Abstract
Initiation and maintenance of atrial fibrillation (AF) is often associated with pharmacologically or pathologically induced bradycardic states. Even drugs specifically developed in order to counteract cardiac arrhythmias often combine their action with bradycardia and, in turn, with development of AF, via still largely unknown mechanisms. This study aims to simulate action potential (AP) conduction between sinoatrial node (SAN) and atrial cells, either arranged in cell pairs or in a one-dimensional strand, where the relative amount of SAN membrane is made varying, in turn, with junctional resistance. The source-sink relationship between the two membrane types is studied in control conditions and under different simulated chronotropic interventions, in order to define a safety factor for pacemaker-to-atrial AP conduction (SASF) for each treatment. Whereas antiarrhythmic-like interventions which involve downregulation of calcium channels or of calcium handling decrease SASF, the simulation of Ivabradine administration does so to a lesser extent. Particularly interesting is the increase of SASF observed when downregulation G Kr, which simulates the administration of class III antiarrhythmic agents and is likely sustained by an increase in I CaL. Also, the increase in SASF is accompanied by a decreased conduction delay and a better entrainment of repolarization, which is significant to anti-AF strategies.
Highlights
Atrial fibrillation (AF) is the most common cardiac arrhythmia, characterized by high morbidity and mortality; the mechanisms underlying its initiation, known to be complex and multifactorial, are still largely unexplained [1]
The dynamical behavior of the cell pair can be summarized in 3 different types of response: high values of RJ correspond to a condition when sinoatrial node (SAN) pacing occurs but does not provide enough electrotonic current to drive the atrial cell at its own frequency (“pace and not drive,” P&ND, red in panel (d))
This is shown in panels (c1) and (c2): in (c1) RJ is set to be infinitely high, cells are practically uncoupled, and SAN cell displays its intrinsic spontaneous rhythm whereas atrial cell is quiescent at its resting potential (Vr = −75 mV)
Summary
Atrial fibrillation (AF) is the most common cardiac arrhythmia, characterized by high morbidity and mortality; the mechanisms underlying its initiation, known to be complex and multifactorial, are still largely unexplained [1]. The most generally recognized causes of initiation and maintenance of AF are conduction abnormalities along interatrial accessory pathways [2, 3], abnormal interaction between sinoatrial node (SAN) cells and cardiac tissue nearby the insertion of pulmonary veins [4], increased fibrotic deposition within atrial tissue [5], electrical and calcium handling remodeling per se [6, 7] or secondary to atrial tachycardia (AT) [8, 9], and altered connexins ratio (Cx40/Cx43) leading to heterogeneity of conduction velocity [10, 11] This complex scenario basically underlies two main pro-AF mechanisms, that is, triggered activity and reentry [12]. Analogous adverse effect is commonly found with Dobutamine and with other antiarrhythmic
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