Fatty acids are the best fuel for overloaded hearts

This editorial refers to ‘Glucose is preferentially utilized for biomass synthesis in pressure-overloaded hearts: evidence from fatty acid-binding protein-4 and -5 knockout mice’ by Y. Umbarawan et al., pp. 1132–1144. The high energetic demand of the heart, needed for continuous contraction, is met mostly by oxidation of fatty acids (FA), while glucose oxidation plays a minor role. Pathological states of the heart may determine a shift in cardiac metabolism. Heart failure is associated to a reduced utilization of FA and a greater dependence upon glucose.1 In contrast, metabolic diseases such as diabetes lead to increased cardiac FA uptake.2 These findings prompted several researchers to ask whether contrasting cardiac metabolic shift could improve or aggravate cardiomyopathy. Thus, several animal models have been developed to induce a change in cardiac metabolism, in order to check its consequences on cardiac structure and function. As different cardiac disease are linked to different changes in cardiac metabolism, interventions hampering cardiac FA utilization, by acting on different steps of FA metabolism, have different effects. During a metabolic stress, increasing FA levels by modulating autophagy deteriorates heart function.3 Similarly, heart failure in response to a metabolic stress, diabetes + hypoxia, is rescued by harmacological blockade of CD36, a plasma membrane transporter facilitating uptake of FA by cardiomyocyte.4 Specific CD36 ablation in cardiomyocytes, like pharmacological inhibition, leads to decreased FA oxidation in the heart and conversely to greater glucose oxidation.4,5 However, in response to a different stress such as aortic constriction (TAC), which increases workload with consequent need of more energy, these mice develop an early cardiac dysfunction.5 The same happens when blocking the enzyme carnitine palmiotyltransferase 1 (CPT-1), which facilitates FA entry into mitochondria where they are oxidized to produce energy. Complete deletion of the muscle-specific CPT-1b isoform is lethal. However, mice heterozygous for this muscle-specific deletion are viable and apparently healthy, though using more glucose instead of FA in their heart.6 Also in this case, the stress induced by TAC leads to dysfunction. In this issue of Cardiovascular Research, the article by Umbarawan et al.7 takes the exploration of the effects of FA entry in the cardiomyocytes one step back. In a previous work, they studied an animal model in which they ablated Fatty Acid Binding Protein (FABP)4 and FABP5, two FA transporters expressed in several cell types.8 In the heart, FABP4 and FABP5 are involved in the uptake of FA in the endothelium, and thus critical in mediating FA transport from coronary arteries to the cardiac tissue. In this article, they have investigated how the whole-body absence of FABP4 and FABP5 affects cardiac function. Their results are similar to those observed in other models of defective utilization of FA by cardiomyocytes. This shift in cardiac metabolism does not affect basal function, but it compromises a correct response to a haemodynamic challenge such as TAC. Such a result was obtained in a model where the myocardium was just indirectly affected, since the two proteins are not expressed in cardiomyocytes. Thus, it highlights once more how the heart is a complex organ, where a correct interaction among all cellular components, from endothelium to cardiomyocytes, from fibroblasts to immune cells, is fundamental for a correct function.9 A notable contribution of this recent work is the detailed characterization of several metabolic pathways in the overloaded heart in conditions of reduced FA uptake. Actually, the Authors have measured the levels of metabolites in the heart both physiologically and following injection of radiolabelled glucose, to ascertain which metabolites are coming from that precursor. These data seem to indicate that glucose in the overloaded heart is preferentially used for de novo synthesis of biomolecules, rather than providing the energy needed to preserve cardiac function in spite of increased workload. This detailed metabolic characterization may hopefully be of help in understanding the exact metabolic abnormalities occurring in heart failure and thus planning future metabolic interventions. On this issue, cardiac dysfunction in the FABP4/FABP5 model was prevented by administration of medium-chain FA, circumventing the genetic absence of transporters for long-chain FA. This intervention had already demonstrated its utility in mice with cardiomyocyte specific ablation of the transporter CD36.5 However, the usefulness of this approach in non-genetic heart failure seems dubious. We must admit that we are at the beginning of this characterization of metabolic alterations in cardiac dysfunction. For example, a more precise characterization of metabolic derangements in cardiomyocytes, as well as in other cardiac cells, would add further relevant details that are missing in the whole-heart characterization performed here. Unfortunately, the characterization in terms of cardiac structure was not equally detailed. It appears that the glucose-induced biosynthesis in this overloaded heart does not determine a greater increase in cardiac mass. Instead, FABP4/FABP5 KO hearts do not respond to haemodynamic overload with a compensatory hypertrophy, but with a maladaptive chamber dilation without thickening of the ventricular walls. This cardiac dilatation phenotype is probably responsible for the early loss of cardiac function. Is cardiac uptake of FA alone responsible for the observed phenotype? Well, probably, although the FABP4/FABP5 model was not specifically targeted to the endothelium. Until endothelium-specific absence of FABP4 and FABP5 is investigated, one cannot exclude another possibility. In fact, FABP4 and FABP5 are also strongly expressed in various immune cells.10 Inflammation is strictly involved in cardiac remodelling following different pathological insults, including TAC9 and metabolic diseases.11,12 More specifically, fat metabolism is fundamental for immune cell fate ad survival.13 FABP4 and FABP5 are involved in this process, since T-cell specific ablation of the two proteins decreases memory T cell survival by inhibiting FA oxidation in the mitochondria.14 Thus, future studies should investigate the participation of inflammatory and immune mechanisms to the cardiomyopathy observed in absence of FABP proteins. In conclusion, the study adds a distinctive piece of information to the dissection of the role of metabolic substrates in determining cardiac response to pressure overload, and it indicates a way to dissect the molecular consequences of substrate utilization. Many questions are still open, and would require years of research. We look forward to further advances in this field of investigation, which could bring in novel therapeutic strategies for prevention of heart failure in hypertensive patients. G.L. acknowledges support from Italian Ministry of Health (Ricerca Corrente). Conflict of interest: none declared.