fragmented mitochondrial and a lower lipid droplet density in cardiomyocytes from HFD-fed pigs (38 per 10 µm3 [34, 50] vs 96 [78, 124], p = 0.022), and this was accompanied by increased expression of genes involved in fatty acid metabolism and downregulation of genes encoding glucose import proteins. In conclusion, in a large animal model of HFrEF secondary to myocardial dysfunction with a metabolic switch, a nutritional intervention based on HFD feeding was associated with a cardiac metabolic restoration of fatty acid substrate use, restoration of cardiomyocyte lipid trafficking and significantly improved systolic function.This work is part of project PCI2024-153440, funded by MCIU/AEI/10.13039/501100011033 and co-funded by the European Union under the Partnership Fostering a European Research Area for Health (ERA4Health) (ERA4HEALTHCVD-091) (Grant Agreement No. 101095426, EU Horizon Europe Research and Innovation Programme). The study also received funding from the ERA-CVD Joint Transnational Call AC16/00021, the Spanish Ministry of Science and Innovation (PID2022-140176OB-I00), and the Comunidad de Madrid (S2022/BMD-7403, RENIM-CM). The CNIC is supported by the ISCIII, the Ministry of Science, Innovation and Universities, and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (CEX2020-001041-S).engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/Heart failureHigh-fat dietMagnetic resonance imagingMitochondriaAttribution-NonCommercial-NoDerivatives 4.0 International41894020BASIC RESEARCH IN CARDIOLOGYopen access