The fascinating and elusive life of cardiac fatty acids

Kudej et al. attempted to elucidate the role of fatty acids (FAs) in the second window of protection of the chronically underperfused myocardium. Using the in vivo conscious swine heart model, they elegantly showed that ischaemic preconditioning resulted in less severe thinning of the left ventricular (LV) wall 24 h after the onset of ischaemia. The improved mechanical function of the ischaemic region was not due to changes in residual blood flow and, hence, increased supply of oxygen. The contribution of FAs to cardiac oxidative ATP production was estimated by infusion of C-palmitate and subsequent in vitro NMR analysis of palmitate-derived acetyl-CoA. The contribution of FA to oxidative energy production declined in the ischaemic LV wall accompanied by decreased malonyl-CoA levels in the ischaemic subendocardium. Interestingly, preconditioning substantially enhanced the relative contribution of FA oxidation to oxidative energy production in association with a three-fold increase in malonyl-CoA concentration. The study of Kudej et al. deserves special attention especially for its iconoclastic message. Two important paradigms concerning cardiac FA utilization read that first, myocardial FA oxidation is detrimental under challenging conditions and, secondly, cardiac FA oxidation is controlled by malonyl-CoA, in that elevated malonylCoA levels are inhibitory. The present study, however, clearly shows that improvement of regional myocardial function under chronically ischaemic conditions is associated with enhanced FA utilization and that increased FA oxidation coincides with increased tissue malonyl-CoA levels. Agreement exists that FAs are important fuel for the myocardium. Blood-borne FAs are efficiently extracted during a single passage of blood through the coronary system and preferentially oxidized in the working heart. Under challenging conditions such as ischaemia and/or reperfusion, FA could exert a detrimental effect on cardiac function. Theoretically, the negative effect of FA oxidation may relate to the fact that FAs require 10% more oxygen than glucose to produce the same amount of ATP. This property renders FAs less favourable as substrates when oxygen supply is limited. In addition, enhanced supply and tissue concentration of FAs (or their derivatives) may exert a toxic effect on the heart. Although experimental findings strengthen the notion that FAs are detrimental for the ischaemic/reperfused heart, other studies, in particular those applying the in vivo heart model, are less supportive. For instance, contractile recovery of the post-ischaemic, stunned myocardium of conscious dogs was more marked when FA levels were elevated by Intralipid administration. Pre-treatment with oxfenicine to inhibit FA oxidation completely abolished the beneficial effect of elevated FA supply. Yue et al. enhanced post-ischaemic FA oxidation in the in vivo mouse heart and observed a significant decline in infarct size. The present study in conscious pigs showed that preconditioning increased FA oxidation in association with improved local mechanical activity. One may argue that mechanical recovery would have been much better if FA oxidation was inhibited instead of increased. The answer to this question is found in a publication of Stanley et al., who treated the regional ischaemic heart with dichloroacetate. Despite a significant decline in cardiac FA utilization, no beneficial effect on LV wall thinning of the underperfused region was observed. This finding indicates that in the present study, increased FA oxidation in the preconditioned ischaemic region did not prevent a more marked contractile recovery. It is comprehensible that myocardial FA utilization is adjusted to the cardiac need of energy and that mechanisms are present to balance the contribution of carbohydrates and lipids to cardiac fuel consumption. In contrast to glucose utilization, mechanisms underlying the regulation of cardiac FA uptake and intracellular metabolism are still incompletely elucidated. Cardiac FA uptake seems to a great extent to be governed by the amount of blood-borne FA supplied to the heart. The transfer of FA to the mitochondrion is facilitated by a fatty acid-binding protein. Uptake of FA through the mitochondrial membranes is dependent on the carnitine shuttle involving carnitine palmitoyltransferase I (CPT-I). Inside the mitochondrion, FAs are degraded via the b-oxidation pathway to acetyl-CoA, whose acetyl moiety, after entering the citric acid cycle, is oxidized to yield ATP. The rate of FA oxidation is regulated by the concentration of cofactors such as free CoA, acetyl-CoA, NADH, and NAD+. 6 A paramount role of malonyl-CoA has been advocated in regulating the entry of FA into the mitochondrion. The beauty of this putative feedback loop lies in the fact that production of mitochondrial acetyl-CoA is linked to the mitochondrial uptake of FA: both carbohydrates and