This poster illustrates how fatty acids fuel the heart, what happens when this balance is disrupted, and how researchers and clinicians leverage this knowledge to improve outcomes in heart failure and other conditions.

How the heart uses fatty acids

Fatty acids are delivered to the heart through three main sources: non-esterified fatty acids (NEFAs) bound to albumin, and those derived from lipoproteins like chylomicrons and very-low-density lipoproteins (VLDLs). Once inside cardiomyocytes, fatty acids go through the following steps:

1. Uptake – facilitated by transporters like CD36 and fatty acid binding proteins (FABPs).
2. Activation – conversion to fatty acyl-CoA by acyl-CoA synthetase.
3. Transport into mitochondria – long-chain fatty acids require the carnitine shuttle (CPT1 and CPT2).
4. Oxidation – β-oxidation in the mitochondrial matrix produces acetyl-CoA, NADH, and FADH₂, which feed into the TCA cycle and electron transport chain to generate ATP.

This tightly regulated process ensures the heart has a steady supply of energy to maintain contractile function and cellular homeostasis.

Download our myocardial fatty acid metabolism pathway poster

Metabolic flexibility and disease

In healthy hearts, fatty acid oxidation (FAO) dominates. However, in disease states like heart failure, diabetes, and obesity, this balance shifts. The heart may switch to glucose metabolism, or in some cases, over-rely on FAO, leading to lipotoxicity and mitochondrial dysfunction.

For example, in heart failure with preserved ejection fraction (HFpEF), often seen in patients with metabolic syndrome, insulin resistance impairs glucose uptake. This forces the heart to depend more on fatty acids, which can accumulate and disrupt mitochondrial function. Ceramides and diacylglycerols, byproducts of lipid metabolism, have been implicated in promoting inflammation and fibrosis¹.

Regulatory mechanisms

Several molecular players regulate myocardial fatty acid metabolism:

• CD36: Facilitates fatty acid uptake. Its overexpression can lead to excessive lipid accumulation.
• CPT1: Controls mitochondrial entry of long-chain fatty acids. Inhibited by malonyl-CoA, which is elevated in insulin-resistant states.
• PPARs (α, γ, δ): Nuclear receptors that regulate genes involved in FA transport and oxidation.
• PGC-1α: Coactivator that promotes mitochondrial biogenesis and oxidative metabolism.
• AMPK: Energy sensor that enhances FAO during energy stress.

Disruption in these pathways can impair energy production and contribute to cardiac dysfunction².

Dietary influences and therapeutic potential

Diet plays a significant role in shaping myocardial fatty acid metabolism. Short-chain fatty acids (SCFAs), derived from fiber fermentation in the gut, have anti-inflammatory effects and improve endothelial function. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) help modulate lipid metabolism and reduce cardiovascular risk. In contrast, saturated fatty acids (SFAs) may promote oxidative stress and vascular remodeling³.

Therapeutic strategies are emerging that target these metabolic pathways. For instance:

• PPARα agonists aim to enhance FAO and reduce lipid accumulation.
• CPT1 inhibitors may help shift substrate preference toward glucose in failing hearts.
• AMPK activators support energy balance and mitochondrial health.

These approaches are still under investigation, and their effectiveness may vary depending on the patient’s metabolic profile.

Real-world insights

Clinical studies have shown that patients with CD36 deficiency exhibit reduced myocardial fatty acid uptake, highlighting the importance of this transporter in cardiac energy metabolism². In heart failure, imaging techniques like PET scans reveal altered substrate utilization, which can guide personalized treatment strategies.

Moreover, animal models have helped clarify how genetic modifications in PPARs or ERRs affect cardiac function. For example, mice lacking cardiac-specific PPARα show reduced FAO and increased susceptibility to pressure overload-induced dysfunction².

Understanding myocardial fatty acid metabolism opens new avenues for diagnostics and therapeutics. As research continues, we may see more targeted interventions that restore metabolic balance and improve cardiac outcomes.

For researchers and healthcare professionals, staying informed about these developments is key. Whether you're exploring new drug targets or designing dietary interventions, the metabolic landscape of the heart offers valuable insights.

References

1. Yang, R.  et al.  Molecular mechanisms of aberrant fatty acids metabolism in driving cardiovascular diseases: key regulatory targets and dietary interventions.  Food Funct.   15,  5961-5993 (2025).

2. Da Dalt, L.  et al.  Cardiac lipid metabolism, mitochondrial function, and heart failure.  Cardiovasc. Res.  119, 1905–1914 (2023).

3. Actis Dato, V.  et al.  Metabolic flexibility of the heart: the role of fatty acid metabolism in health, heart failure, and cardiometabolic diseases.  Int. J. Mol. Sci.  25, 1211 (2024).