Response to Comment on Kolwicz et al. Enhancing Cardiac Triacylglycerol Metabolism Improves Recovery From Ischemic Stress. Diabetes 2015;64:2817-2827.

In their comment, Zaugg et al. (1) highlighted some of their recent work investigating the effects of Intralipid administration on postischemic outcomes in rat models of both healthy nondiabetic (2) and early diabetic hearts (3). This was prodded by a discussion point raised in a recent article by my colleagues and I on whether the provision of a mixture of unsaturated fats, such as Intralipid, could improve functional recovery in the ischemic, diabetic myocardium (4). In their studies, Zaugg and colleagues nicely demonstrated that Intralipid infusion given during the reperfusion period improves recovery from ischemia by inhibiting complex IV of the electron transport chain, leading to elevated levels of reactive oxygen species and activation of the reperfusion injury salvage kinase (RISK) signaling cascade (2). Unfortunately, infusion of Intralipid in rats with early type 2 diabetes failed to reproduce the beneficial effects observed in nondiabetic, ischemic myocardium (3). Although the work of Zaugg and colleagues (2,3) clearly suggests that Intralipid infusion to a diabetic heart may not be an appropriate strategy to improve postischemic outcomes, it does highlight an important point from our recent article (4) that requires further examination. In our study, we showed that the recovery from ischemia in the myosin heavy-chain–mediated cardiac-specific overexpression of diacylglycerol acyltransferase 1 (MHC-DGAT1) transgenic heart was improved when the heart was provided a physiologic mixture of both saturated and unsaturated long-chain fatty acids but was impaired when only the saturated fatty acid, palmitate, was provided. This impaired recovery in the palmitate-only condition was accompanied by an accumulation of C16:0 ceramides during the ischemic period, which was further increased during reperfusion (4). As these increases were not observed in MHC-DGAT1 transgenic hearts perfused with the long-chain fatty acid mixture, the increased C16:0 ceramide content could be, in part, a mechanistic culprit. Clinical and epidemiologic data overwhelmingly suggest that diabetic hearts have an increased risk of ischemic injury (5). However, experimental data have been inconsistent in elucidating the metabolic and molecular mechanisms involved (6–8) and, thus, have limited progress for new therapeutic targets. One probable issue is that the majority of perfused heart studies are limited to palmitate as the exogenous source of fatty acids. This is problematic as the in vivo situation provides a variety of fatty acids to the heart. In their work, Zaugg and colleagues (2,3) performed their isolated heart perfusion experiments with palmitate as the sole source of exogenous fatty acids. It is possible that the accumulation of ceramides or other lipid species could have occurred during the ischemic period and contributed to the inability of Intralipid to provide cardioprotective benefits in the diabetic heart. Therefore, it would be interesting to see if a differential effect of Intralipid postconditioning would be observed if the supply of exogenous fatty acids to the diabetic myocardium was of a more physiologic composition.