Palmitate attenuates myocardial contractility through augmentation of repolarizing Kv currents.

There is considerable evidence to support a role for lipotoxicity in the development of diabetic cardiomyopathy, although the molecular links between enhanced saturated fatty acid uptake/metabolism and impaired cardiac function are poorly understood. In the present study, the effects of acute exposure to the saturated fatty acid, palmitate, on myocardial contractility and excitability were examined directly. Exposure of isolated (adult mouse) ventricular myocytes to palmitate, complexed to bovine serum albumin (palmitate:BSA) as in blood, rapidly reduced (by 54+/-4%) mean (+/-SEM) unloaded fractional cell shortening. The amplitudes of intracellular Ca(2+) transients decreased in parallel. Current-clamp recordings revealed that exposure to palmitate:BSA markedly shortened action potential durations at 20%, 50%, and 90% repolarization. These effects were reversible and were occluded when the K(+) in the recording pipettes was replaced with Cs(+), suggesting a direct effect on repolarizing K(+) currents. Indeed, voltage-clamp recordings revealed that palmitate:BSA reversibly and selectively increased peak outward voltage-gated K(+) (Kv) current amplitudes by 20+/-2%, whereas inwardly rectifying K(+) (Kir) currents and voltage-gated Ca(2+) currents were unaffected. Further analyses revealed that the individual Kv current components I(to,f), I(K,slow) and I(ss), were all increased (by 12+/-2%, 37+/-4%, and 34+/-4%, respectively) in cells exposed to palmitate:BSA. Consistent with effects on both components of I(K,slow) (I(K,slow1) and I(K,slow)(2)) the magnitude of the palmitate-induced increase was attenuated in ventricular myocytes isolated from animals in which the Kv1.5 (I(K,slow)(1)) or the Kv2.1 (I(K,slow)(2)) locus was disrupted and I(K,slow)(1) or I(K,slow2) is eliminated. Both the enhancement of I(K,slow) and the negative inotropic effect of palmitate:BSA were reduced in the presence of the Kv1.5 selective channel blocker, diphenyl phosphine oxide-1 (DPO-1).Taken together, these results suggest that elevations in circulating saturated free fatty acids, as occurs in diabetes, can directly augment repolarizing myocardial Kv currents and impair excitation-contraction coupling.