Jérôme Kalifa

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

BACKGROUND Spectral analysis identifies localized sites of high-frequency activity during atrial fibrillation (AF). OBJECTIVE This study sought to determine the effectiveness of using real-time dominant frequency (DF) mapping for radiofrequency ablation of maximal DF (DFmax) sites and elimination of left-to-right frequency gradients in the long-term maintenance of sinus rhythm (SR) in AF patients. METHODS DF mapping was performed in 50 patients during ongoing AF (32 paroxysmal, 18 persistent), acquiring a mean of 117 +/- 38 points. Ablation was performed targeting DFmax sites, followed by circumferential pulmonary vein isolation. RESULTS Ablation significantly reduced DFs (Hz) in the LA (7.9 +/- 1.4 vs. 5.7 +/- 1.3, P <.001), coronary sinus (CS) (5.7 +/- 1.1 vs. 5.3 +/- 1.2, P = .006), and RA (6.3 +/- 1.4 vs. 5.4 +/- 1.3, P <.001) abolishing baseline left-to-right atrial DF gradient (1.7 +/- 1.7 vs. 0.2 +/- 0.9; P <.001). Only a significant reduction in DFs in all chambers with a loss of the left-to-right atrial gradient after ablation was associated with a higher probability of long-term SR maintenance in both paroxysmal and persistent AF patients. After a mean follow-up of 9.3 +/- 5.4 months, 88% of paroxysmal and 56% of persistent AF patients were free of AF (P = .02). Ablation of DFmax sites was associated with a higher probability of remaining both free of arrhythmias (78% vs. 20%; P = .001) and free of AF (88% vs. 30%; P <.001). CONCLUSION Radiofrequency ablation leading to elimination of LA-to-RA frequency gradients predicts long-term SR maintenance in AF patients.

Rotor Meandering Contributes to Irregularity in Electrograms during Atrial Fibrillation

BACKGROUND Radiofrequency ablation therapy of atrial fibrillation (AF) recently incorporated the analysis of dominant frequency (DF) and/or electrogram fractionation for guidance. However, the relationships between DF, fractionation, and spatiotemporal characteristics of the AF source remain unclear. OBJECTIVE We hypothesize that a meandering reentrant AF source contributes to the wave fractionation and is reflected in the power spectrum of local electrograms elsewhere in the rotors surroundings. METHODS Meandering rotors as AF sources were simulated in 2-dimensional models of human atrial tissue and recorded in isolated sheep hearts. Nondominant elements of the signals were differentiated from the dominant elements using singular value decomposition, whereby the purely periodic constituent (PC) relating to the rotors DF was eliminated rendering a residual constituent (RC) that consisted of all other activity. RESULTS Spectral analysis of the decomposed constituents revealed peaks corresponding to the meandering frequency of the rotor tip, the magnitudes of which were proportional to the size of and the distance to the rotor core. Similar analyses on epicardial optical signals and electrograms from isolated sheep hearts, as well as human complex fractionated atrial electrograms, showed applicability of the approach. CONCLUSION Increased meandering of the rotor driving AF reduces activation periodicity and increases fractionation. The spectral manifestation of the rotor activity beyond the meandering region makes it possible to characterize AF source stability, as well as DF in humans using electrode mapping.

Heterogeneous atrial wall thickness and stretch promote scroll waves anchoring during atrial fibrillation

