Heart failure (HF) continues to be a leading cause of morbidity and mortality worldwide, despite advances in treatment. HF is often characterized by an altered metabolism in the heart, where glucose is favored over fatty acids as the primary energy substrate. This metabolic shift has been hypothesized to contribute to disease progression. Previous studies using animal models have demonstrated that restoring fatty acid metabolism through dietary intervention can reverse the adverse metabolic effects and improve heart function. A transgenic murine model with mitochondrial defects, for instance, exhibited improved cardiac function after an HFD intervention. These findings were reinforced by a translational pig model of non-ischemic DCM, where a high-fat diet significantly improved LVEF compared to a standard diet.

Building upon these promising preclinical results, a small-scale human study showed that lipid infusion, rather than glucose, improved cardiac function in HF patients. However, the long-term benefits of a HFD in heart failure patients have yet to be thoroughly explored. The HF4HF trial aims to fill this gap by evaluating the effects of an HFD over a two-month period in patients with non-ischemic DCM and reduced LVEF.

The "High Fat Diet for Heart Failure" (HF4HF) study is a proof-of-concept randomized controlled trial designed to investigate the efficacy of a high-fat diet (HFD) as a therapeutic intervention in patients with non-ischemic dilated cardiomyopathy (DCM) and reduced left ventricular ejection fraction (LVEF). The study hypothesizes that cardiac metabolic reprogramming, achieved through a controlled nutritional intervention involving an HFD, can enhance systolic function, myocardial energetics, and overall heart function in heart failure (HF) patients. Cofunded by the European Commission and national entities, the trial is spearheaded by a consortium of cardiovascular research centers across four countries: Spain, Italy, France, and Romania.

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.

Inclusion Criteria:

• Patients of both sexes and ≥18 years old
• Patients diagnosed with HF secondary to non-ischemic DCM, according to ESC guidelines definition,1 with or without a known genetic basis.
• LVEF ≤49% according to the baseline CMR.
• Optimized HF guideline-directed medical therapy for at least 3 months prior to inclusion.
• Patients who have provided informed consent.

Exclusion Criteria:

• Prior diagnosis of ischemic DCM.
• Prior diagnosis of established atherosclerotic cardiovascular disease (angina/myocardial infarction, transient ischemic attack/stroke, lower limb ischemia or at any other peripheral level).
• Changes in HF therapies within the last 3 months.
• HF decompensation within the previous 3 months, including HF hospitalization or the need of ambulatory intravenous diuretic or inotropic treatment such as levosimendan.
• Uncontrolled dyslipidemia, defined as LDL-cholesterol >160 mg/dL and/or triglycerides >200 mg/dL, despite treatment.
• Any contraindication for CMR:

Severe claustrophobia. Any device which is known to threaten or pose hazard in all MR environments. //www.mrisafety.com/ Patients with implanted biomedical devices (cardiac artefacts): pacemakers, cardiac defibrillators or cardiac resynchronization therapy.

• Liver and biliary diseases, including prior diagnosis of non-alcoholic fatty liver disease and unoperated cholelithiasis.
• Prior episodes of acute pancreatitis or chronic pancreatitis.
• Prior fish or nut allergy.
• Life expectancy less than 12 months.
• Pregnancy or planned pregnancy for the next 4 months.
• Current lactation.
• Patients participating in other randomized clinical trial.
• Impossibility to consent or undergo study follow-up

Individual participant data (IPD) will not be shared to protect participants' privacy.

Masking will be maintained for data analysts.