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<p>Most 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 (<i>n</i> = 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 <sup>18</sup>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], <i>p</i> = 0.036) but remained unchanged in control-diet pigs (36% [35, 45] to 41% [38, 43], <i>p</i> = 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], <i>p</i> = 0.0047). On <sup>18</sup>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], <i>p</i> = 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], <i>p</i> = 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.</p>

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A high-fat diet nutritional intervention reprograms cardiac metabolism and improves systolic function in a pig model of heart failure with reduced ejection fraction

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月27日

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  • Carlos Galán-Arriola,
  • Daniel Pérez-Camargo,
  • Alessia Ferrarini,
  • Annalaura Mastrangelo,
  • María Isabel Higuero-Verdejo,
  • Gonzalo Javier López-Martín,
  • Ana Devesa,
  • Rocío Villena Gutiérrez,
  • Miguel Fernández-Tocino,
  • Anabel Díaz-Guerra,
  • Lourdes Montero-Cruces,
  • Manuel Carnero,
  • Rodrigo Fernández-Jiménez,
  • Valentin Fuster,
  • Javier Sánchez-González,
  • Borja Ibáñez

摘要

Most 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 18FDG-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 18FDG-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.