Human Atrial Fibrillation Research Articles

Bi-Atrial Electrical and Structural Remodelling in Heart Failure: Electroanatomic Mapping in Persistent Atrial Fibrillation in Humans

Bi-Atrial Electrical and Structural Remodelling in Heart Failure: Electroanatomic Mapping in Persistent Atrial Fibrillation in Humans

Comparison of Two-Dimensional vs Three-Dimensional Phase Mapping in the Detection of Rotors During Human Persistent Atrial Fibrillation

Comparison of Two-Dimensional vs Three-Dimensional Phase Mapping in the Detection of Rotors During Human Persistent Atrial Fibrillation

Three-Dimensional Wavemapping of Human Persistent Atrial Fibrillation

Three-Dimensional Wavemapping of Human Persistent Atrial Fibrillation

The Efficacy of Multipolar Basket Catheters in Mapping the Entire Left Atrium in Human Persistent Atrial Fibrillation

The Efficacy of Multipolar Basket Catheters in Mapping the Entire Left Atrium in Human Persistent Atrial Fibrillation

The Spatiotemporal Stability of Dominant Frequency Sites in In-Silico Modeling of 3-Dimensional Left Atrial Mapping of Atrial Fibrillation.

BackgroundWe previously reported that stable rotors were observed in in-silico human atrial fibrillation (AF) models, and were well represented by dominant frequency (DF). We explored the spatiotemporal stability of DF sites in 3D-AF models imported from patient CT images of the left atrium (LA).MethodsWe integrated 3-D CT images of the LA obtained from ten patients with persistent AF (male 80%, 61.8 ± 13.5 years old) into an in-silico AF model. After induction, we obtained 6 seconds of AF simulation data for DF analyses in 30 second intervals (T1–T9). The LA was divided into ten sections. Spatiotemporal changes and variations in the temporal consistency of DF were evaluated at each section of the LA. The high DF area was defined as the area with the highest 10% DF.Results1. There was no spatial consistency in the high DF distribution at each LA section during T1–T9 except in one patient (p = 0.027). 2. Coefficients of variation for the high DF area were highly different among the ten LA sections (p < 0.001), and they were significantly higher in the four pulmonary vein (PV) areas, the LA appendage, and the peri-mitral area than in the other LA sections (p < 0.001). 3. When we conducted virtual ablation of 10%, 15%, and 20% of the highest DF areas (n = 270 cases), AF was changed to atrial tachycardia (AT) or terminated at a rate of 40%, 57%, and 76%, respectively.ConclusionsSpatiotemporal consistency of the DF area was observed in 10% of AF patients, and high DF areas were temporally variable. Virtual ablation of DF is moderately effective in AF termination and AF changing into AT.

Differential left-to-right atria gene expression ratio in human sinus rhythm and atrial fibrillation: Implications for arrhythmogenesis and thrombogenesis

BackgroundAtrial fibrillation (AF) causes atrial remodeling, and the left atrium (LA) is the favored substrate for maintaining AF. It remains unclear if AF remodels both atria differently and contributes to LA arrhythmogenesis and thrombogenesis. Therefore, we wished to characterize the transcript profiles in the LA and right atrium (RA) in sinus rhythm (SR) and AF respectively. MethodsPaired LA and RA appendages acquired from patients receiving cardiac surgery were used for ion-channel- and whole-exome-based transcriptome analysis. The ultrastructure was evaluated by immunohistochemistry. ResultsTwenty-two and twenty ion-channels and transporters were differentially expressed between the LA and RA in AF and SR, respectively. Among these, 15 genes were differentially expressed in parallel between AF and SR. AF was associated with increased LA/RA expression ratio in 9 ion channel-related genes, including genes related to calcium handling. In microarray, AF was associated with a differential LA/RA gene expression ratio in 309 genes, and was involved in atherosclerosis-related signaling. AF was associated with the upregulation of thrombogenesis-related genes in the LA appendage, including P2Y12, CD 36 and ApoE. Immunohistochemistry showed higher expressions of collagen-1, oxidative stress and TGF-β1 in the RA compared to the LA. ConclusionsAF was associated with differential LA-to-RA gene expression related to specific ion channels and pathways as well as upregulation of thrombogenesis-related genes in the LA appendage. Targeting the molecular mechanisms underlying the LA-to-RA difference and AF-related remodeling in the LA appendage may help provide new therapeutic options in treating AF and preventing thromboembolism in AF.

