OBJECTIVE: Diabetes and obesity are associated with increased plasma nonesterified fatty acid (NEFA) levels, myocardial triglyceride accumulation, and myocardial dysfunction. Because a very low-calorie diet (VLCD) also increases plasma NEFA levels, we studied the effect of a VLCD on myocardial triglyceride content and cardiac function in healthy subjects. RESEARCH DESIGN AND METHODS: Fourteen healthy nonobese men underwent (1)H-magnetic resonance spectroscopy (MRS) to determine myocardial and hepatic triglyceride content, (31)P-MRS to assess myocardial high-energy phosphate (HEP) metabolism (phosphocreatine/ATP), and magnetic resonance imaging of myocardial function at baseline and after a 3-day VLCD. RESULTS: After the dietary intervention, plasma NEFA levels increased compared with those at baseline (from 0.5 +/- 0.1 to 1.1 +/- 0.1 mmol/l, P < 0.05). Concomitantly, myocardial triglyceride content increased by approximately 55% compared with that at baseline (from 0.38 +/- 0.05 to 0.59 +/- 0.06%, P < 0.05), whereas liver triglyceride content decreased by approximately 32% (from 2.2 +/- 0.5 to 1.5 +/- 0.4%, P < 0.05). The VLCD did not change myocardial phosphocreatine-to-ATP ratio (2.33 +/- 0.15 vs. 2.33 +/- 0.08, P > 0.05) or systolic function. Interestingly, deceleration of the early diastolic flow across the mitral valve decreased after the VLCD (from 3.37 +/- 0.20 to 2.91 +/- 0.16 ml/s(2) x 10(-3), P < 0.05). This decrease in diastolic function was significantly correlated with the increase in myocardial triglyceride content. CONCLUSIONS: Short-term VLCD induces accumulation of myocardial triglycerides. In addition, VLCD decreases left ventricular diastolic function, without alterations in myocardial HEP metabolism. This study documents diet-dependent physiological variations in myocardial triglyceride content and diastolic function in healthy subjects.