Atrial fibrillation, sinoatrial and atrioventricular node dysfunction in a mouse model of heart failure with preserved ejection fraction

Abstract

Millions of people are affected by atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF), two disorders frequently found simultaneously. However, the interrelationship between these intertwined disorders is poorly understood, partly owing to the lack of preclinical models. We aimed to evaluate whether a recently developed mouse model of HFpEF could also be used as a model of AF and, potentially, to study the co-occurrence and interrelationship between the two conditions. Mice were fed a dietary regimen of high-fat diet and N^ω-nitro-l-arginine methyl ester in the drinking water to induce HFpEF. Twenty-four-hour ECG recordings acquired by telemetry were analysed for autonomic imbalance. After 24 h ECG recording, mice received isoprenaline, and a further 1 h of recording was assessed for chronotropic incompetence, susceptibility to atrial arrhythmia and conduction impairment. Evaluation of diastolic function was achieved by transcarotid catheterization and histological analysis performed on the hearts. Resting heart rate was significantly increased after 3 weeks of the dietary regimen, with a trend observed as early as 1 week. Premature atrial contractions, sinus pauses and atrioventricular blocks occurred significantly after 3 weeks of the dietary regimen. Significant diastolic dysfunction, chronotropic incompetence and higher occurrence of AF after isoprenaline stimulation were observed in the HFpEF group at 6 weeks of the dietary regimen. Our study revealed that sinoatrial node and atrial dysfunction precede the simultaneous occurrence of AF, diastolic dysfunction and chronotropic incompetence. This mouse HFpEF model might be helpful for studying the interdependence between AF and HFpEF.

Keywords: atrial fibrillation; atrioventricular block; chronotropic incompetence; diastolic dysfunction; heart failure with preserved ejection fraction; sinoatrial node dysfunction; sinus pauses.