Acute effects of unilateral temporary stellate ganglion block on human atrial electrophysiological properties and atrial fibrillation inducibility

In experimental models, stellate ganglion block (SGB) reduces the induction of atrial fibrillation (AF), while data in humans are limited. The aim of this study was to assess the effect of unilateral SGB on atrial electrophysiological properties and AF induction in patients with paroxysmal AF. Thirty-six patients with paroxysmal AF were randomized in a 2:1 order to temporary, transcutaneous, pharmaceutical SGB with lidocaine or placebo before pulmonary vein isolation. Lidocaine was 1:1 randomly infused to the right or left ganglion. Before and after randomization, atrial effective refractory period (ERP) of each atrium, difference between right and left atrial ERP, intra- and interatrial conduction time, AF inducibility, and AF duration were assessed. After SGB, right atrial ERP was prolonged from a median (1st-3rd quartile) of 240 (220-268) ms to 260 (240-300) ms (P < .01) and left atrial ERP from 235 (220-260) ms to 245 (240-280) ms (P < .01). AF was induced by atrial pacing in all 24 patients before SGB, but only in 13 patients (54%) after the intervention (P < .01). AF duration was shorter after SGB: 1.5 (0.0-5.8) minutes from 5.5 (3.0-12.0) minutes (P < .01). Intra- and interatrial conduction time was not significantly prolonged. No significant differences were observed between right and left SGB. No changes were observed in the placebo group. Unilateral temporary SGB prolonged atrial ERP, reduced AF inducibility, and decreased AF duration. An equivalent effect of right and left SGB on both atria was observed. These findings may have a clinical implication in the prevention of drug refractory and postsurgery AF and deserve further clinical investigation.

Selective downregulation of mitochondrial electron transport chain activity and increased oxidative stress in human atrial fibrillation.

Mitochondria are critical for maintaining normal cardiac function, and a deficit in mitochondrial energetics can lead to the development of the substrate that promotes atrial fibrillation (AF) and its progression. However, the link between mitochondrial dysfunction and AF in humans is still not fully defined. The aim of this study was to elucidate differences in the functional activity of mitochondrial oxidative phosphorylation (OXPHOS) complexes and oxidative stress in right atrial tissue from patients without (non-AF) and with AF (AF) who were undergoing open-heart surgery and were not significantly different for age, sex, major comorbidities, and medications. The overall functional activity of the electron transport chain (ETC), NADH:O2 oxidoreductase activity, was reduced by 30% in atrial tissue from AF compared with non-AF patients. This was predominantly due to a selective reduction in complex I (0.06 ± 0.007 vs. 0.09 ± 0.006 nmol·min(-1)·citrate synthase activity(-1), P = 0.02) and II (0.11 ± 0.012 vs. 0.16 ± 0.012 nmol·min(-1)·citrate synthase activity(-1), P = 0.003) functional activity in AF patients. Conversely, complex V activity was significantly increased in AF patients (0.21 ± 0.027 vs. 0.12 ± 0.01 nmol·min(-1)·citrate synthase activity(-1), P = 0.005). In addition, AF patients exhibited a higher oxidative stress with increased production of mitochondrial superoxide (73 ± 17 vs. 11 ± 2 arbitrary units, P = 0.03) and 4-hydroxynonenal level (77.64 ± 30.2 vs. 9.83 ± 2.83 ng·mg(-1) protein, P = 0.048). Our findings suggest that AF is associated with selective downregulation of ETC activity and increased oxidative stress that can contribute to the progression of the substrate for AF.

209-03: Noninvasive Phase Mapping of Atrial Fibrillation in Humans: Comparison with Invasive Mapping by PentaRay Nav Catheters

209-03: Noninvasive Phase Mapping of Atrial Fibrillation in Humans: Comparison with Invasive Mapping by PentaRay Nav Catheters

Ablating atrial fibrillation: A translational science perspective for clinicians

Although considerable progress has been made in developing ablation approaches to cure atrial fibrillation (AF), outcomes are still suboptimal, especially for persistent and long-lasting persistent AF. In this topical review, we review the arrhythmia mechanisms, both reentrant and nonreentrant, that are potentially relevant to human AF at various stages/settings. We describe arrhythmia mapping techniques used to distinguish between the different mechanisms, with a particular focus on the detection of rotors. We discuss which arrhythmia mechanisms are likely to respond to ablation, and the challenges and prospects for improving upon current ablation strategies to achieve better outcomes.

Up-regulation of miR-31 in human atrial fibrillation begets the arrhythmia by depleting dystrophin and neuronal nitric oxide synthase.

