Myocardial long-chain fatty acid uptake and metabolism pathway

The myocardial long-chain fatty acid (LCFA) uptake and metabolism pathway is the primary energy-producing system in the healthy adult heart, providing approximately 60-90% of the heart's ATP requirements [1]. This complex process involves several key steps: the uptake of LCFAs from the blood via transporters like CD36 and fatty acid transport proteins (FATPs), their activation into acyl-CoA by long-chain acyl-CoA synthetases (ACSL), and their transport into the mitochondria through the carnitine shuttle involving CPT1 and CPT2 [2]. Once inside the mitochondria, LCFAs undergo beta-oxidation to produce acetyl-CoA, which enters the Krebs cycle for ATP generation. In various cardiac pathologies, such as heart failure or diabetic cardiomyopathy, this pathway becomes dysregulated, often leading to metabolic inflexibility, lipotoxicity, or energetic deficiency [3, 4]. Therapeutic strategies often aim to modulate this pathway—either by inhibiting fatty acid oxidation to promote more oxygen-efficient glucose oxidation (e.g., trimetazidine, perhexiline) or by enhancing metabolic efficiency through PPAR activation [5].

Other names

Cardiac fatty acid oxidationMyocardial lipid metabolismFatty acid beta-oxidation pathway

Pharmacological agents modulate this pathway by inhibiting key enzymes such as carnitine palmitoyltransferase 1 (CPT1) or long-chain 3-ketoacyl-CoA thiolase (3-KAT), thereby shifting myocardial energy metabolism from fatty acid oxidation to the more oxygen-efficient glucose oxidation process [1, 5].