Study of electrophysiological, structural, and mitochondrial metabolism remodelling in a sheep model of atrial fibrillation monitored by telemetry

Abstract

Atrial Fibrillation (AF) stabilization depends on remodelling processes affecting the electrophysiological, metabolic, and structural properties of the atrial muscle. Develop an AF Sheep model to study the electrophysiogical, structural and bioenergetic remodelling of the cardiac tissue. An algorithm controlled pacemaker stimulating repeatedly the right atria at 10 Hz during 30 sec followed by 5 sec of sinus rhythm (SR) detection was used to induce AF. Its development was monitored by telemetry. Electrophysiological remodelling was studied in vivo by contact mapping and ex vivo by optical mapping. Structural remodelling was studied at the organ level using computed tomography (μCT) and at the mitochondrial level by electronic microscopy. Bioenergetic remodelling was evaluated on isolated mitochondria. AF sheep were kept 75 days before being studied. AF induction rate was 80%. AF developed and stabilized after 25 and 48 days, respectively. Animals remained less than 0.02 ± 0.03% in SR once AF was installed. In vivo contact mapping revealed a decreased voltage in AF atria compared to Sham. The highest AF frequencies were localised in the pulmonary veins. When compared to Sham, AF induced: (1) a 50% decrease of the atrial effective refractory periods; (2) a left atrial decrease in action potential duration; (3) an increase in atrial volumes; (4) Fat infiltration; (5) a decrease in mitochondrial cristae density; (6) a decrease in ATP synthesis rate; (7) an increased oxidation of the mitochondrial NAD(P)H pool; (9) an increased mitochondrial H2O2 emission, independently of the respiratory substrates used to fuel the electron transport chain. The AF Sheep model developed is characterized by occurrence of remodelling processes at different levels. Further studies will establish the time course of development of remodelling processes in order to improve AF therapeutics strategies by targeting atrial remodelling.