Atrial fibrillation (AF) is a growing public health burden, and its treatment remains a challenge. AF leads to electrical remodeling of the atria, which in turn promotes AF maintenance and resistance to treatment. Although remodeling has long been a therapeutic target in AF, its causes remain poorly understood. We show that atrial-specific up-regulation of microRNA-31 (miR-31) in goat and human AF depletes neuronal nitric oxide synthase (nNOS) by accelerating mRNA decay and alters nNOS subcellular localization by repressing dystrophin translation. By shortening action potential duration and abolishing rate-dependent adaptation of the action potential duration, miR-31 overexpression and/or disruption of nNOS signaling recapitulates features of AF-induced remodeling and significantly increases AF inducibility in mice in vivo. By contrast, silencing miR-31 in atrial myocytes from patients with AF restores dystrophin and nNOS and normalizes action potential duration and its rate dependency. These findings identify atrial-specific up-regulation of miR-31 in human AF as a key mechanism causing atrial dystrophin and nNOS depletion, which in turn contributes to the atrial phenotype begetting this arrhythmia. miR-31 may therefore represent a potential therapeutic target in AF.

Intermittent drivers anchoring to structural heterogeneities as a major pathophysiological mechanism of human persistent atrial fibrillation.

The mechanisms responsible for perpetuation of human persistent atrial fibrillation (AF) are controversial and probably vary between individuals. A wide spectrum of mechanisms have been described in experimental studies, ranging from a single localized stable (focal/reentrant) source, to multiple sources, up to diffuse bi-atrial wavelets. We characterized AF drivers in patients with persistent AF (lasting less than 1year) using novel high resolution mapping, imaging and modelling approaches with the objective of evaluating their relationship to atrial structural heterogeneities. Using panoramic non-invasive mapping in humans, focal or reentrant sources driving AF waves were identified, originating from multiple distinct regions and exhibiting short lifespans and periodic recurrences in the same locations. The reentrant driver regions harboured long, fractionated electrograms covering most of the fibrillatory cycle lengths with varying beat-to-beat sequences suggestive of unstable trajectories attached to slow conducting heterogeneous tissue. MRI atrial imaging demonstrated that such drivers preferentially clustered at the borders of fibrotic atrial regions. In patient-specific computer simulations, sustained AF was shown to be driven by meandering transitory reentries attached to fibrosis borders expressing specific metrics in density and extent. Finally, random microstructural alterations devoid of cellular electrical changes were modelled, showing that a percolation mechanism could also explain atrial reentries and complex fractionated electrograms. These data from clinical, imaging and computational studies strongly suggest that intermittent and spatially unstable drivers anchoring to structural heterogeneities are a major pathophysiological mechanism in human persistent atrial fibrillation.

Direct Proof of Endo-Epicardial Asynchrony of the Atrial Wall During Atrial Fibrillation in Humans.

The presence of focal fibrillation waves during atrial fibrillation (AF) can, besides ectopic activity, also be explained by asynchronous activation of the atrial endo- and epicardial layer and transmurally propagating fibrillation waves. To provide direct proof of endo-epicardial asynchrony, we performed simultaneous high-resolution mapping of the right atrial endo- and epicardial wall during AF in humans. Intraoperative mapping of the endo- and epicardial right atrial wall was performed during (induced) AF in 10 patients with AF (paroxysmal: n=3; persistent: n=4; and longstanding persistent: n=3) and 4 patients without a history of AF. A clamp made of 2 rectangular 8×16 electrode arrays (interelectrode distance 2 mm) was inserted into the incision in the right atrial appendage. Recordings of 10 seconds of AF were analyzed to determine the incidence of asynchronous endo-epicardial activation times (≥15 ms) of opposite electrodes. Asynchronous endo-epicardial activation ranged between 0.9 and 55.9% without preference for either side. Focal waves appeared equally frequent at endocardium and epicardium (11% versus 13%; ITALIC! P=0.18). Using strict criteria for breakthrough (presence of an opposite wave within 4 mm and ≤14 ms before the origin of the focal wave), the majority (65%) of all focal fibrillation waves could be attributed to endo-epicardial excitation. We provided the first evidence for asynchronous activation of the endo-epicardial wall during AF in humans. Endo-epicardial asynchrony may play a major role in the pathophysiology of AF and may offer an explanation why in some patients therapy fails.

