Cardiac Metabolic Reprogramming by a Nutritional Intervention: the High Fat Diet for Heart Failure (HF4HF) Study, a proof-of Concept Randomized Controlled Trial

Despite the notable therapeutic advancements, heart failure (HF) remains a significant cause of morbi-mortality worldwide, that justifies the need of identifying novel treatment strategies targeting non-redundant disease pathways.The heart, being the organ with the highest energy demands, produces over 5 kg of adenosine triphosphate (ATP) per day under normal conditions to support its functions. To meet this substantial energy requirement, the myocardium utilizes various substrates, being the oxidation of fatty acids the primary source, due to their efficiency in ATP production compared to carbohydrates and amino acids.However, HF, regardless of its etiology and across the entire spectrum of left ventricular ejection fraction (LVEF), often involves an altered cardiac metabolism characterized by a preference for glucose over fatty acids as an energy source.While previously considered a protective mechanism, recent findings challenge this notion.

Preclinical investigations using a transgenic murine model with mitochondrial alterations in cardiomyocytes revealed a shift in energy substrate utilization from fatty acids to glucose, resulting in progressive dilated cardiomyopathy (DCM) with reduced ejection fraction. Administering a high-fat diet (HFD) to these mice restored normal myocardial metabolism, leading to disease regression.Building upon these findings, a subsequent study was conducted by members of HF4HF Consortium, in a translational pig model of non-ischemic DCM and LVEF <50%, through the generation of hibernated myocardium. These pigs were randomly assigned to either a standard diet (regular chow) or a HFD (80% regular chow plus 20% lard, rich in palmitic, oleic, stearic and linoleic acids). Following a two-month intervention, pigs receiving the HFD showed a significant increase in LVEF from 41% to 56%, compared to controls whose LVEF only slightly changed from 40% to 38% (p 0.012).

At the end of the protocol, the cardiomyocytes from pigs who were on regular diet displayed fragmented mitochondria and presence of abundant lipid droplets, suggestive of poor lipid trafficking and storage. At a molecular level, hibernated myocardium with HF was associated with a significant downregulation of proteins involved in lipid import from cytosol to mitochondria (CRAT and ACOX1), along with a compensatory upregulation of glucose transport proteins (GLUT1), something that was completely restored after 2 months of HFD. Altogether, these data show that HF is associated with an impaired intracellular fatty acid traffic responsible for the metabolic switch. HFD was able to revert the altered lipid handling, allowing a metabolic reprograming having mitochondria use again fatty acids. The metabolic reprograming was further reinforced by the in vivo 18F-FDG PET studies, which showed a significant modification in the glucose uptake in HFD versus control diet pigs. All these outstanding results underscored the potential of high-fat dietary intervention in ameliorating systolic function in non-ischemic DCM.

Finally, a recent human study involving 20 patients with non-ischemic HF and reduced LVEF examined the effects of intravenous glucose plus insulin infusion versus lipid infusion of long-chain fatty acids, in terms of cardiac function and energetics, assessed by cardiovascular magnetic resonance (CMR) and MR spectroscopy 1 hour after the infusion. The lipid infusion notably enhanced cardiac function, increasing LVEF from 35% to 40%, whereas glucose plus insulin infusion showed no impact on disease parameters. Moreover, significant improvements in diastolic function, and myocardial energetics, assessed by 13P and the phosphocreatine/ATP ratio, were reported after intralipid infusion; findings that support the hypothesis of remaining metabolic substrate flexibility of the failing heart. However, this study only assessed the acute effects of lipid exposure on cardiac function and energetics, lacking long-term evidence regarding the efficacy of employing a high-fat dietary pattern in HF management. Nonetheless, this novel approach holds promise in the medical-nutritional management of this prevalent disease.