Intra-cardiac transfer of fatty acids from capillary to cardiomyocyte

Blood-borne fatty acids (Fa) are important substrates for energy conversion in the mammalian heart. After release from plasma albumin, Fa traverse the endothelium and the interstitial compartment to cross the sarcolemma prior to oxidation in the cardiomyocytal mitochondria. The aims of the present study were to elucidate the site with lowest Fa permeability (i.e., highest Fa resistance) in the overall Fa trajectory from capillary to cardiomyocyte and the relative contribution of unbound Fa (detach pathway, characterized by the dissociation time constant τ(AlbFa)) and albumin-bound Fa (contact pathway, characterized by the membrane reaction rate parameter d(Alb)) in delivering Fa to the cellular membranes. In this study, an extensive set of 34 multiple indicator dilution experiments with radiolabeled albumin and palmitate on isolated rabbit hearts was analysed by means of a previously developed mathematical model of Fa transfer dynamics. In these experiments, the ratio of the concentration of palmitate to albumin was set at 0.91. The analysis shows that total cardiac Fa permeability, P(tot), is indeed related to the albumin concentration in the extracellular compartment as predicted by the mathematical model. The analysis also reveals that the lowest permeability may reside in the boundary zones containing albumin in the microvascular and interstitial compartment. However, the permeability of the endothelial cytoplasm, P(ec,) may influence overall Fa permeability, P(tot), as well. The model analysis predicts that the most likely value of τ(AlbFa) ranges from about 200 to 400 ms. In case τ(AlbFa) is fast, i.e., about 200 ms, the extracellular contact pathway appears to be of minor importance in delivering Fa to the cell membrane. If Fa dissociation from albumin is slower, e.g. τ(AlbFa) equals 400 ms, the contribution of the contact pathway may vary from minimal (d(Alb)≤5 nm) to substantial (d(Alb) about 100 nm). In the latter case, the permeability of the endothelial cytoplasm varies from infinite (no hindrance) to low (substantial hindrance) to keep the overall Fa flux at a fixed level. Definitive estimation of the impact of endothelial permeability on P(tot) and the precise contribution of the contact pathway to overall transfer of Fa in boundary zones containing albumin requires adequate physicochemical experimentation to delineate the true value of, among others, τ(AlbFa), under physiologically relevant circumstances. Our analysis also implies that concentration differences of unbound Fa are the driving force of intra-cardiac Fa transfer; an active, energy requiring transport mechanism is not necessarily involved. Membrane-associated proteins may facilitate Fa transfer in the boundary zones containing albumin by modulating the membrane reaction rate parameter, d(Alb), and, hence, the contribution of the contact pathway to intra-cardiac Fa transfer.