Dominant Frequency Increase Rate Predicts Transition from Paroxysmal to Long-Term Persistent Atrial Fibrillation

Abstract

Background Little is known about the mechanisms underlying the transition from paroxysmal to persistent atrial fibrillation (AF). In an ovine model of long-standing persistent AF (LS-PAF) we tested the hypothesis that the rate of electrical and/or structural remodeling, assessed by dominant frequency (DF) changes, determines the time at which AF becomes persistent. Methods and Results Self-sustained AF was induced by atrial tachypacing. Seven sheep were sacrificed 11.5±2.3 days after the transition to persistent AF and without reversal to sinus rhythm (SR); 7 sheep were sacrificed after 341.3±16.7 days of LS-PAF. Seven sham-operated animals were in SR for 1 year. DF was monitored continuously in each group. RT-PCR, western blotting, patch-clamping and histological analyses were used to determine changes in functional ion channel expression and structural remodeling. Atrial dilatation, mitral valve regurgitation, myocyte hypertrophy, and atrial fibrosis occurred progressively and became statistically significant after the transition to persistent AF, with no evidence for left ventricular dysfunction. DF increased progressively during the paroxysmal-to-persistent AF transition and stabilized when AF became persistent. Importantly, the rate of DF increase (dDF/dt) correlated strongly with the time to persistent AF. Significant action potential duration (APD) abbreviation, secondary to functional ion channel protein expression changes (CaV1.2, NaV1.5 and KV4.2 decrease; Kir2.3 increase), was already present at the transition and persisted for one-year follow up. Conclusions In the sheep model of LS-PAF, the rate of DF increase predicts the time at which AF stabilizes and becomes persistent, reflecting changes in APD and densities of sodium, L-type calcium and inward rectifier currents.

Role of atrial tissue remodeling on rotor dynamics: an in vitro study

“…Our results are consistent with these experiments and further indicate that HL-1 cells maintained under spontaneously induced fibrillation present a reduction in I Na, I CaL , I to , and Cx43 ion channel gene expressions and an increase in I K1 gene expression, whereas nonfibrillating long-term HL-1 cell cultures did not present this gene expression remodeling, and, therefore, these changes can be attributed to fibrillationinduced remodeling and not culture time. This electrical remodeling is similar to what has been observed in the sheep atrial cardiomyocytes (20) and in patients with long-term AF (10). However, the analysis of other currents that may play an important role in AF remodeling (e.g., Cx40, Cx45, and I Kr ) did not show significant variations between early and late stages neither in the fibrillating group nor in the nonfibrillating group.…”

“…A critical obstacle for the elucidation of mechanisms responsible for chronic AF lies in the practical challenges associated with the development of experimental models that reproduce the electrophysiological characteristics of atrial remodeling. Animal models involve subjecting animals to weeks or months of sustained atrial arrhythmias, which implies significant economical, ethical, and time burdens (11,20). Other experimental models include in vitro cell cultures, which are typically obtained from neonatal rat hearts.…”

“…Persistent AF is usually characterized by higher DFs than paroxysmal AF, both in animals and patients (2,20). These higher DFs have been associated with a reduction in the time required by a rotor to complete a period due to 1) the reduction of the area of reentry (i.e., rotor meandering) and 2) an increase of the CV as a consequence of a higher sodium channel availability consequence of the cell hyperpolarization linked with the I K1 upregulation (25).…”

Electrophysiological characteristics of permanent atrial fibrillation: insights from research models of cardiac remodeling

“…Recently, a novel sheep model of long-term persistent AF, in which the tachypacing was stopped once AF was self-maintained [14], was used to indirectly corroborate the essential role of rotors in AF maintenance. This model reproduced the shortening in the dominant atrial cycle length (or an increase in the atrial dominant frequency) observed in persistent AF patients during the remodeling process [15]. Unfortunately, current mapping technology does not allow simultaneous evaluation of the global atrial activity and the tracking of each individual rotor which precludes the identification of the specific mechanisms responsible for AF maintenance.…”

Ablation of Driver Domains During Persistent Atrial Fibrillation

“…First, intensely remodeled and fibrotic atria are more difficult to ablate than normal atria. After an intense electrophysiological and structural remodeling during the transition from PAF to PsAF, 12 any region in the atrium is capable of maintaining PsAF. 13 Second, ablation approaches, even if often extensive, miss key regions that mechanistically maintain the fibrillatory activity.…”