AIMS Atrial dilatation and myocardial stretch are strongly associated with atrial fibrillation (AF). However, the mechanisms by which the three-dimensional (3D) atrial architecture and heterogeneous stretch contribute to AF perpetuation are incompletely understood. We compared AF dynamics during stretch-related AF (pressure: 12 cmH(2)O) in normal sheep hearts (n = 5) and in persistent AF (PtAF, n = 8)-remodelled hearts subjected to prolonged atrial tachypacing. We hypothesized that, in the presence of stretch, meandering 3D atrial scroll waves (ASWs) anchor in regions of large spatial gradients in wall thickness. METHODS AND RESULTS We implemented a high-resolution optical mapping set-up that enabled simultaneous epicardial- and endoscopy-guided endocardial recordings of the intact atria in Langendorff-perfused normal and PtAF (AF duration: 21.3 ± 11.9 days) hearts. The numbers and lifespan of long-lasting ASWs (>3 rotations) were greater in PtAF than normal (lifespan 0.9 ± 0.5 vs. 0.4 ± 0.2 s/(3 s of AF), P< 0.05). Than normal hearts, focal breakthroughs interacted with ASWs at the posterior left atrium and left atrial appendage to maintain AF. In PtAF hearts, ASW filaments seemed to span the atrial wall from endocardium to epicardium. Numerical simulations using 3D atrial geometries (Courtemanche-Ramirez-Nattel human atrial model) predicted that, similar to experiments, filaments of meandering ASWs stabilized at locations with large gradients in myocardial thickness. Moreover, simulations predicted that ionic remodelling and heterogeneous distribution of stretch-activated channel conductances contributed to filament stabilization. CONCLUSION The heterogeneous atrial wall thickness and atrial stretch, together with ionic and anatomic remodelling caused by AF, are the main factors allowing ASW and AF maintenance.

Mechanisms of stretch-induced atrial fibrillation in the presence and the absence of adrenocholinergic stimulation: Interplay between rotors and focal discharges

BACKGROUND Both atrial stretch and combined adrenocholinergic stimulation (ACS) have been shown to favor initiation and maintenance of atrial fibrillation (AF). Their respective contributions to the electrophysiological mechanism remains, however, incompletely understood. OBJECTIVE This study endeavored to determine the mechanism of maintenance of stretch-related AF (SRAF) in the presence and absence of ACS and to assess how focal discharges interact with rotors to modify the level of complexity in the activation patterns to perpetuate AF. METHODS Video imaging of AF dynamics was carried out using a SRAF model in isolated sheep hearts (n = 24). Pharmacological approaches were used to (1) mimic ACS with acetylcholine (1 microM) plus isoproterenol (0.03 microM), and (2) abolish triggered activity, in response to sarcoplasmic reticulum calcium release, with caffeine (5 mM, CA) or ryanodine (10 to 40 microM, RYA). RESULTS In the absence of ACS, on perfusion of CA or RYA, focal discharges were abolished and SRAF was terminated in most of the cases (10 of 13 experiments). In the presence of ACS, multiple drifting rotors as well as a large number of focal discharges were identified and only 1 of 11 AF episodes was terminated. CONCLUSIONS In the absence of ACS, SRAF is maintained by high-frequency focal discharges that generate fibrillatory conduction and wave breaks. In the presence of ACS, SRAF dynamics is characterized by multiple high frequency rotors that are rendered unstable by spatially distributed focal discharges.

Left versus right atrial difference in dominant frequency, K+ channel transcripts, and fibrosis in patients developing atrial fibrillation after cardiac surgery

BACKGROUND The development of atrial fibrillation (AF) after cardiac surgery is associated with adverse outcomes; however, the mechanism(s) that trigger and maintain AF in these patients are unknown. OBJECTIVE The purpose of this study was to test our hypothesis that postoperative AF is maintained by high-frequency sources in the left atrium (LA) resulting from ion channel and structural features that differ from the right atrium (RA). METHODS Forty-four patients with no previous history of AF who underwent cardiac surgery consented to LA and RA biopsies. Histologic sections evaluated fatty infiltration, fibrosis, and iron deposition; quantitative reverse transcription-polymerase chain reaction (RT-PCR) assessed ion channel expression. In a subset of 27 patients, LA and RA unipolar recording leads were also placed. In patients who developed AF, the dominant frequency (DF) for each lead was calculated using fast Fourier transform. RESULTS DFs during AF were LA 6.26 +/- 0.8 Hz, RA 4.56 +/- 0.7 Hz (P <.01). RT-PCR revealed LA-to-RA differences in mRNA abundance for Kir2.3 (1.8:1) and Kir3.4 (2.3:1). While LA fibrosis was greater in patients developing AF compared with those remaining in normal sinus rhythm (10.8% +/- 11% vs. 3.8% +/- 3.5%; P = .03), the amount of LA fibrosis inversely correlated with the LA DF. CONCLUSIONS This is the first demonstration of LA-to-RA frequency differences during postoperative AF, which are associated with LA-to-RA differences in mRNA levels for potassium channel proteins and LA fibrosis. These results strongly suggest that sources of AF after cardiac surgery are located in the LA and are stabilized by LA fibrosis.

