Mechanisms of atrial fibrillation: rotors, ionic determinants, and excitation frequency

Abstract

Atrial fibrillation (AF) is the most common cardiac arrhythmia; however, therapy is suboptimal. We review recent data on dynamics of wave propagation during AF and its mechanistic link to the substrate. Data show that the dominant frequency (DF) increase during transition to persistent AF may be explained by rotor acceleration. We discuss how translation of experimentally derived understanding of the rotors may find its way into the clinic, focusing on studies analyzing spatial distribution of DF in the atria of patients with paroxysmal versus persistent AF, and how that knowledge might contribute to improve the outcome of AF ablation procedures.

Keywords: Atrial fibrillation; Dominant frequency; Remodeling; Rotors.

Figure 1

Computer model of action potential propagation from a pectinate muscle to the atrial wall. A 3-dimensional (60×60×60 elements) model includes a 1-dimensional bundle attached to a 2-dimensional sheet (left panel). Periodic stimulation (Stim) was applied at the top edge of the bundle and the impulse was allowed to propagate downward with conduction velocity of ~0.29 m/sec and to invade the two dimensional sheet. The voltage time series and corresponding power spectra are shown for a site near the stimulation point and a site at the sheet. Comparison between the points indicates a 3:2 pattern of propagation into the sheet with a concomitant spectral transformation and a DF shift from 8.4 to 5.7 Hz. From Jalife J, Berenfeld O, Skanes A, Mandapati R. Mechanisms of atrial fibrillation: Mother rotors or multiple daughter wavelets, or both? J.Cardiovasc.Electrophysiol. 1998;9:S2–S12; with permission.

Figure 2

The `breakdown frequency' in a sheep heart. A. Endocardial and epicardial DF maps of same isolated RA preparation paced at 5.0 and 7.7 Hz. Note appearance of heterogeneous DF domains at 7.7 Hz. B. Response DFs versus the pacing rate (n=5). Each symbol represents one experiment. Pacing BB at rates below ~6.7 Hz, results in 1:1 activation. At higher rates, the number of domains increases but the DFs' value decrease. SVC, superior vena cava; CT, crista terminalis. From Berenfeld O, Zaitsev AV, Mironov SF, Pertsov AM, Jalife J. Frequency-dependent breakdown of wave propagation into fibrillatory conduction across the pectinate muscle network in the isolated sheep right atrium. Circ.Res. 2002;90:1173–1180; with permission.

Figure 3

Patterns of activation in the PLA and LAA of isolated hearts during AF. A. snapshots from a phase movie show a rotor appearing in the field of view of the LAA. The patterns of activation switch from breakthroughs (0-to-113 ms) to a meandering rotor (301-to-541 ms). B. the DF_max is in the LAA when the rotor stays in the field of view and goes back to PLA when the rotor drifts outside the LAA. Adapted from Filgueiras-Rama D, Price NF, Martins RP, Yamazaki M, Avula UM, Kaur K, Kalifa J, Ennis SR, Hwang E, Devabhaktuni V, Jalife J, Berenfeld O. Long-term frequency gradients during persistent atrial fibrillation in sheep are associated with stable sources in the left atrium. Circulation. Arrhythmia and electrophysiology. 2012;5:1160–1167; with permission.

Figure 4

Rate of increase in DF during paroxysmal AF predicts transition to persistent AF. A. representative graphs for three animals. Left, sheep with the highest dDF/dt (0.14 Hz/day, time to transition 19 days); middle, intermediate dDF/dt (0.03 Hz/day, time to transition 46 days); right, lowest dDF/dt (0.003 Hz/day, time to transition 346 days); left and right from transition group, middle from LS-PAF group. B. log-log plots of time from first episode to onset of self-sustained persistent AF versus dDF/dt for the RA (intracardiac electrode), LA (loop recorder) and ECG (surface Lead 1). Each point represents an animal. dDF/dt correlated with time to develop self-sustained persistent AF. N=14 for RA and ECG, N=8 for LA. From Martins RP, Kaur K, Hwang E, Ramirez RJ, Willis BC, Filgueiras-Rama D, Ennis SR, Takemoto Y, Ponce-Balbuena D, Zarzoso M, O'Connell RP, Musa H, Guerrero-Serna G, Avula UM, Swartz MF, Bhushal S, Deo M, Pandit SV, Berenfeld O, Jalife J. Dominant frequency increase rate predicts transition from paroxysmal to long-term persistent atrial fibrillation. Circulation. 2014;129:1472–1482; with permission.

