Rat Atrial Cardiomyocytes

Succinate and Atrial Arrhythmia Susceptibility in a Rodent Model

Atrial fibrillation (AF) often progresses from paroxysmal to stable forms, but the underlying mechanisms are unclear. The results of this study indicate that in the ovine model, AF stabilization is associated with TCA cycle remodeling, mitochondrial succinate accumulation, and mitochondrial oxidation. The succinate accumulation may contribute to the metabolic disturbances that stabilize AF in AF-S sheep.

To evaluate the role of succinate accumulation in AF, Caluori et al. assessed whether acute exposure of atrial cardiomyocytes to exogenous succinate could alter atrial metabolism, ROS emission, and NAD(P)H fluorescence in beating rat hearts and isolated rat atrial cardiomyocytes (RACMs). Succinate, a dicarboxylate, is transported across the membrane only in acidic conditions (e.g., ischemia or intense exercise). RACMs were incubated with a high concentration of succinate (5 mmol/L), and its impact on TCA cycle metabolites was assessed by mass spectrometry. Following succinate incubation, intracellular metabolite levels were analyzed using deuterium-labeled succinate and internal oxalate for signal correction and normalization. This showed increased intracellular concentrations of succinate, fumarate, and L-malate, with trends towards increased citrate and alpha-ketoglutarate (Fig. 1B-D and Fig. 2A-B). Glycolytic intermediates (glucose-6-phosphate, fructose-1,6-bisphosphate, and pyruvate) remained unchanged (Fig. 2C-E). Succinate incubation significantly increased intracellular succinate concentration by 3.8-fold (Fig. 2F). Functionally, succinate incubation of RACMs significantly increased ROS emission (Fig. 1E-F and Fig. 2G). Succinate perfusion of Langendorff-perfused beating rat hearts significantly increased NAD(P)H and MitoPY1 LAA fluorescence (Fig. 1G-J). H₂O₂ perfusion had no impact on NAD(P)H fluorescence but increased MitoPY1 fluorescence (Fig. 2H-K).