Pathophysiology of atrial fibrillation: From initiation to maintenance

Atrial fibrillation (AF) is the most common arrhythmia in adults; it affects approximately 0.8 million patients in Japan alone. Yet despite many years of basic and clinical research, the exact mechanisms underlying the initiation and maintenance of AF remain poorly understood. In this review article, we summarize recent high‐resolution optical mapping studies in isolated sheep hearts, which have provided new insights into the dynamics and mechanisms of AF. We focus on 3 models of AF. First, we discuss results from experiments on AF induced by atrial stretch that revealed the presence of spatio‐temporally organized waves emerging from the posterior wall of the left atrium. In the presence of adreno‐cholinergic stimulation and stretch, AF was governed by evolving interactions between reentry and spontaneous focal discharges. Next, we outline the results obtained from a persistent AF model (average AF duration: 21.3 day) induced by intermittent rapid atrial pacing. By using simultaneous optical mapping of epicardial and endocardial activation patterns, we demonstrated that AF in this model was maintained by 3‐dimensional scroll waves with I‐shaped filaments anchored to junctions between thin and thick myocardium. Numerical simulation results predicted that wall thickness‐dependent activation of stretch‐activated channels and the filament tension dynamics were sufficient to explain the specific localization of the I‐shaped filament. In a final set of studies discussed herein, we investigated AF in sheep with tachypacing‐induced heart failure and found that micro‐reentry in the left atria was a major mechanism of AF maintenance, although focal discharges at the pulmonary vein area also played a role. Large fibrotic patches in failing hearts may serve as potential anchoring sites for micro‐reentry in this model. Thus, the 3 different experimental results in isolated sheep hearts presented here clearly suggest that self‐sustained rotors do exist in the atria and that such rotors are in fact the high frequency sources that determine the complex patterns of activation that characterize AF.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142071/1/joa3129.pd

Spatial gradients in action potential duration created by regional magnetofection of hERG are a substrate for wavebreak and turbulent propagation in cardiomyocyte monolayers

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95178/1/jphysiol.2012.238758.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/95178/2/TJP_5439_sm_SuppMat.pd

Spatial gradients in action potential duration created by regional magnetofection of hERG are a substrate for wavebreak and turbulent propagation in cardiomyocyte monolayers

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95178/1/jphysiol.2012.238758.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/95178/2/TJP_5439_sm_SuppMat.pd

A null mutation of the neuronal sodium channel NaV1.6 disrupts action potential propagation and excitation‐contraction coupling in the mouse heart

Evidence supports the expression of brain‐type sodium channels in the heart. Their functional role, however, remains controversial. We used global NaV1.6‐null mice to test the hypothesis that NaV1.6 contributes to the maintenance of propagation in the myocardium and to excitation‐contraction (EC) coupling. We demonstrated expression of transcripts encoding full‐length NaV1.6 in isolated ventricular myocytes and confirmed the striated pattern of NaV1.6 fluorescence in myocytes. On the ECG, the PR and QRS intervals were prolonged in the null mice, and the Ca2+ transients were longer in the null cells. Under patch clamping, at holding potential (HP) = –120 mV, the peak INa was similar in both phenotypes. However, at HP = –70 mV, the peak INa was smaller in the nulls. In optical mapping, at 4 mM [K+]o, 17 null hearts showed slight (7%) reduction of ventricular conduction velocity (CV) compared to 16 wild‐type hearts. At 12 mM [K+]o, CV was 25% slower in a subset of 9 null vs. 9 wild‐type hearts. These results highlight the importance of neuronal sodium channels in the heart, whereby NaV1.6 participates in EC coupling, and represents an intrinsic depolarizing reserve that contributes to excitation.—Noujaim, S. F., Kaur, K., Milstein, M., Jones, J. M., Furspan, P., Jiang, D., Auerbach, D. S., Herron, T., Meisler, M. H., Jalife, J. A null mutation of the neuronal sodium channel NaV1.6 disrupts action potential propagation and excitation‐contraction coupling in the mouse heart. FASEB J. 26, 63–72 (2012). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154524/1/fsb2fj10179770.pd

Ventricular Tachycardia and Early Fibrillation in Patients With Brugada Syndrome and Ischemic Cardiomyopathy Show Predictable Frequency-Phase Properties on the Precordial ECG Consistent With the Respective Arrhythmogenic Substrate

