Metabolic Inflexibility as a Pathogenic Basis for Atrial Fibrillation

Abstract

Atrial fibrillation (AF), the most common sustained arrhythmia, is closely intertwined with metabolic abnormalities. Recently, a metabolic paradox in AF pathogenesis has been suggested: under different forms of pathogenesis, the metabolic balance shifts either towards (e.g., obesity and diabetes) or away from (e.g., aging, heart failure, and hypertension) fatty acid oxidation, yet they all increase the risk of AF. This has raised the urgent need for a general consensus regarding the metabolic changes that predispose patients to AF. "Metabolic flexibility" aptly describes switches between substrates (fatty acids, glucose, amino acids, and ketones) in response to various energy stresses depending on availability and requirements. AF, characterized by irregular high-frequency excitation and the contraction of the atria, is an energy challenge and triggers a metabolic switch from preferential fatty acid utilization to glucose metabolism to increase the efficiency of ATP produced in relation to oxygen consumed. Therefore, the heart needs metabolic flexibility. In this review, we will briefly discuss (1) the current understanding of cardiac metabolic flexibility with an emphasis on the specificity of atrial metabolic characteristics; (2) metabolic heterogeneity among AF pathogenesis and metabolic inflexibility as a common pathological basis for AF; and (3) the substrate-metabolism mechanism underlying metabolic inflexibility in AF pathogenesis.

Keywords: Randle cycle; Warburg effect; atrial fibrillation; insulin resistance; metabolic flexibility.

Figure 1

Metabolism in the healthy atrium.

Figure 2

A negative correlation between the AF risk and cardiac metabolic flexibility.

Figure 3

The substrate-metabolism mechanism underlying metabolic inflexibility. GL, Glycolysis; GO, Glucose oxidation; FAO, Fatty acid oxidation; FAU, Fatty acid uptake.