The two-pore domain potassium channel, TWIK-1, has a role in the regulation of heart rate and atrial size

The two-pore domain potassium (K+) channel TWIK-1 (or K2P1.1) contributes to background K+ conductance in diverse cell types. TWIK-1, encoded by the KCNK1 gene, is present in the human heart with robust expression in the atria, however its physiological significance is unknown. To evaluate the cardiac effects of TWIK-1 deficiency, we studied zebrafish embryos after knockdown of the two KCNK1 orthologues, kcnk1a and kcnk1b. Knockdown of kcnk1a or kcnk1b individually caused bradycardia and atrial dilation (p<0.001 vs. controls), while ventricular stroke volume was preserved. Combined knockdown of both kcnk1a and kcnk1b resulted in a more severe phenotype, which was partially reversed by co-injection of wild-type human KCNK1 mRNA, but not by a dominant negative variant of human KCNK1 mRNA. To determine whether genetic variants in KCNK1 might cause atrial fibrillation (AF), we sequenced protein-coding regions in two independent cohorts of patients (373 subjects) and identified three non-synonymous variants, p.R171H, p.I198M and p.G236S, that were all located in highly conserved amino acid residues. In transfected mammalian cells, zebrafish and wild-type human TWIK-1 channels had a similar cellular distribution with predominant localization in the endosomal compartment. Two-electrode voltage-clamp experiments using Xenopus oocytes showed that both zebrafish and wild-type human TWIK-1 channels produced K+ currents that are sensitive to external K+ concentration as well as acidic pH. There were no effects of the three KCNK1 variants on cellular localization, current amplitude or reversal potential at pH7.4 or pH6. Our data indicate that TWIK-1 has a highly conserved role in cardiac function and is required for normal heart rate and atrial morphology. Despite the functional importance of TWIK-1 in the atrium, genetic variation in KCNK1 is not a common primary cause of human AF.

Identification of Rotors during Human Atrial Fibrillation Using Contact Mapping and Phase Singularity Detection: Technical Considerations.

To explore technical challenges of phase singularity (PS) mapping during atrial fibrillation (AF) using direct contact electrograms. AF mapping was performed in high-density epicardial recordings of human paroxysmal (PAF) or persistent (PersAF) (N = 20 pts) AF with an array of 16×16 electrodes placed on atrial epicardium. PS points were detected using subsets of electrodes forming rings of varying sizes. PS detection using a 2×2 electrode ring identified 0.88±1.00 PS/s in PAF group and 3.91 ± 2.51 per s in PersAF group (p < 0.001) in 2.4 × 2.4 cm mapping area. All detected PS had a short lifespan with the longest being 1100 ms (6.8 rotations). Exploration of the PS detection in a numerical model demonstrated that at least eight electrodes are required to avoid frequent false positive PS detection due to chance. Application of a detection grid consisting a double ring of electrodes (2 × 2 and 4 × 4 rings) decreased the number of false positive detections. The double ring was more resilient to electrode swapping (with just three instances of false positives versus 4380 false positives using 2 × 2 ring). The number of detected rotors critically depends upon the parameters of the detection algorithm, especially the number of electrodes used to detect PS. Based on our results, we recommend double ring comprised of 2 × 2 and 4 × 4 grid of electrodes for robust rotor detection. Great methodological care has to be taken before equating detected PS with rotating waves and using PS detection algorithms to guide catheter ablation of AF.

THE MECHANISMS OF THE ATRIAL FIBRILLATION TERMINATION

Understanding of the mechanisms of the atrial fibrillation (AF) termination may lead to improvement of AF treatment. The aim of this study was to investigate termination of AF in humans. We studied 6 patients (48.7±2.8 years old, 1 female) with paroxysmal AF undergoing a noninvasive ECG imaging (

0218 : Multiple components of voltage-activated calcium current in rat pulmonary vein cardiomyocytes

Ectopic activity arising from cardiomyocytes (CM) in the pulmonary vein (PV) plays a prominent role in the onset of atrial fibrillation in humans. Norepinephrine induces an automatic activity occurring in bursts in rat PV CM (but not in left atria; LA) which depends on Ca channels. Thus, the aim of this study was to compare the Ca current I Ca in rat PV and LA CM (and for comparison, left ventricle – LV) from adult male Wistar rats. Whole cell I Ca (2mM CaCl 2 ) was recorded with classical Na + - and K + -free solutions. Peak I Ca density at +15mV is significantly higher in PV (4.64±0.20pA/pF, n=56) than in LA CM (3.44±0.19pA/pF, n=25, P<0.01) and identical to that of LV CM (5.00±0.39 pA/pF, n=25). The IV curve is biphasic in PV and LA CM due to an I Ca T-like current present between -55 and -30mV representing respectively 10% and 5% of maximum peak I Ca . Although it is insensitive to nifedipine (NIF, 5 and 10μM), increased by CaCl 2 (2 to 5mM) and suppressed by its removal, the lack of effect of NiCl 2 (40μM) and of TTA-A2 (10 and 100nM) suggest that Ca v 3.1 and Ca v 3.2 expressed in the rat heart are not involved in this fast activating and inactivating current. Moreover, its blockade by 10μM TTX and its mid inactivation potential of –85 mV strongly suggest that this I Ca TTX is due to Ca permeation through Na channels. A second TTX-insensitive low threshold activated I Ca with slower kinetics is also present (half inactivation at –65mV). NIF (5μM) inhibited the major high-threshold I Ca component activating at ~-30mV with the sequence LV (-80.0±5.0%, n=6) > LA (–71.0±5.6%, n=5) ≥ PV (-63.4±3.05%, n=9) and NiCl 2 (40μM) with PV (–78.6±4.8%, n=9) > LA (-69.9±4.2%, n=6) > LV (-62.2±3.9%, n=6), suggesting that part of the current flows through Ca v 3.2 channels. However, TTAA2 (10nM) was found not so specific of Ca v 3.x as it partially inhibited I Ca in both PV and LV CM and decreased NIF efficacy. In conclusion, at least three components of Ca current are present in rat PV and LA CM. The author hereby declares no conflict of interest

