Investigating the Mechanisms Underlying the Elevated Risk of Atrial Fibrillation in Metabolic Syndrome: A Tissue Level Mapping Study

Abstract

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and the overall prevalence of AF is estimated at 33.5 million patients worldwide. AF significantly increases morbidity and mortality. Current treatment of AF is suboptimal, as a one-size-fits-all treatment formula is used, regardless of the presence or absence of concomitant diseases which precipitate AF. It is well established that AF is a complex disease associated with obesity, diabetes, hypertension, and metabolic syndrome (MetS). MetS is a cluster of three of five atherosclerotic risk factors: abdominal obesity, elevated blood pressure, insulin resistance, high serum triglycerides and low levels of high-density lipoprotein. The prevalence of MetS is increasing rapidly and it is associated with a sedentary lifestyle, environmental stresses, and excessive caloric intake. Individual components of the syndrome are all linked with increased AF susceptibility, but the characteristics of the overall risk profile in patients with MetS remain unclear. Our overarching goal was to develop a mechanism-based understanding of the factors that elevate AF risk in MetS as a step toward effective upstream therapy for AF in patients with this syndrome. To address this issue, we established a diet-induced rabbit model of MetS and focussed on how atrial electrical and structural remodelling contributes to elevated AF risk in these animals. An advantage of using rabbits is that this species shares key atrial electrophysiological traits with humans. Our study in New Zealand white male rabbits over 40 weeks (6 MetS and 2 age-matched controls) showed that the animal model replicated key clinical components of MetS in humans: abdominal contours and body-mass-index were increased, indicating obesity; systolic, diastolic and mean arterial pressures were increased, consistent with early-stage hypertension; glucose metabolism times were longer, leading to pre-diabetic insulin resistance. Key plasma properties were also elevated, including triglycerides, cholesterol, and liver damage biomarkers. Atrial electrical properties characterised using a purpose-developed optical mapping system demonstrated significant electrical dysfunction and instability in the atria of MetS rabbits. Action potential duration (APD) and effective refractory period were prolonged, while conduction velocity (CV) was reduced. The slopes of APD and CV restitution relationships were increased dramatically at short coupling intervals – a known arrhythmogenic phenotype. Regional electrophysiological differences were also evident among the left atrium, right atrium and pulmonary veins. Finally, atrial arrhythmias were more easily induced, lasted longer, and were more stable in MetS animals than controls. Novel confocal imaging protocols were developed to characterise structural remodelling at the subcellular-to-tissue levels in MetS rabbit hearts to verify the presence of AF substrates at varying biological scales. We observed atrial dilation, extensive interstitial fibrosis, and cell hypertrophy, accompanied by reduced density of intracellular tubules associated with atrial calcium homeostasis. This study has contributed to improved understanding of the mechanisms that underlie MetS-induced AF by establishing a robust animal model of this syndrome and through the development of novel methods for characterising atrial electrical and structural remodelling in these animals. We speculate that the spatial APD heterogeneity, amplified at fast atrial rates, and upregulated fibrosis, may explain elevated AF risk in MetS. However, the mechanisms underlying APD prolongation/heterogeneity and the potential role of calcium haemodynamics in MetS are unclear. A major limitation of this study was that we only included limited rabbit numbers due to the impact of COVID-19 on our animal facility. A future larger-scale study to validate and further elaborate our results is warranted.