Mechanisms of atrial fibrillation in aged rats with heart failure with preserved ejection fraction

ABSTRACT Background Although ∼20% of the elderly develop atrial fibrillation (AF), little is known about the mechanisms. Heart failure with preserved ejection fraction (HFpEF), which is associated with AF, is more common in aged females than in males Objective To identify potential mechanisms of AF in an age-related HFpEF model. Methods In aged (21-24-month-old) female Fischer F344 rats, which are prone to HFpEF, we induced AF by atrial pacing. Young Fischer F344 (3-4-month-old) and age-matched Sprague Dawley rats (27-month-old) female rats served as controls. Phenotyping included echocardiography to assess left ventricular (LV) structure/function; in vivo electrophysiology and ex vivo high-resolution optical mapping to assess AF vulnerability; systemic and atrial inflammatory profiling; atrial histology; and expression of inflammasome signaling proteins. Results Aged rats developed LV hypertrophy, left atrial enlargement, diastolic dysfunction, and pulmonary congestion, without EF impairment, thus meeting the criteria for HFpEF. Increased serum inflammatory markers, hypertension, and obesity further characterize aged females. Sinoatrial and atrioventricular node dysfunction were associated with high inducibility of AF in aged rats. Ex vivo electric activation mapping revealed abnormal β-adrenergic responsiveness and slowed conduction velocity. Atrial inflammasome signaling was enhanced in aged rats, which may contribute to fibrotic remodeling and high AF susceptibility. Conclusions Together, our data demonstrate that aging-related atrial remodeling and HFpEF are associated with atrial enlargement, fibrosis, conduction abnormalities, and nodal dysfunction, favoring a substrate conducive to AF.