Effects of selective mineralocorticoid receptor antagonism on atrial ion currents and early ionic tachycardia-induced electrical remodelling in rabbits

Abstract

Over the past years, the importance of the renin-angiotensin-aldosterone system in atrial fibrillation (AF) pathophysiology has been recognised. Lately, the role of aldosterone in AF pathophysiology and mineralocorticoid receptor (MR) antagonism in "upstream" AF treatment is discussed. Hypothesising that selective MR antagonism might also influence atrial ion currents (L-type calcium current [I (Ca,L)], transient outward potassium current [I (to)], sustained outward potassium current [I (sus)]) and their tachycardia-induced remodelling, the effects of an eplerenone treatment were studied in a rabbit model. Six groups each with four animals were built. Animals of the control group received atrial pacing leads, but in contrast to the pacing groups, no atrial tachypacing (600 per minute for 24 and 120 h immediately before heart removal) was applied. Animals of the eplerenone groups were instrumented/paced as the corresponding control/pacing groups, but were additionally treated with eplerenone (7 days before heart removal). Atrial tachypacing was associated with a reduction of I (Ca,L). I (to) was decreased after 24 h of tachypacing, but returned to control values after 120 h. In the absence of rapid atrial pacing, MR antagonism reduced I (Ca,L) to a similar extent as 120 h of tachypacing alone. Based on this lower "take-off level", I (Ca,L) was not further decreased by high-rate pacing. I (to) and its expected tachycardia-induced alterations were not influenced by MR antagonism. In our experiments, selective MR antagonism influenced atrial I (Ca,L) and its tachycardia-induced alterations. As changes of I (Ca,L) are closely linked with atrial calcium signalling, the relevance of these alterations in AF pathophysiology and, accordingly, AF treatment is likely and has to be further evaluated.

Attenuated Ventricular β-Adrenergic Response and Reduced Repolarization Reserve in a Rabbit Model of Chronic Heart Failure

“…In our study, QT prolongation was not present before week 7 (Fig. 2B), pointing to frequency dependency of the time-course of QT prolongation when comparing with that of Tsuji et al 6 The possible frequency dependency in time-course of HF induction by tachypacing is further supported by the findings of Laszlo et al, 9 where atrial tachypacing, leading to a 25% increase in ventricular rate, for 5 days did not lead to any signs of HF. Furthermore, we did not observe any mortality during induction of HF, which is an indication of a chronic HF model, whereas sudden cardiac death is a common phenomenon in acute HF.…”

“…One of these animal models uses long-term tachypacing, which over time will lead to HF due to the increased persistent workload on the heart. 4,5 These studies have been done in several species, among which rabbits have been extensively used [6][7][8][9][10][11] and have shown that besides structural remodeling, electrical remodeling is a common consequence of HF. Most of the tachypacinginduced HF studies have utilized a high-frequency and short-duration pacing protocol.…”

Aldosterone-Specific Activation of Cardiomyocyte Mineralocorticoid Receptor In Vivo

“…Indeed, this model highlighted the role of MR in electrophysiological remodeling, and subsequent posterior studies in nontransgenic models such as rats and rabbits confirmed these findings. 22,23 Most importantly, MR-Cardio mice allowed us to demonstrate that MR triggers cardiac arrhythmias and particularly promotes ventricular premature complexes, 12 suggesting that MR blockers may be effective in the treatment of arrhythmias. This was recently confirmed by a meta-analysis showing that MR blockers reduced episodes of ventricular premature complexes and ventricular tachycardia in humans.…”

The Effect of Renal Sympathetic Denervation (RSD) in Atrial Fibrillation (AF) Inducibility

“…It has been shown that Ang II increases the intracellular calcium concentration significantly in atrial myocytes in rat heart [18]. Recently, Laszlo et al demonstrated that selective mineralocorticoid receptor antagonist (eplerenone) influenced ICa,L in the early tachycardia-induced atrial electrical remodelling [19]. …”