Over the last thirty years, there has been extensive research on using metabolic treatments to treat heart diseases, with a particular focus on cardiac FA utilization. However, there is no agreement on how myocardial FA oxidation should be modified in HF. While some researchers have suggested inhibiting FA oxidation as a potential metabolic strategy for treating HF [155,156], there is an increasing body of evidence that challenges this viewpoint. Studies on rodent models of pressure overload, myocardial infarction or genetic cardiomyopathy have shown protective effects associated with high-fat diets [157]. Additionally, stimulating myocardial FA oxidation has been found to preserve cardiac function in pressure overload [158,159] or myocardial infarction [160]. Because the transport of most fatty acids into the mitochondria matrix is dependent on L-carnitine, stimulating L-carnitine is crucial for the maintenance of FA oxidation. In a hypertensive rat model of HFpEF, L-carnitine supplementation reduced ventricular fibrosis, prevented pulmonary congestion and improved survival [161]. In addition to stimulating uptake and oxidation of fatty acids, L-carnitine may also increase glucose oxidation by stimulating pyruvate dehydrogenase in conditions of high levels of free FAs [162]. In our systematic review and meta-analysis, we found that approaches that promote cardiac FA oxidation significantly improve heart function while those that lower FA oxidation showed no effects [163].

Pathological hypertrophy has been associated with a redirection of glucose towards biosynthetic and regulatory pathways [33], which may limit the ability of glucose oxidation to compensate for the reduction in FA oxidation. To improve cardiac energetics, it may, therefore, be beneficial to stimulate glucose oxidation through the PDH complex. The most investigated PDH stimulator is dichloroacetate (DCA). DCA treatment reduced ventricular hypertrophy and improved cardiac function and survival in Dahl salt-sensitive rats with hypertension [12]. The observed effects were associated with enhanced flux through the pentose phosphate pathways, increased energy reserves and less oxidative damage and apoptosis [12]. DCA also improved postischemic cardiac output in hypertrophied rats [164]. Our meta-analysis revealed that approaches increasing cardiac glucose oxidation significantly enhance ventricular function, while those inhibiting glucose oxidation are detrimental [163]. While there is compelling preclinical evidence supporting the advantages of improving myocardial glucose oxidation, the clinical significance of this metabolic approach is yet to be determined. Data on short-term effects of DCA in HF patients are inconsistent [165,166] and long-term data are lacking, possibly because of the risk of peripheral neuropathy in chronic treatment [167]. There is a need for novel drugs that target myocardial glucose oxidation. In a previous study, we found that treatment with glucagon-like peptide-1 (GLP-1) improved diastolic function and increased survival rates in a rat model of HFpEF. Notably, these effects were accompanied by a preservation of cardiac glucose oxidation. Our findings not only imply that GLP-1 may boost glucose oxidation in the failing myocardium but also suggest enhancing cardiac glucose oxidation for HFpEF [168].

Ketone bodies may serve as additional or alternative substrates for the heart. In HF, increased myocardial utilization of ketone bodies has been consistently observed [169,170,171]. Since inhibition of ketone body oxidation in pressure-overloaded mouse hearts aggravated ventricular dysfunction [172,173], this change most likely represents a necessary metabolic adaptation to maintain ATP production. In keeping with this notion, ventricular remodeling and dysfunction in mice subjected to transverse aortic constriction and in canines with pacing-induced cardiomyopathy were ameliorated by feeding with a ketogenic diet [173]. It is noteworthy that sodium–glucose cotransporter-2 (SGLT2) inhibitors, which have been established as potent drugs for treating both HFrEF and HFpEF, are also associated with increased ketone body utilization. While ketone bodies may enhance the energy status of the failing heart by acting as alternative substrates, potential mechanisms underlying their cardioprotective effects have been discovered. For instance, in a mouse model of HFpEF, raising β-hydroxybutyrate levels reduced the formation of NLPR3 inflammasomes, mitochondrial hyperacetylation and dysfunction, as well as myocardial fibrosis [174]. Considering the effects of ketone bodies on multiple pathways, including histone deacetylation and redox signaling [175,176], additional mechanisms are likely but remain to be evaluated in the context of HF.

As illustrated above, the TCA cycle pool is depleted, potentially resulting from an increased recruitment of amino acids for hypertrophic growth. Restoring the activity of the TCA cycle can be achieved by supplementing anaplerotic substrates. Inhibition of BCAA catabolism, which generates acetyl CoA and propionyl CoA, occurs in the failing heart [125]. Although activation of BCAA catabolism has been associated with reduced oxidative stress [125] and inflammation [146], the enrichment of the TCA cycle with acetyl CoA and propionyl CoA may also contribute to its therapeutic effects. Both acetyl CoA and propionyl CoA can be supplied by odd-chain ketone bodies. We previously showed that feeding rats triheptanoin, which provides C5-ketone bodies to the heart, resulted in increased cardiac glucose oxidation and reduced ventricular hypertrophy and diastolic dysfunction following aortic constriction [177]. Similarly, supplementation of alpha-ketoglutarate in mice with aortic constriction ameliorated left ventricular hypertrophy, fibrosis and systolic dysfunction [178].

Another method to maintain cardiac anaplerotic activity is to provide the heart with exogenous amino acids. At first glance, this concept seems to contradict the benefits of activating BCAA catabolism. Nevertheless, if the downregulation of amino acid catabolism in the failing heart reflects its higher demand for amino acids, providing exogenous amino acids may prevent this maladaptation and retain anaplerosis. In line with this hypothesis, cardioprotection following amino acid supplementation has been reported in rats [179] and patients [180,181,182] with HF.

Because PGC-1α signaling, which governs mitochondrial biogenesis and FA utilization, is downregulated in HF, activation of this pathway has been considered a promising approach to protect mitochondrial and heart function. However, studies have failed to demonstrate functional benefits of overexpressing PGC-1α in mice with aortic constriction [183,184]. Interestingly, overexpression of TFAM, a downstream signal of PGC-1α, reduced LV remodeling and preserved cardiac function in mice with myocardial infarction [185]. TFAM may protect mtDNA and mitigate Ca²⁺ mishandling and excessive ROS production. The import of exogenous TFAM with the help of TFAM-packed exosomes might represent one feasible way to improve mitochondrial biogenesis and function in HF [186].

Other interventions target mitochondrial morphology and dynamics. Pharmacologic inhibition of poly(ADP-ribose) polymerase (PARP) prevented mitochondrial fragmentation, increased mitochondria size and cristae density and prevented left ventricular hypertrophy in spontaneous hypertensive rats [187]. Efforts to restore mitochondrial phospholipid content by administration of exogenous cardiolipin were successful in cells [188]. However, similar attempts failed in a knock-down mouse model mimicking Barth syndrome with cardiomyopathy [188]. In mice with pressure overload-induced HF, treatment with the mitochondrial division inhibitor (Mdivi) decreased ventricular fibrosis and preserved cardiac function [79]. Finally, treatment with berberine activated mitophagy via the PINK1/Parkin pathway and preserved ventricular function in mice subjected to pressure overload [189].