The Atrial Septopulmonary Bundle of the Posterior Left Atrium Provides a Substrate for AF Initiation in a Model of Vagally Mediated Pulmonary Vein Tachycardia of the Structurally Normal Heart

Background— The posterior left atrium (PLA) and pulmonary veins (PVs) have been shown to be critical for atrial fibrillation (AF) initiation. However, the detailed mechanisms of reentry and AF initiation by PV impulses are poorly understood. We hypothesized that PV impulses trigger reentry and AF by undergoing wavebreaks as a result of sink-to-source mismatch at specific PV-PLA transitions along the septopulmonary bundle, where there are changes in thickness and fiber direction. Methods and Results— In 7 Langendorff-perfused sheep hearts AF was initiated by a burst of 6 pulses (CL 80 to 150ms) delivered to the left inferior or right superior PV ostium 100 to 150 ms after the sinus impulse in the presence of 0.5 &mgr;mol/L acetylcholine. The exposed septal-PLA endocardial area was mapped with high spatio-temporal resolution (DI-4-ANEPPS, 1000-fr/s) during AF initiation. Isochronal maps for each paced beat preceding AF onset were constructed to localize areas of conduction delay and block. Phase movies allowed the determination of the wavebreak sites at the onset of AF. Thereafter, the PLA myocardial wall thickness was quantified by echocardiography, and the fiber direction in the optical field of view was determined after peeling off the endocardium. Finally, isochrone, phase and conduction velocity maps were superimposed on the corresponding anatomic pictures for each of the 28 episodes of AF initiation. The longest delays of the paced PV impulses, as well as the first wavebreak, occurred at those boundaries along the septopulmonary bundle that showed sharp changes in fiber direction and the largest and most abrupt increase in myocardial thickness. Conclusion— Waves propagating from the PVs into the PLA originating from a simulated PV tachycardia triggered reentry and vagally mediated AF by breaking at boundaries along the septopulmonary bundle where abrupt changes in thickness and fiber direction resulted in sink-to-source mismatch and low safety for propagation.

Long-Term Frequency Gradients During Persistent Atrial Fibrillation in Sheep Are Associated With Stable Sources in the Left Atrium

Background— Dominant frequencies (DFs) of activation are higher in the atria of patients with persistent than paroxysmal atrial fibrillation (AF), and left atrial (LA)-to-right atrial (RA) DF gradients have been identified in both. However, whether such gradients are maintained as long-term persistent AF is established remains unexplored. We aimed at determining in vivo the time course in atrial DF values from paroxysmal to persistent AF in sheep and testing the hypothesis that an LA-to-RA DF difference is associated with LA drivers in persistent AF. Methods and Results— AF was induced using RA tachypacing (n=8). Electrograms were obtained weekly from an RA lead and an implantable loop recorder implanted near the LA. DFs were determined for 5-second-long electrograms (QRST subtracted) during AF in vivo and in ex vivo optical mapping. Underlying structural changes were compared with weight-matched controls (n=4). After the first AF episode, DF increased gradually during a 2-week period (7±0.21 to 9.92±0.31 Hz; n=6; P<0.05). During 9 to 24 weeks of AF, the DF values on the implantable loop recorder were higher than the RA (10.6±0.08 versus 9.3±0.1 Hz, respectively; n=7; P<0.0001). Subsequent optical mapping confirmed a DF gradient from posterior LA-to-RA (9.1±1.0 to 6.9±0.9 Hz; P<0.05) and demonstrated patterns of activation compatible with drifting rotors in the posterior LA. Persistent AF sheep showed significant enlargement of the posterior LA compared with controls. Conclusions— In the sheep, transition from paroxysmal to persistent AF shows continuous LA-to-RA DF gradients in vivo together with enlargement of the posterior LA, which harbors the highest frequency domains and patterns of activation compatible with drifting rotors.

