Ionic mechanisms underlying atrial electrical remodeling after a fontan-style operation in a canine model

Abstract

Atrial arrhythmia is an important cause of late death in patients after the Fontan-Style operation. However, the detailed electrophysiological characteristics of the post-Fontan atrium and its underlying mechanisms are largely unknown. In this study, we investigated electrophysiological characteristics and the ionic remodeling in the right atrium (RA) of a canine model after the Fontan operation. We performed the operation of RA to pulmonary artery connection to mimic the Fontan operation. We undertook hemodynamic measurements, cardiac electrophysiological studies, and ion current measurements. The expression of ionic channels was analyzed by PCR and western-blotting. Our Fontan model induced RA hypertension, enlarged the size of RA, and increased atrial fibrosis, representing the classic characteristic of Fontan patients. In the Fontan group, the atrial effective refractory period and the active potential duration were reduced, and the atrial tachycardia has been more often to be induced. The electrical conduction mapping showed that the Fontan group reduced the conduction velocity. The Fontan operation significantly down-regulated the expression of KCND3/Kv4.3, CACNA1C/Cav1.2 and SCN5A, but up-regulated the expression of KCNJ2/Kir2.1. Correspondingly, The Fontan operation reduced transient-outward (I to) and L-type Ca2 (I Ca,L) and I Na currents, while increasing the inward-rectifier current (I K1). Thus, the net shortening of the action potential in the post-Fontan atrium is associated with the altered expression of ionic channels which disturbed the balance between inward and outward currents. Taken together, the Fontan operation induces the ionic remodeling, and thus altered electrophysiological characteristics of the right atrium, improving our understanding on the pathophysiology of atrial arrhythmias in Fontan patients.

Arrhythmias in adults with congenital heart disease and heart failure

“…In a canine model mimicking Fontan surgery (ie, right atrium-to-pulmonary artery connection), changes in sodium, potassium, and calcium currents resulted in a net reduction in conduction velocity, shortening of the atrial action potential duration, and a reduction in the atrial effective refractory period, occasioning a higher proportion of inducible atrial arrhythmias. 12 Similarly, in a porcine model mimicking tetralogy of Fallot, optical mapping revealed a reduction in ventricular conduction velocity with a prolonged ventricular conduction time and regions of slow conduction remote from surgical scar. 13 Intramural heterogeneity in action potential duration and more frequent spontaneous arrhythmias were likewise noted.…”

Role and Applications of Experimental Animal Models of Fontan Circulation

“…However, it still remained an acute model without the effect of atrial dilatation or tissue remodeling [38,39]. In 2019, Wu et al explored the electrophysiological and histological changes in a canine model of atriopulmonary Fontan connection [40]. The authors observed spontaneous non-sustainable AF in five out of seven subjects at one-week post-procedure.…”

“…The authors observed spontaneous non-sustainable AF in five out of seven subjects at one-week post-procedure. Electrophysiological studies performed at one week showed a shortening of the atrial refractory period and reduced action potential duration due to changes in ionic channel expression, thereby creating a substrate for atrial arrhythmias; the histological study showed fibrotic remodeling after only one week [40]. The same team studied calcium homeostasis in atrial cells 14 days after the Fontan procedure in the same canine atriopulmonary connection model [41].…”

The immediate trends in atrial electrical remodeling for paroxysmal atrial fibrillation across different modes of catheter ablation

“…To date, the time course and pattern of AER are still not entirely clear 7 . There has been limited information on AER after ablation for PAF regarding short‐term trends, mostly in animal or in vitro experiments, and immediate trends, only from surface electrocardiogram studies in vivo 8‐11 . Electrophysiological studies and mappings always placed emphasis on long‐term trends after months or a year 7 .…”