Figure 5

Simulations predict consequences of ion channel remodeling on rotor frequency. A. Action potential traces for sham, paroxysmal and transition AF predicted by experimentally derived ion channel changes. APD₉₀ was abbreviated in both paroxysmal and transition AF compared to sham. Resting membrane potential was hyperpolarized −2 mV. B. Rotor in paroxysmal (left) had lower frequency than transition AF. C. Rotors in paroxysmal AF meandered considerably and eventually self-terminated upon collision with boundary. In transition AF, the rotor was stable, had higher frequency and persisted throughout the simulation. From Martins RP, Kaur K, Hwang E, Ramirez RJ, Willis BC, Filgueiras-Rama D, Ennis SR, Takemoto Y, Ponce-Balbuena D, Zarzoso M, O'Connell RP, Musa H, Guerrero-Serna G, Avula UM, Swartz MF, Bhushal S, Deo M, Pandit SV, Berenfeld O, Jalife J. Dominant frequency increase rate predicts transition from paroxysmal to long-term persistent atrial fibrillation. Circulation. 2014;129:1472–1482; with permission.

Figure 6

DF analysis in AF patients. A. Bipolar electrograms and corresponding power spectra obtained from the RIPV (left) and posterior RA in a patient with spontaneous paroxysmal AF. Each site shows distinct DF (8.1 and 4.2 Hz in RIPV and RA, respectively) demonstrating the utility of spectral analysis. B. DF map in a patient with paroxysmal AF (Posterior-anterior view; 6 hours). Note HDF sites in each of the PVs. Ablation sequence in this patient was LSPV, LIPV RSPV and RIPV (site of AF termination, black arrow); AFCL increased by 10 ms, 25 ms, 9 ms and 75 ms, respectively, before termination. C. DF map in a patient with permanent AF (24 months). The maximal DF and atrial frequency are higher than the patient in panel A. In addition, HDF sites are located outside the PVs (red arrows). Ablation sequence in this patient was RIPV, RSPV, LSPV and LIPV; AFCL increased by 5 ms, 2 ms, 0 ms and 5 ms respectively. Color-bar, DF scale in Hz. PAF: paroxysmal AF, CAF: permanent AF, LSPV, LIPV, RSPV, RIPV: Left/right superior/inferior pulmonary veins (PVs). From Sanders P, Berenfeld O, Hocini M, Jais P, Vaidyanathan R, Hsu LF, Garrigue S, Takahashi Y, Rotter M, Sacher F, Scavee C, Ploutz-Snyder R, Jalife J, Haissaguerre M. Spectral analysis identifies sites of high-frequency activity maintaining atrial fibrillation in humans. Circulation. 2005;112:789–797; with permission.

Figure 7

A, Real-time atrial DF map (posterior view; CARTO system) in a paroxysmal AF patient. Purple, primary DFmax site (red arrow) on right intermediate PV (RIPV). Red dots, circumferential ablation line. B, bipolar recording (top) of primary DFmax site and its power spectrum (bottom) prior to ablation. C, surface ECG leads and intracardiac lasso catheter electrograms within RIPV; ablation catheter in the encircled area, CS and HRA catheter during isolation of right-sided PVs. Catheters recording outside the encircled area (CS, HRA) show conversion to SR (star) whereas the lasso catheter inside RIPV demonstrates ongoing AF. From Atienza F, Almendral J, Jalife J, Zlochiver S, Ploutz-Snyder R, Torrecilla EG, Arenal A, Kalifa J, Fernandez-Aviles F, Berenfeld O. Real-time dominant frequency mapping and ablation of dominant frequency sites in atrial fibrillation with left-to-right frequency gradients predicts long-term maintenance of sinus rhythm. Heart rhythm : the official journal of the Heart Rhythm Society. 2009;6:33–40; with permission.