Anaplerotic filling in heart failure: a review of mechanism and potential therapeutics

Abstract

Heart failure (HF) is a complex syndrome and a leading cause of mortality worldwide. While current medical treatment is based on known pathophysiology and is effective for many patients, the underlying cellular mechanisms are poorly understood. Energy deficiency is a characteristic of HF, marked by complex alterations in metabolism. Within the tricarboxylic acid cycle, anaplerosis emerges as an essential metabolic process responsible for replenishing lost intermediates, thereby playing a crucial role in sustaining energy metabolism and consequently cardiac function. Alterations in cardiac anaplerosis are commonly observed in HF, demonstrating potential for therapeutic intervention. This review discusses recent advances in understanding the anaplerotic adaptations that occur in HF. We also explore therapeutics that can directly modulate anaplerosis or are likely to confer cardioprotective effects through anaplerosis, which could potentially be implemented to rescue the failing heart.

Keywords: Anaplerosis; Cardiac metabolism; Cardiovascular disease; Heart failure; Mitochondria.

Graphical Abstract

Figure 1

Overview of metabolism in healthy cardiomyocytes. Under aerobic conditions, FAs, glucose, lactate, ketone bodies, and BCAAs are converted to acetyl-CoA which enters the TCA cycle and permits the generation of reducing equivalents NADH and FADH₂ which transfer electrons to the mitochondrial ETC for the production of ATP. AcAc, acetoacetate; BHB, β-hydroxybutyrate; BCKA, branched chain keto acids; IMS, intermembrane space; MM, mitochondrial matrix. Figure created using Biorender.

Figure 2

Anaplerotic and cataplerotic pathways with entry points, anaplerotic enzymes, and the molecules directly or indirectly involved in anaplerosis in the TCA cycle. Double-headed arrows represent reversible reactions involved in anaplerosis and cataplerosis. Single-headed arrows indicating non-reversible anaplerotic reactions. Blue single-headed arrows indicate cataplerotic efflux of TCA cycle intermediates. PC, pyruvate carboxylase; ME, malic enzyme; AT, aminotransferases; GLS, glutaminase; GDH, glutamate dehydrogenase; PCC, propionyl-CoA carboxylase; ADSL, adenylosuccinate lyase. Figure created in Biorender.