High Fat Diet for Cardiac Metabolic Reprogramming

Overview

The heart is a unique organ that performs an incessant work to pump blood throughout the body. For this massive effort, it requires a very high supply of energy. Mitochondria are small components of the cells responsible for the production of energy. To produce energy, mitochondria from cardiac cells can use fuel of different origins (fats, glucose, proteins, etc). In normal circumstances, cardiac mitochondria use preferentially fats since they are more efficient in terms of quantify of energy produced. Recent data from our consortium has demonstrated that if the cardiac mitochondria switch the primary source of fuel (from fats to glucose), this results in a poor performance of the organ, which cannot supply the whole body with enough blood. This is known as heart failure. In experimental models of heart failure, we have demonstrated that a high fat diet is able to reverse the metabolic switch and make the cardiac cells mitochondria use again fats as the primary substrate to produce energy. This translates into a recovery of heart failure. In the present project, we plan to bring this concept to the human setting and perform a pilot clinical study where patients with heart failure are put in a dietary program consisting of high fat diet. The effect of this nutritional approach will be evaluated by state-of-the-art non-invasive imaging technology.

Heart failure (HF) is a progressive condition in which the heart muscle is unable to pump blood effectively to meet the body's needs. It affects millions of people globally and imposes a significant burden on healthcare systems due to its high morbidity, mortality, and economic costs. As the prevalence of HF continues to rise, exploring targeted and innovative treatment strategies is becoming increasingly important. The heart sustains high energy demands and primarily relies on fatty acids as its energy source in the fasting state, with a smaller contribution from glucose. During the progression of HF, there is a shift in cardiac substrate preference toward increased glucose reliance and reduced fatty acid utilization. Initially considered a protective adaptation against oxygen deficiency and lipotoxicity, this metabolic shift led to suggestions that inhibiting fatty acid oxidation could be a therapeutic strategy for HF. However, more recent evidence indicates that enhancing fatty acid utilization through a high-fat diet may attenuate cardiac dysfunction. Animal studies have demonstrated that increasing fatty acid utilization can reverse myocardial metabolic alterations and improve cardiac function in models of progressive dilated cardiomyopathy (DCM) with reduced ejection fraction. In one study, the administration of a high-fat diet restored normal myocardial metabolism, resulting in disease regression. Similarly, research using large animal models has shown that high-fat diets can significantly improve left ventricular ejection fraction (LVEF), further supporting the potential benefits of this approach. In human studies, preliminary findings suggest that lipid-based interventions may acutely improve cardiac function in individuals with HF and reduced LVEF. However, evidence on the long-term efficacy and safety of high-fat dietary patterns in HF management remains limited. This study aims to compare the effects of a high-fat diet versus a standard diet with a conventional macronutrient composition on non-ischemic DCM with reduced LVEF. The primary objective is to evaluate and compare the impact of a high-fat diet versus a standard diet on LVEF. Secondary objectives include assessing the effects on left ventricular strain, diastolic function, and blood parameters, as well as evaluating the feasibility and degree of adherence to each dietary intervention.