Therapeutic Intervention Improves Communications and Rewires Functional Cardiac Networks of Human Atrial Fibrillation

Therapeutic Intervention Improves Communications and Rewires Functional Cardiac Networks of Human Atrial Fibrillation

Percolation as a mechanism to explain atrial fractionated electrograms and reentry in a fibrosis model based on imaging data

Complex fractionated atrial electrograms (CFAEs) have long been associated with proarrhythmic alterations in atrial structure or electrophysiology. Structural alterations disrupt and slow smoothly propagating wavefronts, leading to wavebreaks and electrogram (EGM) fractionation, but the exact nature and characteristics for arrhythmia remain unknown. Clinically, in atrial fibrillation (AF) patients, increases in frequency, whether by pacing or fibrillation, increase EGM fractionation and duration, and reentry can occur in relation with the conduction disturbance. Recently, percolation has been proposed as an arrhythmogenic mechanism, but its role in AF has not been investigated. We sought to determine if percolation can explain reentry formation and EGM behavior observed in AF patients. Computer models of fibrotic tissue with different densities were generated based on late gadolinium-enhanced magnetic resonance images, using pixel intensity as a fibrosis probability to avoid an arbitrary binary threshold. Clinical pacing protocols were followed to induce AF, and EGMs were computed. Reentry could be elicited, with a biphasic behavior dependent on fibrotic density. CFAEs were recorded above fibrotic regions, and consistent with clinical data, EGM duration and fractionation increased with more rapid pacing. These findings confirm percolation as a potential mechanism to explain AF in humans and give new insights into dynamics underlying conduction distortions and fractionated signals in excitable media, which correlate well with the experimental findings in fibrotic regions. The greater understanding of the different patterns of conduction changes and related EGMs could lead to more individualized and effective approaches to AF ablation therapy.

The Contribution of Ionic Currents to Rate-Dependent Action Potential Duration and Pattern of Reentry in a Mathematical Model of Human Atrial Fibrillation.

Persistent atrial fibrillation (PeAF) in humans is characterized by shortening of action potential duration (APD) and attenuation of APD rate-adaptation. However, the quantitative influences of particular ionic current alterations on rate-dependent APD changes, and effects on patterns of reentry in atrial tissue, have not been systematically investigated. Using mathematical models of human atrial cells and tissue and performing parameter sensitivity analysis, we evaluated the quantitative contributions to action potential (AP) shortening and APD rate-adaptation of ionic current remodeling seen with PeAF. Ionic remodeling in PeAF was simulated by reducing L-type Ca2+ channel current (ICaL), increasing inward rectifier K+ current (IK1) and modulating five other ionic currents. Parameter sensitivity analysis, which quantified how each ionic current influenced APD in control and PeAF conditions, identified interesting results, including a negative effect of Na+/Ca2+ exchange on APD only in the PeAF condition. At high pacing rate (2 Hz), electrical remodeling in IK1 alone accounts for the APD reduction of PeAF, but at slow pacing rate (0.5 Hz) both electrical remodeling in ICaL alone (-70%) and IK1 alone (+100%) contribute equally to the APD reduction. Furthermore, AP rate-adaptation was affected by IKur in control and by INaCa in the PeAF condition. In a 2D tissue model, a large reduction (-70%) of ICaL becomes a dominant factor leading to a stable spiral wave in PeAF. Our study provides a quantitative and unifying understanding of the roles of ionic current remodeling in determining rate-dependent APD changes at the cellular level and spatial reentry patterns in tissue.