Universal scaling law of electrical turbulence in the mammalian heart

Many biological processes, such as metabolic rate and life span, scale with body mass (BM) according to the universal law of allometric scaling: Y = aBMb (Y, biological process; b, scaling exponent). We investigated whether the temporal properties of ventricular fibrillation (VF), the major cause of sudden and unexpected cardiac death, scale with BM. By using high-resolution optical mapping, numerical simulations and metaanalysis of VF data in 11 mammalian species, we demonstrate that the interbeat interval of VF scales as VFcycle length = 53 × BM1/4, spanning more than four orders of magnitude in BM from mouse to horse.

Time- and frequency-domain analyses of atrial fibrillation activation rate: The optical mapping reference

BACKGROUND Time- and frequency-domain estimates of activation rate have been proposed to guide atrial fibrillation (AF) ablation in patients, but their electrophysiological correlates are unclear. OBJECTIVE This study sought to examine the relative correlation of average electrical cycle length (CL) and dominant frequency (DF) during AF with reference optical mapping measures. METHODS Eight sheep hearts were Langendorff-perfused and superfused with oxygenated Tyrode solution inside a tank representing the human thorax. Optical mapping (DI-4-ANEPPS) of 4 × 4 cm2 in the left atrium was performed at 0.5 mm/pixel and 600 fps. A 20-pole catheter was placed in the optical field of view to acquire 1.2-kHz unipolar recordings by the EnSite NavX System (ENS; St. Jude Medical, St. Paul, MN) optimized for CL and DF calculation. During AF, 5-second-long simultaneous optical and electrical signals were analyzed for CL and DF. RESULTS During pacing, DF measurements had fewer false results than CL (6.6% to 2.5% vs. 21.5% to 4.4% depending on filtering, P <.001). During AF in regions showing periodic waves on both sides of the catheter optical 1,000/CL versus DF correlation showed 95% confidence identity and was better than unipolar measurements in the ENS (adjusted R(2): 0.58879 vs. 0.12902; P < 10(-6)). DFs of unipolar signals correlated better than CLs with DFs of optical signals. Similarly, bipolar DF correlation with optical DF was not different from identity (P >.157), but the bipolar CL showed smaller identity with the optical CL (P <.0004). CONCLUSION DF values of unipolar and bipolar signals correlate with those of optical signals better than CL values for the respective signals.

Inhibition of platelet-derived growth factor-AB signaling prevents electromechanical remodeling of adult atrial myocytes that contact myofibroblasts

BACKGROUND Persistent atrial fibrillation (PAF) results in electromechanical and structural remodeling by mechanisms that are poorly understood. Myofibroblast proliferation and fibrosis are major sources of structural remodeling in PAF. Myofibroblasts also interact with atrial myocytes via direct physical contact and release of signaling molecules, which may contribute to remodeling. OBJECTIVE To determine whether myofibroblasts contribute to atrial myocyte electromechanical remodeling via direct physical contact and platelet-derived growth factor (PDGF) signaling. METHODS Myofibroblasts and myocytes from adult sheep atria were co-cultured for 24 hours. Alternatively adult sheep atrial myocytes were exposed to 1 ng/mL recombitant PDGF AB peptide for 24 hours. RESULTS Myocytes making contact with myofibroblasts demonstrated significant reduction (P ≤ .05) in peak L-type calcium current density, shortening of action potential duration (APD), and reduction in calcium transients. These effects were blocked by pretreatment with a PDGF-AB neutralizing anti-body. Heterocellular contact also severely disturbed the localization of the L-type calcium channel. Myocytes exposed to recombinant PDGF-AB peptide for 24 hours demonstrated reduced APD50, APD80 and Peak L-type calcium current. Pretreatment with a PDGF-AB neutralizing antibody prevented these effects. Finally, while control atrial myocytes did not respond in a 1:1 manner to pacing frequencies of 3 Hz or higher, atrial myocytes from hearts that were tachypaced for 2 months and normal myocytes treated with PDGF-AB for 24 hours could be paced up to 10 Hz. CONCLUSIONS In addition to leading to fibrosis, atrial myofibroblasts contribute to electromechanical remodeling of myocytes via direct physical contact and release of PDGF-AB, which may be a factor in PAF-induced remodeling.