[EN] Background¿ Ventricular fibrillation (VF) has been proposed to be maintained by localized high-frequency sources. We tested whether spectral-phase analysis of the precordial ECG enabled identification of periodic activation patterns generated by such sources. Methods and Results¿Precordial ECGs were recorded from 15 ischemic cardiomyopathy and 15 Brugada syndrome (type 1 ECG) patients during induced VF and analyzed in the frequency-phase domain. Despite temporal variability, induced VF episodes lasting 19.6±7.9 s displayed distinctly high power at a common frequency (shared frequency, 5.7±1.1 Hz) in all leads about half of the time. In patients with Brugada syndrome, phase analysis of shared frequency showed a V1¿V6 sequence as would be expected from patients displaying a type 1 ECG pattern (P<0.001). Hilbert-based phases confirmed that the most stable sequence over the whole VF duration was V1¿V6. Analysis of shared frequency in ischemic cardiomyopathy patients with anteroseptal (n=4), apical (n=3), and inferolateral (n=4) myocardial infarction displayed a sequence starting at V1¿V2, V3¿V4, and V5¿V6, respectively, consistent with an activation origin at the scar location (P=0.005). Sequences correlated with the Hilbert-based phase analysis (P<0.001). Posterior infarction (n=4) displayed no specific sequence. On paired comparison, phase sequences during monomorphic ventricular tachycardia correlated moderately with VF (P<0.001). Moreover, there was a dominant frequency gradient from precordial leads facing the scar region to the contralateral leads (5.8±0.8 versus 5.4±1.1 Hz; P=0.004). Conclusions¿Noninvasive analysis of ventricular tachycardia and early VF in patients with Brugada syndrome and ischemic cardiomyopathy shows a predictable sequence in the frequency-phase domain, consistent with anatomic location of the arrhythmogenic substrate.This study was supported by the National Heart, Lung and Blood Institute (P01-HL039707, P01-HL087226 R01-HL118304); the Spanish Society of Cardiology, Arrhythmia and Electrophysiology Section; the Leducq Foundation, Paris, France; Centro Nacional de Investigaciones Cientificas, Madrid, Spain; Generalitat Valenciana, Valencia, Spain (PROMETEO/2012/030); VI Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica from the Ministerio de Economia y Competitividad of Spain (TIN2012-37546-C03-01); and the European Commission (European Regional Development Funds [ERDF]-FEDER)Calvo, D.; Atienza, F.; Saiz Rodríguez, FJ.; Martinez, L.; Ávila, P.; Rubín, J.; Herreros, B.... (2015). 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Panoramic Endocardial Optical Mapping Demonstrates Serial Rotors Acceleration and Increasing Complexity of Activity During Onset of Cholinergic Atrial Fibrillation.

BACKGROUND: Activation during onset of atrial fibrillation is poorly understood. We aimed at developing a panoramic optical mapping system for the atria and test the hypothesis that sequential rotors underlie acceleration of atrial fibrillation during onset. METHODS AND RESULTS: Five sheep hearts were Langendorff perfused in the presence of 0.25 μmol/L carbachol. Novel optical system recorded activations simultaneously from the entire left and right atrial endocardial surfaces. Twenty sustained (>40 s) atrial fibrillation episodes were induced by a train and premature stimuli protocol. Movies obtained immediately (Initiation stage) and 30 s (Early Stabilization stage) after premature stimulus were analyzed. Serial rotor formation was observed in all sustained inductions and none in nonsustained inductions. In sustained episodes maximal dominant frequency increased from (mean±SD) 11.5±1.74 Hz during Initiation to 14.79±1.30 Hz at Early Stabilization (P<0.0001) and stabilized thereafter. At rotor sites, mean cycle length (CL) during 10 prerotor activations increased every cycle by 0.53% (P=0.0303) during Initiation and 0.34% (P=0.0003) during Early Stabilization. In contrast, CLs at rotor sites showed abrupt decreases after the rotors appearances by a mean of 9.65% (P<0.0001) during both stages. At Initiation, atria-wide accelerations and decelerations during rotors showed a net acceleration result whereby post-rotors atria-wide minimal CL (CLmin) were 95.5±6.8% of the prerotor CLmin (P=0.0042). In contrast, during Early Stabilization, there was no net acceleration in CLmin during accelerating rotors (prerotor=84.9±11.0% versus postrotor=85.8±10.8% of Initiation, P=0.4029). Levels of rotor drift distance and velocity correlated with atria-wide acceleration. Nonrotor phase singularity points did not accelerate atria-wide activation but multiplied during Initiation until Early Stabilization. Increasing number of singularity points, indicating increased complexity, correlated with atria-wide CLmin reduction (P<0.0001). CONCLUSIONS: Novel panoramic optical mapping of the atria demonstrates shortening CL at rotor sites during cholinergic atrial fibrillation onset. Atrial fibrillation acceleration toward Early Stabilization correlates with the net result of atria-wide accelerations during drifting rotors activity.post-print3906 K

Transcriptome and proteome mapping in the sheep atria reveal molecular featurets of atrial fibrillation progression.

