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<p><b>AIM: </b>Long-term high-fat diet (HFD) induces both cardiac remodelling and myocardial dysfunction in murine models. The aim was to assess the time course and mechanisms of metabolic and cardiac modifications induced by short-term HFD in wild-type (WT) mice.</p><p><b>METHODS AND RESULTS: </b>Thirty-three WT mice were subjected to HFD (60% fat, n = 16) and chow diet (CD, 13% fat, n = 17). Metabolic and echocardiographic data were collected at baseline and every 5 weeks for 20 weeks. Invasive haemodynamic data and myocardial samples were collected at 5 and 20 weeks. Echocardiographic data included left ventricular (LV) diameters and thickness, and systolic function using radial strain rate (SR). Histological assessment of cardiomyocyte and adipocyte sizes, interstitial fibrosis, and apoptosis index were performed. During follow-up, body weight, and glycaemia levels were higher in HFD than in CD mice, in association with an early adipose tissue remodelling. Despite no difference between both groups in blood pressure and LV mass at 5 weeks, an early LV dysfunction was observed in HFD mice as assessed by radial SR (21 ± 0.8 vs. 27 ± 0.8 unit/s, P < 0.001) and haemodynamic assessment. During follow-up, both groups demonstrated a progressive systolic and diastolic LV dysfunction and remodelling including dilatation and hypertrophy, which were more severe in HFD mice. Compared with CD mice, the early LV impairment in HFD mice was coupled with a higher cardiomyocyte apoptosis level (0.95 vs. 0.02%, P < 0.05) associated with an interstitial fibrosis process (2.3 vs. 0.2%, P < 0.05), which worsen during follow-up.</p><p><b>CONCLUSION: </b>The HFD promoted early metabolic and cardiac dysfunctions, and adipose and myocardial tissues remodelling.</p>