MP. Changes in myofilament proteins, but not Ca 2ϩ regulation, are associated with a high-fat diet-induced improvement in contractile function in heart failure. Am J Physiol Heart Circ Physiol 301: H1438 -H1446, 2011. First published July 15, 2011 doi:10.1152/ajpheart.00440.2011.-Pathological conditions such as diabetes, insulin resistance, and obesity are characterized by elevated plasma and myocardial lipid levels and have been reported to exacerbate the progression of heart failure (HF). Alterations in cardiomyocyte Ca 2ϩ regulatory properties and myofilament proteins have also been implicated in contractile dysfunction in HF. However, our prior studies reported that high saturated fat (SAT) feeding improves in vivo myocardial contractile function, thereby exerting a cardioprotective effect in HF. Therefore, we hypothesized that SAT feeding improves contractile function by altering Ca 2ϩ regulatory properties and myofilament protein expression in HF. Male Wistar rats underwent coronary artery ligation (HF) or sham surgery (SH) and were fed normal chow (SHNC and HFNC groups) or a SAT diet (SHSAT and HFSAT groups) for 8 wk. Contractile properties were measured in vivo [echocardiography and left ventricular (LV) cannulation] and in isolated LV cardiomyocytes. In vivo measures of contractility (peak LV ϩdP/dt and ϪdP/dt) were depressed in the HFNC versus SHNC group but improved in the HFSAT group. Isolated cardiomyocytes from both HF groups were hypertrophied and had decreased percent cell shortening and a prolonged time to half-decay of the Ca 2ϩ transient versus the SH group; however, SAT feeding reduced in vivo myocyte hypertrophy in the HFSAT group only. The peak velocity of cell shortening was reduced in the HFNC group but not the HFSAT group and was positively correlated with in vivo contractile function (peak LV ϩdP/dt). The HFNC group demonstrated a myosin heavy chain (MHC) isoform switch from fast MHC-␣ to slow MHC-, which was prevented in the HFSAT group. Alterations in Ca 2ϩ transients, L-type Ca 2ϩ currents, and protein expression of sarco(endo)plasmic reticulum Ca 2ϩ -ATPase and phosphorylated phospholamban could not account for the changes in the in vivo contractile properties. In conclusion, the cardioprotective effects associated with SAT feeding in HF may occur at the level of the isolated cardiomyocyte, specifically involving changes in myofilament function but not sarcoplasmic reticulum Ca 2ϩ regulatory properties. contractile function; calcium; dietary fat HEART FAILURE (HF) is a progressive disorder often associated with hypertension, obesity, insulin resistance, and diabetes (17a). At the whole heart level, HF is characterized by deteriorating left ventricular (LV) function and at the cellular level, by decreased cell shortening, a prolonged relaxation time, and blunted responsiveness to -adrenergic stimuli. In consideration of the comorbidities associated with HF (e.g., obesity, hypertension, and diabetes), dietary guidelines have traditionally recommended a low-fat/high-carbohydrate die...