Atrial fibrillation (AF) is a progressive cardiac arrhythmia that increases the risk of hospitalization and adverse cardiovascular events. There is a clear demand for more inclusive and large-scale approaches to understand the molecular drivers responsible for AF, as well as the fundamental mechanisms governing the transition from paroxysmal to persistent and permanent forms. In this study, we aimed to create a molecular map of AF and find the distinct molecular programmes underlying cell type-specific atrial remodelling and AF progression. We used a sheep model of long-standing, tachypacing-induced AF, sampled right and left atrial tissue, and isolated cardiomyocytes (CMs) from control, intermediate (transition), and late time points during AF progression, and performed transcriptomic and proteome profiling. We have merged all these layers of information into a meaningful three-component space in which we explored the genes and proteins detected and their common patterns of expression. Our data-driven analysis points at extracellular matrix remodelling, inflammation, ion channel, myofibril structure, mitochondrial complexes, chromatin remodelling, and genes related to neural function, as well as critical regulators of cell proliferation as hallmarks of AF progression. Most important, we prove that these changes occur at early transitional stages of the disease, but not at later stages, and that the left atrium undergoes significantly more profound changes than the right atrium in its expression programme. The pattern of dynamic changes in gene and protein expression replicate the electrical and structural remodelling demonstrated previously in the sheep and in humans, and uncover novel mechanisms potentially relevant for disease treatment. Transcriptomic and proteomic analysis of AF progression in a large animal model shows that significant changes occur at early stages, and that among others involve previously undescribed increase in mitochondria, changes to the chromatin of atrial CMs, and genes related to neural function and cell proliferation.This work was supported by the Spanish government (BFU2017-84914-P to M.M.; FPI Fellowship to A.A.-F.; FPU Fellowship to R.R.), and in part by grants to J.J. from the National Heart, Lung and Blood Institute (R01 grant HL122352 NIH/NHLBI), the Leducq Foundation (Transatlantic Network of Excellence Program on Structural Alterations in the Myocardium and the Substrate for Cardiac Fibrillation), and the University of Michigan Health System–Peking University Health Science Center Joint Institute for Translational and Clinical Research (UMHS-PUHSC; project: Molecular Mechanisms of Fibrosis and the Progression from Paroxysmal to Persistent Atrial Fibrillation). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505).S

Personalized monitoring of electrical remodelling during atrial fibrillation progression via remote transmissions from implantable devices

Aims: Atrial electrical remodelling (AER) is a transitional period associated with the progression and long-term maintenance of atrial fibrillation (AF). We aimed to study the progression of AER in individual patients with implantable devices and AF episodes. Methods and results: Observational multicentre study (51 centres) including 4618 patients with implantable cardioverter-defibrillator +/-resynchronization therapy (ICD/CRT-D) and 352 patients (2 centres) with pacemakers (median follow-up: 3.4 years). Atrial activation rate (AAR) was quantified as the frequency of the dominant peak in the signal spectrum of AF episodes with atrial bipolar electrograms. Patients with complete progression of AER, from paroxysmal AF episodes to electrically remodelled persistent AF, were used to depict patient-specific AER slopes. A total of 34 712 AF tracings from 830 patients (87 with pacemakers) were suitable for the study. Complete progression of AER was documented in 216 patients (16 with pacemakers). Patients with persistent AF after completion of AER showed ∼30% faster AAR than patients with paroxysmal AF. The slope of AAR changes during AF progression revealed patient-specific patterns that correlated with the time-to-completion of AER (R2 = 0.85). Pacemaker patients were older than patients with ICD/CRT-Ds (78.3 vs. 67.2 year olds, respectively, P < 0.001) and had a shorter median time-to-completion of AER (24.9 vs. 93.5 days, respectively, P = 0.016). Remote transmissions in patients with ICD/CRT-D devices enabled the estimation of the time-to-completion of AER using the predicted slope of AAR changes from initiation to completion of electrical remodelling (R2 = 0.45). Conclusion: The AF progression shows patient-specific patterns of AER, which can be estimated using available remote-monitoring technology