Resistance to atrial fibrillation domestication and mitochondrial dysfunction in sheep: a potential key role of the TCA cycle and mitochondrial redox state.

BACKGROUND

Atrial fibrillation (AF) often progresses from paroxysmal to more stable forms. It is well-recognized that patients vary in their AF progression, but the underlying mechanisms remain unclear. This work, performed in a sheep AF-model, aimed to identify atrial redox and energetic status differences between animals developing stable AF (AF-S) versus those resistant to AF-stabilization (AF-R).

METHODS

AF was induced with bursts of atrial tachystimulation, maintained whenever sinus rhythm resumed, and monitored with telemetry. Electrophysiological and structural remodeling were assessed via contact mapping, and histology, respectively. Proteomic, metabolomic, enzymatic, and bioenergetic remodeling were evaluated using left atrial appendage (LAA) tissues and isolated LAA mitochondria. Healthy rats were used to investigate whether a metabolic challenge stabilizes electrically induced AF episodes.

RESULTS

AF-S (N = 12) sheep developed stable AF after 13 days on average, whereas AF-R (N = 8) sheep failed to develop self-sustained AF despite 120 days of tachypacing. Contact mapping and histological analysis revealed that AF-S animals presented reduced atrial conduction velocity, and increased endomysial fibrosis. Metabolic analysis showed significant differences in tricarboxylic acid cycle (TCA) enzymes activities and a 45% succinate content increase in AF-S LAA versus AF-R. AF-S mitochondria showed abnormal succinate oxidation, decreased ATP synthesis rate, and increased ROS emission. The ratios of ATP/ADP, NAD+/NADH, and Complex I/II activities were disturbed in AF-S compared to AF-R. Calculated mitochondrial NAD+/NADH ratios suggest an oxidized state in AF-S while AF-R showed a reduced state. Exogenous succinate was metabolized when incubated with rat atrial cardiomyocytes, while intravenous succinate injection stabilized atrial arrhythmias electrically-induced in vivo.

CONCLUSIONS

AF-S sheep showed TCA cycle, energetic and redox adaptations compared to AF-R. In this animal model, TCA cycle remodeling and associated redox and energetic responses determined the resistance to AF domestication, with potential relevance to identify new mechanistic determinants of AF progression in humans.