LAUSR

Background: The association between low carbohydrate diet (LCD) and cardiovascular disease and mortality remains unknown. Results from meta-analyses have reported that cardiovascular mortality increased when the carbohydrate in LCD was replaced for animal-derived fat, whereas mortality decreased when the substitution was plant-derived fat. However, the molecular mechanism is yet to be elucidated. We aimed to assess the effects of the LCD under two conditions, LCD with animal-derived fat (LCD-A) and LCD with plant-derived fat (LCD-P), on mouse cardiac function. Methods: Using 10-week old male C57B/6J mice, we performed transverse aortic constriction surgery to generate a pressure overload model of heart failure and subjected them to either normal diet, LCD-A or LCD-P for 4 weeks. Cardiac function was measured by echocardiography at 4 weeks after surgery, and the extent of inflammation was assessed by immunohistological analysis. Expression levels of genes were assessed with RNA sequence. Results: LCD-A accelerated left ventricular dilatation and systolic dysfunction (P<0.01 vs. normal diet), whereas LCD-P ameliorated cardiac hypertrophy (P<0.01 vs. normal diet) as revealed by echocardiograpy. Immunohistological analysis demonstrated that LCD-A resulted in a significant increase in the infiltration of F4/80-positive macrophages, reflecting exacerbated inflammation (P<0.01 vs. LCD-P, P<0.01 vs. normal diet). Consistent with histological findings, inflammation-related and cell cycle-related gene expressions were upregulated only in LCD-A. On the other hand, mitochondrial fatty acid oxidation gene expression including PPARα targets such as Cpt1a, Slc25a20, Acadvl, Hadha and Acaa2 were upregulated only in LCD-P (P<0.05, vs. normal diet), which may indicate the preserved energy metabolism during the pathogenic process of heart failure. Conclusions: These results suggest that the effects of the LCD on cardiac function vary between the sources of fat alternatives to carbohydrate intake. LCD-P induces PPARα activation, an important regulator of mitochondrial lipid metabolism, that may be therapeutically relevant for heart failure treatment. Further studies are required to unveil the precise molecular mechanism.