Po-02-148 unravelling the mechanisms underlying the elevated risk of atrial fibrillation in metabolic syndrome

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. It is well established that AF is a complex disease closely associated with metabolic syndrome (MetS). However, the mechanism underlying MetS-induced AF remains unclear. In addition, current treatment for AF is one-size-fits-all and does not consider the presence of concurrent antagonistic diseases which impair AF treatment. To develop a mechanism-based understanding of the factors that elevate AF risk in MetS. A diet induced MetS rabbit model was established to characterise atrial remodelling. Male New Zealand white rabbits in the MetS group were fed a high-fat, high-sucrose diet ad libitum, while the control had a standard diet (five MetS and two controls). At 40 weeks, animals were euthanised, hearts were excised and coronary perfused for optical mapping (DaVinci CMOS camera) at spatial and temporal resolutions of 20 μm2 and 1 kHz. AF inducibility and key cardiac electrophysiological biomarkers including action potential duration (APD) and conduction velocity (CV) were estimated using burst pacing, S1-S1 and S1-S2 protocols. Hearts were arrested, fixed and stored at 4°C. Key atrial regions were imaged from subcellular-to-tissue levels using epifluorescence imaging (Olympus FV1000 microscope, pixel-resolution 0.2 μm3), to characterise structural remodelling. Our animal model results show that, the obesogenic rabbits replicated key clinical components of MetS, including increased body-mass indices, increased blood pressure, prolonged glucose metabolism, and dyslipidaemia (Figure A). Our optical mapping illustrates that MetS hearts had prolonged APD (122.07 ± 14.18 ms vs 95.32 ± 5.62 ms, p<0.01), reduced CV and longer stable arrhythmic episodes. APD and CV restitution relationship slopes increased dramatically with reduction in diastolic intervals (Figure B), leading to reduced wavelength of re-entry. Finally, our structural analysis demonstrates increased atrial dilation, extensive fibrosis (3.16 ± 2.12 % vs 1.82 ± 0.68%, p<0.001), cell hypertrophy and reduced intracellular tubules in MetS (Figure C). This study has established a robust animal model in rabbits for studying the impact of MetS on cardiac diseases. Importantly, our results indicate that shortened wavelength, amplified by fast atrial rates and upregulated fibrosis, may be the primary tissue/organ level mechanism underlying the elevated AF risk in MetS.